We would like to acknowledge all patients in the EFFECTS study as well as all personnel in the EFFECTS Trial Collaboration: Ann Charlotte Laska, Department of Neurology, Danderyd Hospital; Bjarni Gudmundsson, Department of Neurology, Karolinska University Hospital Solna; Björn Cederin, Department of Medicine, Skaraborg Hospital Skövde; Magnus Esbjörnsson, Department of Internal Medicine, Hässleholm Hospital; Bernice Wiberg, Department of Public Health and Caring Sciences, Geriatrics, Uppsala University Hospital; Maria Lantz, Department of Neurology, Karolinska University Hospital Huddinge; Jörg Teichert, Department of Medicine, Mora Hospital; Magnus Bergmann, Department of Medicine, Falu Hospital; Lennart Welin, Department of Medicine, Skaraborg Hospital Lidköping; Ulrika Löfmark, Department of Neurology, Capio St. Göran Hospital; Sven-Erik Bysell, Department of Medicine, Visby Hospital; Xiaolei Hu, Department of Community Medicine and Rehabilitation, University Hospital of Umeå; Axel Andersson, Department of Medicine and Rehabilitation, Central Hospital Kristianstad; Moa Gunnarsson, Department of Medicine, Norrtälje Hospital; Pernilla Sandgren, Department of Neurology and Stroke, Helsingborg Hospital; Eva Ask, Department of Neurology, Skåne University Hospital Malmö, Sweden; Peter Thomasson Sommer, Department of Neurology, Halland Hospital Halmstad; Bo Danielsson, Department of Medicine, Mälarsjukhuset Eskilstuna; Liisa Hopia, Rehab Station Stockholm; Andreas Arvidsson, Department of Neurology, Skåne University Hospital Lund; Fredrik Björck, Department of Neurology, Sundsvall Hospital; Anke Brederlau, Rehabilitation Medicine, Sahlgrenska University Hospital; Trandur Ulfarsson, Högsbo Rehabilitation Hospital; Mehran Taklif, Stora Sköndal Neurologic Rehabilitation Clinic; Magnus Gibson, Department of Heart, Neurology and Rehabilitation, Östersund Hospital; Brita Eklund, Department of Medicine, Alingsås Hospital; Björn Hedström, Department of Stroke and Rehabilitation, Ängelholm Hospital; Ellinore Richardsson, Stockholm Sjukhem Neurologic Rehabilitation Center; Daniel Merrick, Rehabilitation Medicine, Örebro University Hospital; Per Broman, Department of Neurology and Rehabilitation, Northern Älvsborg County Hospital Trollhättan; Max Mademyr-Larsson, Stockholm Sjukhem Geriatrics; Andreas Ranhem, Department of Medicine, Västmanland Hospital Västerås; Camilla Ronnheden, Dalen Hospital; Martin Johansson, Department of Medicine, Lindesberg Hospital; Anette Onkenhout, Department of Medicine, Hudiksvall Hospital. All from Sweden.
Management
Co-ordination centre
The co-ordination centre was located at Karolinska Institutet Department of Clinical Sciences Danderyd Hospital, and those responsible for the day-to-day management were chief investigator Erik Lundström, trial manager Eva Isaksson and trial manager assistant Nina Greilert.
Steering Committee’s responsibilities
The Steering Committee is responsible for following the development of the study, assisting the chief investigator with advice and support when required.
The Steering Committee is also responsible for:
1. Ensuring that the protocol for the study is followed.
2. Policies, superior organisational issues and any technical issues.
3. Analysing the reports from the Data Management Committee.
4. Monitoring finances in collaboration with Karolinska Institutet, which is the financial manager and manages the funds.
5. Overseeing staff; however, Karolinska Institutet has the responsibility for personnel.
6. Considering the need for any protocol changes.
7. If any sub-studies are planned within the framework of the main study, they should be presented orally first, on condition that the Steering Committee considers the study to be feasible and scientifically sound, and that it does not affect the main study. A written project report has to be submitted and approved by the Steering Committee before any application is sent. A signed (by the chair of the Steering Committee after approval by the Steering Committee) project plan should be filed at Karolinska Institutet. When submitting an application for ethics approval or funds, the chair of the Steering Committee and the chief investigator should be informed of this before submission. No changes may be made to an approved protocol without this being approved and signed in accordance with the conditions presented above.
Members of the Steering Committee
The Steering Committee consists of Professor Katharina Stibrant Sunnerhagen (chair), Professor Per Wester, Professor Bo Norrving, Professor Håkan Wallén, Senior Professor Jörgen Borg, Senior Associate Professor Björn Mårtensson, Associate Professor/statistician Per Näsman, chief investigator/Associate Professor Erik Lundström, and trial manager Eva Isaksson. The co-chief investigators from FOCUS and AFFINITY were affiliated to the Steering Committee. We have not had any patient involvement in the Steering Committee nor when we wrote the protocol.
Monitoring of EFFECTS
Most of the monitoring was carried out centrally, however, online onsite monitoring and detailed source data verification by Karolinska Trial Alliance was also carried out (Additional file
7).
External monitoring by Karolinska Trial Alliance
Regular onsite monitoring visits were performed during the study depending on the enrolment rate and according to a specific monitoring plan.
Monitoring was performed according to ICH-GCP, Declaration of Helsinki, CRO SOPs for monitoring and the monitoring plan.
The first routine study monitoring visit was performed at each site when a few patients were randomised into the study, to confirm informed consent procedure, subject eligibility, ensure that the site was familiar with study drug management, detect possible problems and provide advice on how to complete the eCRF.
Source data verification was performed according to the monitoring plan throughout the study. The monitor ensured that 100% of all patients had signed the informed consent and verified that essential documents were available and up to date in the Investigator Study File continuously during the study. In addition, the external monitors carried out a 10% source data verification and drug accountability.
After each monitoring visit, the monitor sent a report to the sites and a copy of the report to the co-ordinating centre at Karolinska Institutet, and the representative for the sponsor. The report included a summary of the monitoring and highlighted issues that need to be followed up by the sites.
Close-out visit:
When the last patient has completed the study or when a site has been closed in advance, the monitor carried out a close-out visit at each site. At this visit the following were discussed:
• Possible remaining unsolved eCRF queries
• Investigator Study File completeness
• Possible remaining unresolved issues
• Patients: screened, randomised and complete
• Study drug accountability log completed
• Safety reporting (adverse events/serious adverse events)
• Information to study team regarding study report and archiving
Study drugs returned by the patients and remaining study drugs at the sites were sent for destruction to Apoteket AB, Sweden.
Dissemination policy
The Steering Committee ensured that a good publication policy was applied to the protocol, which states that publications are prepared by persons approved by the Steering Committee. The study is dependent on collaboration with a large number of doctors, nurses, patients and relatives. Those included in the local centre (who were on the delegation list) were included in a list (Additional file
6). The publication was prepared by a writing committee following the current International Committee of Medical Journals Editors Recommendations [
19].
Data management and data cleaning
The task of data management, quality and integrity was shared by the centres, co-ordination centre at Karolinska Institutet, Karolinska Trial Alliance and personnel from EDC Scandinavia AB (Additional files
8 and
9).
We used OpenClinica® as our eCRF. Data entries in the eCRF were done at each at centre. Almost all variables in our eCRF have mandatory checks for inconsistent values.
In addition, there is an audit trail and the possibility to send queries within the system.
The data cleaning process was carried out by the co-ordination centre at Karolinska Institutet and began when the first 500 patients had finalised their 12-month follow-up. The process was ongoing until the last patient was followed up.
All central follow-ups at 6 and 12 months were mailed out from the co-ordination centre. If the study subjects did not return their questionnaire, we reminded the patient by telephone; then the patient either returned the questionnaire or more often the patient gave their answers over the telephone.
All follow-up forms were processed by a research assistant, and another research assistant cross-checked 100% of the primary outcome (smRSq) and 10% of data.
Confidentiality
All study-related information was stored securely at the local centre in locked filing cabinets in areas with limited access. All reports, data collection, processes and administrative forms are identified by an EFFECTS trial ID number to maintain patients’ confidentiality. All records that contain names or other personal identifiers, such as informed consent forms, are stored separately from study records identified by code number. The central database is located at a secure server with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to other identifying information are stored in a separate, locked file in an area with limited access as well as in Karolinska Institutet’s electronic notebook [
20].
Access to data
The final cleaned data set will be saved in Karolinska Institutet’s electronic notebook [
20]. Trial statistician (PN) and chief investigator (EL) will have access to the data. A limited number of variables will be shared with the FOCUS and AFFINITY trials enabling the planned individual patient data (IPD) meta-analysis. All data will be stored anonymised, using the EFFECTS trial ID.
Details of assessment and collection as well as processes to promote data quality can be found in the (Additional files
8 and
9).
Data collection forms (in Swedish) can be found on our homepage,
www.effects.se.
In summary, the responsibilities were divided up as follows:
Database design | EDC Scandinavia |
eCRF design | EDC Scandinavia, Co-ordination Centre at Karolinska Institutet and Karolinska Trial Alliance |
Server management | EDC Scandinavia |
Data collection | Centre and Co-ordination Centre at Karolinska Institutet |
Data manager | EDC Scandinavia |
CRF annotation | Centre, Co-ordination Centre at Karolinska Institutet and Karolinska Trial Alliance |
Data entry | Centre, Co-ordination Centre at Karolinska Institutet and Karolinska Trial Alliance |
Monitoring | Karolinska Trial Alliance |
Source data verifications | Karolinska Trial Alliance |
Issue and resolve data correction forms | Co-ordination Centre at Karolinska Institutet and Karolinska Trial Alliance |
Medical coding | Co-ordination Centre at Karolinska Institutet |
Data validation | EDC Scandinavia and Co-ordination Centre at Karolinska Institutet |
Discrepancy management | Centre, Co-ordination Centre at Karolinska Institutet and Karolinska Trial Alliance |
Database lock. The database will be preserved according to Karolinska Institutet’s rules, the electronic notebook [ 20]. | EDC Scandinavia |
Data Monitoring Committee
The Data Monitoring Committee (DMC) independently monitored patient safety and efficacy information during the trial (Additional file
10). The DMC comprised of two experienced stroke physicians: Senior Professor Kjell Asplund (chair), Senior Associate Professor Kerstin Hulter Åsberg, and a biostatistician, Anders Ljungström.
DMC members were not involved as principal investigators or sub-investigators in the study. In addition, DMC members were not allowed to have a conflict of interest that would bias their review of trial data (e.g. financial interests that could be substantially affected by the outcome of the study, strong views on the relative merits of the study drug, relationships with individuals in trial leadership positions that could be considered reasonably likely to affect their objectivity, or involvement in any potential competing trial).
The unblinded statistician – Anders Ljungström – prepared data and reports for the DMC to review. The chief investigator served as a primary contact person for the DMC and DMC issues.
Review meetings for the DMC
The DMC chairman ensured that DMC contacts and consultants were not inappropriately exposed to unblinded data made available to the DMC.
The DMC was an independent expert advisory group commissioned and charged with the responsibility for evaluating cumulative safety, efficacy and other clinical trial data at regular intervals. As such, the primary objective of the DMC was to monitor the safety of the subjects in the study by reviewing the available clinical data at scheduled time points including at least yearly meetings (which may be face to face or via teleconference) and on an ad hoc basis as required.
After the review of each data report was completed, the DMC chair provided the official DMC recommendation to the sponsor, the chief investigator and the chair of the Steering Committee regarding the appropriateness of continuing the study, from a safety and efficacy perspective, as well as any other recommendations relevant to study conduct and/or patient safety.
Specifically, the DMC members were authorised and expected to perform the following functions:
• Safeguard the interests of trial participants.
• Provide approval for and operate in accordance with the specifications outlined in the DMC Charter.
• Monitor the safety and efficacy of the trial intervention, through scheduled review of accumulating clinical data from the EFFECTS study and taking into account information from external sources.
• Consider the need for additional unscheduled reviews of study data.
• Review and evaluate the content of all unblinded data reports received.
• Ensure the confidentiality of all information received relating to the trial.
• In the event of further funding being required, to provide the Steering Committee and funder(s) with appropriate information and advice on the data gathered to date in a manner that will as far as possible protect the integrity of the study.
• Participate in and vote on DMC recommendations, bearing in mind the fact that ethical considerations are of prime importance.
• Make clear recommendations to the Steering Committee, with the Steering Committee chair as the principal contact.
• The DMC reviewed safety outcomes, including serious adverse events. Review of safety data occurred after 150, 300, 600, 900 and 1200 patients’ 6-month follow-up data. No formal boundaries were used for terminating the study for safety reasons, but clear and consistent evidence of net harm that overrides any benefit should be apparent.
• A formal interim analysis to assess efficacy was done when approximately 67% of the planned primary efficacy events had accrued. The DMC was able to recommend early termination of the trial for the overwhelming superiority of fluoxetine over control. A modified Haybittle-Peto monitoring boundary was used as a guideline. If the primary efficacy comparison exceeds four standard errors in value, the DMC will initiate another interim analysis to be performed a minimum of 3 months later. If the monitoring boundary remains crossed, the DMC may recommend that the trial for the overwhelming superior efficacy of fluoxetine be terminated early. No adjustment of the significance level for the final analysis is required.
The DMC did not make any recommendations on whether the trial should be stopped on the basis of futility, i.e. that the trial – if it recruits to its target sample size – is unlikely to demonstrate a benefit from the trial of fluoxetine.
Throughout the trial, the DMC chair took responsibility for the committee’s operations and authorised and assigned the following responsibilities:
• Chair DMC data review meetings.
• Ensured that all relevant data have been reviewed by the DMC members and that all issues have been addressed.
• Ensured that blinded individuals (i.e. the DMC coordinator, DMC contacts, and DMC consultants) were not inappropriately exposed to confidential and/or unblinded data.
• Ensured that only the members of the DMC were present during DMC deliberations, when DMC recommendations were discussed, and DMC voting procedures were conducted.
• Ensured the generation of confidential, written minutes of all closed sessions of any DMC meetings and maintained these minutes as confidential to DMC members only, until the final (end of study) database lock was completed.
• Ensured DMC approval of minutes of open and final sessions of all DMC meetings.
• Communicated, authored, signed, and provided the official, final recommendations of the DMC within specified timelines and according to the specifications outlined in the charter. If the DMC was divided in opinion on any major issue affecting the DMC’s recommendation to the sponsor and EFFECTS Steering Committee, the DMC chair was responsible for assembling and presenting the majority and dissenting opinions for all recommendations considered.
• Arranged for consultation(s) and/or request additional data, as deemed necessary.
• If deemed appropriate by the DMC, at appropriate intervals, arrange a teleconference meeting with the chairs of the DMC committees for the FOCUS (Professor Peter Langhorne) and AFFINITY (Professor Robert Herbert, Australia) trials. If necessary, to discuss accumulating data in strict confidence and any implications for the continuation of each of the trials. Each chair may then subsequently need to consider whether to arrange a meeting of their respective trial DCM to discuss any issues that may arise from this liaison group.
• Maintain a secure central file of all data outputs received for DMC review and all minutes of all sessions of DMC meetings. Provide the sponsor with a copy of this file, through the chief investigator, once the final (end of study) database lock is complete.
Principal Investigator at each centre
At each participating centre, a PI is responsible for identification, recruitment, data collection and completion of CRFs, along with follow-up of study patients and adherence to the study protocol and the investigators’ brochure. The PI is not part of the Steering Committee.