A 40-week study comparing the efficacy, safety and patient-reported outcomes of once weekly IcoSema and once or twice daily insulin degludec/insulin aspart 100 units/mL, both treatment arms with or without oral anti-diabetic drugs, in participants with type 2 diabetes inadequately controlled with daily pre-mixed insulin. COMBINE 5

This study evaluates the efficacy, safety, and patient-reported outcomes of once-weekly IcoSema compared to once or twice daily insulin degludec/insulin aspart, both with or without oral anti-diabetic drugs, in participants with type 2 diabetes inadequately controlled with daily pre-mixed insulin treatment over a 40-week period. The primary objective is to confirm non-inferiority of once-weekly IcoSema versus once or twice daily insulin degludec/insulin aspart with respect to glycaemic control measured by change in HbA1c from baseline after 40 weeks, using a non-inferiority margin of 0.3%-point. This objective is clinically relevant as it assesses whether the investigational weekly regimen achieves comparable glycaemic control to the established daily insulin therapy in patients failing pre-mixed insulin treatment. The secondary objectives include: confirming superiority of once-weekly IcoSema versus once or twice daily insulin degludec/insulin aspart regarding change in body weight from baseline after 40 weeks, number of clinically significant hypoglycaemic (level 2) or severe hypoglycaemic (level 3) episodes during 40 weeks and the 5-week follow-up period, weekly insulin dose (total) from week 38 to week 40, change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) total treatment satisfaction from baseline after 40 weeks, and change in HbA1c from baseline after 40 weeks; and comparing parameters of glycaemic control, patient-reported outcomes, and safety of once-weekly IcoSema versus once or twice daily insulin degludec/insulin aspart in this patient population.

The clinical trial enrolled a total of **608 participants** diagnosed with **type 2 diabetes**. The study population included both **male and female** individuals aged **18 years or above**. Participants were required to have been diagnosed with type 2 diabetes at least 180 days prior to screening and to have **HbA1c** levels between 7.0% and 10.0% (53.0-85.8 mmol/mol) at baseline. All enrolled subjects had been inadequately controlled on their current treatment regimen consisting of once-daily or twice-daily **pre-mixed insulin** (containing 25%, 30%, or 50% fast/rapid acting component) at doses ranging from 20 to 80 units per day for at least 90 days before screening. Participants could be receiving concomitant **oral antidiabetic drugs** including **metformin**, **sulfonylureas**, **meglitinides**, **DPP-4 inhibitors**, **sodium-glucose co-transporter 2 inhibitors**, **alpha-glucosidase inhibitors**, or **thiazolidinediones**, provided these medications had been administered at stable daily doses for at least 90 days prior to screening. The trial population was selected to include individuals with a **body mass index** of 40.0 kg/m² or less. The study did not include vulnerable populations.

This is a Phase III clinical trial evaluating the efficacy, safety, and patient-reported outcomes of two insulin-based treatment regimens in participants with type 2 diabetes who are inadequately controlled with pre-mixed insulin therapy. The study compares once-weekly IcoSema (a combination of insulin icodec and semaglutide) administered as a solution for injection via the subcutaneous route, with once or twice daily insulin degludec/insulin aspart (Ryzodeg) 100 units/mL, also administered subcutaneously as a solution for injection in a pre-filled pen. Both treatment arms may be used with or without oral anti-diabetic drugs. The trial is designed to confirm non-inferiority of once-weekly IcoSema versus the comparator regimen with respect to glycaemic control, measured by change in HbA1c from baseline after 40 weeks, using a non-inferiority margin of 0.3 percentage points.

The primary endpoint is the change in HbA1c from baseline to week 40. Secondary endpoints include change in body weight, number of clinically significant hypoglycaemic episodes (level 2, defined as blood glucose less than 3.0 mmol/L or 54 mg/dL confirmed by blood glucose meter) or severe hypoglycaemic episodes (level 3), weekly total insulin dose, change in diabetes treatment satisfaction questionnaire status (DTSQs) total treatment satisfaction score, change in mean 7-point self-monitored plasma glucose profiles, change in mean post-prandial glucose increment, time spent below 3.0 mmol/L, time spent above 10.0 mmol/L, change in time in range (3.9-10.0 mmol/L or 70-180 mg/dL), change in fasting plasma glucose, change in Treatment Related Impact Measure - Diabetes (TRIM-D) score, change in EQ-5D-5L score, and separate analysis of clinically significant and severe hypoglycaemic episodes.

Principal inclusion criteria require participants to be male or female, aged 18 years or above at the time of informed consent, diagnosed with type 2 diabetes at least 180 days before screening, and having an HbA1c level between 7.0% and 10.0% (53.0-85.8 mmol/mol) inclusive as assessed by central laboratory on the day of screening. Participants must be treated with once-daily or twice-daily pre-mixed insulin (containing 25%, 30%, or 50% fast/rapid acting component) at a dose of 20-80 units per day for at least 90 days before screening. Treatment may be with or without specific oral anti-diabetic drugs at stable daily doses for at least 90 days before screening, including metformin, sulfonylureas, meglitinides, DPP-4 inhibitors, sodium-glucose co-transporter 2 inhibitors, alpha-glucosidase inhibitors, thiazolidinediones, or marketed oral combination products containing only these agents. Participants must have a body mass index (BMI) of 40.0 kg/m² or less.

The maximum treatment period for both investigational products is 40 weeks. The estimated recruitment start date is 2 March 2026, and the estimated end date of the trial is 10 November 2027. Participant involvement spans the duration of the 40-week treatment period plus screening and follow-up visits. The study includes a screening visit to assess eligibility, regular follow-up visits during the treatment period to monitor efficacy and safety parameters, and an end-of-study visit to evaluate final outcomes. Early termination from the study may occur under specific conditions as defined in the protocol, though these are not detailed in the available information.

The experimental medication **IcoSema** is a combination product containing **insulin icodec** and **semaglutide** as active substances. The product is formulated as a solution for injection with a concentration of 700 U/mL insulin icodec and 2 mg/mL semaglutide. The pharmaceutical form is a solution for injection administered via the **subcutaneous route**. The medication is administered once weekly throughout the treatment period of 40 weeks. The product may be used with or without concomitant oral anti-diabetic drugs. IcoSema serves as the test treatment in this clinical trial for participants with **type 2 diabetes** inadequately controlled with pre-mixed insulin.

The comparator treatment is **Ryzodeg 100 units/mL FlexTouch**, a marketed combination insulin product containing **insulin aspart** and **insulin degludec** as active substances. The product is presented as a solution for injection in a pre-filled pen with a concentration of 100 units/mL. The pharmaceutical form is a solution for injection administered via the subcutaneous route. The medication is administered once or twice daily, depending on individual participant requirements, over the 40-week treatment period. Similar to the experimental treatment, Ryzodeg may be used with or without concomitant oral anti-diabetic drugs. The product holds marketing authorization in the European Union under the authorization number EU/1/12/806/001 and is manufactured by Novo Nordisk A/S.

Both treatment arms allow for the concurrent use of oral anti-diabetic drugs as background therapy, reflecting real-world clinical practice in the management of type 2 diabetes. The maximum treatment period for both investigational products is 40 weeks. Dose units for both products are expressed in units (U). The trial aims to confirm non-inferiority of the once-weekly experimental treatment compared to the once or twice daily comparator treatment with respect to glycaemic control measured by change in **HbA1c** from baseline after 40 weeks, using a non-inferiority margin of 0.3 percentage points.

Efficacy will be assessed through multiple parameters in this clinical trial. The primary endpoint is the change in **HbA1c** from baseline after 40 weeks of treatment. Secondary efficacy endpoints include change in body weight, number of clinically significant hypoglycaemic episodes (level 2, defined as blood glucose less than 3.0 mmol/L or 54 mg/dL confirmed by blood glucose meter) or severe hypoglycaemic episodes (level 3), weekly total insulin dose, change in Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) total treatment satisfaction score, change in HbA1c, change in mean 7-point self-monitored plasma glucose profiles, change in mean post-prandial glucose increment over all meals, time spent below 3.0 mmol/L (54 mg/dL), time spent above 10.0 mmol/L (180 mg/dL), change in time in range 3.9-10.0 mmol/L (70-180 mg/dL), change in fasting plasma glucose, change in Treatment Related Impact Measure - Diabetes (TRIM-D) score, change in EQ-5D-5L score, number of clinically significant hypoglycaemic episodes (level 2), and number of severe hypoglycaemic episodes (level 3). Glycaemic control will be measured by HbA1c as assessed by central laboratory. Hypoglycaemic episodes will be confirmed by blood glucose meter readings. Patient-reported outcomes will be collected using validated instruments including the DTSQs, TRIM-D, and EQ-5D-5L.