FROM THE DEPARTMENT OF CLINICAL NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden RECRUITMENT TO MULTICENTRE RANDOMISED CONTROLLED TRIALS IN STROKE. LESSONS LEARNT FROM THE EFFECTS TRIAL

Isaksson. E. 2021. Recruitment to a multicentre randomised controlled trial in stroke. Lessons learnt from the EFFECTS trial. Randomised controlled trials are the gold standard for evaluation treatments. Nevertheless, recruitment into trials is still challenging and many trials fail to meet their recruitment goals within the predetermined time. Less than one third of the trials managed to recruit according to their original plan. This can lead to studies being prolonged and these may never reach their goals. There is a clear need for evidence-based recruitment strategies. This thesis aims to explore barriers and success in recruitment of patients in randomised controlled trials, and to investigate if an intervention could enhance recruitment and discover if using simple validated ways to carry out follow-ups, can increase the recruitment of patients. Furthermore, we wanted to explore in what way those who lead a trial can influence recruitment, using EFFECTS as an example. We carried out these studies embedded in Study I, Efficacy oF Fluoxetine a randomisEd Controlled Trial in Stroke (EFFECTS), an investigator led Swedish-based, multicentre, parallel group, double blind placebo-controlled trial. EFFECTS investigated whether administration of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), 20 mg daily for six months after acute stroke improves patient’s functional outcome. Patients ≥18 years old with clinical diagnosis of ischemic or haemorrhagic stroke, with persisting focal neurological deficits at randomisation, were randomised between two and 15 days after stroke onset and allocated to fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measured by the modified Rankin scale (mRS) at six months was neutral. Although the recruitment rate in EFFECTS was good, we saw a trend indicating it decreased over time. For this reason, we decided to embed the following studies into the EFFECTS trial. In order to explore what factors study personnel consider to be of importance in recruitment to a clinical trial, we constructed a questionnaire and sent it electronically to 148 study personnel (physicians and nurses) in EFFECTS. Responses were received from 94% (139/148) of the study personnel. The five most important factors at central level for enhancing recruitment were that the research question was important (97%), a simple procedure for providing information and gaining consent (92%), a highly engaged local principal investigator and research nurse (both 87%), and that study-related follow-ups are practically feasible and possible to coordinate with the clinical follow-up (87%). The most significant barrier at the local centre was lack of time and resources devoted to research (72%). Important patient-related barriers were fear of side effects (35%) and language problems (30%). We investigated whether a teleconference with the study personnel and the head of department accompanied by a commitment contract could enhance recruitment in the EFFECTS trial 60 days post-intervention, compared to 60 days pre-intervention. We used a stepped wedge design with cluster randomisation. Recruitment of patients increased 30 days after the intervention, especially at low-recruitment centres. However, this increase did not persist at 60 days, which was our primary endpoint. We also noticed that the inclusion of patients increased after the first contact with each centre where we announced that there would be a conference. In order to facilitate a simplified way of evaluating the key endpoint in most stroke studies, we tested the validity of a Swedish translation of the simplified modified Rankin Scale questionnaire (smRSq) answered by the patient as compared to the modified Rankin Scale (mRS) assessed face-to-face six months after stroke. The smRSq was sent out to 108 consecutive stroke patients in the EFFECTS trial six months after stroke. The patients were assessed by face-to-face mRS by seven certified health professionals at four Swedish stroke centres. There was good agreement between postal smRSq, answered by the patients, and the mRS face-to-face. Accordingly, our data support that using postal smRSq directly to the patient is time and resource saving and could be used in quality registers and large clinical trials. In summary, our results suggest that for recruitment in a randomised controlled trial to be successful, the research question has to be relevant, and the study design and the protocol should be simple and easy to implement in the daily routine. The research team should have allocated time and daily routines for doing research which should be integrated in the day-today work of the clinic. Trialists should include recruitment strategies when planning a study and find simple ways to do follow-ups, however still using validated instruments. Consequently, this can make multicentre trials and quality registers with a large number of patients more feasible and timesaving.