Box 10.

Exemplars on reporting item 6a elements

Example 1. SSR; description of the adaptation and primary outcomes “The primary endpoint is a composite of survival free of debilitating stroke (modified Rankin score > 3) or the need for a pump exchange. The short-term endpoint will be assessed at 6 months and the long-term endpoint at 24 months (primary). Patients who are urgently transplanted due to a device complication before a pre-specified endpoint will be considered study failures. All other transplants or device explants due to myocardial recovery that occur before a pre-specified endpoint will be considered study successes ... The adaptation was based on interim short-term outcome rates.” [164] Example 2. Seamless phase 2/3 Bayesian AD with treatment selection; details of adaptation outcomes “Four efficacy and safety measures were considered important for dose selection based on early phase dulaglutide data: HbA1c, weight, pulse rate and diastolic blood pressure (DBP) [165]. These measures were used to define criteria for dose selection. The selected dulaglutide dose(s) had to have a mean change of ≤ + 5 beats per minute (bpm) for PR and ≤ + 2 mmHg for DBP relative to placebo at 26 weeks. In addition, if a dose was weight neutral versus placebo, it had to show HbA1c reduction ≥1.0% and/or be superior to sitagliptin at 52 weeks. If a dose reduced weight relative to placebo ≥2.5 kg, then non-inferiority to sitagliptin would be acceptable. A clinical utility index was incorporated in the algorithm to facilitate adaptive randomization and dose selection [154, 166] based on the same parameters used to define dose-selection criteria described above (not shown here).” [93] Example 3. Seamless phase 2/3 AD with treatment selection; details of adaptation outcomes “For the dose selection, the joint primary efficacy outcomes were the trough FEV1 on Day 15 (mean of measurements at 23 h 10 min and 23 h 45 min after the morning dose on Day 14) and standardized (average) FEV1 area under the curve (AUC) between 1 and 4 h after the morning dose on Day 14 (FEV1AUC1–4h), for the treatment comparisons detailed below (not shown here).” [141] Example 4. MAMS AD; adaptation rationale (part of item 3b); rationale for adaption outcome different from the primary outcome; description of the adaptation and primary outcomes “This seamless phase 2/3 design starts with several trial arms and uses an intermediate outcome to adaptively focus accrual away from the less encouraging research arms, continuing accrual only with the more active interventions. The definitive primary outcome of the STAMPEDE trial is overall survival (defined as time from randomisation to death from any cause). The intermediate primary outcome is failure-free survival (FFS) defined as the first of: PSA failure (PSA > 4 ng/mL and PSA > 50% above nadir); local progression; nodal progression; progression of existing metastases or development of new metastases; or death from prostate cancer. FFS is used as a screening method for activity on the assumption that any treatment that shows an advantage in overall survival will probably show an advantage in FFS beforehand, and that a survival advantage is unlikely if an advantage in FFS is not seen. Therefore, FFS can be used to triage treatments that are unlikely to be of sufficient benefit. It is not assumed that FFS is a surrogate for overall survival; an advantage in FFS might not necessarily translate into a survival advantage.” [167]