Real World Effectiveness of Golimumab Therapy in Ulcerative Colitis Regardless of Prior TNF Exposure

Real World Effectiveness of Golimumab Therapy in Ulcerative Colitis Regardless of Prior TNF Exposure Background: The efficacy of golimumab to induce and maintain remission in biologic-naïve patients with ulcerative colitis (UC) is established from placebo-controlled trials. However, golimumab’s real- world effectiveness, important to physicians and payers, remains unexplored. Aim: The goal of this study was to describe real-world use and rate of persistence among UC patients with golimumab therapy and to assess factors that predict discontinuation during golimumab mainte- nance treatment. Methods: A retrospective study of UC patients receiving golimumab maintenance therapy (August 2012–August 2015)  was conducted on dosing data from a national case management program. Treatment persistence, defined as time from index prescription to the last dose (gap in dose >60 days), was assessed using Kaplan-Meier survival analysis. Predictors of treatment persistence were explored with Cox proportional hazards regression. Results: One hundred thirty-six patients (50.7% male) with a mean (SD) age of 44.4 (15.6) years were included. At golimumab initiation, 72.1% were naïve to anti-TNFs; 77.2% received 200 mg, while 4.4% and 18.4% received 50  mg and 100  mg, respectively, every 4 weeks (induction therapy). The median time to discontinuation was 530 days, with a cumulative probability of 63% to remain on ther- apy at one year. Age, gender, golimumab induction, golimumab maintenance dose and prior anti-TNF exposure were not significantly associated with treatment persistence. Dose adjustment occurred in 7.4% of patients during maintenance treatment. Conclusions: Overall, the persistence rate of golimumab observed in the current real-world study is similar to that described in previous single-centre UC cohorts and consistent with that seen in con- trolled clinical trials. Keywords: Biologics; Compliance/adherence; Inflammatory bowel disease; Ulcerative colitis The current guidelines for clinical management of ulcerative demonstrated in previous clinical trials (4–8). The efficacy of colitis (UC) recommend anti-TNF therapy for immunosup- golimumab to induce and maintain remission in biologic-naïve pressant-refractory, steroid-refractory or steroid-dependent patients with moderate to severe UC has been demonstrated patients (1–3). To date, three anti-TNF agents have been in recently published, large, randomized controlled trials licensed for the treatment of UC: infliximab, adalimumab and (5, 9–11). Although the efficacy of golimumab has been golimumab. The efficacy of infliximab and adalimumab has been assessed in controlled settings and restricted patient populations © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 129 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 130 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 (12), its effectiveness across diverse patient populations seen in RESULTS routine clinical practice remains largely unexplored. This real- A total of 136 eligible patients were included in the analysis. The world effectiveness—important to patients, physicians and mean duration of follow-up was 188  days (median, 126 days). payers—can be efficiently and effectively be described using As of August 31, 2015, patients had been followed for a total of observational methods (13). 70 patient-years. UC is characterized as a lifelong disease, with periods of quies- Table  1 summarizes the patient population’s baseline char- cence. Increased persistence and a well-established measure of drug acteristics. The mean (SD) age was 44.4 (15.6) years, approxi - effectiveness encompassing factors such as drug tolerability, treat - mately half (50.7%) the patients were male, and the majority of ment compliance and clinical efficacy have been shown to improve patients (72.1%) were anti-TNF naïve. the health benefits of approved treatments (14) and reduce health Based on survival analysis, patients persisted on golimumab care expenditure (15, 16). To date, few single-centre studies have for a median of 530  days, and the cumulative probability to explored the rate of drug persistence with golimumab (17). remain on therapy ae ft r one year was 63% ( Figure 1). Figures 2 The current study aimed to examine the persistence with and 3 describe persistence on golimumab by prior anti-TNF golimumab of UC patients within the nationwide case manage- experience (P=0.71) and by gender (P=0.59), respectively, ment program BioAdvance and to explore patient factors asso- showing no significant association of either parameter with ciated with time to golimumab discontinuation. the outcome. In multivariate analysis, no statistical associ- ation between time to golimumab discontinuation and age (HR=1.01, P=0.34), gender (HR=1.20, P=0.59), golimumab MATERIALS AND METHODS induction dose (HR=1.33, P=0.46), golimumab mainte- Study design and population nance dose (HR=1.56, P=0.99), or prior anti-TNF exposure This was a retrospective analysis of data collected through (HR=1.14, P=0.71) was detected (Table 2). a nationwide Canadian case management program (CMP; Table 3 summarizes golimumab dose by prior biologic expe- BioAdvance ) from August 2012 to August 2015 on golimum- rience. The majority of patients (77.2%) received 200  mg of ab-treated patients with UC. Data collection from physician and golimumab at induction, regardless of prior anti-TNF experi- patient questionnaires includes patient demographics, prior bio- ence (naïve: 77.6%, experienced: 76.3%). Among anti-TNF- logic use and prescription data. Eligible patients for the analysis naïve patients, 71.6% of patients received a maintenance dose included adults (18–80  years) enrolled in the CMP that con- of 100  mg every four weeks. During the maintenance period, sented to have their data analyzed anonymously in aggregate, at a median time of 126.5 days, 10 (7.4%) patients underwent had a physician-confirmed diagnosis of UC and had received dose adjustment, corresponding to 8.2% of anti-TNF naïve at least one dose of golimumab. Patients with incomplete data patients and 5.3% of those previously treated with an anti-TNF. were excluded. A sample size of 130 patients would provide 80% power to detect a hazard ratio above 1.85 for a predictive factor Table 1. Overall patient and treatment characteristics for golimumab discontinuation with an alpha of 0.05. Variable Level Total Statistical analysis N=136 The main objective of the study was to provide an estimate of Gender discontinuation-free survival (persistence) of golimumab for Female n (%) 67 (49.3) UC. Time to discontinuation, defined as the time from the index Male n (%) 69 (50.7) prescription to the last dose before a gap in dose >60 days, was Age Mean (SD) 44.4 (15.7) assessed with the Kaplan-Meier survival method (right-censor- Region* ing patients still on continuous treatment at their last assess- Western Canada n (%) 45 (33.1) ment). The secondary objective was to assess factors that predict Maritimes n (%) 13 (9.6) golimumab discontinuation during golimumab maintenance Ontario n (%) 44 (32.4) treatment. Both univariate- and multivariate-adjusted logistic Quebec n (%) 34 (25.0) regression analyses were used to assess potential risk factors, Biologic Naive n (%) which included prior treatment with anti-TNF therapy, gender, No n (%) 38 (27.9) age and golimumab induction and maintenance doses. Dose Yes n (%) 98 (72.1) optimization was defined as any golimumab maintenance dose that differed (increased or decreased) from the first maintenance *Maritimes includes these provinces: Nova Scotia and New dose. Statistical analyses were carried out using SPSS 21.0 (SPSS Brunswick. Western Canada includes these provinces: Alberta, British Inc., Chicago, IL) and SAS 9.4 (SAS Institute, Cary, NC). Columbia, Manitoba and Saskatchewan. Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 131 Figure  1. Persistence on golimumab therapy (nonpersistence >60  days gap)—overall. Figure 3. Persistence on golimumab therapy (nonpersistence >60 days gap) by gender. median persistence was 530 days. of patients remained on therapy ae ft r one year (median per - sistence of 530 days). In comparison, the clinical response rate at week 60 that was observed in the placebo-controlled, phase 3 PURSUIT trial, which included anti-TNF-naïve patients only, was 50% (9, 11, 20). Thus, the outcomes appear similar—if not bee tt r—in this cohort, which includes TNF-naïve and TNF- failure patients. This observation suggests that results of the PURSUIT randomized controlled trials could be generalized to the diverse patient populations seen in clinical practice. To our knowledge, no prior studies have assessed per- sistence with golimumab treatment in UC patients in Canada. Furthermore, even though previous publications have reported data on persistence with anti-TNF agents, none have restricted the patient population to UC patients (21, 22), thus not allow- ing an indirect comparison with our study. Figure  2. Persistence on golimumab therapy (nonpersistence >60  days gap) by prior anti- UC is a lifelong disease with an unpredictable pathogenesis TNF experience. marked by potentially long periods of inactivity. Uninterrupted maintenance treatment is recommended, even during periods Of these, seven patients had their golimumab dose increased, of asymptomatic remission (14, 23). This is particularly import - and three received a dose reduction. ant in chronic conditions where patients are at high risk for non- adherence (14, 24, 25). To date, this represents the first study DISCUSSION aiming to identify significant predictors of discontinuation of The efficacy of golimumab in refractory moderate to severe UC golimumab maintenance treatment of UC. We did not identify has been shown in restricted populations of patients across sev- significant predictive factors of golimumab persistence includ - eral controlled clinical trials (7, 9, 11). In this study, we eval- ing, among others, previous biologic experience and gender. uated the persistence of golimumab therapy across a diverse The study by Renna et  al. evaluating the real-world effective- patient population seen in routine clinical practice using dos- ness of golimumab and adalimumab identified no significant ing data from a comprehensive case management program. predictors of golimumab response and observed no differences Persistence with therapy, defined as the amount of time that between groups, based on previous biologic experience (anti- a patient remains on drug therapy, is an established surrogate TNF naïve versus experienced) among patients who persisted measure of drug effectiveness in long-term observational and on golimumab for eight weeks. However, these results should real-world studies, which incorporates several domains includ- be compared to the present study findings with caution, due to ing drug tolerability, treatment compliance and clinical efficacy the differing outcomes (response versus discontinuation) and (18). Regarding the lae tt r, previous studies have reported that follow-up periods (26). persistence with anti-TNF therapy is associated with main- Although to our knowledge no studies have directly evalu- tained clinical response (9, 11, 19). In the present study, 63% ated persistence and potential predictive factors of golimumab Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 132 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Table 2. Predictors of time to golimumab discontinuation- multivariate analysis Parameter N Hazard Ratio 95 % Confidence interval P-value Anti-TNF naïve 136 1.14 0.56–2.21 0.71 Female gender 136 1.20 0.63–2.27 0.59 Age (years) 136 1.01 0.99–1.03 0.34 Induction dose (200 mg vs. 100 mg) 136 1.33 0.63–2.83 0.46 Maintenance dose (50 mg vs. 100 mg) 136 1.56 0.65–3.76 0.99 Table 3. Golimumab dose by prior anti-TNF experience Variable Level Anti-TNF Naïve N=98 Anti-TNF Experienced N=38 Total N=136 Golimumab Induction 50 mg n (%) 4 (4.1) 2 (5.3) 6 (4.4) 100 mg n (%) 18 (18.4) 7 (18.4) 25 (18.4) 200 mg n (%) 76 (77.6) 29 (76.3) 105 (77.2) Golimumab Maintenance 50 mg n (%) 16 (16.3) 5 (13.2) 21 (15.4) 100 mg n (%) 53 (54.1) 30 (78.9) 83 (61.0) 200 mg n (%) 5 (5.1) 0 (0.0) 5 (3.7) Missing n (%) 24 (24.5) 3 (7.9) 27 (19.9) Dose Adjustment Unchanged n (%) 90 (91.8) 36 (94.7) 126 (92.6) Optimized n (%) 8 (8.2) 2 (5.3) 10 (7.4) discontinuation in UC, similar studies have aimed to iden- and anti-TNF-experienced patients (17). Specifically, Detrez tify predictors of medication adherence (16, 23, 27–29). For et  al. reported 61.9% of patients maintaining a stable dose instance, Lachaine et  al. assessed medication adherence to during follow-up without a significant difference between the any of the mesalamine-delayed/extended-release tablets using anti-TNF-naïve and anti-TNF-experienced groups. Canadian prescription claims. This study identified male gender This study has several limitations. Persistence was used as a (odds ratio [OR]=1.3; 95% confidence interval [CI], 1.1–1.6), surrogate measure for efficacy (i.e., we assumed that a patient older age (>60  years; OR=1.6; 95% CI,  1.3–2.0) and current staying on golimumab is, in fact, continuing to have a response use of corticosteroids (OR=1.4; 95% CI,  1.1–1.8) as predic- worthy of ongoing therapy). Due to the nature of the database, tors of high medication adherence (28). A study by Kane et al. disease activity was not possible to be assessed. The fact that the assessing adherence with maintenance mesalamine in quiescent majority of patients in this cohort were anti-TNF-naïve in an UC showed that males were twice as likely as females to be non- era where two other biologics are available for treatment of UC adherent with their UC treatment (24). However, our study suggests that both the patient and treating physician felt ongo- did not assess medication adherence, but rather, persistence ing use of golimumab was appropriate based on the clinical with golimumab treatment, which may explain the different benefit. The assumption that patients who experience positive findings. In rheumatoid arthritis, adherence to biologic ther - outcomes are more likely to persist treatment further solidifies apies has been linked to lower health care resource utilization this premise. Another limitation is that information on smok- and the need for concomitant therapies such as corticosteroids ing and concomitant immunosuppressant use, which might (30). A study in rheumatoid arthritis (31) suggested that goli- influence drug persistence, was not available. While immuno - mumab’s every four-week dosing schedule may account for suppressant use was not associated with golimumab response some increased persistence compared to other subcutaneous in the PURSUIT trial (9), combination therapy is generally therapies. thought to improve outcomes, especially in bio-naïve, immu- A minority of patients underwent dose adjustment (~7%) nosuppressant-naïve UC (33). Patient selection for treatment during a median follow-up time of 126.5 days. Our results concur with golimumab was based on the judgement of the treating with Detrez et al., who reported that adequate exposure to goli- physicians, which may have resulted in selection bias; however, mumab serum concentrations drives clinical response. Similar this is in line with the observational nature of the current study, to our study, both study populations included anti-TNF-naïve and one would argue that the study population is reflective of Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 133 the real-world. In addition, the database design, which is similar by Janssen Inc. Writing support was provided by all authors, as well as Clare Pollock and Angela Karellis, both of JSS Medical Research Inc., to claims data but with richer patient-level information, does and funded by Janssen Inc. not include some disease-related or patient-specific informa - tion such as biomarkers and concomitant medications that may be included in patient charts. Nonetheless, the present study References design was selected due to statistical power afforded by such an 1. Dignass A, Lindsay JO, Sturm A, et  al. Second European evi- approach, allowing us to examine the effectiveness of this prod - dence-based consensus on the diagnosis and management of uct in a multi-centre real world setting. Furthermore, the study ulcerative colitis part 2: Current management. J Crohns Colitis was powered to detect a hazard ratio above 1.75; therefore, any 2012;6(10):991–1030. weaker effects would not be able to be detected as statistically 2. Kornbluth A, Sachar DB; Practice Parameters Committee of the significant in our study. Finally, time to golimumab discontinu- American College of Gastroenterology. Ulcerative colitis prac- tice guidelines in adults: American College of Gastroenterology, ation due to any reason was evaluated, and nonpersistence with Practice Parameters Committee. Am J Gastroenterol golimumab could not be attributed to lack of efficacy or toler - 2010;105(3):501–23; quiz 524. ability issues. 3. Bressler B, Marshall JK, Bernstein CN, et al.; Toronto Ulcerative The major strength of the study is that it includes a large Colitis Consensus Group. Clinical practice guidelines for the number of patients seen in real-world by both academic- and medical management of nonhospitalized ulcerative colitis: The community-based gastroenterologists. This enhances the gen- Toronto consensus. Gastroenterology 2015;148(5):1035–58. eralization of the findings to the UC population and broadens e1033. the possible use of golimumab into a TNF-exposed patient 4. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induc - population. tion and maintenance therapy for ulcerative colitis. N Engl J Med In summary, the results of the current study have shown that 2005;353:2462–76. the majority of patients persisted with golimumab therapy ae ft r 5. Sandborn WJ, van Assche G, Reinisch W, et  al. Adalimumab one year, with a median of persistence of 530 days. A minority induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology of patients underwent dose adjustment (~7%) during the fol- 2012;142(2):257–65. e251–3. low-up period. These real-world data demonstrate the effec - 6. Armuzzi A, Pugliese D, Danese S, et  al. Long-term combination tiveness of subcutaneous golimumab in the treatment of UC therapy with infliximab plus azathioprine predicts sustained ste- patients and suggest comparable or higher effectiveness com- roid-free clinical benefit in steroid-dependent ulcerative colitis. pared with clinical trials across a broader patient population Inflamm Bowel Dis 2014;20(8):1368–74. than those included in registration trials. 7. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: Results of a randomised controlled trial. Gut Acknowledgments 2011;60(6):780–7. The authors wish to thank Ms. Clare Pollock and Dr. Angela Karellis 8. Ferrante M, Vermeire S, Fidder H, et  al. Long-term outcome for manuscript writing support. This work was supported by Janssen ae ft r infliximab for refractory ulcerative colitis. J Crohns Colitis Inc. 2008;2(3):219–25. All authors have made substantial contributions to all of the following: 9. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golim- (1) the conception and design of the study, or acquisition of data, or umab maintains clinical response in patients with moderate-to-se- analysis and interpretation of data; (2) drafting the article or revising vere ulcerative colitis. Gastroenterology 2014;146(1):96–109. it critically for important intellectual content; and (3) final approval e101. of the version to be submitted. BB made substantial contributions to 10. Lowenberg M, de Boer N, Hoentjen F. Golimumab for study design, data interpretation and manuscript preparation. MW the treatment of ulcerative colitis. Clin Exp Gastroenterol made substantial contributions to study design, data collection, data 2014;7:53–9. interpretation and manuscript preparation. BS made substantial 11. Sandborn WJ, Feagan BG, Marano C, et  al. Subcutaneous goli- contributions to study design, data interpretation and manuscript mumab induces clinical response and remission in patients preparation. FC made substantial contributions to study design, data with moderate-to-severe ulcerative colitis. Gastroenterology collection and data interpretation. AHS made substantial contribu- 2014;146(1):85–95; quiz e14-85. tions to study design, data interpretation and manuscript preparation. 12. Shealy DJ, Cai A, Staquet K , et al. Characterization of golimumab, All authors approved the final submitted manuscript. a human monoclonal antibody specific for human tumor necrosis factor alpha. MAbs 2010;2(4):428–39. Conflicts of Interest 13. Roche N, Reddel H, Martin R, et  al. Quality standards for real- BB and AHS have served as consultants and have received hono- world research. Focus on observational database studies of raria and grants. MW and BS are employees of Janssen Inc. FC has comparative effectiveness. Ann Am Thorac Soc 2014;11(Suppl served as a consultant of Janssen Inc. This study was funded in part 2):S99–104. Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 134 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 14. Kane SV. Systematic review: Adherence issues in the treatment of 25. Kane S, Huo D, Aikens J, et al. Medication nonadherence and the ulcerative colitis. Aliment Pharmacol Ther 2006;23(5):577–85. outcomes of patients with quiescent ulcerative colitis. Am J Med 15. Hawthorne AB, Rubin G, Ghosh S. Review article: Medication 2003;114(1):39–43. non-adherence in ulcerative colitis—strategies to improve adher- 26. Renna S, Orlando E, Macaluso FS, et al. Lee tt r: A prospective real ence with mesalazine and other maintenance therapies. Aliment life comparison of the efficacy of adalimumab vs. golimumab in Pharmacol Ther 2008;27(12):1157–66. moderate to severe ulcerative colitis. Aliment Pharmacol Ther 16. Kane S, Katz S, Jamal MM, et  al. Strategies in maintenance for 2016;44(3):310–1. patients receiving long-term therapy (SIMPLE): A study of MMX 27. Kane S, Huo D, Magnanti K. A pilot feasibility study of mesalamine for the long-term maintenance of quiescent ulcer- once daily versus conventional dosing mesalamine for main- ative colitis. Inflamm Bowel Dis 2012;18(8):1026–33. tenance of ulcerative colitis. Clin Gastroenterol Hepatol 17. Detrez I, Dreesen E, Van Stappen T, et  al. Variability in golim- 2003;1(3):170–3. umab exposure: A ‘Real-Life’ observational study in active ulcer- 28. Lachaine J, Yen L, Beauchemin C, et  al. Medication adherence ative colitis. J Crohns Colitis 2016;10(5):575–81. and persistence in the treatment of Canadian ulcerative colitis 18. Wolfe F. The epidemiology of drug treatment failure in rheuma - patients: Analyses with the RAMQ database. BMC Gastroenterol toid arthritis. Baillieres Clin Rheumatol 1995;9(4):619–32. 2013;13:23. 19. Castro-Laria L, Arguelles-Arias F, Garcia-Sanchez V, et al. Initial 29. Cerveny P, Bortlik M, Kubena A, et al. Nonadherence in inflam- experience with golimumab in clinical practice for ulcerative coli- matory bowel disease: Results of factor analysis. Inflamm Bowel tis. Rev Esp Enferm Dig 2016;108(3):129–32. Dis 2007;13(10):1244–9. 20. Rutgeerts P, Feagan BG, Marano CW, et  al. Randomised clini- 30. Lathia U, Ewara EM, Nantel F. Impact of adherence to biological cal trial: A  placebo-controlled study of intravenous golimumab agents on health care resource utilization for patients over the age induction therapy for ulcerative colitis. Aliment Pharmacol Ther of 65  years with rheumatoid arthritis. Patient Prefer Adherence 2015;42(5):504–14. 2017;11:1133–42. 21. Degli Esposti L, Sangiorgi D, Perrone V, et  al. Adherence and 31. Bhoi P, Bessee L tt , Bell M, et  al. AB1040 comparison of adher - resource use among patients treated with biologic drugs: Findings ence and dosing interval of subcutaneous anti-TNF biologics in from BEETLE study. Clinicoecon Outcomes Res 2014;6:401–7. inflammatory arthritis from A Canadian administrative database. 22. Bonafede M, Fox KM, Watson C, et al. Treatment pae tt rns in the Ann Rheum Dis 2016;75:1257–8. first year ae ft r initiating tumor necrosis factor blockers in real- 32. Kohn A, Daperno M, Armuzzi A, et  al. Infliximab in severe world settings. Adv Ther 2012;29(8):664–74. ulcerative colitis: Short-term results of different infusion reg - 23. Ediger JP, Walker JR, Graff L, et  al. Predictors of medication imens and long-term follow-up. Aliment Pharmacol Ther adherence in inflammatory bowel disease. Am J Gastroenterol 2007;26(5):747–56. 2007;102(7):1417–26. 33. Panaccione R, Ghosh S, Middleton S, et  al. Combination ther- 24. Kane SV, Cohen RD, Aikens JE, et al. Prevalence of nonadherence apy with infliximab and azathioprine is superior to monother - with maintenance mesalamine in quiescent ulcerative colitis. Am apy with either agent in ulcerative colitis. Gastroenterology J Gastroenterol 2001;96(10):2929–33. 2014;146(2):392–400.e393. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Canadian Association of Gastroenterology Oxford University Press

Real World Effectiveness of Golimumab Therapy in Ulcerative Colitis Regardless of Prior TNF Exposure

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Abstract

Background: The efficacy of golimumab to induce and maintain remission in biologic-naïve patients with ulcerative colitis (UC) is established from placebo-controlled trials. However, golimumab’s real- world effectiveness, important to physicians and payers, remains unexplored. Aim: The goal of this study was to describe real-world use and rate of persistence among UC patients with golimumab therapy and to assess factors that predict discontinuation during golimumab mainte- nance treatment. Methods: A retrospective study of UC patients receiving golimumab maintenance therapy (August 2012–August 2015)  was conducted on dosing data from a national case management program. Treatment persistence, defined as time from index prescription to the last dose (gap in dose >60 days), was assessed using Kaplan-Meier survival analysis. Predictors of treatment persistence were explored with Cox proportional hazards regression. Results: One hundred thirty-six patients (50.7% male) with a mean (SD) age of 44.4 (15.6) years were included. At golimumab initiation, 72.1% were naïve to anti-TNFs; 77.2% received 200 mg, while 4.4% and 18.4% received 50  mg and 100  mg, respectively, every 4 weeks (induction therapy). The median time to discontinuation was 530 days, with a cumulative probability of 63% to remain on ther- apy at one year. Age, gender, golimumab induction, golimumab maintenance dose and prior anti-TNF exposure were not significantly associated with treatment persistence. Dose adjustment occurred in 7.4% of patients during maintenance treatment. Conclusions: Overall, the persistence rate of golimumab observed in the current real-world study is similar to that described in previous single-centre UC cohorts and consistent with that seen in con- trolled clinical trials. Keywords: Biologics; Compliance/adherence; Inflammatory bowel disease; Ulcerative colitis The current guidelines for clinical management of ulcerative demonstrated in previous clinical trials (4–8). The efficacy of colitis (UC) recommend anti-TNF therapy for immunosup- golimumab to induce and maintain remission in biologic-naïve pressant-refractory, steroid-refractory or steroid-dependent patients with moderate to severe UC has been demonstrated patients (1–3). To date, three anti-TNF agents have been in recently published, large, randomized controlled trials licensed for the treatment of UC: infliximab, adalimumab and (5, 9–11). Although the efficacy of golimumab has been golimumab. The efficacy of infliximab and adalimumab has been assessed in controlled settings and restricted patient populations © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 129 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 130 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 (12), its effectiveness across diverse patient populations seen in RESULTS routine clinical practice remains largely unexplored. This real- A total of 136 eligible patients were included in the analysis. The world effectiveness—important to patients, physicians and mean duration of follow-up was 188  days (median, 126 days). payers—can be efficiently and effectively be described using As of August 31, 2015, patients had been followed for a total of observational methods (13). 70 patient-years. UC is characterized as a lifelong disease, with periods of quies- Table  1 summarizes the patient population’s baseline char- cence. Increased persistence and a well-established measure of drug acteristics. The mean (SD) age was 44.4 (15.6) years, approxi - effectiveness encompassing factors such as drug tolerability, treat - mately half (50.7%) the patients were male, and the majority of ment compliance and clinical efficacy have been shown to improve patients (72.1%) were anti-TNF naïve. the health benefits of approved treatments (14) and reduce health Based on survival analysis, patients persisted on golimumab care expenditure (15, 16). To date, few single-centre studies have for a median of 530  days, and the cumulative probability to explored the rate of drug persistence with golimumab (17). remain on therapy ae ft r one year was 63% ( Figure 1). Figures 2 The current study aimed to examine the persistence with and 3 describe persistence on golimumab by prior anti-TNF golimumab of UC patients within the nationwide case manage- experience (P=0.71) and by gender (P=0.59), respectively, ment program BioAdvance and to explore patient factors asso- showing no significant association of either parameter with ciated with time to golimumab discontinuation. the outcome. In multivariate analysis, no statistical associ- ation between time to golimumab discontinuation and age (HR=1.01, P=0.34), gender (HR=1.20, P=0.59), golimumab MATERIALS AND METHODS induction dose (HR=1.33, P=0.46), golimumab mainte- Study design and population nance dose (HR=1.56, P=0.99), or prior anti-TNF exposure This was a retrospective analysis of data collected through (HR=1.14, P=0.71) was detected (Table 2). a nationwide Canadian case management program (CMP; Table 3 summarizes golimumab dose by prior biologic expe- BioAdvance ) from August 2012 to August 2015 on golimum- rience. The majority of patients (77.2%) received 200  mg of ab-treated patients with UC. Data collection from physician and golimumab at induction, regardless of prior anti-TNF experi- patient questionnaires includes patient demographics, prior bio- ence (naïve: 77.6%, experienced: 76.3%). Among anti-TNF- logic use and prescription data. Eligible patients for the analysis naïve patients, 71.6% of patients received a maintenance dose included adults (18–80  years) enrolled in the CMP that con- of 100  mg every four weeks. During the maintenance period, sented to have their data analyzed anonymously in aggregate, at a median time of 126.5 days, 10 (7.4%) patients underwent had a physician-confirmed diagnosis of UC and had received dose adjustment, corresponding to 8.2% of anti-TNF naïve at least one dose of golimumab. Patients with incomplete data patients and 5.3% of those previously treated with an anti-TNF. were excluded. A sample size of 130 patients would provide 80% power to detect a hazard ratio above 1.85 for a predictive factor Table 1. Overall patient and treatment characteristics for golimumab discontinuation with an alpha of 0.05. Variable Level Total Statistical analysis N=136 The main objective of the study was to provide an estimate of Gender discontinuation-free survival (persistence) of golimumab for Female n (%) 67 (49.3) UC. Time to discontinuation, defined as the time from the index Male n (%) 69 (50.7) prescription to the last dose before a gap in dose >60 days, was Age Mean (SD) 44.4 (15.7) assessed with the Kaplan-Meier survival method (right-censor- Region* ing patients still on continuous treatment at their last assess- Western Canada n (%) 45 (33.1) ment). The secondary objective was to assess factors that predict Maritimes n (%) 13 (9.6) golimumab discontinuation during golimumab maintenance Ontario n (%) 44 (32.4) treatment. Both univariate- and multivariate-adjusted logistic Quebec n (%) 34 (25.0) regression analyses were used to assess potential risk factors, Biologic Naive n (%) which included prior treatment with anti-TNF therapy, gender, No n (%) 38 (27.9) age and golimumab induction and maintenance doses. Dose Yes n (%) 98 (72.1) optimization was defined as any golimumab maintenance dose that differed (increased or decreased) from the first maintenance *Maritimes includes these provinces: Nova Scotia and New dose. Statistical analyses were carried out using SPSS 21.0 (SPSS Brunswick. Western Canada includes these provinces: Alberta, British Inc., Chicago, IL) and SAS 9.4 (SAS Institute, Cary, NC). Columbia, Manitoba and Saskatchewan. Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 131 Figure  1. Persistence on golimumab therapy (nonpersistence >60  days gap)—overall. Figure 3. Persistence on golimumab therapy (nonpersistence >60 days gap) by gender. median persistence was 530 days. of patients remained on therapy ae ft r one year (median per - sistence of 530 days). In comparison, the clinical response rate at week 60 that was observed in the placebo-controlled, phase 3 PURSUIT trial, which included anti-TNF-naïve patients only, was 50% (9, 11, 20). Thus, the outcomes appear similar—if not bee tt r—in this cohort, which includes TNF-naïve and TNF- failure patients. This observation suggests that results of the PURSUIT randomized controlled trials could be generalized to the diverse patient populations seen in clinical practice. To our knowledge, no prior studies have assessed per- sistence with golimumab treatment in UC patients in Canada. Furthermore, even though previous publications have reported data on persistence with anti-TNF agents, none have restricted the patient population to UC patients (21, 22), thus not allow- ing an indirect comparison with our study. Figure  2. Persistence on golimumab therapy (nonpersistence >60  days gap) by prior anti- UC is a lifelong disease with an unpredictable pathogenesis TNF experience. marked by potentially long periods of inactivity. Uninterrupted maintenance treatment is recommended, even during periods Of these, seven patients had their golimumab dose increased, of asymptomatic remission (14, 23). This is particularly import - and three received a dose reduction. ant in chronic conditions where patients are at high risk for non- adherence (14, 24, 25). To date, this represents the first study DISCUSSION aiming to identify significant predictors of discontinuation of The efficacy of golimumab in refractory moderate to severe UC golimumab maintenance treatment of UC. We did not identify has been shown in restricted populations of patients across sev- significant predictive factors of golimumab persistence includ - eral controlled clinical trials (7, 9, 11). In this study, we eval- ing, among others, previous biologic experience and gender. uated the persistence of golimumab therapy across a diverse The study by Renna et  al. evaluating the real-world effective- patient population seen in routine clinical practice using dos- ness of golimumab and adalimumab identified no significant ing data from a comprehensive case management program. predictors of golimumab response and observed no differences Persistence with therapy, defined as the amount of time that between groups, based on previous biologic experience (anti- a patient remains on drug therapy, is an established surrogate TNF naïve versus experienced) among patients who persisted measure of drug effectiveness in long-term observational and on golimumab for eight weeks. However, these results should real-world studies, which incorporates several domains includ- be compared to the present study findings with caution, due to ing drug tolerability, treatment compliance and clinical efficacy the differing outcomes (response versus discontinuation) and (18). Regarding the lae tt r, previous studies have reported that follow-up periods (26). persistence with anti-TNF therapy is associated with main- Although to our knowledge no studies have directly evalu- tained clinical response (9, 11, 19). In the present study, 63% ated persistence and potential predictive factors of golimumab Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 132 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Table 2. Predictors of time to golimumab discontinuation- multivariate analysis Parameter N Hazard Ratio 95 % Confidence interval P-value Anti-TNF naïve 136 1.14 0.56–2.21 0.71 Female gender 136 1.20 0.63–2.27 0.59 Age (years) 136 1.01 0.99–1.03 0.34 Induction dose (200 mg vs. 100 mg) 136 1.33 0.63–2.83 0.46 Maintenance dose (50 mg vs. 100 mg) 136 1.56 0.65–3.76 0.99 Table 3. Golimumab dose by prior anti-TNF experience Variable Level Anti-TNF Naïve N=98 Anti-TNF Experienced N=38 Total N=136 Golimumab Induction 50 mg n (%) 4 (4.1) 2 (5.3) 6 (4.4) 100 mg n (%) 18 (18.4) 7 (18.4) 25 (18.4) 200 mg n (%) 76 (77.6) 29 (76.3) 105 (77.2) Golimumab Maintenance 50 mg n (%) 16 (16.3) 5 (13.2) 21 (15.4) 100 mg n (%) 53 (54.1) 30 (78.9) 83 (61.0) 200 mg n (%) 5 (5.1) 0 (0.0) 5 (3.7) Missing n (%) 24 (24.5) 3 (7.9) 27 (19.9) Dose Adjustment Unchanged n (%) 90 (91.8) 36 (94.7) 126 (92.6) Optimized n (%) 8 (8.2) 2 (5.3) 10 (7.4) discontinuation in UC, similar studies have aimed to iden- and anti-TNF-experienced patients (17). Specifically, Detrez tify predictors of medication adherence (16, 23, 27–29). For et  al. reported 61.9% of patients maintaining a stable dose instance, Lachaine et  al. assessed medication adherence to during follow-up without a significant difference between the any of the mesalamine-delayed/extended-release tablets using anti-TNF-naïve and anti-TNF-experienced groups. Canadian prescription claims. This study identified male gender This study has several limitations. Persistence was used as a (odds ratio [OR]=1.3; 95% confidence interval [CI], 1.1–1.6), surrogate measure for efficacy (i.e., we assumed that a patient older age (>60  years; OR=1.6; 95% CI,  1.3–2.0) and current staying on golimumab is, in fact, continuing to have a response use of corticosteroids (OR=1.4; 95% CI,  1.1–1.8) as predic- worthy of ongoing therapy). Due to the nature of the database, tors of high medication adherence (28). A study by Kane et al. disease activity was not possible to be assessed. The fact that the assessing adherence with maintenance mesalamine in quiescent majority of patients in this cohort were anti-TNF-naïve in an UC showed that males were twice as likely as females to be non- era where two other biologics are available for treatment of UC adherent with their UC treatment (24). However, our study suggests that both the patient and treating physician felt ongo- did not assess medication adherence, but rather, persistence ing use of golimumab was appropriate based on the clinical with golimumab treatment, which may explain the different benefit. The assumption that patients who experience positive findings. In rheumatoid arthritis, adherence to biologic ther - outcomes are more likely to persist treatment further solidifies apies has been linked to lower health care resource utilization this premise. Another limitation is that information on smok- and the need for concomitant therapies such as corticosteroids ing and concomitant immunosuppressant use, which might (30). A study in rheumatoid arthritis (31) suggested that goli- influence drug persistence, was not available. While immuno - mumab’s every four-week dosing schedule may account for suppressant use was not associated with golimumab response some increased persistence compared to other subcutaneous in the PURSUIT trial (9), combination therapy is generally therapies. thought to improve outcomes, especially in bio-naïve, immu- A minority of patients underwent dose adjustment (~7%) nosuppressant-naïve UC (33). Patient selection for treatment during a median follow-up time of 126.5 days. Our results concur with golimumab was based on the judgement of the treating with Detrez et al., who reported that adequate exposure to goli- physicians, which may have resulted in selection bias; however, mumab serum concentrations drives clinical response. Similar this is in line with the observational nature of the current study, to our study, both study populations included anti-TNF-naïve and one would argue that the study population is reflective of Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/129/4994398 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 133 the real-world. In addition, the database design, which is similar by Janssen Inc. Writing support was provided by all authors, as well as Clare Pollock and Angela Karellis, both of JSS Medical Research Inc., to claims data but with richer patient-level information, does and funded by Janssen Inc. not include some disease-related or patient-specific informa - tion such as biomarkers and concomitant medications that may be included in patient charts. Nonetheless, the present study References design was selected due to statistical power afforded by such an 1. Dignass A, Lindsay JO, Sturm A, et  al. Second European evi- approach, allowing us to examine the effectiveness of this prod - dence-based consensus on the diagnosis and management of uct in a multi-centre real world setting. Furthermore, the study ulcerative colitis part 2: Current management. J Crohns Colitis was powered to detect a hazard ratio above 1.75; therefore, any 2012;6(10):991–1030. weaker effects would not be able to be detected as statistically 2. Kornbluth A, Sachar DB; Practice Parameters Committee of the significant in our study. Finally, time to golimumab discontinu- American College of Gastroenterology. Ulcerative colitis prac- tice guidelines in adults: American College of Gastroenterology, ation due to any reason was evaluated, and nonpersistence with Practice Parameters Committee. Am J Gastroenterol golimumab could not be attributed to lack of efficacy or toler - 2010;105(3):501–23; quiz 524. ability issues. 3. Bressler B, Marshall JK, Bernstein CN, et al.; Toronto Ulcerative The major strength of the study is that it includes a large Colitis Consensus Group. Clinical practice guidelines for the number of patients seen in real-world by both academic- and medical management of nonhospitalized ulcerative colitis: The community-based gastroenterologists. This enhances the gen- Toronto consensus. Gastroenterology 2015;148(5):1035–58. eralization of the findings to the UC population and broadens e1033. the possible use of golimumab into a TNF-exposed patient 4. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induc - population. tion and maintenance therapy for ulcerative colitis. N Engl J Med In summary, the results of the current study have shown that 2005;353:2462–76. the majority of patients persisted with golimumab therapy ae ft r 5. Sandborn WJ, van Assche G, Reinisch W, et  al. Adalimumab one year, with a median of persistence of 530 days. A minority induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology of patients underwent dose adjustment (~7%) during the fol- 2012;142(2):257–65. e251–3. low-up period. These real-world data demonstrate the effec - 6. Armuzzi A, Pugliese D, Danese S, et  al. Long-term combination tiveness of subcutaneous golimumab in the treatment of UC therapy with infliximab plus azathioprine predicts sustained ste- patients and suggest comparable or higher effectiveness com- roid-free clinical benefit in steroid-dependent ulcerative colitis. pared with clinical trials across a broader patient population Inflamm Bowel Dis 2014;20(8):1368–74. than those included in registration trials. 7. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: Results of a randomised controlled trial. Gut Acknowledgments 2011;60(6):780–7. The authors wish to thank Ms. Clare Pollock and Dr. Angela Karellis 8. Ferrante M, Vermeire S, Fidder H, et  al. Long-term outcome for manuscript writing support. This work was supported by Janssen ae ft r infliximab for refractory ulcerative colitis. J Crohns Colitis Inc. 2008;2(3):219–25. All authors have made substantial contributions to all of the following: 9. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golim- (1) the conception and design of the study, or acquisition of data, or umab maintains clinical response in patients with moderate-to-se- analysis and interpretation of data; (2) drafting the article or revising vere ulcerative colitis. Gastroenterology 2014;146(1):96–109. it critically for important intellectual content; and (3) final approval e101. of the version to be submitted. BB made substantial contributions to 10. Lowenberg M, de Boer N, Hoentjen F. Golimumab for study design, data interpretation and manuscript preparation. MW the treatment of ulcerative colitis. Clin Exp Gastroenterol made substantial contributions to study design, data collection, data 2014;7:53–9. interpretation and manuscript preparation. BS made substantial 11. Sandborn WJ, Feagan BG, Marano C, et  al. 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Journal of the Canadian Association of GastroenterologyOxford University Press

Published: Sep 12, 2018

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