A Research Study to See How Well CagriSema Compared to Semaglutide, Cagrilintide and Placebo Lowers Blood Sugar and Body Weight in People With Type 2 Diabetes Treated With Metformin With or Without an SGLT2 Inhibitor

Study Overview
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Brief Summary
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The study will look at how well CagriSema helps people lower their blood sugar and body weight. CagriSema is a new weekly medicine that combines two medicines called semaglutide and cagrilintide. CagriSema will be compared to the two medicines semaglutide and cagrilintide, when they are taken alone. CagriSema will also be compared to a dummy medicine without any active ingredient. The study will be done in participants who have type 2 diabetes. Participants will take the study medicine together with the current diabetes medicine (metformin with or without an SGLT2 inhibitor).

Official Title
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Efficacy and Safety of Co-administered Cagrilintide and Semaglutide (CagriSema) s.c. in Doses 2.4/2.4 mg and 1.0/1.0 mg Once Weekly Versus Semaglutide 2.4 mg and 1.0 mg, Cagrilintide 2.4 mg and Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Metformin With or Without an SGLT2 Inhibitor

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Cagrilintide
* Drug: Semaglutide
* Drug: Placebo cagrilintide
* Drug: Placebo semaglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female. Age 18 years or above at the time of signing the informed consent. Diagnosed with type 2 diabetes mellitus greater than or equal to 180 days before screening. Stable daily dose(s) greater than or equal to 90 days before screening of any of the following antidiabetic drug(s) or combination regimen(s) at effective or maximum tolerated dose as judged by the investigator: metformin with or without Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors. Glycated haemoglobin (HbA1c) 7.0-10.5 percent (53-91 millimoles per mole [mmol/mol]) (both inclusive) as determined by central laboratory at screening. Body Mass Index (BMI) greater than or equal to 25 kilogram per square metre ( kg/m^2) at screening. BMI will be calculated in the electronic case report form (eCRF) based on height and body weight at screening. Exclusion Criteria: Renal impairment with estimated Glomerular Filtration Rate (eGFR) less than 30 milliliters per minute per 1.73 square metre (mL/min/1.73 m^2) as determined by central laboratory at screening. Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening. However, short term insulin treatment for a maximum of 14 consecutive days and prior insulin treatment for gestational diabetes are allowed. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within 90 days before screening or in the period between screening and randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CagriSema 2.4 mg/2.4 mg<br>Participants will receive once-weekly subcutaneous (s.c) injections of 2.4 mg cagrilintide and 2.4 mg semaglutide for 68 weeks. | Drug: Cagrilintide<br>* Participants will receive once-weekly s.c injection of cagrilintide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of cagrilintide is reached.<br>Drug: Semaglutide<br>* Participants will receive once-weekly s.c injection of semaglutide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of semaglutide is reached.<br>|
| Experimental: CagriSema 1.0 mg/1.0 mg<br>Participants will receive once-weekly s.c injections of 1.0 mg cagrilintide and 1.0 mg semaglutide for 68 weeks. | Drug: Cagrilintide<br>* Participants will receive once-weekly s.c injection of cagrilintide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of cagrilintide is reached.<br>Drug: Semaglutide<br>* Participants will receive once-weekly s.c injection of semaglutide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of semaglutide is reached.<br>|
| Active Comparator: Semaglutide 2.4 mg<br>Participants will receive once-weekly s.c injection of 2.4 mg semaglutide for 68 weeks. | Drug: Semaglutide<br>* Participants will receive once-weekly s.c injection of semaglutide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of semaglutide is reached.<br>|
| Active Comparator: Semaglutide 1.0 mg<br>Participants will receive once-weekly s.c injection of 1.0 mg semaglutide for 68 weeks. | Drug: Semaglutide<br>* Participants will receive once-weekly s.c injection of semaglutide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of semaglutide is reached.<br>|
| Active Comparator: Cagrilintide 2.4 mg<br>Participants will receive once-weekly s.c injection of 2.4 mg cagrilintide for 68 weeks. | Drug: Cagrilintide<br>* Participants will receive once-weekly s.c injection of cagrilintide at escalating doses every week until maintenance dose of 2.4 mg and 1.0 mg of cagrilintide is reached.<br>|
| Placebo Comparator: Placebo 2.4 mg/2.4 mg<br>Participants will receive once-weekly s.c injection of placebo matched to 2.4 mg cagrilintide and 2.4 mg semaglutide for 68 weeks. | Drug: Placebo cagrilintide<br>* Participants will receive placebo matched to cagrilintide subcutaneously.<br>Drug: Placebo semaglutide<br>* Participants will receive placebo matched to semaglutide subcutaneously.<br>|
| Placebo Comparator: Placebo 1.0 mg/1.0 mg<br>Participants will receive once-weekly s.c injection of placebo matched to 1.0 mg cagrilintide and 1.0 mg semaglutide for 68 weeks. | Drug: Placebo cagrilintide<br>* Participants will receive placebo matched to cagrilintide subcutaneously.<br>Drug: Placebo semaglutide<br>* Participants will receive placebo matched to semaglutide subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg versus 1.0 mg): Change in glycated haemoglobin (HbA1c) | Measured in percentage-points. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg versus 1.0 mg): Relative change in body weight | Measured in percentage. | From baseline (week 0) to end of treatment (week 68) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CagriSema 2.4 mg/2.4 mg versus cagrilintide 2.4 mg: Change in HbA1c | Measured in percentage-points. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema 2.4 mg/2.4 mg versus cagrilintide 2.4 mg: Relative change in body weight | Measured in percentage. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema 2.4 mg/2.4 mg versus semaglutide 1.0 mg: Change in HbA1c | Measured in percentage-points. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema 2.4 mg/2.4 mg versus semaglutide 1.0 mg: Relative change in body weight | Measured in percentage. | From baseline (week 0) to end of treatment (week 68) | 
| Cagrilintide 2.4 mg versus placebo: Change in HbA1c | Measured in percentage-points. | From baseline (week 0) to end of treatment (week 68) | 
| Cagrilintide 2.4 mg versus placebo: Relative change in body weight | Measured in percentage. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Achievement of greater than or equal to (>=) 10 percent (%) weight reduction | Measured as count of participants. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Achievement of >= 15 % weight reduction | Measured as count of participants. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Achievement of >= 20 % weight reduction | Measured as count of participants. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): CGM - Change in time in Tight Target Range (TITR) 3.9-7.8 millimoles per litre (mmol/L) (70-140 milligrams per decilitre [mg/dL]) | Measured in percentage-points. | From baseline (week -3) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in Systolic Blood Pressure (SBP) | Measured in millimeters of mercury (mmHg). | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in triglycerides | Measured as ratio of triglycerides. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in non-High Density Lipoprotein (HDL) cholesterols | Measured as ratio of non-HDL cholesterol. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): CGM - Change in Time In Range (TIR) 3.9-10.0 mmol/L (70-180 mg/dL) | Measured in percentage-points. | From baseline (week -3) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in high sensitivity C-Reactive Protein (hsCRP) | Measured as ratio of hsCRP. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in Fasting Plasma Glucose (FPG) | Measured in mmol/L. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Achievement of HbA1c target values of less than (<) 7.0% (<53 millimoles per mole [mmol/mol]) | Measured as count of participants. | At end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Achievement of HbA1c target values of less than or equal to (≤)6.5% (≤48 mmol/mol) | Measured as count of participants. | At end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): CGM - Change in time above range, >10.0 mmol/L (>180 mg/dL) | Measured in percentage-points. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): CGM - Change in time above range, >13.9 mmol/L (>250 mg/dL) | Measured in percentage-points. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): CGM - Within-day glycaemic variability (% coefficient of variation [CV]) | Measured in percentage. | At end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg versus 1.0 mg): Achievement of ≥ 5 % weight reduction | Measured as count of participants. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in waist circumference | Measured in centimetre. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in Diastolic Blood Pressure (DBP) | Measured in mmHg. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in total cholesterol | Measured as ratio of total cholesterol. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in HDL cholesterol | Measured as ratio of HDL cholesterol. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in low-density lipoprotein (LDL) cholesterol | Measured as ratio of LDL cholesterol. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in very low-density lipoprotein (VLDL) cholesterol | Measured as ratio of VLDL. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Ratio to baseline in free fatty acids | Measured as ratio of free fatty acids. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in Short Form (SF)-36v score- Physical component summary score | SF-36v2 measure consists of 36 items yielding 8 health domain scores and 2 component summary scores. SF-36v2 acute scores are norm-based scores, i.e. transformed to a scale where the 2009 US general population has a mean of 50 and an standard deviation of 10. Physical component summary score range from 6.1 to 79.7, with higher scores indicating better functional health and well-being. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in SF-36v2 score- Mental component summary score | SF-36v2 measure consists of 36 items yielding 8 health domain scores and 2 component summary scores. SF-36v2 acute scores are norm-based scores, i.e. transformed to a scale where the 2009 US general population has a mean of 50 and an standard deviation of 10. Mental component summary score range from -3.8 to 78.7, with higher scores indicating better functional health and well-being. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ) score | DTSQc measures treatment satisfaction and diabetes-specific quality of life (QoL). The measure consists of 8 items yielding 1 global score and 2 single item scores. Total treatment satisfaction scores range from 0-36, with higher scores indicating greater satisfaction; the perceived frequency of hyperglycemia/hypoglycemia items are scored separately, with lower scores indicating better perceived blood glucose control. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema versus semaglutide (2.4 mg/2.4 mg versus 2.4 mg and 1.0 mg/1.0 mg vs 1.0 mg): Change in Treatment Related Impact Measure for Diabetes (TRIM-D) score | TRIM-D measures impact of diabetes treatment. The measure consists of 28 items yielding 5 domain scores and a total score. The scores were transformed to a 0-100 scale with higher scores indicating a better health state. | From baseline (week 0) to end of treatment (week 68) | 
| CagriSema (2.4 mg/2.4 mg and 1.0 mg/1.0 mg) versus semaglutide (2.4 mg and 1.0 mg), placebo and cagrilintide 2.4 mg: Number of treatment emergent adverse events (TEAEs) | Measured as count of events. | From baseline (week 0) to end of study (week 75) | 
| CagriSema (2.4 mg/2.4 mg and 1.0 mg/1.0 mg) versus semaglutide (2.4 mg and 1.0 mg), placebo and cagrilintide 2.4 mg: Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) | Measured as count of episodes. | From baseline (week 0) to end of study (week 75) | 
| CagriSema (2.4 mg/2.4 mg and 1.0 mg/1.0 mg) versus semaglutide (2.4 mg and 1.0 mg), placebo and cagrilintide 2.4 mg: Number of severe hypoglycaemic episodes (level 3) | Measured as count of episodes. Hypoglycaemia episodes (level 3) are the episodes associated with severe cognitive impairment requiring external assistance for recovery, with no specific glucose threshold. | From baseline (week 0) to end of study (week 75) |