Table 3.

Summary of data of adaptive design considerations (N=317)

	N	%
Were there any unplanned changes to the trial design?	22/317	7
Examples of unplanned changes:	3	13.6
• sample size	1	4.5
• inclusion criteria	1	4.5
• Randomization	3	13.6
• intervention dose/ administration	1	4.5
• outcomes	1	4.5
• statistical design	1	4.5
• interim analysis	1	4.5
• duration of study	1	4.5
• study sites	1	4.5
Justification provided for unplanned changes	21/317
Reasons provided for unplanned changes were to enroll additional participants, to include additional recruitment sites, to review safety of the drug, to exclude patients who are high risk of GI bleeding, to facilitate enrolment rates or to reduce the time required for participants to stay at the clinic, poor accrual rate and extended funding were the main reasons for addition of new participating sites		95.5
All adaptation criteria pre-specified	135/317	42.6
Special efforts were made to explain adaptiveness to the participants	3/317	0.9
Patients or parent/caregivers were consulted during the trial design process	0	0.0
Reported a separate adaptation committee (distinct from DSMB)?	19/317	6
Who was on the trial adaptation committee?
• Researchers/Scientists	10	52.6
• Others/not reported	9	47.4
• Statistician	2	10.5
• Physician/Nurse/Dentist	1	5.3
Was there a separate trial adaptation committee? Yes
Ref.	Who was on the trial adaptation committee and description of these committees
[15]	Statistical analysis committee (members NR): The regional coordinating centres forward the data to SAC; and International Steering Committee, the trial is overseen by ITSC, which can add strata, domains and interventions (members NR)
[16]	Trial Steering Committee (individuals independent of the project and the institutions involved.). The Data Monitoring Committee is using the results of these analyses to advise the Trial Steering Committee on adapting the trial design to either (1) stop prematurely for futility (no prospect of establishing a treatment effect of at least 10%) or (2) stop prematurely if proof beyond a reasonable doubt is established that there is a convincing treatment benefit of at least 10%
[17]	The institutional review boards (members NR), which for all participating institutions approved the protocol after consultation with the local community and public disclosure.
[18]	Institutional and National Ethics Committees (members NR). The protocol was approved in Ethiopia, Sudan and UK by the authors of these committees
[19]	toxicity monitoring committee (members NR)
[20]	Research Ethics Committee (members NR) Fatal or life-threatening SUSARs will be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics Committee (REC) within 7 days. The MHRA and REC will be notified immediately if a significant safety issue is identified during the trial
[21]	Trial Steering Committee, the trial is overseen by a trial, steering committee (TSC) and an independent DSMB to oversee safety and ensure appropriate trial conduct. However, TSC has no role in the implementation of the prespecified adaptive design.
[22]	Case Assessment and Data Quality and Evaluation Committee (CADQEC), (members NR), which was formed to ensure the integrity and validity of the trial. The CADQEC was entrusted by the sponsor in order to supervise the quality of the data generated at the trial sites before and after unblinding
[23]	Trial Steering Committee (TSC) (members NR). Sponsor duties are delegated to a trial steering committee comprising the CPI, other investigators and key stakeholders. The DSMC will make recommendations to the trial steering committee via the Coordinating Principal Investigator (CPI)
[24]	Research and Development Committee of the Michael E. Debakey VA Medical Center (members NR). This trial and all its procedures were approved by the Baylor College of Medicine Institutional Review Board and the Research and Development Committee of the Michael E. Debakey VA Medical Center
[25]	Ethics Committee (members NR). Ethical approval has been obtained from National and local Ethics Committees in Kenya and Sudan prior to the start of the trial in each Country. A decision for premature termination will be taken in consultation and agreement with the sponsor, investigators and the DSMB. All relevant ethics committees and regulatory authorities will also be informed of the reason for termination.
[26]	The trial was conducted using a web-based program developed by the Department of Biostatistics and Applied Mathematics at MDACC through which OMCR personnel randomized patients to the 2 arms and updated their current status on an ongoing basis.
[27]	The TSC (Statistician) will meet at least once annually and will provide overall supervision for the trial and provide advice through its independent Chairperson. The ultimate decision for the continuation of the trial lies with the TSC. The TSC will consist of an independent chairperson (with clinical expertise in HIV), two independent statisticians with expertise in adaptive trial design and medical statistics, a user representative, the investigators, representatives of the research networks, sponsors and principal investigators.
[28]	An external review board (member NR): The review board recommended a two-group definitive phase 3 design, and the protocol was modified on August 23, 2011, to revise primary and secondary endpoints, sample size and study power, and remove some prespecified stopping rules.
[29]	A dose- escalation steering committee (member NR) was established to facilitate the trial conduct process
[30]	The external Statistical Analysis Center (SAC) (member NR) performed all interim data analyses for the DMC, evaluated the decision rules and provided the randomization updates for the adaptive algorithm.
[1]	Dose-escalation steering committee (member NR) was established to facilitate the trial conduct process
[31]	The Dose and Frequency Committee (DFC) (Physician, /Nurse/ Dentist, Statistician, Resarcher/Scientist will determine the rules that govern the optimal dose and dose frequency of Proleukin to be given to participants in the next group.
[32]	Trial Steering Committee (member NR). The study was not originally designed as an adaptive trial however good recruitment and the emergence of data on novel combinations led to trial adaptation. These changes were proposed by the Trial Management Group and approved by the independent Data Monitoring and Ethics Committee and Trial Steering Committee.