Source of STEP trial programme

{{Infobox concept | name = STEP trial programme | subtitle = Phase 3 programme | image = trial-bars.svg | caption = Placebo-adjusted weight change across the principal STEP trials. | Full name = Semaglutide Treatment Effect in People with obesity | Drug = [[Semaglutide|Semaglutide]] 2.4 mg weekly | Indication = Chronic weight management | Principal duration = 68 weeks }} The '''STEP trial programme''' is the series of phase 3 randomised trials that established weekly [[Semaglutide|semaglutide]] 2.4 mg for chronic weight management. Its constituent trials differ in population — with and without type 2 diabetes, with and without intensive behavioural therapy, and in the comparison made — and each addresses a distinct question.{{r|wilding2021}} STEP 1, the largest and most cited, randomised 1,961 adults with obesity and without diabetes to semaglutide 2.4 mg or placebo for 68 weeks, both arms receiving lifestyle intervention. Mean weight change was −14.9% on active treatment and −2.4% on placebo.{{r|wilding2021}} The placebo arm is essential to interpreting that figure. Both arms received counselling on diet and physical activity, so the −2.4% is not a no-treatment baseline, and the [[Placebo-adjusted effect|placebo-adjusted difference]] of about 12.4 percentage points is the quantity attributable to the drug.{{r|davies2021}} == The constituent trials == | Trial | Population | Comparison | Weight change, active vs comparator | |---|---|---|---| | STEP 1 | Obesity, no diabetes | Placebo | −14.9% vs −2.4% | | STEP 2 | Obesity with type 2 diabetes | Placebo and 1.0 mg | −9.6% vs −3.4% | | STEP 3 | Obesity, intensive behavioural therapy | Placebo | −16.0% vs −5.7% | | STEP 4 | Randomised withdrawal after run-in | Continue vs switch to placebo | Continued loss vs regain | | STEP 8 | Obesity, no diabetes | [[Liraglutide]] 3.0 mg | −15.8% vs −6.4% | STEP 2 illustrates a consistent finding in this field: weight response is attenuated in people with type 2 diabetes, for reasons that are not established. STEP 3 shows that intensive behavioural support raises both arms rather than only the placebo arm.{{r|davies2021}} STEP 4 is the informative one for discontinuation. Participants who reached the maintenance dose during a run-in were randomised either to continue or to switch to placebo; the switched group regained weight steadily thereafter. See [[Weight regain after discontinuation]].{{r|rubino2021}} == Design features that shape the figures == All the principal trials ran 68 weeks with a 16-week escalation to the maintenance dose, so roughly a quarter of the trial was spent below the studied dose. Effect at 68 weeks is therefore not effect after 68 weeks at 2.4 mg.{{r|wilding2021}} Both arms received lifestyle intervention — reduced-calorie diet and increased physical activity, with regular counselling. This is standard for obesity trials and it raises the placebo arm, which is why placebo-arm weight change in these trials is not zero. Analysis populations matter. The primary estimand in several of these trials treats data after treatment discontinuation in a defined way, and the "treatment policy" and "trial product" estimands give different numbers from the same data. See [[Intention-to-treat analysis]].{{r|davies2021}} == What the programme does and does not establish == It establishes efficacy for weight reduction against placebo in the studied populations over the studied durations, and it establishes the adverse-effect profile at those doses — gastrointestinal events dominating and concentrated in escalation.{{r|wilding2021,ich_e9}} It does not establish outcomes. Weight is an intermediate endpoint; the cardiovascular outcome question was addressed separately by [[SELECT trial|SELECT]]. Nor does it establish durability beyond the trial durations, or effect in populations not studied. Mean figures conceal a wide distribution. In STEP 1 roughly a third of participants on active treatment lost 20% or more and roughly one in seven lost less than 5%. Reporting only the mean, as most secondary coverage does, describes an individual who may not exist.{{r|rubino2021}} == References == {{reflist}} <ref name="wilding2021">Wilding JPH, Batterham RL, Calanna S, et al. "Once-weekly semaglutide in adults with overweight or obesity." ''New England Journal of Medicine'' 384(11):989–1002 (2021). DOI:10.1056/NEJMoa2032183. PMID 33567185.</ref> <ref name="davies2021">Davies M, Færch L, Jeppesen OK, et al. "Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2)." ''The Lancet'' 397(10278):971–984 (2021). PMID 33667417.</ref> <ref name="rubino2021">Rubino D, Abrahamsson N, Davies M, et al. "Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance (STEP 4)." ''JAMA'' 325(14):1414–1425 (2021). PMID 33755728.</ref> <ref name="ich_e9">International Council for Harmonisation, ''E9(R1): Estimands and Sensitivity Analysis in Clinical Trials'' (2019).</ref> == External links == * [https://clinicaltrials.gov/study/NCT03548935 STEP 1 — NCT03548935] — Registry record for the pivotal trial. == See also == * [[Semaglutide]] * [[SELECT trial]] * [[SUSTAIN trial programme]] * [[Placebo-adjusted effect]] * [[Weight regain after discontinuation]] * [[Intention-to-treat analysis]] {{DEFAULTSORT:STEP trial programme}} [[Category:Clinical trial programmes]] [[Category:Obesity trials]] [[Category:Clinical evidence]]