Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

Julie Martinkova; Frances-Catherine Quevenco; Helene Karcher; Alberto Ferrari; Else Charlotte Sandset; Cassandra Szoeke; Jakub Hort; Reinhold Schmidt; Antonella Santuccione Chadha; Maria Teresa Ferretti

doi:10.1001/jamanetworkopen.2021.24124

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

Martinkova, Julie; Quevenco, Frances-Catherine; Karcher, Helene; Ferrari, Alberto; Sandset, Else Charlotte; Szoeke, Cassandra; Hort, Jakub; Schmidt, Reinhold; Chadha, Antonella Santuccione; Ferretti, Maria Teresa 2021-09-13 00:00:00 Key Points Question What is the proportion of IMPORTANCE Women represent two-thirds of patients with Alzheimer disease (AD), and sex women in large randomized clinical trials differences might affect results of randomized clinical trials (RCTs). However, little information exists for Alzheimer disease (AD), and are sex on differences in sex as reported in RCTs for AD. differences reported? Findings In this systematic review and OBJECTIVE To assess the ratio of females to males and the reporting of sex-stratified data in large meta-analysis of 56 randomized clinical pharmaceutical RCTs for AD. trials for AD with 39 575 total participants, 59.0% of patients overall DATA SOURCES A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, and a mean of 57.9% in trials of using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were experimental drugs were women, identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted significantly lower proportions of between September 4 and October 31, 2019, and between April 15 and May 31, 2020. women than in the US and European population with AD. Only 12.5% of STUDY SELECTION Controlled RCTs that had more than 100 participants and tested the efficacy of articles reported sex-stratified results, drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore but this proportion appeared to increase screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, over time. 13 secondary articles on AD, and 8 articles on mild cognitive impairment. Meaning Although the findings suggest DATA EXTRACTION AND SYNTHESIS The location and date of publication; number, sex, and age of that current clinical trials for AD enroll patients enrolled; disease severity; experimental or approved status of the drug; and whether the more women than men, strategies to study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 increase women’s participation in reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for clinical trials for AD should be discussed Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed- and the reporting of trial outcomes by effects model. sex should be encouraged. MAIN OUTCOMES AND MEASURES The mean proportion of women enrolled in the trials and the Invited Commentary associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied. Supplemental content Author affiliations and article information are RESULTS In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) listed at the end of this article. were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, −4.56% [95% CI, −6.29% to −2.87%]; P < .001) and Europe (68.2%; difference, −10.67% [95% CI, −12.39% to −8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 1/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Abstract (continued) the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P =.02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03). CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 Introduction Alzheimer disease (AD) is the leading cause of dementia in the older population and affects more than 50 million individuals worldwide. Current treatment of AD is symptomatic and at the time of this study was based on 4 approved pharmaceuticals (galantamine, rivastigmine, donepezil, and memantine). Substantial heterogeneity in risk factors, presentation, and progression among patients has 2,3 hindered the clinical development of precise diagnostics and disease-modifying therapies. Sex differences are potential causes of disease heterogeneity. Women represent most patients with AD 4,5 and related dementias (a mean of 68.2% of patients with AD in Europe and 62.1% in the US ). In 6-14 addition, sex-related differences occur in disease symptoms, progression, and biomarkers and in 15,16 genetic risk associated with the apolipoprotein E ε4 (APOE4) allele. These differences between men and women are likely associated with the efficacy of a tested drug in randomized clinical trials (RCTs). However, in RCTs among patients with AD, little attention has been given to the role of sex and gender differences. In a meta-analysis of 48 trials of approved AD therapeutics, trials enrolled more women than men (a mean of 63.8% women per trial), but none of the trials reported sex-stratified data. In contrast to RCTs for approved drugs, an overview of several phase 3 RCTs for experimental AD drugs reported that some trials enrolled approximately 50% men and 50% women. Whether and how sex is considered in current trials of experimental drugs remain to be established systematically. Therefore, we performed a systematic review and meta-analysis of articles related to RCTs for AD to examine the sex distribution of patients in the RCTs, the proportion of articles that reported sex-stratified data, and temporal trends in the findings. Methods Identification of Trials and Definition of Primary vs Secondary Articles This systematic review and meta-analysis was conducted according to a prespecified protocol (reviewregistry855). We used a systematic stepwise approach similar to that used in previous 18-20 articles (Figure 1). This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. First, we identified RCTs using the keyword Alzheimer disease at ClinicalTrials.gov, a large, web-based database resource maintained by the National Institutes of Health. All clinical trials performed in the US or to be used for US Food and Drug Administration submissions must be registered on ClinicalTrials.gov, but the database also includes trials not conducted in the US, making it one of the most complete trial databases. Only interventional trials in phase 1, 2, or 3 were included. The search was conducted on September 4, 2019. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 2/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Next, articles related to the RCTs found at ClinicalTrials.gov were identified by searching publicly available databases. PubMed was searched by one of us (F.C.Q.) on September 4, 2019, using the national clinical trial identifier, the principal investigator, and/or the trial name. Google Scholar and Scopus were searched by one of us (J.M.) between September 4 and October 31, 2019, and between April 15 and May 31, 2020, using each trial’s national clinical trial identifier and, when available, principal investigator and trial name. In addition, the reference list of each identified article was searched for other relevant trials. Further details on the search strategy are provided in eAppendix 1 the Supplement. In cases in which several peer-reviewed articles had been published on the same trial, the chronologically first publication of the main results was considered as the primary article; the others, considered secondary articles, were subject to the same selection and extraction process but were not included in the meta-analysis. Selection of Trials Published trials were selected according to predefined inclusion and exclusion criteria (eTable 1 in the Supplement) by 2 independent reviewers (J.M., M.T.F.). In case of disagreement, a third reviewer (A.S.C.) adjudicated. Only RCTs with more than 100 participants that included both sexes and enrolled patients with AD dementia or biomarker-confirmed mild cognitive impairment owing to AD (also referred to as prodromal AD) were selected. We included only RCTs studying the clinical efficacy of pharmacological, biological, or genetic agents or herbal extracts. Because efficacy is assessed even in early stages of trials, we did not limit our selection by trial phase. We focused on trials with more than 100 individuals because they are the most informative for the assessment of the benefit and Figure 1. Article Selection Flowchart 1047 Records identified from ClinicalTrials.gov 409 Records identified as published 405 Databases 278 PubMed 123 Google Scholar 4 Scopus 4 References 70 Duplicate records removed 339 Records screened 240 Records excluded 99 Population 41 Intervention 47 Outcome 53 Study type 99 Reports sought for retrieval 2 Reports not retrieved 97 Reports assessed for eligibility 20 Records excluded 9 Population 1 Outcome 2 Comparator 8 Arbitration Primary articles were defined as the chronologically 77 Studies included in review 8 Prodromal AD first article containing the main results of a trial; all 13 Secondary other articles on the trial were considered secondary. 56 Primary studies on AD included in meta-analysis AD indicates Alzheimer disease. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 3/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease safety profile of a given compound and they inform clinical practice; they also allow the robust calculation of the effects of sex. Because the scope of this review was to inform pharmaceutical RCT design, we excluded behavioral interventions, caregiver support, devices, and dietary supplements. Bias Assessment The risk of bias was assessed in each of the 56 primary articles on AD by 2 reviewers (F.C.Q., M.T.F.) using the Cochrane bias assessment. Details are given in eAppendix 1 in the Supplement. Data Extraction For each study included in this review, 1 reviewer (J.M.) extracted the required information into a prespecified extraction table according to the protocol. In brief, this included basic information on the trial, publication year, numbers of participants (men, women, and total), and a binary yes-or-no assessment of sex stratification in the methods, results, and protocol. The status of the drug (experimental or approved) was also recorded; we considered approved drugs as 1 of the 4 drugs currently in use for the treatment of AD (memantine, rivastigmine, donepezil, and galantamine). More details are available in eAppendix 1 in the Supplement. Statistical Analysis We analyzed both primary and secondary articles using a specific rationale that avoided overfitting. Primary articles that included information about how many men and women were included in the study design were used to investigate the sex ratio in a trial overall, in prespecified subgroups, and across time. To study temporal trends in the reporting of sex in study results, we analyzed pooled primary and secondary articles together because secondary articles (with additional analysis of existing data) might have reported sex-stratified results. A total of 56 primary articles for AD dementia and 8 for prodromal AD were analyzed separately per protocol; the analyses for prodromal AD did not find significant differences in sex ratios between subgroups, likely owing to low statistical power, and are not reported in this article. Pooling the results did not affect the overall conclusions of this study. Within the primary articles, we examined sex ratios at baseline in prespecified subgroups (including approved vs experimental drugs, trial phase, and location) and the effect of prespecified variables (including the mean baseline Mini-Mental State Examination [MMSE] score, baseline age, trial duration in weeks, publication year, and year of trial start). Basic characteristics were calculated on a per-trial basis. If the mean value per trial was not given (eg, for age or MMSE), we calculated the weighted mean of the subgroups for which these data were available. Sex Proportion An analysis of sex proportion was performed only for the 56 primary articles on AD. The total baseline percentage of women was calculated per trial arm and for the whole trial population by calculating the mean proportions of female individuals in each trial (ie, on a per-trial basis); in addition, we obtained similar proportions by pooling patients from all trials (Figure 2). We used Wilcoxon signed rank tests to compare the trial-based results with a fixed value of the proportion of women in the 5 4 real-world population with AD based on published US (62.1%) and European (68.2%) statistics. To assess the associations between prespecified variables, we used a multivariate mixed-effect logistic regression model of the probability that an enrolled patient was a woman. A logistic regression model was used because sex is a binary variable. We used 2 main models. Model 1 excluded location variables, and model 2 included all variables. To account for different sample sizes of the trials and intertrial variability, we added a random intercept at the trial level and estimated the 22,23 corresponding variance parameter. Subsequently, a Spearman nonparametric correlation matrix was used to characterize the correlation between different trial characteristics. A series of pairwise comparisons was run between the coefficients of different locations using Bonferroni adjustment for multiple comparisons. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 4/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Pearson correlations were calculated to examine whether there was a temporal trend in the proportion of women; significance of the association was assessed using a 2-tailed Wald test. Correlations were weighted based on the total number of trial participants. Sex-Stratified Data Because RCT data may be subject to several analyses, resulting in multiple articles about the same trial, for this study, we used a pooled data set including both the primary and the secondary (later) Figure 2. Proportion of Women in Primary Alzheimer Disease (AD) Articles Study Patients, No. Females, % (95% CI) Experimental drugs Doody et al, 2008 183 66.7 (59.3-73.4) Sevigny et al, 2008 563 57.9 (53.7-62.0) Green et al, 2009 1649 50.9 (48.5-53.4) Maher-Edwards et al, 2011 196 66.8 (59.8-73.4) Gold et al, 2010 553 62.9 (58.8-67.0) Feldman et al, 2010 614 52.0 (47.9-56.0) Maher-Edwards et al, 2010 357 58.0 (52.7-63.2) Aisen et al, 2011 1005 53.0 (49.9-56.2) Alvarez et al, 2011 197 77.2 (70.7-82.8) Salloway et al, 2011 351 56.1 (50.8-61.4) Raffi et al, 2011 210 64.3 (57.4-70.8) Vellas et al, 2011 157 56.1 (47.9-64.0) Harrington et al, 2011 2822 57.7 (55.8-59.5) Coric et al, 2012 209 47.8 (40.9-54.8) Egan et al, 2012 144 54.9 (46.4-63.2) Doody et al, 2013 1534 53.5 (50.9-56.0) Doody et al, 2014 2052 56.3 (54.1-58.4) Marek et al, 2014 267 57.7 (51.5-63.7) Wilkinson et al, 2014 278 70.5 (64.8-75.8) Salloway et al, 2014 2204 53.9 (51.8-56.0) Grove et al, 2014 64.9 (57.8-71.6) Galasko et al, 2014 399 57.1 (52.1-62.1) Maher-Edwards et al, 2015 1231 60.9 (58.1-63.7) Lenz et al, 2015 55.1 (49.6-60.5) Gault et al, 2015 61.3 (55.3-67.1) Wischik et al, 2015 321 53.6 (48.0-59.1) Gauthier et al, 2015 203 51.2 (44.1-58.3) Maher-Edwards et al, 2015 121 50.4 (41.2-59.6) Pasquier et al, 2016 245 56.7 (50.3-63.0) Gauthier et al, 2016 885 61.6 (58.3-64.8) Gault et al, 2016 436 60.8 (56.0-65.4) Florian et al, 2016 434 54.6 (49.8-59.4) Vandenberghe et al, 2016 1917 60.3 (58.0-62.5) Brody et al, 2016 146 57.5 (49.1-65.7) Nave et al, 2017 542 62.7 (58.5-66.8) Relkin et al, 2017 390 54.6 (49.5-59.6) Xiao et al, 2017 273 64.5 (58.5-70.1) Rinne et al, 2016 100 59.0 (48.7-68.7) Egan et al, 2018 1957 55.3 (53.1-57.6) Lawlor et al, 2018 498 61.8 (57.4-66.1) Honig et al, 2018 2129 57.8 (55.7-59.9) Atri et al, 2018 2475 63.4 (61.4-65.3) Fullerton et al, 2018 186 54.3 (46.9-61.6) Voss et al, 2018 239 54.0 (47.4-60.4) Cummings et al, 2018 433 52.7 (47.8-57.4) Schneider et al, 2019 469 53.7 (49.1-58.3) van Dyck et al, 2019 159 45.3 (37.4-53.4) Subtotal 32 535 57.5 (56.9-58.0) Approved drugs 407 80.8 (76.7-84.5) Burns et al, 2009 Farlow et al, 2010 1434 62.8 (60.3-65.3) Nakamura et al, 2011 855 68.3 (65.1-71.4) Cummings et al, 2012 567 64.7 (60.6-68.7) Grossberg et al, 2013 676 72.0 (68.5-75.4) Percentages were obtained by pooling raw data of all Hager et al, 2014 2045 64.8 (62.7-66.9) patients in 56 primary articles, defined as the Nakamura et al, 2015 215 67.4 (60.7-73.7) chronologically first publication of the main results of a Zhang et al, 2016 501 55.7 (51.2-60.1) Homma et al, 2016 340 69.4 (64.2-74.3) trial. Squares represent percentages, with horizontal Subtotal 7040 66.1 (65.0-67.2) lines indicating binomial 95% CIs. Diamonds represent Total 39 575 59.0 (58.5-59.5) pooled estimates, with points of the lines indicating 95% CIs. The marker size is proportional to the 45 50 55 60 65 70 75 80 Females, % (95% CI) precision of the estimate. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 5/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease articles. We calculated the percentages of articles that included a data analysis by sex in the study protocol, in the methods, and/or in the results sections of the article. Temporal trends were calculated using logistic regression of the probability that the article reported sex-stratified results in the pooled data set of primary and secondary articles. All statistical analyses were conducted using R, version 3.6.2 (R Project for Statistical Computing). Unless otherwise specified, significance was set at 2-tailed P < .05. Table 1. Basic Characteristics of Included Articles Characteristic Articles Articles on AD dementia, No. 56 Participants per article, median (IQR), No. 403.0 (213.8-862.5) Sex, pooled No. (%) Women 23 348 (59.0) Men 16 227 (41.0) Age, mean (SD), y 73.5 (2.5) Trial phase 2 32 (57.1) 3 24 (42.9) Year of publication, median (IQR) 2014.50 (2011.00-2016.00) Year of trial start, median (IQR) 2008.00 (2006.75-2011.25) Year of trial end, median (IQR) 2011.00 (2009.00-2014.00) Trial duration, median (IQR), wk 25.0 (24.0-76.5) Trial location Asia 6 (10.7) Europe 6 (10.7) North America 16 (28.6) Worldwide 28 (50.0) Trial population ITT 34 (60.7) mITT 9 (16.1) Safety 13 (23.2) Severity of AD Mild to moderate 52 (92.9) Severe 4 (7.1) Approval status of drug Approved 9 (16.1) Experimental 47 (83.9) Mean MMSE score at baseline, 19.16 (17.49-20.91) median (IQR) Abbreviations: AD, Alzheimer disease; IQR, interquartile range; ITT, intention to treat; mITT, modified intention to treat; MMSE, Mini-Mental State Examination. Data are presented as the number (percentage) of articles unless otherwise indicated. The mean (SD) is reported for normally distributed variables and the median (IQR) for non–normally distributed variables. Categorical variables are reported as the percentage of the total. All variables were assessed per trial as reported at baseline. Data were available in 55 of the trials. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 6/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Results Basic Characteristics of Included Articles A total of 1047 trials were identified on ClinicalTrials.gov (Figure 1). Among these, 409 published articles were found using PubMed, Google Scholar, Scopus, and article references; 70 articles were removed as duplicates and another 240 were excluded based on title and abstract screening. By applying the predefined set of inclusion and exclusion criteria, we selected 77 articles, of which 64 were categorized as primary (56 on AD dementia and 8 on prodromal AD) and 13 as secondary (all on AD dementia). The most common reasons for excluding an article were population (ie, <100 participants) and study type (ie, not a randomized clinical trial). Agreement between reviewers was 95.6%. 25-80 The 56 selected primary articles on patients with AD dementia reported large phase 2 and 3 trials involving a median of 403.0 participants (interquartile range, 213.8-862.5 participants) with 72-80 a mean (SD) age of 73.5 (2.5) years (Table 1). Nine articles (16.1%) reported results of approved 25-71 drugs and 47 (83.9%) reported results of experimental drugs. Most articles (34 25,26,28,29,31-33,35,37-43,45-50,52,53,56,59,60,62,65,67,71,72,75,79,80 [60.7%]) reported the sex ratio in the intention-to-treat population (Table 1). Basic information on trials and articles regarding prodromal 81-88 AD and pooled trials and articles is available in eTables 2 and 3 in the Supplement. The references for the trials are available in eTable 4 of the Supplement, and a summary of the extracted data are available in eTable 5 in the Supplement. Sex Proportion 25-80 In the 56 primary articles on AD dementia, the overall proportion of women was 59.0% (23 348 of 39 575 total participants) (Table 1 and Figure 2). In a preliminary data analysis, on a trial basis, the 72-80 mean (SD) proportion of women in the trials for approved drugs was 67.3% (6.9%), whereas in 25-71 trials for experimental medications, it was 57.9% (5.9%). The proportion of women in the experimental medications subgroup (57.9%; 95% CI, 55.8%-59.2%) was significantly different from the proportion of women in the population with AD in both in the US (62.1%; difference, −4.56% [95% CI, −6.29% to −2.87%]; P < .001) and Europe (68.2%; difference, −10.67% [95% CI, −12.39% to −8.97%]; P < .001). In model 1 (Table 2), in which location variables were excluded, variables significantly associated with the probability that women were enrolled in a study included the status of the drug (approved vs experimental) and the severity of the participants’ AD (measured by baseline MMSE). Supporting the preliminary data analysis, trials involving drugs with approved status were associated with a higher probability of including women (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). However, we found a lower probability of women being included in trials with a higher mean baseline MMSE (OR, 0.98; 95% CI, 0.97-1.00; P = .02), indicating that trials including participants with more severe cases of AD were more likely to enroll women. The results were confirmed in pairwise comparisons (eTable 6 in the Supplement). When location was included in model 2, fewer associations were found (Table 2 and 25-80 Figure 2). In model 2, location was the only factor significantly associated with inclusion of women in AD trials, with location in Europe associated with a higher probability that the trials included women (OR, 1.26; 95% CI, 1.05-1.52; P = .01) and location in North America associated with a lower probability (OR, 0.81; 95% CI, 0.71-0.93; P = .002) (Table 2; further results are shown in eTable 7 and location pairwise comparisons in eTable 8 in the Supplement). Trial duration, mean baseline age of participants, publication year, and trial start year were not significantly associated with the probability that women were included, based on the results of either model. We did not find any significant temporal trend in the proportion of women included in AD trials over time, either by publication year or by trial start year (R, −0.04; 95% CI, −0.30 to 0.23; P = .79) (eFigure 1 in the Supplement). The variance parameter for the trial random effect was 0.036, confirming the presence of a nonnegligible degree of heterogeneity between trials. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 7/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Reporting of Sex-Stratified Data and Its Temporal Trend We investigated the proportion of primary articles that included sex stratification in the study protocol or methods or reported sex-stratified data in the results (eTable 9 in the Supplement). Most did not include sex-stratified data in the protocol, methods, or results. Of the 56 AD dementia articles, we were able to identify a complete published protocol with a 28,37,40,41,44,45,47,52,54,55,63-66,68,70,71 statistical analysis plan for only 17 (30.4%) ; of these, only 8 40,41,54,55,63,65,68,70 (47.1%) included a sex-specific data analysis in the protocol. Of the 56 total 27,49,54-56,64,67,68 articles, 8 (14.3%) incorporated sex-specific data analysis in the methods section. 27,49,55,56,64,67,68 64 Seven articles (12.5%) reported the results of such analysis, and 1 article showed a potential sex difference in efficacy that favored men, although no significance testing was conducted. No trials stratified trial arms by sex; the most common method of statistical analysis was a prespecified subgroup analysis. To assess whether subsequent articles for a given RCT reported sex-stratified data, we also 89-101 considered the secondary articles. We found that in this group of 13 articles, a sex-specific data 91,92,99,100 analysis was present in 4 (30.8%). Using a pooled data set from primary and secondary articles (Figure 3 and eFigure 2 in the Supplement), we found a statistically significant increasing temporal trend of articles that referenced a sex-specific data analysis in the methods (R, 0.30; 95% CI, 0.05-0.59; P = .03) and a similar trend for sex stratification in the results (R, 0.26; 95% CI, 0.01-0.55; P = .055). The results of the risk-of- bias analysis are provided in eAppendix 2 and eTable 10 in the Supplement. Discussion In this systematic review and meta-analysis, of the 56 selected RCTs, 59.0% of the included participants were women, and 57.9% were women in the subgroup of trials of experimental drugs. Although this indicated greater trial enrollment of women compared with men, these numbers are significantly lower than the proportions of women reported in real-world populations with AD (68.2% in Europe and 62.1% in the US). This suggests that the enrollment of women in RCTs for AD Table 2. Summary of Fixed Effects in Multivariate Mixed Effect Logistic Regression Models of the Probability That an Enrolled Trial Patient Was a Woman Fixed effect OR (95% CI) z score P value Model 1 Intercept 1.51 (1.34-1.69) 6.74 <.001 MMSE 0.98 (0.97-1.00) −2.26 .02 Age 1.02 (0.99-1.05) 1.22 .22 Year started 0.99 (0.96-1.03) −0.47 .64 Year published 1.00 (0.96-1.03) −0.31 .76 Status of drug (approved) 1.26 (1.05-1.52) 2.44 .02 Trial duration 0.93 (0.83-1.05) −1.16 .25 Model 2 Intercept 1.53 (1.37-1.71) 7.70 <.001 MMSE 0.99 (0.97-1.00) −1.79 .07 Age 1.03 (1.00-1.05) 1.83 .07 Year started 1.00 (0.97-1.03) 0.02 .98 Year published 0.98 (0.95-1.01) −1.17 .24 Status of drug (approved) 1.10 (0.91-1.31) 0.98 .33 Abbreviations: MMSE, Mini-Mental State Examination; Trial duration 0.96 (0.86-1.07) −0.74 .46 OR, odds ratio. Location Location excluded. Asia 1.16 (0.94-1.42) 1.39 .16 Significance level P = .01. Europe 1.26 (1.05-1.52) 2.45 .01 Significance level P = .05. North America 0.81 (0.71-0.93) −3.10 .002 Location included. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 8/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease could be further increased. Older women might be a particularly difficult group to enroll; their underrepresentation in RCTs is well-known in stroke research. To gain additional insights for the design of future RCTs, we analyzed factors associated with the probability of enrolling women in trials. A multivariate analysis revealed that trial duration was not associated with enrollment of women, whereas geographical and clinical factors were. This study found that the probability that women were included in RCTs for AD was lower in RCTs in North America compared with other locations (eg, Europe). This observation, if confirmed, might indicate the need for region-specific strategies for enrollment of women in trials. Aside from the location of the trials, drug status (approved vs experimental) was the factor most associated with differences in sex ratios. The RCTs for approved drugs had a significantly higher probability of including women than did RCTs for experimental drugs. The reasons for such differences remain to be elucidated; we are investigating the possibility that a higher ratio of women may be associated with trials in which a drug showed a significant clinical effect. In addition, we found that the probability of women’s inclusion was higher in trials involving more severe cases of AD, but this was not associated with age (Table 2); recruitment and retention of women in AD trials might therefore need to be tailored according to disease stage. Of interest, we found that although an analysis of sex-based data was included in many available study protocols, the results of such analyses were not published in most cases. However, a temporal trend was found, indicating an increase in the inclusion of data analysis by sex in reports of AD trials. The findings of this study may stimulate a global discussion on 3 important aspects associated with diversity in RCTs. First, when studying a multifactorial disease such as AD, properly representing the diverse patient population may be crucial in RCT design. Having a study population similar to the real-world one might be needed to detect relevant outcomes in a trial. For example, RCTs for migraine, a disease that largely affects women and for which several new drugs have been discovered, enroll more women than men, with proportions that reflect the expected real-world sex ratio. Of course, promoting women’s enrollment in RCTs for AD has to be weighed against the wider request by regulatory agencies for equality in RCT participation. Second, participation of women and particularly older women in RCTs might be subject to specific challenges. When living alone, older women affected by AD or stroke might have a disadvantage in joining long and complex trials and might lack a caregiver to accompany them. Another possibility is that inclusion and exclusion criteria for RCTs—for instance, based on educational level—might unintentionally but systematically exclude more women than men. Figure 3. Temporal Trends in the Reporting of Sex-Stratification Analyses A Methods B Results 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 June 2007 January 2010 June 2012 January 2015 June 2017 January 2020 June 2007 January 2010 June 2012 January 2015 June 2017 January 2020 Date of publication Date of publication The trend was significant only for the methods (R, 0.30; 95% CI, 0.05-0.59; P = .03). did not include a sex-specific analysis. Data markers indicate observed data points, and The y-axis represents the probability of inclusion of a sex-specific analysis in a study, with shading, the 95% CI. 1 indicating that the study included a sex-specific analysis and 0 indicating that the study JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 9/17 Probability of including sex-specific analysis Probability of including sex-specific analysis JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Third, the low frequency of sex-stratified results reported in articles is a call to action for better publishing practices. The data analysis revealed a low percentage of trials with complete protocols available (30.4%), a percentage that should increase for the sake of transparency. Describing sex-stratified data (even if no differences are found) should become a routine in clinical data publication, and it is also important for avoiding publication bias. Limitations 18-20 This study has limitations. First, as done in previous studies, we chose to use ClinicalTrials.gov as the primary source of RCT data. ClinicalTrials.gov allows registration of trials from all countries (exemplified by the different locations in the current data analyses). However, because only RCTs in the US are required to register at ClinicalTrials.gov, it is possible that this study’s data analysis was skewed toward RCTs conducted in the US. The highly selective inclusion and exclusion criteria also potentially led to exclusion of some relevant trials but enabled a more focused interpretation of results. Another limitation is that owing to the exclusion of solely pharmacokinetic and safety trials from the data analysis, the potential sex differences in these aspects were not captured. It is well-known that drugs used in AD, such as antipsychotic medications, have different safety and pharmacokinetic profiles in men and women. Sex differences in adverse events have also been observed for 106 107 rivastigmine and memantine. Therefore, further systematic exploration of sex differences in safety profiles is warranted. In addition, some of the data analyses were based on imbalanced groups (for instance, analyses between trials of approved drugs [n = 9] vs trials of experimental drugs [n = 47]). Such imbalances potentially introduced a lack of statistical power for detecting differences. However, because the study’s approach was systematic, this was unlikely to be a source of bias that invalidated the results. Conclusions In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD. ARTICLE INFORMATION Accepted for Publication: July 2, 2021. Published: September 13, 2021. doi:10.1001/jamanetworkopen.2021.24124 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Martinkova Jetal. JAMA Network Open. Corresponding Author: Maria Teresa Ferretti, PhD, Women’s Brain Project, c/o Pfisterwiesstrasse 14, 8352 Guntershausen, Switzerland (mariateresa.ferretti@womensbrainproject.com). Author Affiliations: Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic (Martinkova, Hort); Women’s Brain Project, Guntershausen, Switzerland (Martinkova, Quevenco, Ferrari, Chadha, Ferretti); Roche Diagnostics International Ltd, Rotkreuz, Switzerland (Quevenco); Novartis Pharma AG, Basel, Switzerland (Karcher); Stroke Unit, Department of Neurology, University of Oslo, Oslo, Norway (Sandset); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia (Szoeke); International Clinical Research Center, St Anne’s University Hospital Brno, Brno, Czech Republic (Hort); Department of Neurogeriatrics, University Clinic of Neurology, Medical University Graz, Graz, Austria (Schmidt); Biogen International GMBH, Baar, Switzerland (Chadha). Author Contributions: Drs Martinkova and Ferrari had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 10/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Concept and design: Quevenco, Karcher, Sandset, Szoeke, Hort, Schmidt, Santuccione Chadha, Ferretti. Acquisition, analysis, or interpretation of data: Martinkova, Quevenco, Karcher, Ferrari, Szoeke, Hort, Santuccione Chadha, Ferretti. Drafting of the manuscript: Martinkova, Ferrari, Szoeke, Santuccione Chadha, Ferretti. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Martinkova, Quevenco, Karcher, Ferrari, Santuccione Chadha. Administrative, technical, or material support: Martinkova, Quevenco, Karcher, Szoeke. Supervision: Karcher, Szoeke, Hort, Schmidt, Santuccione Chadha, Ferretti. Conflict of Interest Disclosures: Dr Quevenco reported being an employee of Roche Diagnostics International Ltd during the conduct of the study. Dr Karcher reported being an employee of Novartis during part of the conduct of the study. Dr Ferrari reported being an employee of Women’s Brain Project (WBP) and a consultant at Business & Decision Life Science, Italy, during the conduct of the study. Dr Sandset reported receiving honoraria for lectures from Bayer and Novartis unrelated to the submitted work. Dr Santuccione Chadha reported being an employee of Biogen after completion of this work and being the chief executive officer (unpaid position) of WBP during the conduct of the study. Dr Ferretti reported receiving personal fees from Eli Lilly and Company outside the submitted work and serving as the chief scientific officer of WBP during the conduct of the study. No other disclosures were reported. Funding/Support: Dr Martinkova was supported by project 436119 of the Charles University Grant Agency, Second Faculty of Medicine, and by the Avast Foundation (Nadační fond Avast) together with the Czech Alzheimer’s Foundation (Alzheimer nadační fond). Dr Szoeke was supported by grants 547500, 1032350, and 1062133 from the National Health and Medical Research Council, Australia, and grant NIA320312 from the Alzheimer’s Association. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The opinions expressed in this article are the personal views of Drs Santuccione Chadha, Quevenco, and Karcher and may not be understood or quoted as being made on behalf of or reflecting the position of their employers. Additional Contributions: We thank the WBP community. 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Accessed July 24, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-487_Namenda_Medr_P4.pdf JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 16/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease SUPPLEMENT. eAppendix 1. Supplementary methods eAppendix 2. Supplementary results eFigure 1. Temporal trends in women’s representation in AD trials eFigure 2. Temporal trends in reporting of sex-stratified results by trial start year eTable 1. Inclusion and exclusion criteria according to PICOS eTable 2. Basic characteristics of included publications for prodromal AD, primary publications eTable 3. Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications eTable 4. References for all included studies eTable 5. Overview of study details and extracted data eTable 6. Proportion of women in subgroups: nonparametric correlation matrix eTable 7. Multivariate mixed effect logistic regression model with probability of trial participant being a woman as a dependent variable, Model 3 (location only): summary of fixed effects eTable 8. Odds ratio of female enrollment by location: pairwise comparisons eTable 9. Reporting of sex-stratified data in primary studies (n=56) eTable 10. Bias assessment table eReferences JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 17/17 Supplementary Online Content Martinkova J, Quevenco FC, Karcher H, et al. Proportion of women and reporting of outcomes by sex in clinical trials for Alzheimer disease: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 eAppendix 1. Supplementary methods eAppendix 2. Supplementary results eFigure 1. eFigure 2. Temporal trends in reporting of sex-stratified results by trial start year eTable 1. Inclusion and exclusion criteria according to PICOS eTable 2. Basic characteristics of included publications for prodromal AD, primary publications eTable 3. Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications eTable 4. References for all included studies eTable 5. Overview of study details and extracted data eTable 6. Proportion of women in subgroups: nonparametric correlation matrix eTable 7. Multivariate mixed effect logistic regression model with probability of trial participant being a woman as a dependent variable, Model 3 (location only): summary of fixed effects eTable 8. Odds ratio of female enrollment by location: pairwise comparisons eTable 9. Reporting of sex-stratified data in primary studies (n=56) eTable 10. Bias assessment table eReferences This supplementary material has been provided by the authors to give readers additional information about their work. © 2021 Martinkova J et al. JAMA Network Open. eAppendix 1. Supplementary Methods. Definition of sex and gender Sex refers to the biological characteristics arising from the expression of sex chromosomes (XX for female and XY for male) as well as the effects of exogenous gonadal hormones. Gender refers to the socially-driven definition of being a man and a woman in a particular society . In current RCTs, whether the patient is man or woman is either self-reported or assessed by ‘ referring to self-reported sex. Search strategy and selection The literature review search was conducted in two stages to minimise publication omissions. In the first stage, the following sources were sequentially searched, each by one th reviewer: PubMed (FCQ) on 4 September, using the national clinical trial identifier, AND/OR principal investigator AND/OR trial name. Google Scholar (JM) and Scopus (JM) were searched from 5th September to 31st October 2019, using the national clinical trial identifier, and where available, principal investigator and trial name. Internal analyses revealed that the primary articles on several clinical trials we had selected were not included in these search results. These publications were not available on Pubmed, but were found in Google Scholar. Therefore, a second additional search was conducted by JM from 15th April to 31st May 2020 on Google Scholar and Scopus only, specifically for the clinical trials where no article had been found. Here, only the national clinical identifier was used as search criteria since we observed that this maximized search yield, i.e., the strategy enabled missing primary publications to be included. While the second search was not included in the original protocol, it did not significantly change the results of the study and allowed for inclusion of more publications than the original search. Bias assessment The following risk domains were evaluated: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessment (detection bias); incomplete outcome data (attrition bias); selective reporting (reporting bias); other sources of bias. Each study was rated by two independent researchers (M.T.F. and F.C.Q.) as having low risk of bias (LR), high risk of bias (HR), or unclear risk of bias because of not enough information (NI). Disagreements Data extraction From each trial we extracted: title, authors, date of publications, NCT study identifier, trial start and end date year, and where available, trial sponsor, number and age of subjects enrolled; whether the publication reported the distribution of sex in the study population, the number of subjects of each sex, the population for which sex distribution was reported; whether the study protocol had a pre-specified analysis by sex in Methods, whether sex- stratified results were reported in publication Results; disease severity in study subjects. © 2021 Martinkova J et al. JAMA Network Open. were located on two or more continents), availability of study protocol, sex distribution in control and verum treatment groups, number of verum groups, control type, whether any analysis where the effect of sex could be determined was reported, reported sex difference, trial duration in weeks, mean baseline MMSE per trial and binarized result of the trial (verum effective/not effective) were also recorded. Analysis tools 2 3 All analyses were conducted in R, some utilizing the weights package and the binom 4 5 6 package. Figures were created using the ggplot2 and forestplot packages. Table 1 and eTables 2 and 3 were created using the tableone package . The planned subgroup analyses based on severity categories reported in the original A ‘ A ‘ tead, we utilized mean baseline MMSE per trial as a continuous predictor variable. eAppendix 2. Supplementary results. An analysis of the temporal trend of female proportion by phase of study, for both treatment groups (placebo/verum), and for the North America subgroup, was performed and found not significant. We explored the correlations between different study-level variables and between study- level variables and proportion of women enrolled by a series of multivariate analyses. eTable 6 displays Spearman non-parametric correlation matrix of severity, age, study start date, study publication date, approved versus experimental drug, location variables and proportion of women, with tests on the coefficients. The proportion of women correlated negatively with mean baseline MMSE per trial ((rho= 0.62, p<0.001), indicating a higher proportion of women in trials with lower participant MMSE, i.e. higher severity. There was a positive correlation with approved drug status (rho=0.47, p<0.001). All included location variables have significant correlation with the proportion of women, which is negative in North America (rho= 0.49, p<0.001) and positive in Asia and Europe (rho=0.34, p=0.01 and rho=0.28, p=0.04, respectively). Year of trial start and publication show a trivial significant correlation, while severity decreases with age and is lower in trials with experimental drugs. Finally, later published trials enrolled on average younger patients. Risk of bias We performed a risk of bias assessment according to the Cochrane bias assessment guide (eTable 10). As all publications were double-blind RCTs, selection bias was overall low, even though several publications failed to detail procedure for allocation concealment. In a few publications, we detected elements, which might have potentially caused the breaking of blind by participants (for instance, obvious side effects in verum vs placebo, such as ARIA) or by the experimenter (detection bias). Incomplete outcome data, with imputation methods missing or unclear, and high number of dropouts was found in 10 publications. Finally, the majority of publications did not have a public protocol available, hence we could not evaluate reporting bias. © 2021 Martinkova J et al. JAMA Network Open. Supplementary Figures eFigure 1: eFigure 1: . Proportion of women in AD CTs per publication year (of primary publications) was analyzed by Pearson correlation. When weighted by total population per trial, both year of publication and year of trial start show non-significant results. Shading indicates 95% confidence interval. eFigure 2: Temporal trends in reporting of sex-stratified results by trial start year eFigure 2: Temporal trends in reporting of sex-stratified results by trial start year. The diagram shows a positive trend in the number of publications (Y axis) reporting sex-stratified analysis in the Methods section as measured by trial start year, eFigure 2B shows a similar © 2021 Martinkova J et al. JAMA Network Open. trend for reporting these results in the Results section. Shading indicates 95% confidence interval, y-axis: 1: included sex stratification, 0: did not include it. © 2021 Martinkova J et al. JAMA Network Open. Supplementary Tables eTable 1: Inclusion and exclusion criteria according to PICOS PICOS dimension Inclusion criteria Exclusion criteria Population Study with patients diagnosed Combined studies which with dementia due to AD examined AD dementia and (mild, moderate, or advanced) other dementia types (i.e. vascular) MCI due to AD (based on biomarker evidence) Studies which used healthy volunteers or other dementias. Combined studies of MCI due to AD and AD patients, if data Down Syndrome and familial are reported separately and AD. not pooled Mild cognitive impairment not Study with both men and due to AD. women enrolled Studies with only men or only Studies with at least 100 women participants Studies with less than 100 participants Studies on AD patients focusing on neuropsychiatric symptoms such as agitation, psychosis, insomnia Intervention Pharmacological, biological or Behavioral studies, studies on genetic agents caregivers, devices, dietary Herbal extracts supplements Comparator Any comparator. Placebo Studies examining the effect of controlled, gold standard the discontinuation of a drug controlled Outcome Clinical efficacy on cognition Safety, tolerability, and memory; changes in AD bioavailability ATN biomarker status Study type RCT, phase 1, 2 and 3 Not randomized trials eTable 2: Basic characteristics of included publications for prodromal AD, primary publications © 2021 Martinkova J et al. JAMA Network Open. Basic characteristics of included publications: prodromal AD, primary publications n 8 Total N of subjects (median [IQR]) 297.50 [153.75, 538.25] Sex, pooled [%] Women 1392 (48.1%) Men 1500 (51.9%) Average age [years] (mean (SD)) 71.73 (1.10) Trial phase (%) 1 1 (12.5) 2 5 (62.5) 3 2 (25.0) Year of publication (median [IQR]) 2016.50 [2015.00, 2018.25] Year of trial start (median [IQR]) 2011.00 [2009.75, 2013.50] Year of trial end (median [IQR]) 2017.00 [2013.00, 2018.25] Trial duration [weeks] (median 59.5 [15.75, 104.00] [IQR]) Trial locations (%) Asia 0 Europe 2 (25.0) North America 2 (25.0) Worldwide 4 (50.0) Population (%) ITT 7 (87.5) mITT 0 Safety 1 (12.5) Experimental/approved (%) Approved 0 Experimental 8 (100) Lowest MMSE included (median 22.50 [19.50, 24.00] [IQR]) Highest MMSE included (median 30.00 [30.00, 30.00] [IQR]) © 2021 Martinkova J et al. JAMA Network Open. Basic characteristics of included publications: prodromal AD, primary publications Mean MMSE at baseline* (median 25.35 [24.40, 26.17] [IQR]) eTable 2: Basic characteristics of included publications for prodromal AD, primary publications. Reported in mean (SD) for normally distributed variables and in median [IQR] for non-normally distributed variables, categorical variables reported in % of total. All variables per trial level, as reported at baseline. * where available, n = 6 MMSE = mini mental state examination, IQR = interquartile range, SD = standard deviation, ITT = intention to treat, mITT = modified intention to treat eTable 3: Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications n 64 Total N of subjects (median [IQR]) 394.50 [209.75, 811.50] Sex, pooled [%] Women 24 740 (58.3%) Men 17 727 (41.7%) Average age [years] (mean (SD)) 73.26 (2.43) Trial phase (%) 1 1 (1.6) 2 37 (57.8) 3 26 (40.6) Year of publication (median [IQR]) 2015.00 [2011.75, 2017.00] Year of trial start (median [IQR]) 2009.00 [2007.00, 2012.00] Year of trial end (median [IQR]) 2012.00 [2010.00, 2015.00] Trial duration [weeks] (median 26.00 [24.00, 78.00] [IQR]) Trial locations (%) Asia 6 (9.4) Europe 8 (12.5) © 2021 Martinkova J et al. JAMA Network Open. Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications North America 18 (28.1) Worldwide 32 (50.0) Population (%) ITT 41 (64.1) mITT 9 (14.1) Safety 14 (21.9) Severity (%) Prodromal 8 (12.5) included Mild to moderate 52 (81.2) Severe included 4 (6.2) Experimental/approved (%) Approved 9 (14.1) Experimental 55 (85.9) Lowest MMSE included (median 12.00 [10.00, 16.00] [IQR]) Highest MMSE included (median 26.00 [23.75, 26.00] [IQR]) Mean MMSE at baseline* (median 19.22 [17.49, 21.37] [IQR]) eTable 3: Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications. Reported in mean (SD) for normally distributed variables and in median [IQR] for non-normally distributed variables, categorical variables reported in % of total. All variables per trial level, as reported at baseline. * where available, n = 61 MMSE = mini mental state examination, IQR = interquartile range, SD = standard deviation, ITT = intention to treat, mITT = modified intention to treat eTable 4: References for all included studies Trial ID First author Publication Publication title year NCT01739348 Egan 2018 Randomized Trial of Verubecestat for Mild-to-Moderate NCT02079909 Schneider 2019 Safety and Efficacy of Edonerpic Maleate for Patients With Mild to Moderate Alzheimer Disease: A Phase 2 Randomized Clinical Trial © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT00710684 Maher- 2015 Two randomized controlled trials of SB742457 in mild-to- Edwards NCT00555204 Lenz 2015 Adaptive, Dose-finding Phase 2 Trial Evaluating the Safety and Efficacy of ABT-089 in Mild to Moderate Alzheimer Disease NCT00478205 Farlow 2010 Effectiveness and Tolerability of High-Dose (23 mg/d) Versus Standard-Dose (10 mg/d) Donepezil in Moderate to Severe -Week, Randomized, Double-Blind Study NCT00478205 Ferris 2011 Analyzing the impact of 23 mg/day donepezil on language NCT00478205 Doody 2012 Efficacy and Safety of Donepezil 23 mg versus Donepezil 10 mg for Moderate-to- Analysis in Patients Already Taking or Not Taking Concomitant Memantine NCT00478205 Salloway 2012 Subgroup Analysis of US and Non-US Patients in a Global Study of High-Dose Donepezil (23 mg) in Moderate and Severe NCT00478205 Schmitt 2013 Evaluation of an 8-item Severe Impairment Battery (SIB-8) versus the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study NCT00377715 Doody 2008 Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to- -blind, placebo-controlled study NCT00479557, Pasquier 2016 Two Phase 2 Multiple Ascending Dose Studies of Vanutide NCT00498602 Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate NCT02017340 Lawlor 2018 Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial NCT01689246 Gauthier 2016 Efficacy and safety of tau-aggregation inhibitor therapy in randomised, controlled, double-blind, parallel-arm, phase 3 trial NCT02240693, Frölich 2019 Evaluation of the efficacy, safety and tolerability of orally NCT02337907 administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in NCT02389413 Scheltens 2018 Safety, tolerability and efficacy of the glutaminyl cyclase double-blind, placebo-controlled phase 2a study NCT00679627 Hager 2014 Effects of galantamine in a 2-year, randomized, placebo- NCT00679627 Hager 2016 Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with -hoc analysis of a randomized placebo- controlled study NCT02167256 van Dyck 2019 Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease NCT01900665 Honig 2018 Disease NCT01955161, Atri 2018 Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on NCT02006641, Change in Cognition in Patients With Alzheimer Disease NCT02006654 NCT00348192 Maher- 2010 SB-742457 and donepezil in Alzheimer disease: a randomized, Edwards placebo-controlled study © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT01676935 Gault 2016 ABT-126 monotherapy in mild-to- dementia: randomized doubleblind, placebo and active controlled adaptive trial and open-label extension NCT01549834 Florian 2016 Efficacy and Safety of ABT-126 in Subjects with Mild-to- Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study NCT01677754 Nave 2017 Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD) NCT01677572 Sevigny 2016 disease NCT01712074 Fullerton 2018 A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects neuropsychiatric symptoms on a stable daily dose of donepezil NCT00905372, Doody 2014 Phase 3 Trials of Solanezumab for Mild-to-Moderate NCT00904683 NCT01137526 Marek 2014 Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in NCT01224106 Ostrowiczki 2017 A phase III randomized trial of gantenerumab in prodromal NCT01019421 Wilkinson 2014 Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, randomised, double-blind, placebo-controlled phase 2 trial NCT00818662 Relkin 2017 A phase 3 trial of IV immunoglobulin for Alzheimer disease NCT00948909 Gault 2015 A phase 2 randomized, controlled trial of the a7 agonist ABT- 126 in mild-to- NCT00911807 Alvarez 2011 Randomized, Controlled Trial with Cerebrolysin and Donepezil NCT00594568 Doody 2013 Disease NCT00594568 Doody 2015 -secretase inhibition by NCT00890890 Coric 2015 Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial NCT00676143, Vandenberghe 2016 Bapineuz NCT00667810 global, randomized, phase 3 trials NCT00428090 Gold 2010 Rosiglitazone Monotherapy in Mild-to- Disease: Results from a Randomized, Double-Blind, Placebo- Controlled Phase III Study NCT00810147 Coric 2012 Safety and Tolerability of the -Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease NCT00575055, Salloway 2014 Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate NCT00574132 s Disease NCT00575055 Liu 2015 Amyloid-b 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials NCT00575055 Samtani 2015 -cognitive 11-item progression model in mild-to-moderate trials of bapineuzumab NCT00420420 Egan 2012 Pilot Randomized Controlled Study of a Histamine Receptor Inverse Agonist in the Symptomatic Treatment of AD NCT00074529 Sevigny 2008 Growth hormone secretagogue MK-677 : No clinical effect on AD progression in a randomized trial NCT00506415 Cummings 2012 Randomized, Double-Blind, Parallel-Group, 48-Week Study for Efficacy and Safety of a Higher-Dose Rivastigmine Patch (15 vs. © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT00506415 Molinuevo 2015 Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch NCT00216593 Burns 2009 Safety and efficacy of galantamine (Reminyl) in severe ed, placebo- controlled, double-blind trial NCT01953601 Egan 2019 Disease NCT00322153 Grossberg 2013 The Safety, Tolerability, and Efficacy of Once-Daily Memantine (28 mg): A Multinational, Randomized, Double-Blind, Placebo- Controlled Trial in Patients with Moderate-to-Severe NCT00322153 Grossberg 2018 Memantine ER Maintains Patient Response in Moderate to Disease Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors NCT00105547 Green 2009 Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer Disease: A Randomized Controlled Trial NCT00515333 Wischik 2015 Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 NCT01569516 Xiao 2017 Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild- disease: a Phase II multicenter randomised controlled trial NCT00423085 Nakamura 2011 A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of the Rivastigmine Patch in Japanese Patients with NCT00842816 Gauthier 2015 Effects of the Acetylcholine Release Agent ST101 with Randomized Phase 2 Study NCT01009255 Grove 2014 A Randomized, Double-Blind, Placebo-Controlled, 16-Week Study of the H3 Receptor Antagonist, GSK239512 as a Monotherapy in Subjects with Mild-to- Disease NCT01852110 Voss 2018 Randomized, controlled, proof-of-concept trial of MK-7622 in NCT01324518 Rinne 2017 Tolerability of ORM-12741 and effects on episodic memory in NCT01399125 Zhang 2016 Rivastigmine Patch in Chinese Patients with Probable -week, Randomized, Double-Blind Parallel-Group Study Comparing Rivastigmine Patch (9.5 mg/24 h) with Capsule (6 mg Twice Daily) NCT00568776 Salloway 2011 A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease NCT00566397 Galasko 2014 Clinical trial of an inhibitor of RAGE-Ab interactions in Alzheimer disease NCT01117818 Schneeberger 2015 Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with NCT00083590 Rafii 2011 A phase II trial of huperzine A in mild to moderate Alzheimer disease NCT01428453 Maher- 2015 A 24-week study to evaluate the effect of rilapladib on cognition Edwards NCT00438568 Craft 2012 Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment NCT00814801 Ohnishi 2014 The Prediction of Response to Galantamine Treatment in © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT01614886 Nakamura 2015 A 24-Week, Randomized, Controlled Study to Evaluate the Tolerability, Safety and Efficacy of 2 Different Titration Schemes of the Rivastigmine Patch in Japanese NCT00880412 Vellas 2011 -Month, Randomized, Placebo-Controlled, Double-Blind Study NCT00053599 Feldman 2010 Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease NCT00224497 Maher- 2010 Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Edwards Antagonist, SB- NCT01343966 Cummings 2018 ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease NCT01343966, Yoshida 2020 Pharmacokinetics and pharmacodynamic effect of crenezumab NCT01397578, on plasma and cerebrospinal fluid beta-amyloid in patients with NCT02353598 mild-to- NCT01254773 Brody 2016 A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate NCT00348140 Harrington 2011 Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to- Moderate Alzheimer's Disease: Two Phase 3 Studies NCT00088673 Aisen 2011 Tramiprosate in mild-to- a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study) NCT00088673 Abushakra 2017 Clinical Effects of Tramiprosate in APOE4/4 Homozygous Modification Potential NCT01539031 Homma 2016 Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients Double-Blind Trial eTable 5: Overview of study details and extracted data Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Egan, 2018 primary AD 2012 78 1957 1083 55.34 WW experiment NA 71.83 al Schneider, primary AD 2014 52 469 252 53.73 NoA experiment 18.27 71.83 2019 al Maher- primary AD 2008 35 1231 750 60.90 WW experiment 18.60 73.07 Edwards, al Lenz, primary AD 2007 12 334 184 55.09 NoA experiment 20.70 75.59 2015 al Farlow, primary AD 2007 24 1434 901 62.83 WW approved 13.10 73.87 © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Doody, primary AD 2005 26 183 122 66.67 AS experiment 18.51 68.24 2008 al Pasquier, primary AD 2007 104 245 139 56.73 WW experiment 21.40 69.10 2016 al Lawlor, primary AD 2013 78 498 308 61.85 EU experiment 20.40 72.95 2018 al Gauthier, primary AD 2013 65 885 545 61.58 WW experiment 18.60 70.60 2016 al Hager, primary AD 2008 104 2045 1325 64.79 EU approved 19.00 73.00 van Dyck, primary AD 2014 52 159 72 45.28 NoA experiment 22.47 71.00 2019 al Honig, primary AD 2013 80 2129 1231 57.82 WW experiment 22.70 73.00 2018 al Atri, 2018 primary AD 2014 24 2475 1568 63.35 WW experiment 17.33 74.19 al Maher- primary AD 2006 24 196 131 66.91 WW experiment 18.99 71.20 Edwards, al Gault, primary AD 2012 24 436 265 60.78 WW experiment 18.90 74.20 2016 al Florian, primary AD 2012 24 434 237 54.61 WW experiment 18.93 75.10 2016 al Nave, primary AD 2012 52 542 340 62.73 WW experiment 17.03 73.03 2017 al Fullerton, primary AD 2012 18 186 101 54.30 WW experiment 19.65 75.95 2018 al Doody, primary AD 2009 80 2052 1155 56.29 WW experiment 21.00 73.56 2014 al Marek, primary AD 2010 12 267 154 57.68 WW experiment 19.20 72.00 2014 al Wilkinson, primary AD 2009 24 278 196 70.50 WW experiment 17.00 74.48 2014 al Relkin, primary AD 2008 78 390 213 54.62 NoA experiment 21.30 70.30 2017 al Gault, primary AD 2009 12 274 168 61.31 WW experiment 19.10 73.90 2015 al Alvarez, primary AD 2004 28 197 152 77.16 EU experiment 17.50 75.20 2011 al © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Doody, primary AD 2008 76 1534 820 53.46 WW experiment 20.80 73.20 2013 al Vandenber primary AD 2008 78 1917 1155 60.25 WW experiment 20.88 70.54 ghe, 2016 al Gold, primary AD 2007 24 553 348 62.93 WW experiment 19.23 72.35 2010 al Coric, primary AD 2009 24 209 100 47.85 WW experiment 21.36 73.72 2012 al Salloway, primary AD 2007 78 2204 1188 53.90 NoA experiment 22.95 72.40 2014 al Egan, primary AD 2006 4 144 79 54.86 NoA experiment 22.15 74.05 2012 al Sevigny, primary AD 2003 52 563 326 57.90 NoA experiment 20.65 76.00 2008 al Cummings, primary AD 2007 48 567 367 64.73 WW approved 14.20 75.70 Burns, primary AD 2003 26 407 329 80.84 EU approved 8.95 83.60 Grossberg, primary AD 2005 24 676 487 72.04 WW approved 10.75 76.50 Green, primary AD 2005 78 1649 840 50.94 NoA experiment 23.30 74.60 2009 al Wischik, primary AD 2004 24 321 172 53.58 WW experiment 19.40 73.80 2015 al Xiao, primary AD 2011 16 273 176 64.47 AS experiment 17.43 72.19 2017 al Nakamura, primary AD 2007 24 855 584 68.30 AS approved 16.60 74.60 Gauthier, primary AD 2009 12 203 104 51.23 NoA experiment 17.30 76.60 2015 al Grove, primary AD 2009 16 194 126 64.95 WW experiment 19.95 71.80 2014 al Voss, primary AD 2013 24 239 129 53.97 NoA experiment 18.35 72.10 2018 al Rinne, primary AD 2011 12 100 59 59.00 EU experiment 18.50 72.00 2017 al Zhang, primary AD 2011 24 501 279 55.69 AS approved 16.30 70.10 Salloway, primary AD 2007 78 351 197 56.13 NoA experiment 20.42 73.35 2011 al © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Galasko, primary AD 2007 78 399 228 57.03 NoA experiment 20.40 72.93 2014 al Rafii, primary AD 2004 16 210 135 64.29 NoA experiment 19.12 77.92 2011 al Maher- primary AD 2011 24 121 61 50.53 WW experiment 22.85 73.00 Edwards, al Nakamura, primary AD 2012 24 215 145 67.46 AS approved 17.10 77.50 Vellas, primary AD 2008 12 157 88 56.05 EU experiment 19.21 76.30 2011 al Feldman, primary AD 2002 72 614 319 51.97 NoA experiment 21.85 73.59 2010 al Maher- primary AD 2005 24 357 207 57.96 WW experiment 20.00 69.80 Edwards, al Cummings, primary AD 2011 73 433 228 52.65 WW experiment 21.73 70.70 2018 al Brody, primary AD 2010 104 146 84 57.53 NoA experiment 22.00 72.80 2016 al Harrington, primary AD 2006 48 2822 1627 57.65 WW experiment 18.30 73.66 2011 al Aisen, primary AD 2004 78 1005 533 53.03 NoA experiment 21.10 73.90 2011 al Homma, primary AD 2012 24 340 236 69.41 AS approved 8.70 76.00 Frölich, primary 2015 12 452 231 51.11 WW experiment NA 73.60 2019 prodromal al Scheltens, primary 2015 12 120 64 53.33 EU experiment 25.00 71.40 2018 prodromal al Sevigny, primary 2012 54 165 83 50.30 NoA experiment 24.20 72.60 2016 prodromal al Ostrowiczki primary 2010 104 797 NA NA WW experiment 25.70 70.36 , 2017 prodromal al Coric, primary 2009 104 263 114 43.36 WW experiment 27.00 71.70 2015 prodromal al Egan, primary 2013 104 1454 686 47.18 WW experiment 26.33 71.43 2019 prodromal al Schneeberg primary 2010 65 332 169 50.90 EU experiment 23.30 70.40 er, 2015 prodromal al © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Craft, primary 2006 17 106 45 42.46 NoA experiment NA 72.35 2012 prodromal al Ferris, secondary 2007 24 1371 861 62.80 WW approved 13.10 73.80 Doody, secondary 2007 24 1434 901 62.83 WW approved 13.11 73.80 Salloway, secondary 2007 24 1434 901 62.83 WW approved 13.11 73.80 Schmitt, secondary 2007 24 1371 861 62.80 WW approved NA 73.80 Hager, secondary 2008 104 2045 1325 64.79 EU approved 19.00 73.00 Doody, secondary 2008 76 1534 820 53.46 WW experiment NA 73.20 2015 al Liu, 2015 secondary 2007 78 154 82 53.25 NoA experiment 20.98 71.00 al Samtani, secondary 2007 78 154 82 53.25 NoA experiment NA 71.00 2015 al Molinuevo, secondary 2007 48 568 368 64.79 WW approved NA 76.70 Grossberg, secondary 2005 24 676 487 72.04 WW approved NA 76.50 Ohnishi, secondary 2007 24 574 389 67.77 AS approved NA 75.20 Yoshida, secondary 2011 73 NA NA NA WW experiment NA NA 2020 al Abushakra, secondary 2004 78 257 144 56.03 WW experiment 21.12 71.10 2017 al eTable 5: Overview of study details and extracted data. Tabular overview of main extracted variables for all included studies. Rounded to 0 decimal points, or to 2 decimal points (proportion of women in %, baseline age, baseline MMSE). Designation assigned as follows: primary AD = chronologically first publication publishing primary results of a trial for subsequent publications from the same trial. © 2021 Martinkova J et al. JAMA Network Open. MMSE = mini mental state examination, WW = worldwide (2 continents or more), NoA = North America, AS = Asia, EU = Europe, NA = not available eTable 6: Proportion of women in subgroups: non-parametric correlation matrix MMSE Year Year Age Approved/experi Trial Asia Europe North publish starte mental durati Americ ed d on a Year rho=- publish 0.02, ed p=0.89 Year rho=- rho=0.8 started 0.13, 5, p=0.35 p=<0.00 1** Age rho=- rho=- rho=- 0.27, 0.31, 0.24, p=0.05 p=0.02* p=0.07 Approv rho=- rho=- rho=- rho=0. ed 0.56, 0.18, 0.09, 32, status p=<0.00 p=0.19 p=0.52 p=0.02 1** * Trial rho=0.3 rho=0.0 rho=- rho=- rho=-0.06, p=0.68 duratio 5, 9, 0.03, 0.34, p=0.008 p=0.52 p=0.84 p=0.01 ** * Asia rho=- rho=0.0 rho=0. rho=- rho=0.48, rho=- 0.39, 0, 11, 0.01, p=<0.001** 0.19, p=0.003 p=0.99 p=0.44 p=0.94 p=0.16 ** Europe rho=- rho=- rho=- rho=0.1 rho=0.16, p=0.23 rho=0. 0.15, 0.07, 0.07, 5, 00, p=0.28 p=0.60 p=0.63 p=0.28 p=0.99 North rho=0.4 rho=- rho=- rho=0.0 rho=-0.28, p=0.04* rho=0. Americ 2, 0.06, 0.21, 7, 17, p=0.001 p=0.64 p=0.12 p=0.63 p=0.20 ** Proporti rho=- rho=- rho=- rho=0.1 rho=0.47, rho=- rho=0. rho=0. rho=- on 0.62, 0.23, 0.12, 8, p=<0.001** 0.16, 34, 28, 0.49, women p=<0.00 p=0.09 p=0.37 p=0.19 p=0.23 p=0.01 p=0.04 p=<0.00 * * 1** 1** eTable 6: Proportion of women in subgroups: non-parametric correlation matrix. Correlation matrix using non-parametric Spearman correlation. Significant in bold (* significance level 0.05, ** significance level 0.01). There are several statistically significant correlations, notably between the proportion of women and MMSE (rho= 0.62, p<0.001), approved/experimental status (rho=0.47, p<0.001), and all location variables (Asia: rho=0.34, p=0.01; Europe: rho=0.28, p=0.04; North America: rho= 0.49, p<0.001). A A © 2021 Martinkova J et al. JAMA Network Open. eTable 7: Multivariate mixed effect logistic regression model with probability of trial participant being a women as a dependent variable, Model 3 (location only): summary of fixed effects OR Z value p-value CI Intercept 1.47 9.14 <0.001** (1.36,1.60) Location: Asia 1.28 2.34 0.02* (1.04,1.57) Location: Europe 1.42 3.23 0.001** (1.15,1.75) Location: North America 0.81 -2.92 0.003** (0.71,0.93) eTable 7: Multivariate mixed effect logistic regression model with probability of trial participant being a woman as a dependent variable, Model 3 (location only): summary of fixed effects. Tabular representation of the multivariable mixed effect binomial regression of probability of trial participant being a woman on predictor variables, location variables included. Significant results in bold, significance level denoted by asterisks (* significance level 0.05, ** significance level 0.01). All location predictor variables are statistically significant, with OR varying from to 0.81 for location in North America to 1.42 for location in Europe. OR = odds ratio, CI = 95% confidence interval eTable 8: Odds ratio of female enrolment by location: pairwise comparisons Estimate OR Z value p-value Asia vs. worldwide 1.16 1.39 0.98 Europe vs. worldwide 1.26 2.45 0.08 North America vs. worldwide 0.81 -3.10 0.01 * Europe vs. Asia 1.09 0.65 0.99 North America vs. Asia 0.70 -2.77 0.03 * North America vs. Europe 0.65 -4.37 <0.001 ** eTable 8: Odds ratio of female enrolment by location: pairwise comparisons. eTable 8 shows results of pairwise comparisons the coefficients of different locations, using Bonferroni adjustment for multiple comparisons. The results show a solid correlation of North America with a lower probability of female enrollment (OR 0.81 vs. worldwide, 0.70 and 0.65 vs Asia and Europe respectively). Significant results in bold, significance level denoted by asterisks (* significance level 0.05, ** significance level 0.01). OR = odds ratio © 2021 Martinkova J et al. JAMA Network Open. eTable 9: Reporting of sex-stratified data in primary studies (n=56) N of studies, % Study protocol available 17 (30.4%) Of these, sex-stratified analysis present in protocol in 8/17 (47.1%) Sex-stratified analysis in Methods 8 (14.3%) Sex-stratified data reported in Results 7 (12.5%) Of these, sex differences observed in results in 1/7 (14.3%) eTable 10: Bias assessment table Unique ID Reference Study ID a b c d e f g 1 Egan et al. 2018 6.1 LR LR LR LR LR LR LR 2 Schneider et al 2019 9 LR LR LR LR LR LR LR 3 Maher-Edwards 2015 12 LR LR LR LR LR LR LR 4 Lenz et al 2015 14 LR LR LR LR LR NI LR 5 Farlow et al 2010 15.1 LR LR LR LR LR NI LR 6 Doody et al 2008 17 LR LR LR LR LR NI LR 7 Pasquier et al 2016 20 LR NI LR LR LR NI LR 8 Lawlor 2018 24.1 LR LR LR LR LR LR LR 9 Gauthier 2016 31 LR LR LR LR LR NI LR 10 Frohlich 2019 34 LR LR LR NI LR LR LR 11 Scheltens 2018 40 LR LR LR NI LR LR LR 12 Hager 2014 42.1 LR LR LR LR HR LR LR 13 van Dyck 2019 46 LR LR LR LR LR LR LR 14 Honig 2018 47 LR LR LR LR LR LR LR 15 Atri 2018 51.1 LR LR LR LR LR LR LR 16 Maher-edwards 2010 52 LR NI LR NI LR NI HR 17 Gault 2016 55 LR LR LR NI LR LR LR 18 Florian 2016 56 LR LR LR LR LR NI LR 19 Nave 2017 59 LR LR LR LR LR LR LR 20 Sevigny 2016 60.1 LR LR HR HR LR NI LR 21 Fullerton 2018 62 LR LR LR LR LR LR LR 22 Doody 2014 67.1 LR LR LR LR LR LR LR 23 Marek 2014 69 LR LR LR LR HR NI LR 24 Ostrowitzki 2017 71.2 LR NI LR NI LR NI LR © 2021 Martinkova J et al. JAMA Network Open. Unique ID Reference Study ID a b c d e f g 25 Wilckinson 2014 75 LR LR LR LR LR NI LR 26 Relkin 2017 76 LR LR LR LR LR NI LR 27 Gault 2015 78 LR NI LR LR LR NI LR 28 Alvarez 2011 82 LR LR LR LR LR NI LR 29 Doody 2013 84.1 LR LR LR HR LR LR LR 30 Coric 2015 89 LR LR LR LR NI LR LR 31 Vanderberghe 2016 90.1 LR LR LR LR HR NI LR 32 Gold 2010 92 LR NI LR LR LR NI LR 33 Coric 2012 93 LR LR LR LR NI NI LR 34 Salloway 2014 94.1 LR LR HR LR LR LR LR 35 Egan 2012 99 LR NI LR LR LR NI LR 36 Sevigny 2008 108.1 LR LR LR LR NI NI LR 37 Cummings 2012 112.1 LR NI LR LR LR NI LR 38 Burns 2009 125 LR LR LR LR LR NI LR 39 Egan 2019 131.2 LR LR LR LR HR LR LR 40 Grossberg 2013 134.1 LR LR LR LR LR NI LR 41 Green 2009 161 LR LR LR NI LR NI LR 42 Wischik 2015 174 LR LR HR LR LR LR LR 43 Xiao 2017 199 LR NI LR LR LR NI LR 44 Nakamura et al 2011 200 LR NI LR LR LR NI LR 45 Gauthier 2015 208 LR NI LR LR LR NI LR 46 Grove 2014 210 LR LR LR LR LR NI LR 47 Voss 2018 211 LR LR LR LR HR LR LR 48 Rinne 2017 212 LR LR LR LR LR NI LR 49 Zin Chang 2015 214 LR LR HR LR LR NI LR 50 Salloway 2011 220 LR LR LR LR HR NI HR 51 Galasko 2014 223 LR NI LR LR LR NI LR 52 Schneeberger 2015 226 LR NI LR NI LR NI LR 53 Rafii 2011 231 LR NI LR LR LR NI LR 54 Maher Edwards 2015 8 LR NI LR LR LR NI LR 56 Craft 2012 175 LR NI LR LR LR NI HR 58 Nakamura 2015 230 LR LR LR LR LR NI LR 59 Vellas 2011 215 LR NI LR LR LR NI HR 60 Feldman et al. 2010 LR LR LR LR LR NI LR 61 Maher-Edwards et al. 2010 LR LR LR LR LR NI LR 62 Cummings et al. 2018 LR LR LR LR LR NI LR 63 Brody et al. 2016 LR LR LR LR LR NI LR © 2021 Martinkova J et al. JAMA Network Open. Unique ID Reference Study ID a b c d e f g 64 Harrington et al. 2011 LR NI LR LR LR NI LR 295.1 65 Aisen et al. 2011 LR LR LR LR HR NI LR 67 Homma et al. 2016 LR LR LR LR LR NI LR eTable 10: Bias assessment table. Tabular representation of risk of bias in individual primary studies (56 publications on AD and 8 on prodromal AD) using a modified version of the Cochrane risk of bias tool RoB2. a: random sequence generation (selection bias); b: allocation concealment (selection bias); c: blinding of participants and personnel (performance bias); d: blinding of outcome assessment (detection bias); e: incomplete outcome data (attrition bias); f: selective reporting (reporting bias); g: other sources of bias. Each study was rated as having low (LR), high (HR), or unclear because of not enough information (NI) risk of bias eReferences 1. Gendered Innovations in Science, Health & Medicine, Engineering, and E. Terminology. Stanford University (2011). 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Publisher: American Medical Association
Copyright: Copyright 2021 Martinkova J et al. JAMA Network Open.
eISSN: 2574-3805
DOI: 10.1001/jamanetworkopen.2021.24124
Publisher site: See Article on Publisher Site

Abstract

Key Points Question What is the proportion of IMPORTANCE Women represent two-thirds of patients with Alzheimer disease (AD), and sex women in large randomized clinical trials differences might affect results of randomized clinical trials (RCTs). However, little information exists for Alzheimer disease (AD), and are sex on differences in sex as reported in RCTs for AD. differences reported? Findings In this systematic review and OBJECTIVE To assess the ratio of females to males and the reporting of sex-stratified data in large meta-analysis of 56 randomized clinical pharmaceutical RCTs for AD. trials for AD with 39 575 total participants, 59.0% of patients overall DATA SOURCES A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, and a mean of 57.9% in trials of using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were experimental drugs were women, identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted significantly lower proportions of between September 4 and October 31, 2019, and between April 15 and May 31, 2020. women than in the US and European population with AD. Only 12.5% of STUDY SELECTION Controlled RCTs that had more than 100 participants and tested the efficacy of articles reported sex-stratified results, drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore but this proportion appeared to increase screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, over time. 13 secondary articles on AD, and 8 articles on mild cognitive impairment. Meaning Although the findings suggest DATA EXTRACTION AND SYNTHESIS The location and date of publication; number, sex, and age of that current clinical trials for AD enroll patients enrolled; disease severity; experimental or approved status of the drug; and whether the more women than men, strategies to study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 increase women’s participation in reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for clinical trials for AD should be discussed Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed- and the reporting of trial outcomes by effects model. sex should be encouraged. MAIN OUTCOMES AND MEASURES The mean proportion of women enrolled in the trials and the Invited Commentary associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied. Supplemental content Author affiliations and article information are RESULTS In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) listed at the end of this article. were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, −4.56% [95% CI, −6.29% to −2.87%]; P < .001) and Europe (68.2%; difference, −10.67% [95% CI, −12.39% to −8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 1/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Abstract (continued) the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P =.02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03). CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 Introduction Alzheimer disease (AD) is the leading cause of dementia in the older population and affects more than 50 million individuals worldwide. Current treatment of AD is symptomatic and at the time of this study was based on 4 approved pharmaceuticals (galantamine, rivastigmine, donepezil, and memantine). Substantial heterogeneity in risk factors, presentation, and progression among patients has 2,3 hindered the clinical development of precise diagnostics and disease-modifying therapies. Sex differences are potential causes of disease heterogeneity. Women represent most patients with AD 4,5 and related dementias (a mean of 68.2% of patients with AD in Europe and 62.1% in the US ). In 6-14 addition, sex-related differences occur in disease symptoms, progression, and biomarkers and in 15,16 genetic risk associated with the apolipoprotein E ε4 (APOE4) allele. These differences between men and women are likely associated with the efficacy of a tested drug in randomized clinical trials (RCTs). However, in RCTs among patients with AD, little attention has been given to the role of sex and gender differences. In a meta-analysis of 48 trials of approved AD therapeutics, trials enrolled more women than men (a mean of 63.8% women per trial), but none of the trials reported sex-stratified data. In contrast to RCTs for approved drugs, an overview of several phase 3 RCTs for experimental AD drugs reported that some trials enrolled approximately 50% men and 50% women. Whether and how sex is considered in current trials of experimental drugs remain to be established systematically. Therefore, we performed a systematic review and meta-analysis of articles related to RCTs for AD to examine the sex distribution of patients in the RCTs, the proportion of articles that reported sex-stratified data, and temporal trends in the findings. Methods Identification of Trials and Definition of Primary vs Secondary Articles This systematic review and meta-analysis was conducted according to a prespecified protocol (reviewregistry855). We used a systematic stepwise approach similar to that used in previous 18-20 articles (Figure 1). This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. First, we identified RCTs using the keyword Alzheimer disease at ClinicalTrials.gov, a large, web-based database resource maintained by the National Institutes of Health. All clinical trials performed in the US or to be used for US Food and Drug Administration submissions must be registered on ClinicalTrials.gov, but the database also includes trials not conducted in the US, making it one of the most complete trial databases. Only interventional trials in phase 1, 2, or 3 were included. The search was conducted on September 4, 2019. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 2/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Next, articles related to the RCTs found at ClinicalTrials.gov were identified by searching publicly available databases. PubMed was searched by one of us (F.C.Q.) on September 4, 2019, using the national clinical trial identifier, the principal investigator, and/or the trial name. Google Scholar and Scopus were searched by one of us (J.M.) between September 4 and October 31, 2019, and between April 15 and May 31, 2020, using each trial’s national clinical trial identifier and, when available, principal investigator and trial name. In addition, the reference list of each identified article was searched for other relevant trials. Further details on the search strategy are provided in eAppendix 1 the Supplement. In cases in which several peer-reviewed articles had been published on the same trial, the chronologically first publication of the main results was considered as the primary article; the others, considered secondary articles, were subject to the same selection and extraction process but were not included in the meta-analysis. Selection of Trials Published trials were selected according to predefined inclusion and exclusion criteria (eTable 1 in the Supplement) by 2 independent reviewers (J.M., M.T.F.). In case of disagreement, a third reviewer (A.S.C.) adjudicated. Only RCTs with more than 100 participants that included both sexes and enrolled patients with AD dementia or biomarker-confirmed mild cognitive impairment owing to AD (also referred to as prodromal AD) were selected. We included only RCTs studying the clinical efficacy of pharmacological, biological, or genetic agents or herbal extracts. Because efficacy is assessed even in early stages of trials, we did not limit our selection by trial phase. We focused on trials with more than 100 individuals because they are the most informative for the assessment of the benefit and Figure 1. Article Selection Flowchart 1047 Records identified from ClinicalTrials.gov 409 Records identified as published 405 Databases 278 PubMed 123 Google Scholar 4 Scopus 4 References 70 Duplicate records removed 339 Records screened 240 Records excluded 99 Population 41 Intervention 47 Outcome 53 Study type 99 Reports sought for retrieval 2 Reports not retrieved 97 Reports assessed for eligibility 20 Records excluded 9 Population 1 Outcome 2 Comparator 8 Arbitration Primary articles were defined as the chronologically 77 Studies included in review 8 Prodromal AD first article containing the main results of a trial; all 13 Secondary other articles on the trial were considered secondary. 56 Primary studies on AD included in meta-analysis AD indicates Alzheimer disease. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 3/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease safety profile of a given compound and they inform clinical practice; they also allow the robust calculation of the effects of sex. Because the scope of this review was to inform pharmaceutical RCT design, we excluded behavioral interventions, caregiver support, devices, and dietary supplements. Bias Assessment The risk of bias was assessed in each of the 56 primary articles on AD by 2 reviewers (F.C.Q., M.T.F.) using the Cochrane bias assessment. Details are given in eAppendix 1 in the Supplement. Data Extraction For each study included in this review, 1 reviewer (J.M.) extracted the required information into a prespecified extraction table according to the protocol. In brief, this included basic information on the trial, publication year, numbers of participants (men, women, and total), and a binary yes-or-no assessment of sex stratification in the methods, results, and protocol. The status of the drug (experimental or approved) was also recorded; we considered approved drugs as 1 of the 4 drugs currently in use for the treatment of AD (memantine, rivastigmine, donepezil, and galantamine). More details are available in eAppendix 1 in the Supplement. Statistical Analysis We analyzed both primary and secondary articles using a specific rationale that avoided overfitting. Primary articles that included information about how many men and women were included in the study design were used to investigate the sex ratio in a trial overall, in prespecified subgroups, and across time. To study temporal trends in the reporting of sex in study results, we analyzed pooled primary and secondary articles together because secondary articles (with additional analysis of existing data) might have reported sex-stratified results. A total of 56 primary articles for AD dementia and 8 for prodromal AD were analyzed separately per protocol; the analyses for prodromal AD did not find significant differences in sex ratios between subgroups, likely owing to low statistical power, and are not reported in this article. Pooling the results did not affect the overall conclusions of this study. Within the primary articles, we examined sex ratios at baseline in prespecified subgroups (including approved vs experimental drugs, trial phase, and location) and the effect of prespecified variables (including the mean baseline Mini-Mental State Examination [MMSE] score, baseline age, trial duration in weeks, publication year, and year of trial start). Basic characteristics were calculated on a per-trial basis. If the mean value per trial was not given (eg, for age or MMSE), we calculated the weighted mean of the subgroups for which these data were available. Sex Proportion An analysis of sex proportion was performed only for the 56 primary articles on AD. The total baseline percentage of women was calculated per trial arm and for the whole trial population by calculating the mean proportions of female individuals in each trial (ie, on a per-trial basis); in addition, we obtained similar proportions by pooling patients from all trials (Figure 2). We used Wilcoxon signed rank tests to compare the trial-based results with a fixed value of the proportion of women in the 5 4 real-world population with AD based on published US (62.1%) and European (68.2%) statistics. To assess the associations between prespecified variables, we used a multivariate mixed-effect logistic regression model of the probability that an enrolled patient was a woman. A logistic regression model was used because sex is a binary variable. We used 2 main models. Model 1 excluded location variables, and model 2 included all variables. To account for different sample sizes of the trials and intertrial variability, we added a random intercept at the trial level and estimated the 22,23 corresponding variance parameter. Subsequently, a Spearman nonparametric correlation matrix was used to characterize the correlation between different trial characteristics. A series of pairwise comparisons was run between the coefficients of different locations using Bonferroni adjustment for multiple comparisons. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 4/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Pearson correlations were calculated to examine whether there was a temporal trend in the proportion of women; significance of the association was assessed using a 2-tailed Wald test. Correlations were weighted based on the total number of trial participants. Sex-Stratified Data Because RCT data may be subject to several analyses, resulting in multiple articles about the same trial, for this study, we used a pooled data set including both the primary and the secondary (later) Figure 2. Proportion of Women in Primary Alzheimer Disease (AD) Articles Study Patients, No. Females, % (95% CI) Experimental drugs Doody et al, 2008 183 66.7 (59.3-73.4) Sevigny et al, 2008 563 57.9 (53.7-62.0) Green et al, 2009 1649 50.9 (48.5-53.4) Maher-Edwards et al, 2011 196 66.8 (59.8-73.4) Gold et al, 2010 553 62.9 (58.8-67.0) Feldman et al, 2010 614 52.0 (47.9-56.0) Maher-Edwards et al, 2010 357 58.0 (52.7-63.2) Aisen et al, 2011 1005 53.0 (49.9-56.2) Alvarez et al, 2011 197 77.2 (70.7-82.8) Salloway et al, 2011 351 56.1 (50.8-61.4) Raffi et al, 2011 210 64.3 (57.4-70.8) Vellas et al, 2011 157 56.1 (47.9-64.0) Harrington et al, 2011 2822 57.7 (55.8-59.5) Coric et al, 2012 209 47.8 (40.9-54.8) Egan et al, 2012 144 54.9 (46.4-63.2) Doody et al, 2013 1534 53.5 (50.9-56.0) Doody et al, 2014 2052 56.3 (54.1-58.4) Marek et al, 2014 267 57.7 (51.5-63.7) Wilkinson et al, 2014 278 70.5 (64.8-75.8) Salloway et al, 2014 2204 53.9 (51.8-56.0) Grove et al, 2014 64.9 (57.8-71.6) Galasko et al, 2014 399 57.1 (52.1-62.1) Maher-Edwards et al, 2015 1231 60.9 (58.1-63.7) Lenz et al, 2015 55.1 (49.6-60.5) Gault et al, 2015 61.3 (55.3-67.1) Wischik et al, 2015 321 53.6 (48.0-59.1) Gauthier et al, 2015 203 51.2 (44.1-58.3) Maher-Edwards et al, 2015 121 50.4 (41.2-59.6) Pasquier et al, 2016 245 56.7 (50.3-63.0) Gauthier et al, 2016 885 61.6 (58.3-64.8) Gault et al, 2016 436 60.8 (56.0-65.4) Florian et al, 2016 434 54.6 (49.8-59.4) Vandenberghe et al, 2016 1917 60.3 (58.0-62.5) Brody et al, 2016 146 57.5 (49.1-65.7) Nave et al, 2017 542 62.7 (58.5-66.8) Relkin et al, 2017 390 54.6 (49.5-59.6) Xiao et al, 2017 273 64.5 (58.5-70.1) Rinne et al, 2016 100 59.0 (48.7-68.7) Egan et al, 2018 1957 55.3 (53.1-57.6) Lawlor et al, 2018 498 61.8 (57.4-66.1) Honig et al, 2018 2129 57.8 (55.7-59.9) Atri et al, 2018 2475 63.4 (61.4-65.3) Fullerton et al, 2018 186 54.3 (46.9-61.6) Voss et al, 2018 239 54.0 (47.4-60.4) Cummings et al, 2018 433 52.7 (47.8-57.4) Schneider et al, 2019 469 53.7 (49.1-58.3) van Dyck et al, 2019 159 45.3 (37.4-53.4) Subtotal 32 535 57.5 (56.9-58.0) Approved drugs 407 80.8 (76.7-84.5) Burns et al, 2009 Farlow et al, 2010 1434 62.8 (60.3-65.3) Nakamura et al, 2011 855 68.3 (65.1-71.4) Cummings et al, 2012 567 64.7 (60.6-68.7) Grossberg et al, 2013 676 72.0 (68.5-75.4) Percentages were obtained by pooling raw data of all Hager et al, 2014 2045 64.8 (62.7-66.9) patients in 56 primary articles, defined as the Nakamura et al, 2015 215 67.4 (60.7-73.7) chronologically first publication of the main results of a Zhang et al, 2016 501 55.7 (51.2-60.1) Homma et al, 2016 340 69.4 (64.2-74.3) trial. Squares represent percentages, with horizontal Subtotal 7040 66.1 (65.0-67.2) lines indicating binomial 95% CIs. Diamonds represent Total 39 575 59.0 (58.5-59.5) pooled estimates, with points of the lines indicating 95% CIs. The marker size is proportional to the 45 50 55 60 65 70 75 80 Females, % (95% CI) precision of the estimate. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 5/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease articles. We calculated the percentages of articles that included a data analysis by sex in the study protocol, in the methods, and/or in the results sections of the article. Temporal trends were calculated using logistic regression of the probability that the article reported sex-stratified results in the pooled data set of primary and secondary articles. All statistical analyses were conducted using R, version 3.6.2 (R Project for Statistical Computing). Unless otherwise specified, significance was set at 2-tailed P < .05. Table 1. Basic Characteristics of Included Articles Characteristic Articles Articles on AD dementia, No. 56 Participants per article, median (IQR), No. 403.0 (213.8-862.5) Sex, pooled No. (%) Women 23 348 (59.0) Men 16 227 (41.0) Age, mean (SD), y 73.5 (2.5) Trial phase 2 32 (57.1) 3 24 (42.9) Year of publication, median (IQR) 2014.50 (2011.00-2016.00) Year of trial start, median (IQR) 2008.00 (2006.75-2011.25) Year of trial end, median (IQR) 2011.00 (2009.00-2014.00) Trial duration, median (IQR), wk 25.0 (24.0-76.5) Trial location Asia 6 (10.7) Europe 6 (10.7) North America 16 (28.6) Worldwide 28 (50.0) Trial population ITT 34 (60.7) mITT 9 (16.1) Safety 13 (23.2) Severity of AD Mild to moderate 52 (92.9) Severe 4 (7.1) Approval status of drug Approved 9 (16.1) Experimental 47 (83.9) Mean MMSE score at baseline, 19.16 (17.49-20.91) median (IQR) Abbreviations: AD, Alzheimer disease; IQR, interquartile range; ITT, intention to treat; mITT, modified intention to treat; MMSE, Mini-Mental State Examination. Data are presented as the number (percentage) of articles unless otherwise indicated. The mean (SD) is reported for normally distributed variables and the median (IQR) for non–normally distributed variables. Categorical variables are reported as the percentage of the total. All variables were assessed per trial as reported at baseline. Data were available in 55 of the trials. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 6/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Results Basic Characteristics of Included Articles A total of 1047 trials were identified on ClinicalTrials.gov (Figure 1). Among these, 409 published articles were found using PubMed, Google Scholar, Scopus, and article references; 70 articles were removed as duplicates and another 240 were excluded based on title and abstract screening. By applying the predefined set of inclusion and exclusion criteria, we selected 77 articles, of which 64 were categorized as primary (56 on AD dementia and 8 on prodromal AD) and 13 as secondary (all on AD dementia). The most common reasons for excluding an article were population (ie, <100 participants) and study type (ie, not a randomized clinical trial). Agreement between reviewers was 95.6%. 25-80 The 56 selected primary articles on patients with AD dementia reported large phase 2 and 3 trials involving a median of 403.0 participants (interquartile range, 213.8-862.5 participants) with 72-80 a mean (SD) age of 73.5 (2.5) years (Table 1). Nine articles (16.1%) reported results of approved 25-71 drugs and 47 (83.9%) reported results of experimental drugs. Most articles (34 25,26,28,29,31-33,35,37-43,45-50,52,53,56,59,60,62,65,67,71,72,75,79,80 [60.7%]) reported the sex ratio in the intention-to-treat population (Table 1). Basic information on trials and articles regarding prodromal 81-88 AD and pooled trials and articles is available in eTables 2 and 3 in the Supplement. The references for the trials are available in eTable 4 of the Supplement, and a summary of the extracted data are available in eTable 5 in the Supplement. Sex Proportion 25-80 In the 56 primary articles on AD dementia, the overall proportion of women was 59.0% (23 348 of 39 575 total participants) (Table 1 and Figure 2). In a preliminary data analysis, on a trial basis, the 72-80 mean (SD) proportion of women in the trials for approved drugs was 67.3% (6.9%), whereas in 25-71 trials for experimental medications, it was 57.9% (5.9%). The proportion of women in the experimental medications subgroup (57.9%; 95% CI, 55.8%-59.2%) was significantly different from the proportion of women in the population with AD in both in the US (62.1%; difference, −4.56% [95% CI, −6.29% to −2.87%]; P < .001) and Europe (68.2%; difference, −10.67% [95% CI, −12.39% to −8.97%]; P < .001). In model 1 (Table 2), in which location variables were excluded, variables significantly associated with the probability that women were enrolled in a study included the status of the drug (approved vs experimental) and the severity of the participants’ AD (measured by baseline MMSE). Supporting the preliminary data analysis, trials involving drugs with approved status were associated with a higher probability of including women (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). However, we found a lower probability of women being included in trials with a higher mean baseline MMSE (OR, 0.98; 95% CI, 0.97-1.00; P = .02), indicating that trials including participants with more severe cases of AD were more likely to enroll women. The results were confirmed in pairwise comparisons (eTable 6 in the Supplement). When location was included in model 2, fewer associations were found (Table 2 and 25-80 Figure 2). In model 2, location was the only factor significantly associated with inclusion of women in AD trials, with location in Europe associated with a higher probability that the trials included women (OR, 1.26; 95% CI, 1.05-1.52; P = .01) and location in North America associated with a lower probability (OR, 0.81; 95% CI, 0.71-0.93; P = .002) (Table 2; further results are shown in eTable 7 and location pairwise comparisons in eTable 8 in the Supplement). Trial duration, mean baseline age of participants, publication year, and trial start year were not significantly associated with the probability that women were included, based on the results of either model. We did not find any significant temporal trend in the proportion of women included in AD trials over time, either by publication year or by trial start year (R, −0.04; 95% CI, −0.30 to 0.23; P = .79) (eFigure 1 in the Supplement). The variance parameter for the trial random effect was 0.036, confirming the presence of a nonnegligible degree of heterogeneity between trials. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 7/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Reporting of Sex-Stratified Data and Its Temporal Trend We investigated the proportion of primary articles that included sex stratification in the study protocol or methods or reported sex-stratified data in the results (eTable 9 in the Supplement). Most did not include sex-stratified data in the protocol, methods, or results. Of the 56 AD dementia articles, we were able to identify a complete published protocol with a 28,37,40,41,44,45,47,52,54,55,63-66,68,70,71 statistical analysis plan for only 17 (30.4%) ; of these, only 8 40,41,54,55,63,65,68,70 (47.1%) included a sex-specific data analysis in the protocol. Of the 56 total 27,49,54-56,64,67,68 articles, 8 (14.3%) incorporated sex-specific data analysis in the methods section. 27,49,55,56,64,67,68 64 Seven articles (12.5%) reported the results of such analysis, and 1 article showed a potential sex difference in efficacy that favored men, although no significance testing was conducted. No trials stratified trial arms by sex; the most common method of statistical analysis was a prespecified subgroup analysis. To assess whether subsequent articles for a given RCT reported sex-stratified data, we also 89-101 considered the secondary articles. We found that in this group of 13 articles, a sex-specific data 91,92,99,100 analysis was present in 4 (30.8%). Using a pooled data set from primary and secondary articles (Figure 3 and eFigure 2 in the Supplement), we found a statistically significant increasing temporal trend of articles that referenced a sex-specific data analysis in the methods (R, 0.30; 95% CI, 0.05-0.59; P = .03) and a similar trend for sex stratification in the results (R, 0.26; 95% CI, 0.01-0.55; P = .055). The results of the risk-of- bias analysis are provided in eAppendix 2 and eTable 10 in the Supplement. Discussion In this systematic review and meta-analysis, of the 56 selected RCTs, 59.0% of the included participants were women, and 57.9% were women in the subgroup of trials of experimental drugs. Although this indicated greater trial enrollment of women compared with men, these numbers are significantly lower than the proportions of women reported in real-world populations with AD (68.2% in Europe and 62.1% in the US). This suggests that the enrollment of women in RCTs for AD Table 2. Summary of Fixed Effects in Multivariate Mixed Effect Logistic Regression Models of the Probability That an Enrolled Trial Patient Was a Woman Fixed effect OR (95% CI) z score P value Model 1 Intercept 1.51 (1.34-1.69) 6.74 <.001 MMSE 0.98 (0.97-1.00) −2.26 .02 Age 1.02 (0.99-1.05) 1.22 .22 Year started 0.99 (0.96-1.03) −0.47 .64 Year published 1.00 (0.96-1.03) −0.31 .76 Status of drug (approved) 1.26 (1.05-1.52) 2.44 .02 Trial duration 0.93 (0.83-1.05) −1.16 .25 Model 2 Intercept 1.53 (1.37-1.71) 7.70 <.001 MMSE 0.99 (0.97-1.00) −1.79 .07 Age 1.03 (1.00-1.05) 1.83 .07 Year started 1.00 (0.97-1.03) 0.02 .98 Year published 0.98 (0.95-1.01) −1.17 .24 Status of drug (approved) 1.10 (0.91-1.31) 0.98 .33 Abbreviations: MMSE, Mini-Mental State Examination; Trial duration 0.96 (0.86-1.07) −0.74 .46 OR, odds ratio. Location Location excluded. Asia 1.16 (0.94-1.42) 1.39 .16 Significance level P = .01. Europe 1.26 (1.05-1.52) 2.45 .01 Significance level P = .05. North America 0.81 (0.71-0.93) −3.10 .002 Location included. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 8/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease could be further increased. Older women might be a particularly difficult group to enroll; their underrepresentation in RCTs is well-known in stroke research. To gain additional insights for the design of future RCTs, we analyzed factors associated with the probability of enrolling women in trials. A multivariate analysis revealed that trial duration was not associated with enrollment of women, whereas geographical and clinical factors were. This study found that the probability that women were included in RCTs for AD was lower in RCTs in North America compared with other locations (eg, Europe). This observation, if confirmed, might indicate the need for region-specific strategies for enrollment of women in trials. Aside from the location of the trials, drug status (approved vs experimental) was the factor most associated with differences in sex ratios. The RCTs for approved drugs had a significantly higher probability of including women than did RCTs for experimental drugs. The reasons for such differences remain to be elucidated; we are investigating the possibility that a higher ratio of women may be associated with trials in which a drug showed a significant clinical effect. In addition, we found that the probability of women’s inclusion was higher in trials involving more severe cases of AD, but this was not associated with age (Table 2); recruitment and retention of women in AD trials might therefore need to be tailored according to disease stage. Of interest, we found that although an analysis of sex-based data was included in many available study protocols, the results of such analyses were not published in most cases. However, a temporal trend was found, indicating an increase in the inclusion of data analysis by sex in reports of AD trials. The findings of this study may stimulate a global discussion on 3 important aspects associated with diversity in RCTs. First, when studying a multifactorial disease such as AD, properly representing the diverse patient population may be crucial in RCT design. Having a study population similar to the real-world one might be needed to detect relevant outcomes in a trial. For example, RCTs for migraine, a disease that largely affects women and for which several new drugs have been discovered, enroll more women than men, with proportions that reflect the expected real-world sex ratio. Of course, promoting women’s enrollment in RCTs for AD has to be weighed against the wider request by regulatory agencies for equality in RCT participation. Second, participation of women and particularly older women in RCTs might be subject to specific challenges. When living alone, older women affected by AD or stroke might have a disadvantage in joining long and complex trials and might lack a caregiver to accompany them. Another possibility is that inclusion and exclusion criteria for RCTs—for instance, based on educational level—might unintentionally but systematically exclude more women than men. Figure 3. Temporal Trends in the Reporting of Sex-Stratification Analyses A Methods B Results 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 June 2007 January 2010 June 2012 January 2015 June 2017 January 2020 June 2007 January 2010 June 2012 January 2015 June 2017 January 2020 Date of publication Date of publication The trend was significant only for the methods (R, 0.30; 95% CI, 0.05-0.59; P = .03). did not include a sex-specific analysis. Data markers indicate observed data points, and The y-axis represents the probability of inclusion of a sex-specific analysis in a study, with shading, the 95% CI. 1 indicating that the study included a sex-specific analysis and 0 indicating that the study JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 9/17 Probability of including sex-specific analysis Probability of including sex-specific analysis JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Third, the low frequency of sex-stratified results reported in articles is a call to action for better publishing practices. The data analysis revealed a low percentage of trials with complete protocols available (30.4%), a percentage that should increase for the sake of transparency. Describing sex-stratified data (even if no differences are found) should become a routine in clinical data publication, and it is also important for avoiding publication bias. Limitations 18-20 This study has limitations. First, as done in previous studies, we chose to use ClinicalTrials.gov as the primary source of RCT data. ClinicalTrials.gov allows registration of trials from all countries (exemplified by the different locations in the current data analyses). However, because only RCTs in the US are required to register at ClinicalTrials.gov, it is possible that this study’s data analysis was skewed toward RCTs conducted in the US. The highly selective inclusion and exclusion criteria also potentially led to exclusion of some relevant trials but enabled a more focused interpretation of results. Another limitation is that owing to the exclusion of solely pharmacokinetic and safety trials from the data analysis, the potential sex differences in these aspects were not captured. It is well-known that drugs used in AD, such as antipsychotic medications, have different safety and pharmacokinetic profiles in men and women. Sex differences in adverse events have also been observed for 106 107 rivastigmine and memantine. Therefore, further systematic exploration of sex differences in safety profiles is warranted. In addition, some of the data analyses were based on imbalanced groups (for instance, analyses between trials of approved drugs [n = 9] vs trials of experimental drugs [n = 47]). Such imbalances potentially introduced a lack of statistical power for detecting differences. However, because the study’s approach was systematic, this was unlikely to be a source of bias that invalidated the results. Conclusions In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD. ARTICLE INFORMATION Accepted for Publication: July 2, 2021. Published: September 13, 2021. doi:10.1001/jamanetworkopen.2021.24124 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Martinkova Jetal. JAMA Network Open. Corresponding Author: Maria Teresa Ferretti, PhD, Women’s Brain Project, c/o Pfisterwiesstrasse 14, 8352 Guntershausen, Switzerland (mariateresa.ferretti@womensbrainproject.com). Author Affiliations: Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic (Martinkova, Hort); Women’s Brain Project, Guntershausen, Switzerland (Martinkova, Quevenco, Ferrari, Chadha, Ferretti); Roche Diagnostics International Ltd, Rotkreuz, Switzerland (Quevenco); Novartis Pharma AG, Basel, Switzerland (Karcher); Stroke Unit, Department of Neurology, University of Oslo, Oslo, Norway (Sandset); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia (Szoeke); International Clinical Research Center, St Anne’s University Hospital Brno, Brno, Czech Republic (Hort); Department of Neurogeriatrics, University Clinic of Neurology, Medical University Graz, Graz, Austria (Schmidt); Biogen International GMBH, Baar, Switzerland (Chadha). Author Contributions: Drs Martinkova and Ferrari had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 10/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease Concept and design: Quevenco, Karcher, Sandset, Szoeke, Hort, Schmidt, Santuccione Chadha, Ferretti. Acquisition, analysis, or interpretation of data: Martinkova, Quevenco, Karcher, Ferrari, Szoeke, Hort, Santuccione Chadha, Ferretti. Drafting of the manuscript: Martinkova, Ferrari, Szoeke, Santuccione Chadha, Ferretti. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Martinkova, Quevenco, Karcher, Ferrari, Santuccione Chadha. Administrative, technical, or material support: Martinkova, Quevenco, Karcher, Szoeke. Supervision: Karcher, Szoeke, Hort, Schmidt, Santuccione Chadha, Ferretti. Conflict of Interest Disclosures: Dr Quevenco reported being an employee of Roche Diagnostics International Ltd during the conduct of the study. Dr Karcher reported being an employee of Novartis during part of the conduct of the study. Dr Ferrari reported being an employee of Women’s Brain Project (WBP) and a consultant at Business & Decision Life Science, Italy, during the conduct of the study. Dr Sandset reported receiving honoraria for lectures from Bayer and Novartis unrelated to the submitted work. Dr Santuccione Chadha reported being an employee of Biogen after completion of this work and being the chief executive officer (unpaid position) of WBP during the conduct of the study. Dr Ferretti reported receiving personal fees from Eli Lilly and Company outside the submitted work and serving as the chief scientific officer of WBP during the conduct of the study. No other disclosures were reported. Funding/Support: Dr Martinkova was supported by project 436119 of the Charles University Grant Agency, Second Faculty of Medicine, and by the Avast Foundation (Nadační fond Avast) together with the Czech Alzheimer’s Foundation (Alzheimer nadační fond). Dr Szoeke was supported by grants 547500, 1032350, and 1062133 from the National Health and Medical Research Council, Australia, and grant NIA320312 from the Alzheimer’s Association. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The opinions expressed in this article are the personal views of Drs Santuccione Chadha, Quevenco, and Karcher and may not be understood or quoted as being made on behalf of or reflecting the position of their employers. Additional Contributions: We thank the WBP community. 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Alzheimers Res Ther. 2015;7(1):9. doi:10.1186/s13195-014-0088-8 101. Grossberg GT, Alva G, Hendrix S, Ellison N, Kane MC, Edwards J. Memantine ER maintains patient response in moderate to severe Alzheimer’s disease: post hoc analyses from a randomized, controlled, clinical trial of patients treated with cholinesterase inhibitors. Alzheimer Dis Assoc Disord. 2018;32(3):173-178. doi:10.1097/WAD. 102. Bartlett VL, Dhruva SS, Shah ND, Ryan P, Ross JS. Feasibility of using real-world data to replicate clinical trial evidence. JAMA Netw Open. 2019;2(10):e1912869-e1912869. doi:10.1001/jamanetworkopen.2019.12869 103. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. doi: 10.1001/jamaneurol.2018.1212 104. Boada M. Gender and sex bias in clinical trials, recruitment in Alzheimer’s disease: findings from Fundacio ACE. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) 2019; December 4-7, 2019; San Diego, CA; and Alzheimer’s Association International Conference (AAIC) 2020; July 27-31, 2020. 105. Marshall DL, Hazlet TK, Gardner JS, Blough DK. Neuroleptic drug exposure and incidence of tardive dyskinesia: a records-based case-control study. J Manag Care Pharm. 2002;8(4):259-265. doi:10.18553/jmcp. 2002.8.4.259 106. EXELON (rivastigmine tartrate). Draft package insert. Food and Drug Administration; 2000. Accessed July 24, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20823lbl.pdf 107. Namenda (Memantine HCI) tablets medical review, Part 4. Food and Drug Administration; 2003. Accessed July 24, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-487_Namenda_Medr_P4.pdf JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 16/17 JAMA Network Open | Neurology Proportion of Women and Reporting of Sex in Clinical Trials for Alzheimer Disease SUPPLEMENT. eAppendix 1. Supplementary methods eAppendix 2. Supplementary results eFigure 1. Temporal trends in women’s representation in AD trials eFigure 2. Temporal trends in reporting of sex-stratified results by trial start year eTable 1. Inclusion and exclusion criteria according to PICOS eTable 2. Basic characteristics of included publications for prodromal AD, primary publications eTable 3. Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications eTable 4. References for all included studies eTable 5. Overview of study details and extracted data eTable 6. Proportion of women in subgroups: nonparametric correlation matrix eTable 7. Multivariate mixed effect logistic regression model with probability of trial participant being a woman as a dependent variable, Model 3 (location only): summary of fixed effects eTable 8. Odds ratio of female enrollment by location: pairwise comparisons eTable 9. Reporting of sex-stratified data in primary studies (n=56) eTable 10. Bias assessment table eReferences JAMA Network Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 (Reprinted) September 13, 2021 17/17 Supplementary Online Content Martinkova J, Quevenco FC, Karcher H, et al. Proportion of women and reporting of outcomes by sex in clinical trials for Alzheimer disease: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(9):e2124124. doi:10.1001/jamanetworkopen.2021.24124 eAppendix 1. Supplementary methods eAppendix 2. Supplementary results eFigure 1. eFigure 2. Temporal trends in reporting of sex-stratified results by trial start year eTable 1. Inclusion and exclusion criteria according to PICOS eTable 2. Basic characteristics of included publications for prodromal AD, primary publications eTable 3. Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications eTable 4. References for all included studies eTable 5. Overview of study details and extracted data eTable 6. Proportion of women in subgroups: nonparametric correlation matrix eTable 7. Multivariate mixed effect logistic regression model with probability of trial participant being a woman as a dependent variable, Model 3 (location only): summary of fixed effects eTable 8. Odds ratio of female enrollment by location: pairwise comparisons eTable 9. Reporting of sex-stratified data in primary studies (n=56) eTable 10. Bias assessment table eReferences This supplementary material has been provided by the authors to give readers additional information about their work. © 2021 Martinkova J et al. JAMA Network Open. eAppendix 1. Supplementary Methods. Definition of sex and gender Sex refers to the biological characteristics arising from the expression of sex chromosomes (XX for female and XY for male) as well as the effects of exogenous gonadal hormones. Gender refers to the socially-driven definition of being a man and a woman in a particular society . In current RCTs, whether the patient is man or woman is either self-reported or assessed by ‘ referring to self-reported sex. Search strategy and selection The literature review search was conducted in two stages to minimise publication omissions. In the first stage, the following sources were sequentially searched, each by one th reviewer: PubMed (FCQ) on 4 September, using the national clinical trial identifier, AND/OR principal investigator AND/OR trial name. Google Scholar (JM) and Scopus (JM) were searched from 5th September to 31st October 2019, using the national clinical trial identifier, and where available, principal investigator and trial name. Internal analyses revealed that the primary articles on several clinical trials we had selected were not included in these search results. These publications were not available on Pubmed, but were found in Google Scholar. Therefore, a second additional search was conducted by JM from 15th April to 31st May 2020 on Google Scholar and Scopus only, specifically for the clinical trials where no article had been found. Here, only the national clinical identifier was used as search criteria since we observed that this maximized search yield, i.e., the strategy enabled missing primary publications to be included. While the second search was not included in the original protocol, it did not significantly change the results of the study and allowed for inclusion of more publications than the original search. Bias assessment The following risk domains were evaluated: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessment (detection bias); incomplete outcome data (attrition bias); selective reporting (reporting bias); other sources of bias. Each study was rated by two independent researchers (M.T.F. and F.C.Q.) as having low risk of bias (LR), high risk of bias (HR), or unclear risk of bias because of not enough information (NI). Disagreements Data extraction From each trial we extracted: title, authors, date of publications, NCT study identifier, trial start and end date year, and where available, trial sponsor, number and age of subjects enrolled; whether the publication reported the distribution of sex in the study population, the number of subjects of each sex, the population for which sex distribution was reported; whether the study protocol had a pre-specified analysis by sex in Methods, whether sex- stratified results were reported in publication Results; disease severity in study subjects. © 2021 Martinkova J et al. JAMA Network Open. were located on two or more continents), availability of study protocol, sex distribution in control and verum treatment groups, number of verum groups, control type, whether any analysis where the effect of sex could be determined was reported, reported sex difference, trial duration in weeks, mean baseline MMSE per trial and binarized result of the trial (verum effective/not effective) were also recorded. Analysis tools 2 3 All analyses were conducted in R, some utilizing the weights package and the binom 4 5 6 package. Figures were created using the ggplot2 and forestplot packages. Table 1 and eTables 2 and 3 were created using the tableone package . The planned subgroup analyses based on severity categories reported in the original A ‘ A ‘ tead, we utilized mean baseline MMSE per trial as a continuous predictor variable. eAppendix 2. Supplementary results. An analysis of the temporal trend of female proportion by phase of study, for both treatment groups (placebo/verum), and for the North America subgroup, was performed and found not significant. We explored the correlations between different study-level variables and between study- level variables and proportion of women enrolled by a series of multivariate analyses. eTable 6 displays Spearman non-parametric correlation matrix of severity, age, study start date, study publication date, approved versus experimental drug, location variables and proportion of women, with tests on the coefficients. The proportion of women correlated negatively with mean baseline MMSE per trial ((rho= 0.62, p<0.001), indicating a higher proportion of women in trials with lower participant MMSE, i.e. higher severity. There was a positive correlation with approved drug status (rho=0.47, p<0.001). All included location variables have significant correlation with the proportion of women, which is negative in North America (rho= 0.49, p<0.001) and positive in Asia and Europe (rho=0.34, p=0.01 and rho=0.28, p=0.04, respectively). Year of trial start and publication show a trivial significant correlation, while severity decreases with age and is lower in trials with experimental drugs. Finally, later published trials enrolled on average younger patients. Risk of bias We performed a risk of bias assessment according to the Cochrane bias assessment guide (eTable 10). As all publications were double-blind RCTs, selection bias was overall low, even though several publications failed to detail procedure for allocation concealment. In a few publications, we detected elements, which might have potentially caused the breaking of blind by participants (for instance, obvious side effects in verum vs placebo, such as ARIA) or by the experimenter (detection bias). Incomplete outcome data, with imputation methods missing or unclear, and high number of dropouts was found in 10 publications. Finally, the majority of publications did not have a public protocol available, hence we could not evaluate reporting bias. © 2021 Martinkova J et al. JAMA Network Open. Supplementary Figures eFigure 1: eFigure 1: . Proportion of women in AD CTs per publication year (of primary publications) was analyzed by Pearson correlation. When weighted by total population per trial, both year of publication and year of trial start show non-significant results. Shading indicates 95% confidence interval. eFigure 2: Temporal trends in reporting of sex-stratified results by trial start year eFigure 2: Temporal trends in reporting of sex-stratified results by trial start year. The diagram shows a positive trend in the number of publications (Y axis) reporting sex-stratified analysis in the Methods section as measured by trial start year, eFigure 2B shows a similar © 2021 Martinkova J et al. JAMA Network Open. trend for reporting these results in the Results section. Shading indicates 95% confidence interval, y-axis: 1: included sex stratification, 0: did not include it. © 2021 Martinkova J et al. JAMA Network Open. Supplementary Tables eTable 1: Inclusion and exclusion criteria according to PICOS PICOS dimension Inclusion criteria Exclusion criteria Population Study with patients diagnosed Combined studies which with dementia due to AD examined AD dementia and (mild, moderate, or advanced) other dementia types (i.e. vascular) MCI due to AD (based on biomarker evidence) Studies which used healthy volunteers or other dementias. Combined studies of MCI due to AD and AD patients, if data Down Syndrome and familial are reported separately and AD. not pooled Mild cognitive impairment not Study with both men and due to AD. women enrolled Studies with only men or only Studies with at least 100 women participants Studies with less than 100 participants Studies on AD patients focusing on neuropsychiatric symptoms such as agitation, psychosis, insomnia Intervention Pharmacological, biological or Behavioral studies, studies on genetic agents caregivers, devices, dietary Herbal extracts supplements Comparator Any comparator. Placebo Studies examining the effect of controlled, gold standard the discontinuation of a drug controlled Outcome Clinical efficacy on cognition Safety, tolerability, and memory; changes in AD bioavailability ATN biomarker status Study type RCT, phase 1, 2 and 3 Not randomized trials eTable 2: Basic characteristics of included publications for prodromal AD, primary publications © 2021 Martinkova J et al. JAMA Network Open. Basic characteristics of included publications: prodromal AD, primary publications n 8 Total N of subjects (median [IQR]) 297.50 [153.75, 538.25] Sex, pooled [%] Women 1392 (48.1%) Men 1500 (51.9%) Average age [years] (mean (SD)) 71.73 (1.10) Trial phase (%) 1 1 (12.5) 2 5 (62.5) 3 2 (25.0) Year of publication (median [IQR]) 2016.50 [2015.00, 2018.25] Year of trial start (median [IQR]) 2011.00 [2009.75, 2013.50] Year of trial end (median [IQR]) 2017.00 [2013.00, 2018.25] Trial duration [weeks] (median 59.5 [15.75, 104.00] [IQR]) Trial locations (%) Asia 0 Europe 2 (25.0) North America 2 (25.0) Worldwide 4 (50.0) Population (%) ITT 7 (87.5) mITT 0 Safety 1 (12.5) Experimental/approved (%) Approved 0 Experimental 8 (100) Lowest MMSE included (median 22.50 [19.50, 24.00] [IQR]) Highest MMSE included (median 30.00 [30.00, 30.00] [IQR]) © 2021 Martinkova J et al. JAMA Network Open. Basic characteristics of included publications: prodromal AD, primary publications Mean MMSE at baseline* (median 25.35 [24.40, 26.17] [IQR]) eTable 2: Basic characteristics of included publications for prodromal AD, primary publications. Reported in mean (SD) for normally distributed variables and in median [IQR] for non-normally distributed variables, categorical variables reported in % of total. All variables per trial level, as reported at baseline. * where available, n = 6 MMSE = mini mental state examination, IQR = interquartile range, SD = standard deviation, ITT = intention to treat, mITT = modified intention to treat eTable 3: Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications n 64 Total N of subjects (median [IQR]) 394.50 [209.75, 811.50] Sex, pooled [%] Women 24 740 (58.3%) Men 17 727 (41.7%) Average age [years] (mean (SD)) 73.26 (2.43) Trial phase (%) 1 1 (1.6) 2 37 (57.8) 3 26 (40.6) Year of publication (median [IQR]) 2015.00 [2011.75, 2017.00] Year of trial start (median [IQR]) 2009.00 [2007.00, 2012.00] Year of trial end (median [IQR]) 2012.00 [2010.00, 2015.00] Trial duration [weeks] (median 26.00 [24.00, 78.00] [IQR]) Trial locations (%) Asia 6 (9.4) Europe 8 (12.5) © 2021 Martinkova J et al. JAMA Network Open. Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications North America 18 (28.1) Worldwide 32 (50.0) Population (%) ITT 41 (64.1) mITT 9 (14.1) Safety 14 (21.9) Severity (%) Prodromal 8 (12.5) included Mild to moderate 52 (81.2) Severe included 4 (6.2) Experimental/approved (%) Approved 9 (14.1) Experimental 55 (85.9) Lowest MMSE included (median 12.00 [10.00, 16.00] [IQR]) Highest MMSE included (median 26.00 [23.75, 26.00] [IQR]) Mean MMSE at baseline* (median 19.22 [17.49, 21.37] [IQR]) eTable 3: Basic characteristics of included publications: pooled AD dementia + prodromal AD, primary publications. Reported in mean (SD) for normally distributed variables and in median [IQR] for non-normally distributed variables, categorical variables reported in % of total. All variables per trial level, as reported at baseline. * where available, n = 61 MMSE = mini mental state examination, IQR = interquartile range, SD = standard deviation, ITT = intention to treat, mITT = modified intention to treat eTable 4: References for all included studies Trial ID First author Publication Publication title year NCT01739348 Egan 2018 Randomized Trial of Verubecestat for Mild-to-Moderate NCT02079909 Schneider 2019 Safety and Efficacy of Edonerpic Maleate for Patients With Mild to Moderate Alzheimer Disease: A Phase 2 Randomized Clinical Trial © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT00710684 Maher- 2015 Two randomized controlled trials of SB742457 in mild-to- Edwards NCT00555204 Lenz 2015 Adaptive, Dose-finding Phase 2 Trial Evaluating the Safety and Efficacy of ABT-089 in Mild to Moderate Alzheimer Disease NCT00478205 Farlow 2010 Effectiveness and Tolerability of High-Dose (23 mg/d) Versus Standard-Dose (10 mg/d) Donepezil in Moderate to Severe -Week, Randomized, Double-Blind Study NCT00478205 Ferris 2011 Analyzing the impact of 23 mg/day donepezil on language NCT00478205 Doody 2012 Efficacy and Safety of Donepezil 23 mg versus Donepezil 10 mg for Moderate-to- Analysis in Patients Already Taking or Not Taking Concomitant Memantine NCT00478205 Salloway 2012 Subgroup Analysis of US and Non-US Patients in a Global Study of High-Dose Donepezil (23 mg) in Moderate and Severe NCT00478205 Schmitt 2013 Evaluation of an 8-item Severe Impairment Battery (SIB-8) versus the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study NCT00377715 Doody 2008 Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to- -blind, placebo-controlled study NCT00479557, Pasquier 2016 Two Phase 2 Multiple Ascending Dose Studies of Vanutide NCT00498602 Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate NCT02017340 Lawlor 2018 Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial NCT01689246 Gauthier 2016 Efficacy and safety of tau-aggregation inhibitor therapy in randomised, controlled, double-blind, parallel-arm, phase 3 trial NCT02240693, Frölich 2019 Evaluation of the efficacy, safety and tolerability of orally NCT02337907 administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in NCT02389413 Scheltens 2018 Safety, tolerability and efficacy of the glutaminyl cyclase double-blind, placebo-controlled phase 2a study NCT00679627 Hager 2014 Effects of galantamine in a 2-year, randomized, placebo- NCT00679627 Hager 2016 Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with -hoc analysis of a randomized placebo- controlled study NCT02167256 van Dyck 2019 Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease NCT01900665 Honig 2018 Disease NCT01955161, Atri 2018 Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on NCT02006641, Change in Cognition in Patients With Alzheimer Disease NCT02006654 NCT00348192 Maher- 2010 SB-742457 and donepezil in Alzheimer disease: a randomized, Edwards placebo-controlled study © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT01676935 Gault 2016 ABT-126 monotherapy in mild-to- dementia: randomized doubleblind, placebo and active controlled adaptive trial and open-label extension NCT01549834 Florian 2016 Efficacy and Safety of ABT-126 in Subjects with Mild-to- Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study NCT01677754 Nave 2017 Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD) NCT01677572 Sevigny 2016 disease NCT01712074 Fullerton 2018 A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects neuropsychiatric symptoms on a stable daily dose of donepezil NCT00905372, Doody 2014 Phase 3 Trials of Solanezumab for Mild-to-Moderate NCT00904683 NCT01137526 Marek 2014 Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in NCT01224106 Ostrowiczki 2017 A phase III randomized trial of gantenerumab in prodromal NCT01019421 Wilkinson 2014 Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, randomised, double-blind, placebo-controlled phase 2 trial NCT00818662 Relkin 2017 A phase 3 trial of IV immunoglobulin for Alzheimer disease NCT00948909 Gault 2015 A phase 2 randomized, controlled trial of the a7 agonist ABT- 126 in mild-to- NCT00911807 Alvarez 2011 Randomized, Controlled Trial with Cerebrolysin and Donepezil NCT00594568 Doody 2013 Disease NCT00594568 Doody 2015 -secretase inhibition by NCT00890890 Coric 2015 Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial NCT00676143, Vandenberghe 2016 Bapineuz NCT00667810 global, randomized, phase 3 trials NCT00428090 Gold 2010 Rosiglitazone Monotherapy in Mild-to- Disease: Results from a Randomized, Double-Blind, Placebo- Controlled Phase III Study NCT00810147 Coric 2012 Safety and Tolerability of the -Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease NCT00575055, Salloway 2014 Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate NCT00574132 s Disease NCT00575055 Liu 2015 Amyloid-b 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials NCT00575055 Samtani 2015 -cognitive 11-item progression model in mild-to-moderate trials of bapineuzumab NCT00420420 Egan 2012 Pilot Randomized Controlled Study of a Histamine Receptor Inverse Agonist in the Symptomatic Treatment of AD NCT00074529 Sevigny 2008 Growth hormone secretagogue MK-677 : No clinical effect on AD progression in a randomized trial NCT00506415 Cummings 2012 Randomized, Double-Blind, Parallel-Group, 48-Week Study for Efficacy and Safety of a Higher-Dose Rivastigmine Patch (15 vs. © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT00506415 Molinuevo 2015 Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch NCT00216593 Burns 2009 Safety and efficacy of galantamine (Reminyl) in severe ed, placebo- controlled, double-blind trial NCT01953601 Egan 2019 Disease NCT00322153 Grossberg 2013 The Safety, Tolerability, and Efficacy of Once-Daily Memantine (28 mg): A Multinational, Randomized, Double-Blind, Placebo- Controlled Trial in Patients with Moderate-to-Severe NCT00322153 Grossberg 2018 Memantine ER Maintains Patient Response in Moderate to Disease Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors NCT00105547 Green 2009 Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer Disease: A Randomized Controlled Trial NCT00515333 Wischik 2015 Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 NCT01569516 Xiao 2017 Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild- disease: a Phase II multicenter randomised controlled trial NCT00423085 Nakamura 2011 A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of the Rivastigmine Patch in Japanese Patients with NCT00842816 Gauthier 2015 Effects of the Acetylcholine Release Agent ST101 with Randomized Phase 2 Study NCT01009255 Grove 2014 A Randomized, Double-Blind, Placebo-Controlled, 16-Week Study of the H3 Receptor Antagonist, GSK239512 as a Monotherapy in Subjects with Mild-to- Disease NCT01852110 Voss 2018 Randomized, controlled, proof-of-concept trial of MK-7622 in NCT01324518 Rinne 2017 Tolerability of ORM-12741 and effects on episodic memory in NCT01399125 Zhang 2016 Rivastigmine Patch in Chinese Patients with Probable -week, Randomized, Double-Blind Parallel-Group Study Comparing Rivastigmine Patch (9.5 mg/24 h) with Capsule (6 mg Twice Daily) NCT00568776 Salloway 2011 A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease NCT00566397 Galasko 2014 Clinical trial of an inhibitor of RAGE-Ab interactions in Alzheimer disease NCT01117818 Schneeberger 2015 Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with NCT00083590 Rafii 2011 A phase II trial of huperzine A in mild to moderate Alzheimer disease NCT01428453 Maher- 2015 A 24-week study to evaluate the effect of rilapladib on cognition Edwards NCT00438568 Craft 2012 Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment NCT00814801 Ohnishi 2014 The Prediction of Response to Galantamine Treatment in © 2021 Martinkova J et al. JAMA Network Open. Trial ID First author Publication Publication title year NCT01614886 Nakamura 2015 A 24-Week, Randomized, Controlled Study to Evaluate the Tolerability, Safety and Efficacy of 2 Different Titration Schemes of the Rivastigmine Patch in Japanese NCT00880412 Vellas 2011 -Month, Randomized, Placebo-Controlled, Double-Blind Study NCT00053599 Feldman 2010 Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease NCT00224497 Maher- 2010 Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Edwards Antagonist, SB- NCT01343966 Cummings 2018 ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease NCT01343966, Yoshida 2020 Pharmacokinetics and pharmacodynamic effect of crenezumab NCT01397578, on plasma and cerebrospinal fluid beta-amyloid in patients with NCT02353598 mild-to- NCT01254773 Brody 2016 A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate NCT00348140 Harrington 2011 Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to- Moderate Alzheimer's Disease: Two Phase 3 Studies NCT00088673 Aisen 2011 Tramiprosate in mild-to- a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study) NCT00088673 Abushakra 2017 Clinical Effects of Tramiprosate in APOE4/4 Homozygous Modification Potential NCT01539031 Homma 2016 Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients Double-Blind Trial eTable 5: Overview of study details and extracted data Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Egan, 2018 primary AD 2012 78 1957 1083 55.34 WW experiment NA 71.83 al Schneider, primary AD 2014 52 469 252 53.73 NoA experiment 18.27 71.83 2019 al Maher- primary AD 2008 35 1231 750 60.90 WW experiment 18.60 73.07 Edwards, al Lenz, primary AD 2007 12 334 184 55.09 NoA experiment 20.70 75.59 2015 al Farlow, primary AD 2007 24 1434 901 62.83 WW approved 13.10 73.87 © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Doody, primary AD 2005 26 183 122 66.67 AS experiment 18.51 68.24 2008 al Pasquier, primary AD 2007 104 245 139 56.73 WW experiment 21.40 69.10 2016 al Lawlor, primary AD 2013 78 498 308 61.85 EU experiment 20.40 72.95 2018 al Gauthier, primary AD 2013 65 885 545 61.58 WW experiment 18.60 70.60 2016 al Hager, primary AD 2008 104 2045 1325 64.79 EU approved 19.00 73.00 van Dyck, primary AD 2014 52 159 72 45.28 NoA experiment 22.47 71.00 2019 al Honig, primary AD 2013 80 2129 1231 57.82 WW experiment 22.70 73.00 2018 al Atri, 2018 primary AD 2014 24 2475 1568 63.35 WW experiment 17.33 74.19 al Maher- primary AD 2006 24 196 131 66.91 WW experiment 18.99 71.20 Edwards, al Gault, primary AD 2012 24 436 265 60.78 WW experiment 18.90 74.20 2016 al Florian, primary AD 2012 24 434 237 54.61 WW experiment 18.93 75.10 2016 al Nave, primary AD 2012 52 542 340 62.73 WW experiment 17.03 73.03 2017 al Fullerton, primary AD 2012 18 186 101 54.30 WW experiment 19.65 75.95 2018 al Doody, primary AD 2009 80 2052 1155 56.29 WW experiment 21.00 73.56 2014 al Marek, primary AD 2010 12 267 154 57.68 WW experiment 19.20 72.00 2014 al Wilkinson, primary AD 2009 24 278 196 70.50 WW experiment 17.00 74.48 2014 al Relkin, primary AD 2008 78 390 213 54.62 NoA experiment 21.30 70.30 2017 al Gault, primary AD 2009 12 274 168 61.31 WW experiment 19.10 73.90 2015 al Alvarez, primary AD 2004 28 197 152 77.16 EU experiment 17.50 75.20 2011 al © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Doody, primary AD 2008 76 1534 820 53.46 WW experiment 20.80 73.20 2013 al Vandenber primary AD 2008 78 1917 1155 60.25 WW experiment 20.88 70.54 ghe, 2016 al Gold, primary AD 2007 24 553 348 62.93 WW experiment 19.23 72.35 2010 al Coric, primary AD 2009 24 209 100 47.85 WW experiment 21.36 73.72 2012 al Salloway, primary AD 2007 78 2204 1188 53.90 NoA experiment 22.95 72.40 2014 al Egan, primary AD 2006 4 144 79 54.86 NoA experiment 22.15 74.05 2012 al Sevigny, primary AD 2003 52 563 326 57.90 NoA experiment 20.65 76.00 2008 al Cummings, primary AD 2007 48 567 367 64.73 WW approved 14.20 75.70 Burns, primary AD 2003 26 407 329 80.84 EU approved 8.95 83.60 Grossberg, primary AD 2005 24 676 487 72.04 WW approved 10.75 76.50 Green, primary AD 2005 78 1649 840 50.94 NoA experiment 23.30 74.60 2009 al Wischik, primary AD 2004 24 321 172 53.58 WW experiment 19.40 73.80 2015 al Xiao, primary AD 2011 16 273 176 64.47 AS experiment 17.43 72.19 2017 al Nakamura, primary AD 2007 24 855 584 68.30 AS approved 16.60 74.60 Gauthier, primary AD 2009 12 203 104 51.23 NoA experiment 17.30 76.60 2015 al Grove, primary AD 2009 16 194 126 64.95 WW experiment 19.95 71.80 2014 al Voss, primary AD 2013 24 239 129 53.97 NoA experiment 18.35 72.10 2018 al Rinne, primary AD 2011 12 100 59 59.00 EU experiment 18.50 72.00 2017 al Zhang, primary AD 2011 24 501 279 55.69 AS approved 16.30 70.10 Salloway, primary AD 2007 78 351 197 56.13 NoA experiment 20.42 73.35 2011 al © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Galasko, primary AD 2007 78 399 228 57.03 NoA experiment 20.40 72.93 2014 al Rafii, primary AD 2004 16 210 135 64.29 NoA experiment 19.12 77.92 2011 al Maher- primary AD 2011 24 121 61 50.53 WW experiment 22.85 73.00 Edwards, al Nakamura, primary AD 2012 24 215 145 67.46 AS approved 17.10 77.50 Vellas, primary AD 2008 12 157 88 56.05 EU experiment 19.21 76.30 2011 al Feldman, primary AD 2002 72 614 319 51.97 NoA experiment 21.85 73.59 2010 al Maher- primary AD 2005 24 357 207 57.96 WW experiment 20.00 69.80 Edwards, al Cummings, primary AD 2011 73 433 228 52.65 WW experiment 21.73 70.70 2018 al Brody, primary AD 2010 104 146 84 57.53 NoA experiment 22.00 72.80 2016 al Harrington, primary AD 2006 48 2822 1627 57.65 WW experiment 18.30 73.66 2011 al Aisen, primary AD 2004 78 1005 533 53.03 NoA experiment 21.10 73.90 2011 al Homma, primary AD 2012 24 340 236 69.41 AS approved 8.70 76.00 Frölich, primary 2015 12 452 231 51.11 WW experiment NA 73.60 2019 prodromal al Scheltens, primary 2015 12 120 64 53.33 EU experiment 25.00 71.40 2018 prodromal al Sevigny, primary 2012 54 165 83 50.30 NoA experiment 24.20 72.60 2016 prodromal al Ostrowiczki primary 2010 104 797 NA NA WW experiment 25.70 70.36 , 2017 prodromal al Coric, primary 2009 104 263 114 43.36 WW experiment 27.00 71.70 2015 prodromal al Egan, primary 2013 104 1454 686 47.18 WW experiment 26.33 71.43 2019 prodromal al Schneeberg primary 2010 65 332 169 50.90 EU experiment 23.30 70.40 er, 2015 prodromal al © 2021 Martinkova J et al. JAMA Network Open. Reference Designation Trial Trial Trial Women, Women Location Approved/ Mean Mean baseline start duration participa N [%] experimen baseline age [years] [weeks] nts, N tal MMSE Craft, primary 2006 17 106 45 42.46 NoA experiment NA 72.35 2012 prodromal al Ferris, secondary 2007 24 1371 861 62.80 WW approved 13.10 73.80 Doody, secondary 2007 24 1434 901 62.83 WW approved 13.11 73.80 Salloway, secondary 2007 24 1434 901 62.83 WW approved 13.11 73.80 Schmitt, secondary 2007 24 1371 861 62.80 WW approved NA 73.80 Hager, secondary 2008 104 2045 1325 64.79 EU approved 19.00 73.00 Doody, secondary 2008 76 1534 820 53.46 WW experiment NA 73.20 2015 al Liu, 2015 secondary 2007 78 154 82 53.25 NoA experiment 20.98 71.00 al Samtani, secondary 2007 78 154 82 53.25 NoA experiment NA 71.00 2015 al Molinuevo, secondary 2007 48 568 368 64.79 WW approved NA 76.70 Grossberg, secondary 2005 24 676 487 72.04 WW approved NA 76.50 Ohnishi, secondary 2007 24 574 389 67.77 AS approved NA 75.20 Yoshida, secondary 2011 73 NA NA NA WW experiment NA NA 2020 al Abushakra, secondary 2004 78 257 144 56.03 WW experiment 21.12 71.10 2017 al eTable 5: Overview of study details and extracted data. Tabular overview of main extracted variables for all included studies. Rounded to 0 decimal points, or to 2 decimal points (proportion of women in %, baseline age, baseline MMSE). Designation assigned as follows: primary AD = chronologically first publication publishing primary results of a trial for subsequent publications from the same trial. © 2021 Martinkova J et al. JAMA Network Open. MMSE = mini mental state examination, WW = worldwide (2 continents or more), NoA = North America, AS = Asia, EU = Europe, NA = not available eTable 6: Proportion of women in subgroups: non-parametric correlation matrix MMSE Year Year Age Approved/experi Trial Asia Europe North publish starte mental durati Americ ed d on a Year rho=- publish 0.02, ed p=0.89 Year rho=- rho=0.8 started 0.13, 5, p=0.35 p=<0.00 1** Age rho=- rho=- rho=- 0.27, 0.31, 0.24, p=0.05 p=0.02* p=0.07 Approv rho=- rho=- rho=- rho=0. ed 0.56, 0.18, 0.09, 32, status p=<0.00 p=0.19 p=0.52 p=0.02 1** * Trial rho=0.3 rho=0.0 rho=- rho=- rho=-0.06, p=0.68 duratio 5, 9, 0.03, 0.34, p=0.008 p=0.52 p=0.84 p=0.01 ** * Asia rho=- rho=0.0 rho=0. rho=- rho=0.48, rho=- 0.39, 0, 11, 0.01, p=<0.001** 0.19, p=0.003 p=0.99 p=0.44 p=0.94 p=0.16 ** Europe rho=- rho=- rho=- rho=0.1 rho=0.16, p=0.23 rho=0. 0.15, 0.07, 0.07, 5, 00, p=0.28 p=0.60 p=0.63 p=0.28 p=0.99 North rho=0.4 rho=- rho=- rho=0.0 rho=-0.28, p=0.04* rho=0. Americ 2, 0.06, 0.21, 7, 17, p=0.001 p=0.64 p=0.12 p=0.63 p=0.20 ** Proporti rho=- rho=- rho=- rho=0.1 rho=0.47, rho=- rho=0. rho=0. rho=- on 0.62, 0.23, 0.12, 8, p=<0.001** 0.16, 34, 28, 0.49, women p=<0.00 p=0.09 p=0.37 p=0.19 p=0.23 p=0.01 p=0.04 p=<0.00 * * 1** 1** eTable 6: Proportion of women in subgroups: non-parametric correlation matrix. Correlation matrix using non-parametric Spearman correlation. Significant in bold (* significance level 0.05, ** significance level 0.01). There are several statistically significant correlations, notably between the proportion of women and MMSE (rho= 0.62, p<0.001), approved/experimental status (rho=0.47, p<0.001), and all location variables (Asia: rho=0.34, p=0.01; Europe: rho=0.28, p=0.04; North America: rho= 0.49, p<0.001). A A © 2021 Martinkova J et al. JAMA Network Open. eTable 7: Multivariate mixed effect logistic regression model with probability of trial participant being a women as a dependent variable, Model 3 (location only): summary of fixed effects OR Z value p-value CI Intercept 1.47 9.14 <0.001** (1.36,1.60) Location: Asia 1.28 2.34 0.02* (1.04,1.57) Location: Europe 1.42 3.23 0.001** (1.15,1.75) Location: North America 0.81 -2.92 0.003** (0.71,0.93) eTable 7: Multivariate mixed effect logistic regression model with probability of trial participant being a woman as a dependent variable, Model 3 (location only): summary of fixed effects. Tabular representation of the multivariable mixed effect binomial regression of probability of trial participant being a woman on predictor variables, location variables included. Significant results in bold, significance level denoted by asterisks (* significance level 0.05, ** significance level 0.01). All location predictor variables are statistically significant, with OR varying from to 0.81 for location in North America to 1.42 for location in Europe. OR = odds ratio, CI = 95% confidence interval eTable 8: Odds ratio of female enrolment by location: pairwise comparisons Estimate OR Z value p-value Asia vs. worldwide 1.16 1.39 0.98 Europe vs. worldwide 1.26 2.45 0.08 North America vs. worldwide 0.81 -3.10 0.01 * Europe vs. Asia 1.09 0.65 0.99 North America vs. Asia 0.70 -2.77 0.03 * North America vs. Europe 0.65 -4.37 <0.001 ** eTable 8: Odds ratio of female enrolment by location: pairwise comparisons. eTable 8 shows results of pairwise comparisons the coefficients of different locations, using Bonferroni adjustment for multiple comparisons. The results show a solid correlation of North America with a lower probability of female enrollment (OR 0.81 vs. worldwide, 0.70 and 0.65 vs Asia and Europe respectively). Significant results in bold, significance level denoted by asterisks (* significance level 0.05, ** significance level 0.01). OR = odds ratio © 2021 Martinkova J et al. JAMA Network Open. eTable 9: Reporting of sex-stratified data in primary studies (n=56) N of studies, % Study protocol available 17 (30.4%) Of these, sex-stratified analysis present in protocol in 8/17 (47.1%) Sex-stratified analysis in Methods 8 (14.3%) Sex-stratified data reported in Results 7 (12.5%) Of these, sex differences observed in results in 1/7 (14.3%) eTable 10: Bias assessment table Unique ID Reference Study ID a b c d e f g 1 Egan et al. 2018 6.1 LR LR LR LR LR LR LR 2 Schneider et al 2019 9 LR LR LR LR LR LR LR 3 Maher-Edwards 2015 12 LR LR LR LR LR LR LR 4 Lenz et al 2015 14 LR LR LR LR LR NI LR 5 Farlow et al 2010 15.1 LR LR LR LR LR NI LR 6 Doody et al 2008 17 LR LR LR LR LR NI LR 7 Pasquier et al 2016 20 LR NI LR LR LR NI LR 8 Lawlor 2018 24.1 LR LR LR LR LR LR LR 9 Gauthier 2016 31 LR LR LR LR LR NI LR 10 Frohlich 2019 34 LR LR LR NI LR LR LR 11 Scheltens 2018 40 LR LR LR NI LR LR LR 12 Hager 2014 42.1 LR LR LR LR HR LR LR 13 van Dyck 2019 46 LR LR LR LR LR LR LR 14 Honig 2018 47 LR LR LR LR LR LR LR 15 Atri 2018 51.1 LR LR LR LR LR LR LR 16 Maher-edwards 2010 52 LR NI LR NI LR NI HR 17 Gault 2016 55 LR LR LR NI LR LR LR 18 Florian 2016 56 LR LR LR LR LR NI LR 19 Nave 2017 59 LR LR LR LR LR LR LR 20 Sevigny 2016 60.1 LR LR HR HR LR NI LR 21 Fullerton 2018 62 LR LR LR LR LR LR LR 22 Doody 2014 67.1 LR LR LR LR LR LR LR 23 Marek 2014 69 LR LR LR LR HR NI LR 24 Ostrowitzki 2017 71.2 LR NI LR NI LR NI LR © 2021 Martinkova J et al. JAMA Network Open. Unique ID Reference Study ID a b c d e f g 25 Wilckinson 2014 75 LR LR LR LR LR NI LR 26 Relkin 2017 76 LR LR LR LR LR NI LR 27 Gault 2015 78 LR NI LR LR LR NI LR 28 Alvarez 2011 82 LR LR LR LR LR NI LR 29 Doody 2013 84.1 LR LR LR HR LR LR LR 30 Coric 2015 89 LR LR LR LR NI LR LR 31 Vanderberghe 2016 90.1 LR LR LR LR HR NI LR 32 Gold 2010 92 LR NI LR LR LR NI LR 33 Coric 2012 93 LR LR LR LR NI NI LR 34 Salloway 2014 94.1 LR LR HR LR LR LR LR 35 Egan 2012 99 LR NI LR LR LR NI LR 36 Sevigny 2008 108.1 LR LR LR LR NI NI LR 37 Cummings 2012 112.1 LR NI LR LR LR NI LR 38 Burns 2009 125 LR LR LR LR LR NI LR 39 Egan 2019 131.2 LR LR LR LR HR LR LR 40 Grossberg 2013 134.1 LR LR LR LR LR NI LR 41 Green 2009 161 LR LR LR NI LR NI LR 42 Wischik 2015 174 LR LR HR LR LR LR LR 43 Xiao 2017 199 LR NI LR LR LR NI LR 44 Nakamura et al 2011 200 LR NI LR LR LR NI LR 45 Gauthier 2015 208 LR NI LR LR LR NI LR 46 Grove 2014 210 LR LR LR LR LR NI LR 47 Voss 2018 211 LR LR LR LR HR LR LR 48 Rinne 2017 212 LR LR LR LR LR NI LR 49 Zin Chang 2015 214 LR LR HR LR LR NI LR 50 Salloway 2011 220 LR LR LR LR HR NI HR 51 Galasko 2014 223 LR NI LR LR LR NI LR 52 Schneeberger 2015 226 LR NI LR NI LR NI LR 53 Rafii 2011 231 LR NI LR LR LR NI LR 54 Maher Edwards 2015 8 LR NI LR LR LR NI LR 56 Craft 2012 175 LR NI LR LR LR NI HR 58 Nakamura 2015 230 LR LR LR LR LR NI LR 59 Vellas 2011 215 LR NI LR LR LR NI HR 60 Feldman et al. 2010 LR LR LR LR LR NI LR 61 Maher-Edwards et al. 2010 LR LR LR LR LR NI LR 62 Cummings et al. 2018 LR LR LR LR LR NI LR 63 Brody et al. 2016 LR LR LR LR LR NI LR © 2021 Martinkova J et al. JAMA Network Open. Unique ID Reference Study ID a b c d e f g 64 Harrington et al. 2011 LR NI LR LR LR NI LR 295.1 65 Aisen et al. 2011 LR LR LR LR HR NI LR 67 Homma et al. 2016 LR LR LR LR LR NI LR eTable 10: Bias assessment table. Tabular representation of risk of bias in individual primary studies (56 publications on AD and 8 on prodromal AD) using a modified version of the Cochrane risk of bias tool RoB2. a: random sequence generation (selection bias); b: allocation concealment (selection bias); c: blinding of participants and personnel (performance bias); d: blinding of outcome assessment (detection bias); e: incomplete outcome data (attrition bias); f: selective reporting (reporting bias); g: other sources of bias. Each study was rated as having low (LR), high (HR), or unclear because of not enough information (NI) risk of bias eReferences 1. Gendered Innovations in Science, Health & Medicine, Engineering, and E. Terminology. Stanford University (2011). 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Published: Sep 13, 2021

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Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

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Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

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