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
Primary result · Change in HbA1cResult — go to the resultEstimated treatment difference −0.06 percentage points 95% CI −0.22 to 0.09Authors' conclusion
Once-weekly IcoSema achieved non-inferior HbA1c reduction 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.
Study context
- Population
- Adults ≥18 years with T2D (HbA1c 7.0–10.0%) inadequately controlled on daily basal insulin (20–80 U per day), 109 sites in 14 countriesrandomised 1:1
- Participants
- 679 adults
- Comparison
- Once-weekly IcoSema vs basal-bolus therapy
- IcoSeman = 340
- Basal-bolus therapy (BBT)n = 339reference
- Primary endpoint
- Change in HbA1c from baseline, tested for non-inferiority (0.3 percentage-point margin)
- Follow-up
- Week 52
Methodological detailsopen-label, multicentre, treat-to-target, non-inferiority, phase 3a, 52-week trial; 844 screened; enrolled Nov 30, 2021, to Sept 28, 2022
- Open-label
- Multicentre
- Treat-to-target
- Non-inferiority
- Phase 3a
- 52-week trial; 844 screened; enrolled Nov 30, 2021, to Sept 28, 2022
Primary result
Change in HbA1c
Estimated treatment difference
−0.06 percentage points
95% CI −0.22 to 0.09
P < 0.0001
Change by group
IcoSema
−1.47
estimated mean change · SE 0.05 · percentage points
BBT
−1.40
estimated mean change · SE 0.06 · percentage points
IcoSemavs BBT
estimated treatment difference −0.06 percentage points (95% CI −0.22 to 0.09); P < 0.0001
As reported in the abstract
Secondary outcomes
| Outcome | Estimated treatment difference (kg) (95% CI) | P value | |
|---|---|---|---|
| Change in bodyweight · baseline to week 52Superiority confirmed | −6.72 (−7.58 to −5.86) | P < 0.0001 | |
| −10−505Difference, kg (linear scale) |
| Outcome | Estimated treatment difference (U) (95% CI) | P value | |
|---|---|---|---|
| Weekly total insulin dose · weeks 50-52Superiority confirmed | −270 (−303 to −236) | P < 0.0001 | |
| −400−2000200Difference, U (linear scale) |
Safety
| Outcome | IcoSema | BBT | Estimated rate ratio (95% CI) | P value | |
|---|---|---|---|---|---|
| Clinically significant or severe hypoglycaemia · baseline to week 57Superiority confirmed · episodes per person-year of exposure | 0.21 | 2.23 | 0.12 (0.08–0.17) | P < 0.0001 | |
| 0.050.21520Estimated rate ratio (log scale) |
Most frequent AEs
- Gastrointestinal disorders with IcoSema (443 events)
- 148 [44%] of 340
- Infections and infestations with BBT (193 events)
- 116 [35%] of 328
Original publication
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. Lancet Diabetes Endocrinol. Published 4 June 2025. doi:10.
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