Background: There are high rates of sexually transmitted infections (STIs) in ethnically diverse, sexually active students aged 16–24 years attending London further education (FE) colleges. However, uptake of chlamydia screening remains low. The TnT study aims to assess the feasibility of conducting a future trial in FE colleges to investigate if frequent, rapid, on-site testing and treatment (TnT) reduces chlamydia rates. This article presents the statistical analysis plan for the main study publication as approved and signed off by the Trial Management Group prior to the first data extraction for the final report. Methods/design: TnT is a cluster-randomised feasibility trial conducted over 7 months with parallel qualitative and economic assessments. Colleges will be randomly allocated into the intervention (TnT) or the control group (no TnT). Six FE colleges in London will be included. At each college for 2 days, 80 consecutive sexually active students aged 16–24 years (total 480 students across all six colleges) will be recruited from public areas and asked to provide baseline samples. One and 4 months after recruitment intervention colleges will be visited on two consecutive days by the TnT team where participating students will be texted and invited to come for same-day, on-site, rapid chlamydia testing and, if positive, treatment. Participants in the control colleges will receive ‘thank you’ texts 1 and 4 months after recruitment. Seven months after recruitment, participants from both groups will be invited to complete questionnaires and provide samples for TnT. All samples will be tested, and same-day treatment offered to participants with positive results. Key feasibility outcomes include: recruitment rates, testing and treatment uptake rates (at 1 and 4 months) and follow-up rates (at 7 months). Trial registration: ISRCTN 58038795. Registered on 31 August 2016. Keywords: Statistical analysis plan, Feasibility study, Randomised controlled trial, Rapid chlamydia tests, Screening, Young people, Further education colleges, Test n treat * Correspondence: email@example.com School of Population Health & Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Phillips et al. Trials (2018) 19:312 Page 2 of 7 Background Six FE colleges in London will be included. Colleges There are high rates of sexually transmitted infections were included based on their high proportion of black (STIs) in ethnically diverse, sexually active students aged and ethnic minority students and an even gender split, 16–24 years attending London further education (FE) as well as their close proximity to St George’s, University colleges [1–4], with around 8% testing positive for Chla- of London (SGUL) . At each college, for 2 days, 80 mydia trachomatis. However, uptake of chlamydia consecutive sexually active students aged 16–24 years screening remains low: below 30% annually in 16– will be recruited from public areas (total 480 students 24-year-olds in England [4, 5]. Although chlamydia and across all six colleges). Research assistants will approach gonorrhoea primarily affect young people, the conse- students in common room areas. The students will be quences of infection such as infertility, chronic pelvic asked if they are willing to help with research on sexual pain or epididymitis can last a lifetime. It is estimated health. Potentially eligible students will be invited to that 10–16% of women with untreated chlamydia will come to the study table where recruiters will explain develop clinical pelvic inflammatory disease of whom 8% that as the study is about chlamydia and sexually trans- will have an ectopic pregnancy and 11% will suffer from mitted infections, only students who have had penetra- tubal-factor infertility . The cost of chlamydia and tive sexual intercourse should consider taking part. gonorrhoea to the NHS is estimated to be over £100 Those who are interested will be given a patient infor- million each year. mation sheet and consent form to read and encouraged Barriers to reducing chlamydia rates include low up- to ask questions. take of testing by those most at risk [5, 7] (such as teen- agers, people from ethnic minorities and people who are Exclusion criteria socioeconomically deprived), and long delays in receiv- ing a positive diagnosis or attending for treatment [8, 9]. Students who self-report never having had penetra- Introducing rapid, on-the-spot chlamydia tests and treat- tive sexual intercourse ment into the community could make it easier for young Students with severe learning disability as identified people to get tested and treated faster before they can by college identification badges pass on their infection. It might also prevent complica- tions [10, 11]. These novel tests can have 99% sensitivity Randomisation will take place once recruitment is and 99.4% specificity , and studies have demon- completed and baseline data collected for all colleges. strated their feasibility in remote communities . Colleges will be randomly allocated into the intervention However, there have been no UK trials of rapid sexually (TnT) or the control group (no TnT) in a 1:1 (i.e. equal transmitted infection (STI) tests and same-day, on-site allocation) ratio by the trial statistician. The randomisa- treatment in non-healthcare settings. tion will be constrained to ensure that three colleges are allocated to each group. Recruitment of colleges and participants will take place prior to group allocation to Objective ensure allocation concealment and prevent selection To assess the feasibility of conducting a future trial in bias, and, therefore, the baseline data collection from further education (FE) colleges to investigate if frequent, students will be blind to treatment group. rapid, on-site testing and treatment (TnT) reduces chla- Participants will be asked to provide samples (urine mydia rates in sexually active male and female students for males and self-taken vaginal swabs for females) at aged 16–24 years. baseline and after 7 months and to complete question- naires on sexual lifestyle and healthcare use at both time Methods and design points. Questionnaire data will be collected at the col- TnT is a cluster-randomised feasibility trial conducted lege using encrypted tablet computers. As a contingency, over 7 months with parallel qualitative and economic as- paper questionnaires will be used as back up. All partici- sessments. The outcome is measured within one aca- pants will be informed that baseline samples will not be demic year to optimise follow-up. tested for 7 months and will be advised to get screened Both the current feasibility study and a future, de- separately from the study in the event that they are allo- finitive trial will be cluster randomised. This is to cated to the control group. avoid contamination, which may arise if students were One month after recruitment, each intervention cam- individually randomised within the same college, as pus will be visited on two consecutive days by the TnT sexual partners could potentially be allocated to dif- team. (These will be the same days of the week as at re- ferent groups. The cluster design also reflects how cruitment to optimise participating student attendance.) TnT would be rolled out in practice, with college The 80 participating students in each campus will be visits once each term. invited to provide a sample, but this time the sample will Phillips et al. Trials (2018) 19:312 Page 3 of 7 be tested immediately on site using the Cepheid Gen- Of the total number of students assessed for eXpert system which takes 90 min. Participants will eligibility the proportion who are eligible are be given a card designed by the user group contain- asked to participate in the study ing information about STIs, and links to the Brook Of those eligible the proportion recruited to sexual health website: www.brook.org.uk. Negative re- the study sults will be sent to participants by text. Participants The time to recruit 80 students at each with positive chlamydia results will be telephoned and college invited to come to the college nurse’s room for treat- Age, gender and ethnicity of students ment, partner notification, advice and follow-up by a recruited versus students not recruited visiting dispensing (under Patient Group Directive) (b).Testing and Treatment uptake rates (1 and 4 nurse health adviser. Participants with infections will months after recruitment) (intervention colleges be asked to bring any sexual partners who attend the only): college so they can also be tested and treated. The Of the total number of students recruited in nurse health adviser will arrange for participants who the intervention group the proportion that arepositivefor gonorrhoea to bereviewed byaclin- return at 1 month (and 4 months) and ician on the same or the next day at a genitourinary provide a sample for testing medicine (GUM) clinic. This is for clinical examin- Of those tested, the proportion with positive ation, so that repeat samples can be taken to evaluate test results and the proportion treated gonorrhoea resistance to antibiotics, for intramuscular The time from test to informing the injection of antibiotics and for partner notification. participating student of the result All participants in the three intervention campuses The time from test to treatment of positives will be invited to provide repeat samples for on-site The number of partners confirmed treated TnT 4 months after recruitment (i.e. the next college per index case term), when all the procedures described above will (c). Follow-up rates (at 7 months): be repeated. Of the total number of students recruited the Participants from the three control colleges will not proportion that return at month 7 and get TnT but will receive texts 1 and 4 months after re- provide a sample for testing cruitment thanking them for being in the study. Of those tested, the proportion with positive All participants will be asked to provide samples and test results and the proportion treated to complete questionnaires at college at 7 months. Test- Of the total number of students recruited, ing at 7 months is required in the proposed full trial to the proportion that complete the final calculate the main outcome (prevalence of chlamydia), questionnaires (including data on healthcare and is included here to test the feasibility of collecting usage) these data. Treatment will also be offered to those diag- (d).Prevalence of chlamydia in participants at each nosed with infection at 7 months. This is not part of the college at baseline and at 7 months assessed intervention, but is offered to enhance screen- 2. A perspective on the acceptability of TnT in FE ing uptake, and participation in general among the con- colleges emerging from qualitative interviews, trol group. In addition, at the end of the study, stored including barriers and facilitators to uptake and baseline samples will be tested using standard tests, and possible harms. This will be described in more participants with positive results will be contacted by the detail elsewhere. health adviser. Those not attending for follow-up will be 3. Estimate of the cost per person screened and sent an SMS text with a link to the final questionnaire treated in TnT versus usual care. Detailed analysis to be completed online. They will also be telephoned plans for these health economic assessments will be and offered the opportunity to provide a sample for rou- documented separately by the trial’s health tine (not rapid) testing either in college at a prearranged economist. time or by post. Sample size calculation Assuming a 30% recruitment rate , 1600 students Outcomes will be approached to recruit 480 overall (80 per college across six colleges: three intervention colleges and three 1. The outcomes of this study include key values to control colleges). Estimates of testing uptake at 1 and inform feasibility, sample size and timescales of a 4 months (intervention colleges only) will be based on full trial of TnT in FE colleges. These include: 240 students, and at 7 months will be based on 480 (a). Recruitment rates and associated outcomes: students (all colleges). Phillips et al. Trials (2018) 19:312 Page 4 of 7 Teare et al. recommend that 60 to 100 subjects are but may provide useful information on possible effect sufficient to estimate an event rate with acceptable pre- size to inform future sample size calculations. cision in a feasibility study . Prevalence of chlamydia at baseline will be estimated separately for each of the Statistical analyses six colleges (80 students per college), and these preva- Trial profile lence figures will be used to inform the intraclass correl- The flow of participants will be displayed in the Consoli- ation coefficient (ICC), required for the sample size dated Standards of Reporting Trials (CONSORT) flow- calculation for the main study. From our previous re- chart as shown in Fig. 1 . search involving 11 colleges, the ICC was estimated to be 0.005 (95% confidence interval − 0.013 to 0.026) . Data management and quality assurance Adding data from another six colleges will improve the Contact details will be collected on paper consent forms precision of this ICC, reducing the width of the confi- which will then be entered and stored on an encrypted dence interval by around 20%. Access database by authorised research personnel. At- Assuming 70% followed up at 7 months, final esti- tendance and laboratory data will be initially recorded mates of chlamydia prevalence would be based on 168 on paper worksheets and then entered, by designated re- students in each of the intervention and control groups search personnel, to an online database (REDCap)  . The study is not powered to find a statistically sig- hosted by SGUL. Questionnaire data will be entered nificant difference in chlamydia rates between groups, electronically using the REDCap mobile application on Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) trial flowchart Phillips et al. Trials (2018) 19:312 Page 5 of 7 encrypted tablets where tablets are available, or on paper inter-quartile ranges as appropriate of the time as a back-up. At the end of the visit to each college, the taken to recruit 80 participants at each college. data will be uploaded or entered to the SGUL servers by 3. Age, gender and ethnicity at baseline will be designated research personnel. presented separately for those recruited to the study Research coordinators and the trial manager will and those eligible but not recruited. We will present periodically perform basic checks, such as examining for means and standard deviation or numbers and improbable values and data completeness, as well as proportions as appropriate. random checks on the data. Anomalies will be explored and checked with original source data. Testing and treatment uptake rates, in intervention colleges After the last patient has been followed up, all queries only (1 and 4 months after recruitment) resolved and all data fields completed with data or missing data codes, the database will be locked for final 1. The number and proportion of participants in the analysis and this process will be overseen by the trial intervention group who return at 1 month and statisticians. provide a sample out of the total recruited to the intervention group will be presented. Of those tested, the number and proportion of participants General analysis principles with positive test results and the number and The analysis principles outlined will be followed as proportion of participants treated will be presented. closely as possible in the analysis and reporting of trial These analyses will be repeated for the 4-month data; the statistical analysis plan is not intended to re- visit. Corresponding 95% CIs will be presented. strict exploratory or other sensible and standard report- Where available, the reasons for non-attendance ing practices. There are no plans for any formal will be summarised comparisons between treatment groups until final data- 2. Time from test to treatment of positives will be base lock. Analysis will be undertaken by the trial described. Of the participants who attended the statistician. 1-month intervention visit, were tested and Since this a feasibility study no statistical significance received a positive test result we will calculate testing will be performed. Any confidence intervals pre- the mean and standard deviation or medians sented will be two-sided at the 95% confidence level. and inter-quartile ranges as appropriate of the time between the sample being taken and the Baseline characteristics time treatment was received. This will be repeated Baseline descriptions of students recruited and tested for the 4-month visit. will be presented by treatment group: including means 3. The number of partners confirmed treated per and standard deviation or numbers and proportions as index case will be described. In addition, we will appropriate. This will include demographic characteris- report the number of partner notifications raised tics, history of sexual behaviours and chlamydia and gon- and addressed, the number of participants who orrhoea status (a full list is available in Appendix). These confirm partner treated, the number of participants summaries will be based on observed values and the referred to a GUM clinic and, therefore, partner number of missing observations for each characteristic notification responsibility passed to clinic and the will be reported. number of participants with no information regarding treatment. Main outcomes Recruitment rates (at baseline) Follow-up rates (at 7 months) 1. We will assess eligibility rates by calculating the 1. The number and proportion of participants who proportion of students who were eligible and were return at month 7 and provide a sample out of the asked to participate in the study out of the total total recruited will be presented by treatment number of students who were assessed for group. Of those tested, the number and proportion eligibility. Similarly, the proportion of students who of participants with positive test results and the were recruited to the study out of those eligible will number and proportion of participants treated will be calculated. All proportions will be presented be presented. Corresponding 95% CIs will be with corresponding 95% confidence intervals (CIs). presented. 2. The time taken to recruit 80 participants at each 2. The number and proportion of participants college will be described. We will calculate the completing the final questionnaire will be mean and standard deviation or medians and presented. Descriptions of participants’ responses by Phillips et al. Trials (2018) 19:312 Page 6 of 7 treatment group will be presented (including data 4. Female sexual preference on healthcare usage), by means and standard 5. Male sexual preference deviation or numbers and proportions as 6. Age at first sex appropriate. We will present the number of repeat 7. Number of sexual partners in last year follow-up attempts for non-attendees at 7-month 8. New sexual partner in the past 6 months follow-up. 9. Type of female contraception 10. Condom use Prevalence of chlamydia in participants at each college at 11. Last sexually transmitted infection (STI) check-up baseline and at 7 months 12. STI history Of those tested, the number and proportion of partici- 13. Antibiotics received for an infection in the last 2 pants with positive test results will be presented for each weeks college at baseline and at 7 months. 14. Which antibiotics 15. Any symptoms in the past 6 months (female) Sensitivity analysis 16. Any symptoms in the past 6 months (male) 17. Smoker status Missing data analysis As this is a feasibility study the 18. Vape levels of data completion and follow-up rates are import- 19. Alcohol consumption in past month ant feasibility outcomes. Therefore, no formal analysis 20. Visited GP in the past 6 months will be undertaken to account for missing data. All 21. Number of GP visits in the past 6 months summaries will be based on observations only and the 22. Reason for GP visit number of missing observations for each characteristic 23. Visited GUM clinic in the past 6 months will be reported. 24. Number of GUM clinical visits in the past 6 months Harm data 25. Visited walk-in clinic in the past 6 months Participating student and college staff views of potential 26. Number of visits to a walk-in clinical in the past harms of on-site rapid tests and treatment will be sought 6 months and examined in the qualitative interviews. Analysis 27. Visited A&E/hospital in the past 6 months details will be described elsewhere. 28. Number of visits to A&E/hospital in the past 6 months Trial status 29. Attended healthcare facility for sexual health Recruitment was completed in October 2016. Final reasons follow-up concluded in August 2017. Abbreviations Conclusion CI: Confidence interval; CONSORT: Consolidated Standards of Reporting Trials; FE: Further education; GUM: Genitourinary medicine; ICC: Intraclass Findings from this study are intended to assess the feasi- correlation coefficient; REDCap: Research Electronic Data Capture; SGUL: St bility of running a future definitive trial to investigate George’s, University of London; STI: Sexually transmitted infections; TnT: Test whether a FE college-based TnT model leads to a reduc- n Treat tion in prevalence of chlamydia. In this article, we have described the TnT statistical analysis plan which pro- Acknowledgements vides details about how data from the TnT feasibility We are very grateful to staff and students at the following London FE trial will be analysed. The protocol for the trial is pub- colleges: Kingston College, Lambeth College, Lewisham Southwark College (LESOCO) and South Thames College (Merton and Wandsworth campuses). lished by Kerry-Barnard et al. (in press). By publishing our statistical analysis plan, we believe that we will en- sure a more balanced, accurate and complete report of Funding The research project is funded by NIHR Research for Patient Benefit: PB-PG- our final results. 1014-35007. The funding body will have no role in the design of the study, the collection, analysis or interpretation of the data, or the write-up of the Appendix manuscript. Baseline characteristics The following baseline characteristics will be sum- Authors’ contributions marised by treatment group: RP and FR are the trial statisticians and drafted and finalised the first version of the statistical analysis plan. FR was the statistician on the grant application. PO is a professor of general practice and is the chief investigator 1. Age for the study. SKB is the trial manager and a co-investigator on the study. 2. Sex PO, SKB and FR with others designed the study and obtained the funding. 3. Ethnicity All authors commented on initial drafts and approved the final manuscript. Phillips et al. Trials (2018) 19:312 Page 7 of 7 Ethics approval and consent to participate 15. Teare MD, Dimairo M, Shephard N, Hayman A, Whitehead A, Walters SJ. Ethics approval was granted by the NRES Committee Bromley ref. 15/LO/ Sample size requirements to estimate key design parameters from external 1929. All patients are to provide written informed consent prior to pilot randomised controlled trials: a simulation study. Trials. 2014;15:264. randomisation. 16. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Intern Med. 2010;152 Epub 24 March Competing interests 17. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research The authors declare that they have no competing interests. electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J Author details Biomed Inform. 2009;42(2):377–81. School of Population Health & Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK. Population Health Research Institute St George’s, University of London, London, UK. Received: 29 September 2017 Accepted: 4 May 2018 References 1. Oakeshott P, Aghaizu A, Reid F, Howell-Jones R, Hay PE, Sadiq ST, et al. Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: community based cohort study. BMJ. 2012;344:e4168. 2. Oakeshott P, Aghaizu A, Hay P, Reid F, Kerry S, Atherton H, et al. Is Mycoplasma genitaliium in women the ‘new chlamydia’? Community-based prospective cohort study. Clin Infect Dis. 2010;51:1160–6. 3. Oakeshott P, Kerry S, Aghaizu A, Atherton H, Hay S, Taylor-Robinson D, et al. Randomised controlled trial of screening for Chlamydia trachomatis to prevent pelvic inflammatory disease: the POPI (prevention of pelvic infection) trial. Br Med J. 2010;340:1642. 4. Aghaizu A, Reid F, Kerry S, Hay PE, Mallinson H, Jensen JS, et al. Frequency and risk factors for incident and redetected Chlamydia trachomatis infection in sexually active, young, multi-ethnic women: a community based cohort study. Sex Transm Infect. 2014;90:524–8. 5. National Chlamydia Coalition. Getting more young women screened for chlamydia: findings from qualitative research, vol. 3; 2011. p. 1–17. 6. Public Health England. Opportunistic chlamydia screening of young adults in England. London: Public Health England; 2014. 7. van den Broek IV, van Bergen JE, Brouwers EE, Fennema JS, Gotz HM, Hoebe CJ, et al. Effectiveness of yearly, register based screening for chlamydia in the Netherlands: controlled trial with randomised stepped wedge implementation. BMJ. 2012;345:e4316. 8. McClean H, Sullivan AK, Carne CA, Warwick Z, Menon-Johansson A, Clutterbuck D, on behalf of the National Audit Group of the British Association for Sexual Health and HIV. UK national audit against the key performance indicators in the British Association for Sexual Health and HIV Medical Foundation for AIDS and Sexual Health Sexually Transmitted Infections Management Standards. Int J STD AIDS. 2012;23(10):742–7. 9. Horner PJ. Azithromycin antimicrobial resistance and genital Chlamydia trachomatis infection: duration of therapy may be the key to improving efficacy. Sex Transm Infect. 2012;88(3):154–6. https://doi.org/10.1136/ sextrans-2011-050385. 10. Adams EJ, Ehrlich A, Turner KM, Shah K, Macleod J, Goldenberg S, et al. Mapping patient pathways and estimating resource use for point of care versus standard testing and treatment of chlamydia and gonorrhoea in genitourinary medicine clinics in the UK. BMJ Open. 2014;4(7):e005322. 11. Turner KM, Round J, Horner P, Macleod J, Goldenberg S, Deol A, et al. An early evaluation of clinical and economic costs and benefits of implementing point of care NAAT tests for Chlamydia trachomatis and Neisseria gonorrhoea in genitourinary medicine clinics in England. Sex Transm Infect. 2014;90(2):104–11. 12. Gaydos CA, Van Der Pol B, Jett-Goheen M, Barnes M, Quinn N, Clark C, et al. Performance of the Cepheid CT/NG Xpert Rapid PCR Test for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. J Clin Microbiol. 2013; 51(6):1666–72. 13. Guy RJ, Natoli L, Ward J, Causer L, Hengel B, Whiley D, et al. A randomised trial of point-of-care tests for chlamydia and gonorrhoea infections in remote Aboriginal communities: Test, Treat ANd GO- the ‘TTANGO’ trial protocol. BMC Infect Dis. 2013;13:485. 14. Balendra A, Cousins E, Lamplough H, Oakeshott P, Majewska W, Kerry SR. Pilot study for the ‘Test n Treat’ trial of on-site rapid chlamydia/gonorrhoea tests and same day treatment. Sex Transm Infect. 2017;93(4):283.
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