Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial.

BACKGROUND: IcoSema is a once-weekly combination therapy of basal insulin icodec (icodec) and semaglutide (a GLP-1 analogue) developed for the treatment of type 2 diabetes. We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin. METHODS: COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries. Individuals aged 18 years or older with type 2 diabetes (HbA7·0-10·0% [53·0-85·8 mmol/mol]) receiving daily basal insulin (20-80 U per day) were randomly assigned (1:1) to receive once-weekly IcoSema injection using a pen device or BBT (once-daily insulin glargine U100 with two to four daily insulin aspart injections) using an automated, interactive central web-response system. The primary endpoint was change in HbAfrom baseline to week 52, tested for non-inferiority (0·3 percentage-point margin). Confirmatory secondary endpoints were change in bodyweight from baseline to week 52; weekly total insulin dose during weeks 50-52; and combined clinically significant hypoglycaemic episodes (<3·0 mmol/L [<54 mg/dL], confirmed by blood glucose meter) or severe hypoglycaemic episodes (associated with severe cognitive impairment requiring external assistance for recovery) from baseline to week 57. The primary and confirmatory secondary endpoints were evaluated using the full analysis set (all randomly assigned participants). Descriptive statistics for safety endpoints were based on the safety analysis set (participants exposed to a trial product), with statistical analyses based on the full analysis set. This trial is registered with ClinicalTrials.gov (NCT05013229) and is complete. FINDINGS: Between Nov 30, 2021, and Sept 28, 2022, 844 participants were screened; 679 (mean age 59·6 years [SD 10·4]; 399 [59%] males and 280 [41%] females) were randomly assigned to IcoSema (n=340) or BBT (n=339). At week 52, estimated mean change in HbAwas -1·47 percentage points (SE 0·05; -16·0 mmol/mol [0·6]) with IcoSema and -1·40 percentage points (0·06; -15·3 mmol/mol [0·7]) with BBT, confirming non-inferiority of IcoSema versus BBT (estimated treatment difference [ETD] -0·06 percentage points [95% CI -0·22 to 0·09; -0·70 mmol/mol [-2·39 to 0·99]; p<0·0001). Superiority was confirmed for IcoSema versus BBT for change in bodyweight from baseline to week 52 (ETD -6·72 kg [95% CI -7·58 to -5·86]; p<0·0001), weekly total insulin dose during weeks 50-52 (ETD -270 U [-303 to -236]; p<0·0001), and overall rate of clinically significant or severe hypoglycaemia from baseline to week 57 (0·21 vs 2·23 episodes per person-year of exposure; estimated rate ratio 0·12 [0·08 to 0·17]; p<0·0001). The most frequently reported adverse events during the trial were gastrointestinal disorders with IcoSema (148 [44%] of 340 participants had 443 events) and infections and infestations with BBT (116 [35%] of 328 participants had 193 events). INTERPRETATION: Once-weekly IcoSema achieved non-inferior HbAreduction and superiority in change in bodyweight, weekly total insulin dose, and hypoglycaemia rates versus daily BBT, suggesting that there is a potentially beneficial treatment intensification option for adults with type 2 diabetes. FUNDING: Novo Nordisk.