Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials

Abstract

Background: Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease.

Methods: Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015-2016 and 2018-2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment.

Results: In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility. In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART.

Conclusions: Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design.

Trial registration: MS-SMART: NCT01910259 ; registered July 2013 and MS-STAT2: NCT03387670 ; registered Jan 2018.

Keywords: Clinical trials; Multiple sclerosis; Recruitment.

Conflict of interest statement

TW: has received honoraria for educational talks for Novartis and Merck

SA: no relevant conflict of interest to declare

JB: no relevant conflict of interest to declare

FDA: no relevant conflict of interest to declare

NJ: no relevant conflict of interest to declare

AD: no relevant conflict of interest to declare

JB: no relevant conflict of interest to declare

MB: no relevant conflict of interest to declare

EG: Assistant Director of Research at the MS Society (UK); no relevant conflict of interest to declare

JC: In the last 3 years, JC has received support from the Efficacy and Mechanisms Evaluation Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. He is a local principal investigator for commercial trials funded by Actelion, Novartis and Roche and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche.

© 2022. The Author(s).

Figures

Fig. 1

Participant recruitment and reasons for ineligibility at the lead UCL site for MS-SMART. *As this data is derived from the lead UCL MS-SMART site only, this number (237 participants attending screening) differs from the total number of participants screened across all UK sites (547), which is reported in reference [9]. RRMS, relapsing remitting multiple sclerosis; PPMS, primary progressive multiple sclerosis; EDSS, Expanded Disability Status Scale

Fig. 2

Participant recruitment and reasons for ineligibility at the lead UCL site for MS-STAT2. *As for Fig. 1, as this data is derived from the lead UCL MS-STAT2 site only, the number screened here will be lower that for the whole trial cohort. AHP, allied health professional; DMT, disease-modifying therapy; RRMS, relapsing remitting multiple sclerosis; PPMS, primary progressive multiple sclerosis; EDSS, Expanded Disability Status Scale; QRISK3, cardiovascular risk calculator [13]; OOW, Out of Window (for trial scheduled visit)

Fig. 3

UK-wide potential participants completing the MS-STAT2 Registration of Interest Portal: temporal relationship with identifiable publicity events. The date and time that UK-wide potential participants completed the online portal for the MS-STAT2 study is used to create a 7-day rolling average of online portal responses. This is plotted against time from the launch of the online portal, with the timing of identifiable publicity events added so temporal relationships can be inferred. Note online portal responses are quantified on a log2(count + 1) scale for clarity. ABN, Association of British Neurologists; BBC, British Broadcasting Corporation

Fig. 4

Overall UK-wide recruitment into MS-SMART and MS-STAT2. The overall randomisations in MS-SMART and MS-STAT2 are plotted against time from first randomisation in each study. For MS-STAT2, the timings of the UK National COVID19 Lockdowns are included, although milder / localised restrictions continued outside of these time periods