CagriSema for Cardiovascular Disease

(REDEFINE 3 Trial)

Not currently recruiting at 1153 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

Must be taking: Oral antidiabetics, Basal insulin

Must not be taking: GLP-1 receptor agonists

Disqualifiers: Recent heart attack, Stroke, Heart failure, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 219 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CagriSema, a combination of Semaglutide and Cagrilintide, to determine its effectiveness in reducing heart-related problems like heart attacks and strokes in individuals with cardiovascular disease. Participants will receive either the actual treatment or a placebo, with equal chances of receiving either. Eligible participants should have heart disease with a history of events like a past heart attack or stroke, or symptoms of peripheral artery disease, such as pain when walking. Participants will inject the study medicine once a week for up to 4.5 years, using a thin needle in the stomach, thighs, or upper arms. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, if you are taking a glucagon-like peptide-1 (GLP-1) receptor agonist or a medication with GLP-1 activity, you must stop at least 90 days before screening.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking any glucagon-like peptide-1 (GLP-1) receptor agonist or a medication with GLP-1 activity, you must stop at least 90 days before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CagriSema, a combination of cagrilintide and semaglutide, was safe and well-tolerated in earlier studies. Participants experienced significant weight loss and managed the treatment without major issues. In one study, adults without diabetes lost up to 22.7% of their weight, while those with type 2 diabetes lost up to 15.7%.

These findings suggest that the treatment is generally safe. Although this trial focuses on heart disease, previous research offers some reassurance about the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cardiovascular disease?

Researchers are excited about CagriSema because it combines two active ingredients, cagrilintide and semaglutide, which offer a novel approach to treating cardiovascular disease. Unlike standard treatments that often focus solely on managing symptoms or cholesterol levels, this combination targets both appetite regulation and glucose control, potentially providing a more comprehensive cardiovascular benefit. The once-weekly subcutaneous administration also promises greater convenience compared to daily medications, which could improve patient adherence and outcomes.

What evidence suggests that this trial's treatments could be effective for cardiovascular disease?

In this trial, participants in the CagriSema arm will receive a combination of cagrilintide and semaglutide. Research has shown that CagriSema yields promising health results. One study found that people without diabetes lost up to 22.7% of their weight, while those with type 2 diabetes lost 15.7%. Additionally, it helped lower blood pressure, reduce waist size, improve cholesterol levels, and control blood sugar. These changes are significant because they can reduce the risk of heart problems, such as heart attacks and strokes. Although it hasn't been directly linked to preventing heart disease yet, these improvements suggest potential benefits for heart health. ^{1 2 5 6 7}

Who Is on the Research Team?

Clinical Transparency dept. 2834

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

This trial is for people aged 55 or older with a history of heart attack, stroke, or cardiovascular disease (CVD), and a BMI of at least 30. If they have type 2 diabetes (T2D), they must be diagnosed for over 180 days and meet specific CVD criteria. Excluded are those on dialysis, with recent severe cardiac events, end-stage renal disease, or who've used certain diabetes drugs recently.

Inclusion Criteria

I am either male or female.

Body mass index (BMI) greater than or equal to (>=) 25.0 kilograms per meter square (kg/m^2)

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: Intermittent claudication with an ankle-brachial index (ABI) less than (<) 0.85 at rest, Intermittent claudication with a >= 50% stenosis in a lower extremity peripheral artery documented by X-ray angiography, magnetic resonance (MR) angiography, computed tomography (CT) angiography or Doppler ultrasound, Prior revascularization procedure of a lower extremity peripheral artery, 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 millimoles per mole [mmol/mol]) (both inclusive), as measured by central laboratory at screening, Treatment with either: Lifestyle intervention alone, 1-3 marketed oral antidiabetic drugs (OADs) (metformin, α-glucosidase inhibitors (AGI), glinides, sodium-glucose co-transporter 2 inhibitor (SGLT2i), dipeptidyl peptidase 4 (DPP4)-inhibitors, thiazolidinediones, or sulphonylureas (SU) as a single agent or in combination) according to local label, Basal insulin alone or in combination with up to two marketed OADs, all according to local label

Exclusion Criteria

My kidney function is very low, with an eGFR below 15.

I haven't taken GLP-1 drugs in the last 90 days.

My heart condition severely limits my physical activity.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

3 weeks

Dose Escalation

Participants undergo a dose escalation period to reach the target dose of CagriSema

16 weeks

Treatment

Participants receive CagriSema or placebo once-weekly during the maintenance period

219 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

23 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cagrilintide
• Placebo
• Semaglutide

Trial Overview The study tests the effects of CagriSema versus placebo on preventing heart attacks and strokes in individuals with cardiovascular issues. Participants will receive either the actual drug or placebo by injection once weekly at random. The trial aims to last up to four and a half years.

How Is the Trial Designed?

Group I: CagriSema Experimental Treatment 2 Interventions

Participants will receive cagrilintide and semaglutide subcutaneously (s.c.) once-weekly after a dose escalation period of 16 weeks during the maintenance period of 219 weeks.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive placebo matched to cagrilintide and placebo matched to semaglutide s.c. once weekly for 235 weeks.

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Published Research Related to This Trial

In a study involving 197 subjects, the combination of netupitant and palonosetron (NEPA) showed no significant cardiovascular effects, including QT interval changes, even at higher doses, indicating its safety for heart health.

NEPA treatments were well-tolerated, with treatment-related adverse events similar to those in the placebo group, suggesting that NEPA is a safe option for managing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. Spinelli, T., Moresino, C., Baumann, S., et al.[2022]

In a study involving 1143 cancer patients receiving highly emetogenic chemotherapy, palonosetron demonstrated non-inferior efficacy to granisetron in preventing nausea and vomiting during the acute phase (0-24 hours) and superior efficacy in the delayed phase (24-120 hours).

Both treatments had similar safety profiles, with common side effects including constipation and elevated liver enzymes, but no severe adverse events were reported, indicating that palonosetron is a safe and effective option for managing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Saito, M., Aogi, K., Sekine, I., et al.[2022]

Granisetron is a highly effective and well-tolerated 5-HT3-receptor antagonist for managing nausea and vomiting caused by chemotherapy, radiation, and surgery, supported by extensive clinical trial data.

Its favorable safety profile, minimal drug-drug interactions, and effectiveness in special populations, including children and elderly patients, make granisetron a preferred antiemetic choice, especially for those with complex medical needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granisetron: an update on its clinical use in the management of nausea and vomiting. Aapro, M.[2022]

Cinaciguat, a new treatment for acute decompensated heart failure (ADHF), was shown to effectively unload the heart and cause arterial vasodilation in a study of 56 adult patients, demonstrating predictable pharmacokinetic and pharmacodynamic properties.

The study found that cardiac output significantly influenced the drug's clearance, while factors like age, body weight, and renal function did not, indicating that cinaciguat's effects are consistent across different patient profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics and pharmacodynamics of cinaciguat, a soluble guanylate cyclase activator, in patients with acute decompensated heart failure. Mueck, W., Frey, R.[2021]

In a study involving nasal ciliated cells from 16 healthy volunteers, the antiallergic formulation containing azelastine-HCL (AZL) significantly reduced ciliary beat frequency (CBF) to 0.9 Hz, indicating a strong negative impact on nasal ciliary function compared to control conditions.

Other formulations, such as disodium cromoglycate (DNCG) and dimethindene maleate (DMM), also reduced CBF, but to a lesser extent, suggesting that while these medications may help with allergies, they could potentially impair the important mucociliary clearance mechanism in the nose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of antiallergic intranasal formulations on ciliary beat frequency of human nasal epithelium in vitro. Alberty, J., Stoll, W.[2019]

Sacubitril/valsartan (LCZ696) has been shown to be superior to traditional ACE inhibitors in improving outcomes for patients with heart failure, leading to its inclusion in clinical guidelines for heart failure management.

Recent studies indicate that sacubitril/valsartan is more effective than ARB monotherapy in reducing central aortic systolic pressure and may be particularly beneficial for elderly patients with resistant hypertension, potentially preventing the progression to heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond. Kario, K.[2021]

Nesiritide is an effective treatment for congestive heart failure (CHF), providing rapid improvements in heart function and blood flow compared to traditional treatments like intravenous nitroglycerin, with fewer side effects.

While symptomatic hypotension is a potential adverse effect, it occurs infrequently, making nesiritide a safe option for patients with decompensated CHF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nesiritide for the treatment of congestive heart failure. Iyengar, S., Feldman, DS., Trupp, R., et al.[2019]

Cinaciguat significantly reduces pulmonary capillary wedge pressure and other hemodynamic parameters in patients with acute decompensated heart failure, indicating its efficacy in improving heart function.

The treatment was well tolerated, with a 90% responder rate after 6 hours and only mild to moderate adverse effects reported, primarily hypotension, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Lapp, H., Mitrovic, V., Franz, N., et al.[2016]

In a long-term study involving 177 children aged 1 to 12 with moderate to severe atopic dermatitis, a 4% sodium cromoglicate (SCG) emulsion was found to be well tolerated over 15 months, with most treatment-related events being mild and resolving without intervention.

While the SCG emulsion showed a reduction in SCORAD scores (a measure of dermatitis severity) during the study, the difference in effectiveness compared to the vehicle was not statistically significant during the initial 12-week trial, but there was a notable 56% reduction in SCORAD scores after 12 months of open treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term use of a 4% sodium cromoglicate cutaneous emulsion in the treatment of moderate to severe atopic dermatitis in children. Edwards, AM., Bibawy, D., Matthews, S., et al.[2018]

N-Acetyl-aspartyl magnesium glutamate (NAAGA) is a new topical antiallergic treatment that effectively reduces nasal obstruction and subjective symptoms in patients with perennial allergic rhinitis, as demonstrated in a randomized double-blind placebo-controlled study involving 20 patients.

The treatment was well tolerated overall, although some patients experienced mild side effects like transient nasal burning, indicating a favorable safety profile for NAAGA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effectiveness and tolerance of the C3 convertase inhibitor, N-acetyl-aspartyl-magnesium glutamate in perennial rhinitis. Results of a double-blind, placebo-controlled study]. Harnest, U., Kiehn, R., Sieger, C., et al.[2016]

Azelastine nasal spray did not negatively affect ciliary beat activity in guinea pigs during acute experiments, suggesting it is safe for nasal function.

After 26 weeks of daily application in rats and dogs, azelastine did not cause any inflammatory or atrophic changes in the nasal mucosa, indicating its long-term safety for local use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental studies on acute and chronic action of azelastine on nasal mucosa in guinea pigs, rats and dogs. Achterrath-Tuckermann, U., Berthold, K., Roux, J., et al.[2012]

Nesiritide, a recombinant form of B-type natriuretic peptide, is the first new injectable treatment for heart failure approved by the FDA in over a decade, showing promise in clinical trials with more than 700 participants.

The drug effectively reduces systemic vascular resistance and pulmonary capillary wedge pressure, leading to rapid clinical improvement in patients with acutely decompensated heart failure, making it a strong candidate for first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"BNP" for heart failure: role of nesiritide in cardiovascular therapeutics. Mills, RM., Hobbs, RE., Young, JB.[2019]

Patients receiving palonosetron for chemotherapy-induced nausea and vomiting (CINV) required significantly more hydration (0.9 L) compared to those receiving granisetron extended-release subcutaneous (GERSC) (0.3 L), indicating that palonosetron may lead to higher hydration needs.

Switching from palonosetron to GERSC resulted in lower hydration rates, particularly in patients undergoing highly emetogenic chemotherapy, suggesting that GERSC may be more effective in reducing hydration requirements in CINV management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydration requirements with emetogenic chemotherapy: granisetron extended-release subcutaneous versus palonosetron. Vacirca, J., Caruana, D., Calcanes, G., et al.[2018]

In a study involving 15 patients with extrinsic asthma, both Taleum 1-mg aerosol and Intal powder capsule were found to be equally effective in preventing dyspnea, as measured by peak expiratory flow and reduced need for additional bronchodilator therapy.

No side effects were observed with either medication, and some patients preferred the aerosol form of Taleum over the powder capsule for ease of use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Taleum 1-mg inhalation aerosol in bronchial asthma patients. Lantos, A., Tarján, E., Várnai, Z., et al.[2013]

In a study of 184 chemotherapy-naive patients receiving high-dose cisplatin, granisetron effectively controlled vomiting in 57% to 60% of patients at doses of 10, 20, or 40 micrograms/kg, with complete prevention of vomiting in 40% to 47% of patients.

The 10-micrograms/kg dose was found to be as effective as higher doses (20 and 40 micrograms/kg) in preventing nausea and vomiting, and granisetron was well tolerated, with headache being the most common side effect reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. Navari, RM., Kaplan, HG., Gralla, RJ., et al.[2017]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2502081

Coadministered Cagrilintide and Semaglutide in Adults ... In a phase 2 trial, cagrilintide at a dose of 2.4 mg led to a 9.7% weight reduction by week 26. Because the combination of therapies with ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05669755

NCT05669755 | REDEFINE 3: A Research Study to See ... This study will look at the effects of CagriSema on cardiovascular events (for example heart attack and stroke) in people living with cardiovascular disease.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40544433/

Coadministered Cagrilintide and Semaglutide in Adults ... Conclusions: Cagrilintide-semaglutide provided significant and clinically relevant body-weight reductions in adults with overweight or obesity, ...

4. diabetes.org diabetes.org/newsroom/press-releases/cagrisema-demonstrates-significant-weight-loss-adults-obesity

CagriSema Demonstrates Significant Weight Loss in Adults ... Once-weekly medication results in weight loss of up to 22.7% in adults without diabetes and 15.7% in those with type 2 diabetes.

5. appliedclinicaltrialsonline.com appliedclinicaltrialsonline.com/view/cagrilintide-semaglutide-weight-loss

REDEFINE 1 Trial Finds Cagrilintide–Semaglutide Combo ... The combination therapy significantly improved systolic blood pressure, waist circumference, lipid levels, and glycemic control, with 88% of ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37364590/

Efficacy and safety of co-administered once-weekly ... Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated.

7. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2502081

Coadministered Cagrilintide and Semaglutide in Adults ... Cagrilintide–semaglutide provided significant and clinically relevant body-weight reductions in adults with overweight or obesity, as compared with placebo.