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Box 8 Exemplars on reporting item 3b elements

From: The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

Example 1. Pre-planned adaptations and rationale; inferentially seamless phase 2/3 AD
“The adaptive (inferentially) seamless phase II/III design is a novel approach to drug development that combines phases II and III in a single, two-stage study. The design is adaptive in that the wider choice of doses included in stage 1 is narrowed down to the dose(s) of interest to be evaluated in stage 2. The trial is a seamless experience for both investigators and patients in that there is no interruption of ongoing study treatment between the two phases. Combining the dose-finding and confirmatory phases of development into a single, uninterrupted study has the advantages of speed, efficiency and flexibility [15, 17]… The primary aim of stage 1 of the study was to determine the risk-benefit of four doses of indacaterol (based on efficacy and safety results in a pre-planned interim analysis) in order to select two doses to carry forward into the second stage of the study.” [141]
Example 2. Analytical derivation of statistical information to guide adaptations; population enrichment AD with SSR
Mehta et al. [95] detail formulae used to calculate the conditional power to guide modification of the sample size or to enrich the patient population at an interim analysis for both cutaneous and non-cutaneous patients (full population) and only cutaneous patients (subpopulation) in the supplementary material. In addition, the authors detail formulae used to derive associated conditional powers and p-values used for decision-making to claim evidence of benefit both at the interim and final analysis (linked to item 12b).
Example 3. Pre-planned adaptations; 5-arm 2-stage AD allowing for regimen selection, early stopping for futility and SSR
“This randomized, placebo-controlled, double-blind, phase 2/3 trial had a two-stage adaptive design, with selection of the propranolol regimen (dose and duration) at the end of stage 1 (interim analysis) and further evaluation of the selected regimen in stage 2 [63, 64]. Pre-specified possible adaptations to be made after the interim analysis, as outlined in the protocol and statistical analysis plan (accessible via journal website), were selection of one or two regimens, sample-size reassessment, and non-binding stopping for futility.” [94]
Example 4. Type of AD; pre-planned adaptations and rationale; Bayesian adaptive-enrichment AD allowing for enrichment and early stopping for futility or efficacy
“The DAWN trial was a multicenter, prospective, randomized, open-label trial with a Bayesian adaptive–enrichment design and with blinded assessment of endpoints [12]. The adaptive trial design allowed for a sample size ranging from 150 to 500 patients. During interim analyses, the decision to stop or continue enrolment was based on a pre-specified calculation of the probability that thrombectomy plus standard care would be superior to standard care alone with respect to the first primary endpoint (described in the paper). The enrichment trial design gave us the flexibility to identify whether the benefit of the trial intervention was restricted to a subgroup of patients with relatively small infarct volumes at baseline. The interim analyses, which included patients with available follow-up data at the time of the analysis, were pre-specified to test for the futility, enrichment, and success of the trial.” [96] See supplementary appendix via journal website (from page 39) for details.
Example 5. Rationale; type of AD and pre-planned adaptations; information to inform adaptations; information-based GSD
“Because little was known about the variability of LVMI changes in CKD during the planning stage, we prospectively implemented an information-based (group sequential) adaptive design that allowed sample size re-estimation when 50% of the data were collected [46, 156]. ” [157] Pritchett et al. [46] provide details of the pre-planned adaptations and statistical information used to inform SSR and efficacy early stopping.
Example 6. Pre-planned adaptation and information for SSR
“To reassess the sample size estimate, the protocol specified that a treatment-blinded interim assessment of the standard deviation (SD) about the primary endpoint (change from baseline in total exercise treadmill test duration at trough) would be performed when 231 or one half of the planned completed study patients had been randomized and followed up for 12 weeks. The recalculation of sample size, using only blinded data, was adjusted based on the estimated SD of the primary efficacy parameter (exercise duration at trough) from the aggregate data… [158,159,160] ” [34]