Efficacy and Cardiovascular Safety of Cagrilintide and Semaglutide in Participants with Established Cardiovascular Disease
- Trial ID
- 2023-506924-94-00
- Protocol
- NN9838-4942
- Sponsor
- Novo Nordisk A/S
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to confirm the non-inferiority of cagrilintide and semaglutide combination therapy compared to placebo regarding the time to the first major adverse cardiovascular event (MACE) in participants with established cardiovascular disease. Scope: 4, 5.
The secondary objective includes:
- Confirmation of the superiority of the combination therapy versus placebo with respect to the time to the first MACE.
Participants
This clinical trial involves a total of 4,956 patients. The study population consists of males and females aged 55 years or older. Participants are characterized by a body mass index (BMI) of at least 25.0 kg/m2 and established cardiovascular disease. Evidence of this condition includes a prior myocardial infarction, stroke, or symptomatic peripheral arterial disease. For individuals with type 2 diabetes mellitus, specific requirements include a diagnosis at least 180 days prior to screening and an HbA1c level between 6.5% and 10%. Eligible participants may be managed through lifestyle intervention, specific oral antidiabetic drugs, or basal insulin in combination with oral agents.
Plans and Procedures
This Phase 3a, cardiovascular outcome trial is designed to evaluate the safety and efficacy of a combination of cagrilintide and semaglutide administered via subcutaneous injection once weekly. The study aims to confirm the non-inferiority of the test product compared to a placebo regarding the time to the first occurrence of major adverse cardiovascular event (MACE), which is a composite endpoint comprising cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The methodology involves a randomized approach to compare the investigational treatment against a placebo group. Participants must have established cardiovascular disease and a body mass index (BMI) of at least 25.0 kg/m2. The study includes a screening visit to assess eligibility, followed by treatment and monitoring periods. The overall trial is expected to conclude by October 2027.
Treatment
The experimental treatment consists of a combination of cagrilintide and semaglutide. This medication is provided as a solution for injection for subcutaneous administration. The fixed-dose combination is administered once-weekly.
The control group receives a placebo. This non-experimental treatment is administered as a placebo for both substances.
Efficacy
The primary efficacy endpoint is the time to first occurrence of major adverse cardiovascular event (MACE), which is a composite endpoint including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The study also evaluates an expanded MACE composite endpoint that incorporates coronary revascularisation and unstable angina requiring hospitalisation.
Secondary efficacy parameters include:
- Time to first occurrence of composite endpoints related to renal outcomes, such as the onset of persistent estimated glomerular filtration rate (eGFRcr) reduction, initiation of chronic kidney replacement therapy, kidney death, and the onset of persistent macroalbuminuria.
- Time to first occurrence of all-cause death, fatal or non-fatal myocardial infarction, and fatal or non-fatal stroke.
- Changes in anthropometric and physiological measurements, specifically body weight, waist circumference, waist-to-height ratio, systolic blood pressure, and diastolic blood pressure.
- Alterations in laboratory biomarkers, including HbA1c, lipids (total cholesterol, HDL, LDL, VLDL, triglycerides, and free fatty acids), high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and urinary albumin-to-creatinine ratio (UACR).
- Patient-reported outcomes and health status assessments, including the SF-36v2 Physical and Mental Component Summary scores, pain intensity measured by the Numerical Rating Scale (NRS), and the Pittsburgh Sleep Quality Index (PSQI).
- Changes in neuropathy status and the frequency of severe hypoglycaemic episodes in participants with type 2 diabetes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female
- Age above or equal to 55 years at the time of signing informed consent
- Body mass index (BMI) ≥ 25.0 kg/m2
- Established CVD as evidenced by at least one of the following: • Prior myocardial infarction • Prior stroke (ischemic or haemorrhagic stroke) • Symptomatic peripheral arterial disease (PAD) defined as at least one of the following: a. Intermittent claudication with an ankle-brachial index (ABI) < 0.85 at rest b. Intermittent claudication with a ≥ 50% stenosis in a lower extremity peripheral artery documented by X-ray angiography, MR angiography, CT angiography or Doppler ultrasound c. Prior revascularization procedure of a lower extremity peripheral artery d. Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g., trauma or osteomyelitis)
- For participants with T2D at screening, the following inclusion criteria also apply: Diagnosed with type 2 diabetes mellitus (T2D) ≥ 180 days before screening. HbA1c 6.5%-10% (48-86 mmol/mol) (both inclusive), as measured by central laboratory at screening. Treatment with either: a. Lifestyle intervention alone b. 1-3 marketed oral antidiabetic drugs (OADs) (metformin, α-glucosidase inhibitors (AGI), glinides, sodium-glucose co-transporter 2 inhibitor (SGLT2i), DPP4-inhibitors, thiazolidinediones, or sulphonylureas (SU) as a single agent or in combination) according to local label c. Basal insulin alone or in combination with up to two marketed OADs (refer to b. above), all according to local label
Exclusion Criteria
- Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 60 days before screening
- Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
- Heart failure classified as being in New York Heart Association (NYHA) Class IV at screening
- Treatment with any GLP-1 RA or a medication with GLP-1 activity within 90 days before screening
- End stage renal disease defined as eGFR < 15 mL/min/1.73 m2, as measured by the central laboratory at screening
- Chronic or intermittent haemodialysis or peritoneal dialysis
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 01 Mar 2023 | 400 |
 Denmark | Not Recruiting | 01 Mar 2023 | 105 |
 France | Not Recruiting | 01 Mar 2023 | 80 |
 Germany | Not Recruiting | 01 Mar 2023 | 300 |
 Ireland | Not Recruiting | 01 Mar 2023 | 65 |
 Italy | Not Recruiting | 01 Mar 2023 | 271 |
 The Netherlands | Not Recruiting | 01 Mar 2023 | — |
 Poland | Not Recruiting | 01 Mar 2023 | 470 |
 Spain | Not Recruiting | 01 Mar 2023 | 160 |
| Netherlands | — | — | 160 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
cagrilintide semaglutide | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 4 | PRD8977529 |
cagrilintide semaglutide | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 4 | PRD8977530 |
cagrilintide semaglutide | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 4 | PRD8977528 |
cagrilintide semaglutide | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 219 | PRD8977531 |
Placebo + Placebo | Placebo | N/A | — | — | — | N/A |
cagrilintide semaglutide | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 4 | PRD8977527 |