Efficacy and safety of co-administered cagrilintide and semaglutide (CagriSema) 1.0 mg/1.0 mg s.c. once weekly versus tirzepatide 5 mg s.c. once weekly in participants with type 2 diabetes inadequately controlled on metformin, SGLT2 inhibitor or both

The primary objective is to confirm non-inferiority on change in HbA1c and/or superiority on change in body weight of CagriSema (cagrilintide and semaglutide co-administration) versus tirzepatide 5 mg in participants with type 2 diabetes with inadequate glycaemic control on stable dose of metformin, SGLT2 inhibitor, or both. This objective addresses the critical need to evaluate the comparative efficacy of a novel dual agonist combination therapy against an established treatment in patients who remain suboptimally controlled on standard oral antidiabetic agents, focusing on the two key therapeutic targets of glycaemic control and weight management in type 2 diabetes.

The secondary objectives are:

• To confirm superiority of CagriSema versus tirzepatide 5 mg on change in HbA1c

• To compare the effect of CagriSema versus tirzepatide 5 mg on: other parameters of glycaemic control; achievement of ≥5% weight reduction; achievement of ≥10% weight reduction; achievement of ≥15% weight reduction; achievement of ≥20% weight reduction; blood pressure; waist circumference; lipids; clinical outcome assessments

This clinical trial enrolled a total of **590 participants** diagnosed with **type 2 diabetes mellitus**. The study population included both **male and female** subjects aged **18 years and above**. Participants were required to have been diagnosed with type 2 diabetes for at least 180 days prior to screening and to present with inadequate glycaemic control, defined as **HbA1c** levels between 7.0% and 10.5% (53-91 mmol/mol). All participants had a **body mass index (BMI)** of 30 kg/m² or higher at screening, indicating **obesity**. The trial population was selected based on stable treatment with specific **antidiabetic medications** for at least 90 days before screening, specifically **metformin**, an **SGLT2 inhibitor**, or a combination of both at effective or maximum tolerated doses as determined by the investigator. The study focused on adults with established type 2 diabetes and obesity who demonstrated suboptimal glycaemic control despite ongoing pharmacological management with oral antidiabetic agents.

This is a Phase III, randomized clinical trial designed to evaluate the efficacy and safety of co-administered **cagrilintide** and **semaglutide** (CagriSema) compared to **tirzepatide** in participants with **type 2 diabetes**. The trial employs a comparative design with participants receiving either the test product CagriSema or the **comparator** tirzepatide. All investigational medicinal products are administered via **subcutaneous** injection as a **solution for injection**. The trial is not classified as a low-intervention clinical trial.

The study population consists of male or female participants aged 18 years or above at the time of signing informed consent, who have been diagnosed with type 2 diabetes mellitus at least 180 days before **screening**. Eligible participants must have a **HbA1c** level between 7.0% and 10.5% (53-91 mmol/mol) as determined by central laboratory at screening, and a **body mass index** (BMI) of 30 kg/m² or greater at screening. Participants must be on a stable daily dose for at least 90 days before screening of **metformin**, **SGLT2 inhibitor**, or both, at an effective or maximum tolerated dose as determined by the investigator.

The **primary endpoints** of the trial are the change in HbA1c from baseline (week 0) to end of treatment (week 60) and the relative change in body weight from baseline (week 0) to end of treatment (week 60). The main objective is to confirm non-inferiority on change in HbA1c and/or superiority on change in body weight of CagriSema compared to tirzepatide 5 mg in participants with type 2 diabetes in inadequate glycaemic control on stable doses of metformin, SGLT2 inhibitor, or both.

**Secondary endpoints** include superiority of CagriSema versus tirzepatide on change in HbA1c from baseline to end of treatment, change in **fasting plasma glucose** (FPG), achievement of HbA1c target values of ≤6.5% (≤48 mmol/mol) and <7.0% (<53 mmol/mol), and achievement of weight reduction thresholds of ≥5%, ≥10%, ≥15%, and ≥20% from baseline to end of treatment. Additional secondary endpoints assess changes in **systolic blood pressure**, **diastolic blood pressure**, **waist circumference**, lipid profiles including **total cholesterol**, **HDL cholesterol**, **LDL cholesterol**, **VLDL cholesterol**, **triglycerides**, and **non-HDL cholesterol**, as well as changes in quality of life measures using the **SF-36v2** score (Physical Component Summary score, Mental Component Summary score, and Vitality subscale) and the **IWQOL-Lite-CT** (Physical Function score and Total score). Safety and tolerability are evaluated through the number of **treatment-emergent adverse events** (TEAEs), number of clinically significant **hypoglycaemic episodes** (level 2, defined as blood glucose <3.0 mmol/L or <54 mg/dL confirmed by blood glucose meter), and number of severe hypoglycaemic episodes (level 3, defined as hypoglycaemia associated with severe cognitive impairment requiring external assistance for recovery, with no specific glucose threshold) from baseline to end of treatment.

The treatment period extends for a maximum of 52 to 56 weeks depending on the specific product regimen, with an overall trial duration from the estimated recruitment start date in August 2024 to the estimated end date in May 2026. The screening visit establishes participant eligibility and baseline measurements. **Follow-up visits** occur at regular intervals throughout the treatment period to monitor efficacy parameters, safety assessments, and treatment compliance. The **end-of-study visit** at week 60 marks the completion of the treatment period and includes final efficacy and safety assessments. Participant involvement spans approximately 60 weeks from baseline to end of treatment. Early termination from the study may occur under conditions such as withdrawal of consent, adverse events requiring discontinuation, protocol violations, or investigator decision based on safety or efficacy concerns.

The experimental medication **cagrilintide semaglutide** is a combination product containing two active substances: **cagrilintide** and **semaglutide**. Both active substances are synthetically produced proteins. Cagrilintide is also known by the synonyms NNC0174-0833, NN9838, and N-alfa-[(S)-4-Carboxy-4-(19-carboxynonadecanoylamino)butyryl]-[Glu14,Arg17,Pro25,Pro28,Pro29,Pro37]-human amylin. Semaglutide is also identified by the synonym NNC0113-0217. The product is formulated as a **solution for injection** and is administered via the **subcutaneous route**. The dosage is expressed in **milligrams**. The maximum treatment period varies across different formulations, ranging from 4 weeks to 52 weeks. The product is manufactured by Novo Nordisk A/S.

The comparator medication **tirzepatide** is administered as **Mounjaro**, which is available in two dose strengths: 2.5 mg and 5 mg. Tirzepatide is a synthetically produced protein. The product is presented as a **solution for injection in pre-filled pen** and is administered via the **subcutaneous route** once weekly. The dosage is expressed in **milligrams**. Mounjaro 2.5 mg has a maximum treatment period of 4 weeks, while Mounjaro 5 mg has a maximum treatment period of 56 weeks. The product holds **marketing authorization** in the European Union (EU/1/22/1685) and is manufactured by Eli Lilly Nederland B.V. For this clinical trial, the product is sourced from the United States and subsequently repacked into clinical boxes containing 5 pens, with clinical labels applied over the existing product labels.

Efficacy will be assessed through primary and secondary endpoints evaluated from baseline (week 0) to the end of treatment (week 60). The primary endpoints include change in HbA1c and relative change in body weight from baseline to week 60. Secondary endpoints will evaluate superiority of the investigational treatment on change in HbA1c, as well as changes in fasting plasma glucose from baseline to week 60. Achievement of specific HbA1c target values will be assessed, including targets of ≤6.5% (≤48 mmol/mol) and <7.0% (<53 mmol/mol) at week 60. Weight reduction endpoints will evaluate the proportion of participants achieving ≥5%, ≥10%, ≥15%, and ≥20% weight reduction from baseline to week 60. Additional efficacy parameters include changes in systolic blood pressure, diastolic blood pressure, and waist circumference from baseline to week 60. Lipid parameters will be assessed as ratio to baseline for total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, and non-HDL cholesterol from baseline to week 60. Patient-reported outcomes will be evaluated using the SF-36v2 score, including Physical Component Summary score, Mental Component Summary score, and Vitality subscale, as well as the IWQOL-Lite-CT Physical Function score and Total score, with changes measured from baseline to week 60.