Research Study Investigating How Well NNC0174-0833 Works in People Suffering From Overweight or Obesity.

Study Overview
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Brief Summary
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This study will look at the change in body weight in people taking NNC0174-0833, liraglutide and dummy medicine, from the start to the end of the study. As well as taking the medicine, participants will have talks with study staff about healthy food choices, how to be more physically active and what participants can do to lose weight. Participants will either take NNC0174-0833, liraglutide or dummy medicine - which treatment participants get is decided by chance. Participants will need to take one injection once a week or once a day, depending on the treatment. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. The study will last for about 8 months. Participants will have 12 clinic visits with the study doctor.

Official Title
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Investigation of Safety and Efficacy of NNC0174-0833 for Weight Management - a Dose Finding Trial.

Conditions
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Obesity, Overweight

Intervention / Treatment
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* Drug: NNC0174-0833
* Drug: Placebo (NNC0174-0833)
* Drug: Liraglutide 3.0 mg
* Drug: Placebo (Liraglutide 3.0 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older at the time of signing the informed consent. Female subject of non-childbearing potential or Male subject who is surgically sterilised (vasectomy) or who is willing to use adequate contraceptive methods (as required by local regulation or practice) throughout the trial (until 'end of trial'). BMI equal to 30.0 kg/m^2 or greater or BMI equal to 27.0 kg/m^2 or greater with the presence of at least one of the following weight-related comorbidities (treated or untreated): hypertension or dyslipidaemia (to be assessed at the investigator's discretion). Exclusion Criteria: HbA1c equal to 48 mmol/mol (6.5 percentage) or greater as measured by the central laboratory at screening. A self-reported change in body weight greater than 5 kg (11 lbs) within 90 days prior to screening irrespective of medical records.

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
Interventional Model Description: This is a twelve-armed trial comprising of five (0.3, 0.6, 1.2, 2.4 and 4.5 mg OW) of NNC0174-0833 arms and liraglutide 3.0 mg OD arm as active treatment arms and the corresponding 6 placebo arms as comparators. Participants will be randomised 6:1 between the active treatment arms and the placebo arms. The five different NNC0174-0833 placebo arms and the one liraglutide placebo arm will be pooled into one placebo group for statistical analyses of the results.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NNC0174-0833, 4.5 mg<br>Patients will receive 4.5 mg of NNC0174-0833 once a week as injections for 26 weeks. | Drug: NNC0174-0833<br>* Participants will get one dose of NNC0174-0833 once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Experimental: NNC0174-0833, 2.4 mg<br>Patients will receive 2.4 mg of NNC0174-0833 once a week as injections for 26 weeks. | Drug: NNC0174-0833<br>* Participants will get one dose of NNC0174-0833 once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Experimental: NNC0174-0833, 1.2 mg<br>Patients will receive 1.2 mg of NNC0174-0833 once a week as injections for 26 weeks. | Drug: NNC0174-0833<br>* Participants will get one dose of NNC0174-0833 once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Experimental: NNC0174-0833, 0.6 mg<br>Patients will receive 0.6 mg of NNC0174-0833 once a week as injections for 26 weeks. | Drug: NNC0174-0833<br>* Participants will get one dose of NNC0174-0833 once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Experimental: NNC0174-0833 0.3 mg<br>Patients will receive 0.3 mg of NNC0174-0833 once a week as injections for 26 weeks. | Drug: NNC0174-0833<br>* Participants will get one dose of NNC0174-0833 once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Placebo Comparator: Placebo 2.4 mg (NNC0174-0833)<br>Patients will receive 2.4 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. | Drug: Placebo (NNC0174-0833)<br>* Participants will get one dose of Placebo (NNC0174-0833) once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Placebo Comparator: Placebo 4.5 mg (NNC0174-0833)<br>Patients will receive 4.5 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. | Drug: Placebo (NNC0174-0833)<br>* Participants will get one dose of Placebo (NNC0174-0833) once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Placebo Comparator: Placebo 1.2 mg (NNC0174-0833)<br>Patients will receive 1.2 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. | Drug: Placebo (NNC0174-0833)<br>* Participants will get one dose of Placebo (NNC0174-0833) once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Placebo Comparator: Placebo 0.6 mg (NNC0174-0833)<br>Patients will receive 0.6 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. | Drug: Placebo (NNC0174-0833)<br>* Participants will get one dose of Placebo (NNC0174-0833) once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Placebo Comparator: Placebo 0.3 mg (NNC0174-0833)<br>Patients will receive 0.3 mg of NNC0174-0833 once a week as injections for 26 weeks. | Drug: Placebo (NNC0174-0833)<br>* Participants will get one dose of Placebo (NNC0174-0833) once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks.<br>|
| Active Comparator: Liraglutide 3.0 mg<br>Patients will receive 3.0 mg of liraglutide once daily as injections for 26 weeks. | Drug: Liraglutide 3.0 mg<br>* Participants will get one dose of liraglutide 3.0 mg once daily. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using pre-filled PDS290 pen-injector. Participants will gradually increase their dose every week until they reach the target dose of 3.0 mg daily. The participants will continue on 3.0 mg of liraglutide, once daily up to 26 weeks.<br>|
| Placebo Comparator: Placebo 3.0 mg (Liraglutide)<br>Patients will receive placebo 3.0 mg(liraglutide) once daily as injections for 26 weeks. | Drug: Placebo (Liraglutide 3.0 mg)<br>* Participants will get one dose of Placebo (liraglutide 3.0 mg) once daily. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using pre-filled PDS290 pen-injector. Participants will gradually increase their dose every week until they reach the target dose of 3.0 mg. The participants will continue on Placebo (liraglutide 3.0 mg), once daily up to 26 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (%) | Change in body weight (%) from week 0 to week 26 is presented. For descriptive analysis and statistical analysis the endpoint was evaluated based on the data from in-trial period and treatment adherent period, respectively. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. Treatment-adherent: a participant is treatment adherent until the first time of non-adherence defined as: participant has not been dosed with trial product within the prior 14 days; participant has received other weight management drug or bariatric surgery; participant has not reached target dose at a pre-specified week; After the pre-specified evaluation week for the target dose, the participant has not received the target dose ±10% within the prior 14 days. | From baseline (week 0) to week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Weight Loss of ≥ 5% of Baseline Body Weight at 26 Weeks | Percentage of participants who achieved a weight loss of greater than or equal to (≥) 5% of baseline (week 0) body weight at 26 weeks is presented. The numbers presented are predictions from a logistic regression model. | Week 26 | 
| Percentage of Participants With Weight Loss of ≥ 10% of Baseline Body Weight at 26 Weeks | Percentage of participants who achieved a weight loss ≥ 10% of baseline (week 0) body weight at 26 weeks is presented. The numbers presented are predictions from a logistic regression model. | Week 26 | 
| Change in Body Weight (Kg) | Change in body weight (Kg) from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Waist Circumference | Change in waist circumference from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Total Cholesterol | Change in total cholesterol from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in High Density Lipoprotein (HDL) Cholesterol | Change in HDL cholesterol from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Low Density Lipoprotein (LDL) Cholesterol | Change in LDL cholesterol from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Very Low Density Lipoprotein (VLDL) Cholesterol | Change in VLDL cholesterol from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Triglycerides | Change in triglycerides from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Glycosylated Haemoglobin (HbA1c) (%-Point) | Change in HbA1c (measured as percentage point of HbA1c) from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in HbA1c (mmol/Mol) | Change in HbA1c (measured as millimoles per mole (mmol/mol)) from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Fasting Plasma Glucose (FPG) (mmol/L) | Change in FPG (measured as mmol/L)) from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in FPG (mg/dL) | Change in FPG (measured as milligrams per decilitre (mg/dL)) from week 0 to week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Change in Fasting Insulin | In the below table, fasting insulin data at week 0 and at week 26 is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Percentage Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Percentage change in HOMA-IR from week 0 to week 26 is presented. Insulin resistance is a condition in which cells fail to respond to normal actions of hormone in body. HOMA-IR is calculated using a subject's fasting plasma insulin and glucose levels. HOMA-IR = fasting serum insulin (micro international units per milliliter (μU/ml)) × fasting plasma glucose (millimoles per liter (mmol/l)) / 22.5. HOMA-IR scores are classified as follows: less than 1.0: considered Insulin sensitive, 0.5-1.4: considered Healthy, Above 1.8: considered Early insulin resistance; Above 2.7 is considered significant insulin resistance. HOMA-IR score ranges from 0-infinity (no upper limit). Higher the score, higher the level of insulin resistance. Endpoint was evaluated based on data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in in-trial period. | From baseline (week 0) to week 26 | 
| Change in Homeostatic Model Assessment of Beta-cell Function (HOMA-beta) | Change between the value of HOMA-beta cell function collected at Week 26 and HOMA-beta cell function collected at Week 0 is presented. The homeostatic model assessment estimates steady state beta cell function as a percentage of a normal reference population (%B). HOMA %B = 20 * insulin (micro international units per milliliter (µIU/mL)) / fasting plasma glucose (millimoles per liter (mmol/L)) - 3.5. HOMA-beta score ranges from minus infinity to infinity (no limits). The higher the score the better beta-cell function for HOMA-beta. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. | From baseline (week 0) to week 26 | 
| Number of Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical trial participant administered or used a medicinal product, whether or not considered related to the medicinal product or usage. All AEs reported here are TEAEs. TEAE is defined as an event that had onset date during the on-treatment period. The endpoint was evaluated based on the data from on-treatment period which started from the date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 6 consecutive missed doses for cagrilintide or 6 consecutive weeks of missed dosing with liraglutide. | From week 0 to week 32 | 
| Number of Treatment-emergent Serious Adverse Events (TESAEs) | An AE was any untoward medical occurrence in a clinical trial participant administered or used a medicinal product, whether or not considered related to the medicinal product or usage. Serious AE is an AE that resulted in death, life threatening, persistent or significant incapacity or substantial disruption of ability to conduct normal life functions, hospitalization or prolongation of existing hospitalization, congenital anomaly or birth defect, important medical events that may not result in death, be life threatening, or require hospitalization. All SAEs reported in the below table are TESAEs. The endpoint was evaluated based on the data from on-treatment period which started from the date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 6 consecutive missed doses for cagrilintide or 6 consecutive weeks of missed dosing with liraglutide. | From week 0 to week 32 | 
| Number of Participants With Occurrence of Anti-drug Antibodies Towards Cagrilintide | Number of participants with occurrence of anti-drug antibodies towards cagrilintide from randomisation from week 0 to week 32 is presented. The endpoint was evaluated based on the data from in-trial period. The in-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. Follow-up time for positive antibodies was not included in the in-trial period. This endpoint is applicable only for the cagrilintide treatment arms. | From week 0 to week 32 | 
| Change in Diastolic Blood Pressure (DBP) | Blood pressure was measured in a sitting position after 5 minutes of rest. The end point is evaluated while the subject is treatment-adherent. A participant is treatment adherent until the first time of non-adherence defined as: a) the participant has not been dosed with trial product within the prior 14 days; b) the participant has received other weight management drug or bariatric surgery c) the participant has not reached target dose at a pre-specified week d) After the pre-specified evaluation week for the target dose, the participant has not received the target dose +/- 10 % within the prior 14 days. This endpoint is applicable only for the cagrilintide treatment arms. | From baseline (week 0) to week 26 | 
| Change in Systolic Blood Pressure (SBP) | Blood pressure was measured in a sitting position after 5 minutes of rest. The end point is evaluated while the subject is treatment-adherent. A participant is treatment adherent until the first time of non-adherence defined as: a) the participant has not been dosed with trial product within the prior 14 days; b) the participant has received other weight management drug or bariatric surgery c) the participant has not reached target dose at a pre-specified week d) After the pre-specified evaluation week for the target dose, the participant has not received the target dose +/- 10 % within the prior 14 days. This endpoint is applicable only for the cagrilintide treatment arms. | From baseline (week 0) to week 26 | 
| Change in Pulse | Change in pulse from week 0 to week 26 is presented. The endpoint was evaluated based on the data from on-treatment period which started from the date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 6 consecutive missed doses for cagrilintide or 6 consecutive weeks of missed dosing with liraglutide. | From baseline (week 0) to week 26 | 
| Change in High Sensitivity C-reactive Protein (hsCRP) | In the below table, hsCRP data at week 0 and at week 26 is presented. The endpoint was evaluated based on the data from on-treatment period which started from the date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 6 consecutive missed doses for cagrilintide or 6 consecutive weeks of missed dosing with liraglutide. | From baseline (week 0) to week 26 | 
| Change in Plasminogen Activator Inhibitor-1 (PAI-1) Activity | Due to the assay development issue faced by the laboratory, the Plasminogen Activator Inhibitor-1 (PAI-1) activity (mg/L) was not performed in the study. | From baseline (week 0) to week 26 | 
| Change in Renin Activity | Change in renin activity from week 0 to week 26 is presented. The endpoint was evaluated based on the data from on-treatment period which started from the date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 6 consecutive missed doses for cagrilintide or 6 consecutive weeks of missed dosing with liraglutide. | From baseline (week 0) to week 26 | 
| Change in Aldosterone | Change in aldosterone from week 0 to week 26 is presented. The endpoint was evaluated based on the data from on-treatment period which started from the date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 6 consecutive missed doses for cagrilintide or 6 consecutive weeks of missed dosing with liraglutide. | From baseline (week 0) to week 26 |