Procedures

Mazdutide and placebo were provided as once-weekly and subcutaneous injections in prefilled devices. For each mazdutide dose level, there was a matching placebo with the same injection volume and doing schedule. Mazdutide was administered with one of the three doses: 3 mg (1.5 mg weeks 1–4; 3 mg weeks 5–24), 4.5 mg (1.5 mg weeks 1–4; 3 mg weeks 5–8; 4.5 mg weeks 9–24) and 6 mg (2 mg weeks 1–4; 4 mg weeks 5–8; 6 mg weeks 9–24). The dose escalation schedules are shown in Fig. ^S1.

Participants were required to maintain the original diet, exercise and lifestyle during the trial. Study visits occurred at screening, before and after lead-in, day 1 (randomisation), every week through week 10, week 12, week 16, week 20, week 23, week 24 and every 4 weeks thereafter through week 36. Body weight, vital signs, electrocardiogram and adverse events were monitored at every visit. Waist circumference was measured at screening, end of lead-in, day 1 and every 4 weeks thereafter through week 36. Local laboratory parameters were monitored at screening, day 1, every 4 weeks thereafter through week 24 and week 36. Central laboratory parameters (lipids and HbA1c) were monitored at day 1, week 12 and week 24 (Wuxi AppTec Inc., Shanghai). Pharmacodynamic (fasting plasma glucose and fasting insulin) and immunogenicity parameters were monitored at day 1 and weeks 2, 4, 8, 16, 24 and 32 (Wuxi AppTec Inc., Shanghai). Impact of Weight on Quality of Life–Lite (IWQOL-Lite) questionnaire assessment was conducted at baseline, week 12 and week 24. PHQ-9 and C-SSRS assessment were conducted at baseline and weeks 12, 24 and 36.

Participants who discontinued the study treatment before week 24 were requested to attend the remaining visits. Participants who discontinued the study before week 24 were requested to undergo end-of-study procedures as those who completed the study.