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A trial designed to show a new treatment is not meaningfully worse than the standard, rather than better: used when the new option is shorter, cheaper, less toxic or easier (five radiotherapy fractions instead of 25, six months of trastuzumab instead of twelve).
The sponsor pre-specifies a non-inferiority margin (the largest loss of efficacy considered acceptable, e.g. a hazard ratio upper confidence limit below 1.2) and the trial succeeds if the confidence interval excludes that margin. Because a bad trial (poor adherence, wrong population) tends toward no difference, non-inferiority trials must be run rigorously and are analysed per-protocol as well as intention-to-treat. They underpin most de-escalation (hypofractionation, IDEA 3 vs 6 months FOLFOX, PERSEPHONE, segmentectomy vs lobectomy, SANO active surveillance) and biosimilar approvals. Choosing the margin is contentious: a 'non-inferior' result can still mean some patients are harmed.
Four cycles rather than six for young patients with limited-stage, low-risk aggressive B-cell lymphoma. The saving is two cycles of anthracycline and vincristine in people who will live for decades afterwards.
Confirmation, by a different route from HD18, that the interim scan can safely direct de-escalation in advanced Hodgkin lymphoma, and that most of the toxicity of escalated BEACOPP can be avoided in the 84 per cent of patients who respond early.
The interim scan should be used to intensify treatment in early Hodgkin lymphoma, not to withhold radiotherapy. The 99.0 per cent five-year progression-free survival in the scan-negative favourable group with combined-modality treatment is the number any radiotherapy-sparing strategy has to match.
The basis for four cycles of escalated BEACOPP as the German standard when the interim scan is negative, and the reason rituximab was abandoned as an addition to that regimen. The authors recommend the scan-guided strategy for all patients with advanced-stage disease.
Shares AHL2011, PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study, Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial, PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.
Shares AHL2011, PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study, Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial, PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.
Shares Stepped-wedge design, Control arm and comparator (investigator's choice), Randomised trial, Why trials fail: underpowered, wrong endpoint, control arm drift, subgroup fishing, crossover.
Shares Intention-to-treat (ITT) and per-protocol analysis, Statistical significance (P values, alpha, multiplicity), Estimands and intercurrent events (ICH E9(R1)), Why trials fail: underpowered, wrong endpoint, control arm drift, subgroup fishing, crossover.
Shares Stepped-wedge design, SANO, Randomised trial, Phase 1, 2 and 3 trials.
Shares AHL2011, PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study, Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial, PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.
Shares Randomised trial, De-escalation, escalation and response-adapted therapy, DYNAMIC, Phase 1, 2 and 3 trials.
Shares AHL2011, PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study, EORTC/LYSA/FIL H10, GHSG HD18.