MARIDEBART CAFRAGLUTIDE for Heart failure with preserved ejection fraction (HFpEF) | Heart failure with mildly reduced ejection fraction (HFmrEF) | Obesity

Stratification factors

• Diabetes status (with type 2 diabetes mellitus [T2DM] vs without T2DM)
• Region (Latin America, Asia, Eastern Europe, Western Europe + Australia, United States + Canada)

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years) at the time of informed consent\n- BMI ≥ 30 kg/m2 at randomization\n- HF diagnosed for at least 30 days with NYHA Class II-IV at the time of informed consent\n- Managed with HF standard of care therapies consistent with regional clinical practice guidelines, stable for at least 14 days before randomization, according to investigator judgment\n- Documented LVEF of > 40% measured by any modality within 12 months, from the beginning of screening.\n- Elevated NT-proBNP > 300 pg/mL for patients in sinus rhythm, or > 600 pg/mL for participants in active atrial fibrillation (AF) or atrial flutter (AFL), at screening\n- Participants must have at least one of the following: 1) Structural heart disease criteria documenting at least 1 of the following on echocardiogram within 12 months prior to screening: a. Average E/e´ ≥ 15 b. Left atrial (LA) enlargement (LA width ≥ 3.8 cm, or LA length ≥ 5.0 cm, or LA area ≥ 20.0 cm2, or LA volume ≥ 55 mL, or LA volume index ≥ 34 mL/m2) c. Left ventricular (LV) hypertrophy with septal thickness, or posterior wall thickness ≥ 1.2 cm measured during diastole OR 2) Documented hospitalization with a primary diagnosis of decompensated HF which required IV loop diuretic treatment,> 30 days and <  12 months prior to randomization. OR 3) Evidence of elevated filling pressures within 12 months before randomization: Mean pulmonary wedge pressure ≥ 15 mmHg, or left ventricular end diastolic pressure (LVEDP) ≥ 15 mmHg documented during catheterization at rest, or PA diastolic pressure measured by implantable monitor ≥ 15 mmHg, or pulmonary wedge pressure or LVEDP ≥ 25 mmHg documented during catheterization at exercise\n- For participants with a prior diagnosis of T2DM at screening: Treatment of T2DM with diet, exercise, and/or glucose-lowering medications according to local label with stable dosing for at least 30 days before randomization"}

Exclusion criteria

• {"criterion_text":"- History of any of the following within 60 days prior to or during screening: Type I (spontaneous) MI, valvular replacement or repair, coronary revascularization, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke\n- Heart failure due to: hypertrophic cardiomyopathy (obstructive and non obstructive), infiltrative cardiomyopathy (including cardiac sarcoid, lymphoma, cardiac amyloid, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac tamponade, arrhythmogenic right ventricular or left ventricular cardiomyopathy/dysplasia, uncorrected primary valvular heart disease, clinically significant congenital heart disease\n- Any lifetime history of LVEF ≤ 40%\n- Hospitalized with acute decompensated HF at the time of or during the screening period\n- Recipient of heart transplant or listed for any other major organ transplant, listed for heart transplant, or anticipated to receive chronic mechanical circulatory support or heart transplantation within 12 months from randomization\n- Severe, concomitant disease that is expected to reduce life expectancy to < 1 year\n- History of any other condition that, in the opinion of the investigator, may preclude the participant from following the protocol and completing the study.\n- Use of any GLP-1 RA, GIP agonists or antagonists, or amylin analogs within 90 days prior to or during the screening period or planned use during the conduct of the study\n- Treatment with continuous SC insulin therapy during screening or participants on intensive insulin therapy guided by carbohydrate counting\n- Use within 90 days prior to or during the screening period of medications prescribed for weight loss\n- In the opinion of the investigator, use within 90 days prior to or during the screening period of medications that may cause significant weight gain\n- Any of the following psychiatric history: -History of unstable major depressive disorder or other severe psychiatric disorder within 2 years prior to screening or during the screening period -Lifetime history of suicide attempt -History of non-suicidal self-injury within 5 years prior to screening or during the screening period.\n- Currently receiving treatment in another investigational device or drug study, or less than 90 days (or 5 half-lives, whichever is longer) prior to randomization since ending treatment in another investigational device or drug study(ies)\n- Previous or planned participation in a study that includes maridebart cafraglutide or AMG 598\n- Hospitalization with a primary diagnosis of decompensated HF which required IV loop diuretic treatment, within 30 days prior to randomization\n- Type 1 diabetes mellitus, or any type of diabetes with the exception of T2DM or history of gestational diabetes\n- For participants with a prior diagnosis of T2DM (including those diagnosed during screening): -HbA1c > 10.0% (86 mmol/mol) at screening -Uncontrolled diabetes requiring immediate therapy at randomization in the judgement of the investigator -History of diabetic ketoacidosis or hyperosmolar state/coma within 12 months before randomization -One or more episodes of severe hypoglycemia within 6 months before randomization and/or history of hypoglycemia unawareness -History or presence of either proliferative diabetic retinopathy, or diabetic maculopathy, or severe non-proliferative diabetic retinopathy; or currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema\n- SBP ≥ 180 mmHg during the screening period, or on three or more blood pressure-lowering drugs with a SBP > 160 mmHg during the screening period\n- Calcitonin ≥ 50 ng/L (pg/mL) at screening\n- Acute or chronic hepatitis; signs and symptoms of any liver disease other than MSALD; or ALT > 3.0 x ULN, during screening or TBL > 1.8 x ULN during screening\n- Clinically significant gastric-emptying abnormality\n- Any personal lifetime history of, or family history (first-degree relative[s]) of medullary thyroid carcinoma or MEN-2\n- History of malignancy within the last 5 years prior to screening or during the screening period\n- History of chronic pancreatitis\n- Family (first-degree relative[s]) or personal history of medullary thyroid carcinoma or MEN-2\n- eGFR < 20 mL/min/1.73 m2 according to the 2021 CKD-EPI creatinine (Cr)-cystatin C equation or receiving dialysis at screening\n- Obesity induced by specific endocrinologic disorders or monogenetic or syndromic forms of obesity\n- Planned bariatric surgery at the time of screening, or performed within 180 days of Screening\n- History of acute pancreatitis in the 180 days before screening or during the screening period"}

Primary endpoints

• {"endpoint_text":"- Time to first occurrence of a composite endpoint consisting of: o CV death, or o hospitalization for HF, or o urgent HF visits","definition_or_measurement_approach":"Measured as time-to-event: time from randomization to the first occurrence of the composite endpoint (cardiovascular death, hospitalization for heart failure, or urgent HF visits)."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at week 48 for participants with baseline KCCQ-CSS score ≤ 80","definition_or_measurement_approach":"Change from baseline to week 48 in KCCQ Clinical Summary Score for participants with baseline KCCQ‑CSS ≤ 80."}
• {"endpoint_text":"- Change from baseline in the KCCQ Total Symptom Score (TSS) at week 48 for participants with baseline KCCQ-CSS score ≤80","definition_or_measurement_approach":"Change from baseline to week 48 in KCCQ Total Symptom Score for participants with baseline KCCQ‑CSS ≤ 80."}
• {"endpoint_text":"- Total HF events (first and recurrent time to event) (ReHF events)","definition_or_measurement_approach":"Count/time‑to‑event of first and recurrent heart failure events (total HF events)."}
• {"endpoint_text":"- Time to first occurrence of a composite endpoint consisting of: myocardial infarction (MI), ischemic stroke, CV death (major adverse cardiac events [MACE]), or HF events","definition_or_measurement_approach":"Measured as time from randomization to first occurrence of composite of MI, ischemic stroke, cardiovascular death (MACE), or heart failure events."}

Methods

• Physician referral / Dr-to-patient letters (site HCP outreach and referral letter materials described)
• Digital pre-consent and online study pages (digital pre-consent, study pages, targeted digital advertisements described)
• Patient-facing brochures and pre-enrollment information cards (country-specific patient brochures, pre-enrollment cards)
• HCP fact sheets and physician-facing referral materials
• Third-party recruitment vendors and platforms (e.g. Antidote, Futuremeds, study hub/advertising vendors listed in sponsor third parties)

Primary sponsor

Full Name

Amgen Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Suvoda LLC

Responsibilities

Screening, randomisation, IP dispensing and IP shipment receipt

Name

IQVIA Limited

Responsibilities

Study Hub, eCOA, recruitment and retention, monitoring services (Denmark) and other CRO services

Name

Excelya Greece CRO Single Member S.A.

Responsibilities

Monitoring services and submission activities in Greece

Name

Medidata Solutions Inc.

Responsibilities

Clinical trial systems / data management support

Name

Altasciences Compagnie Inc.

Responsibilities

Laboratory services

Third parties

• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"Screening, randomisation and screen failure of patients. IP dispensing. IP shipment receipt.","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Antidote Technologies Limited","duties_or_roles":"Recruitment and patient-matching/recruitment support","organisation_type":"Hospital/Clinic/Other health care facility (recruitment vendor)"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Electronic data capture / clinical trial systems support","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Study Hub, eCOA, recruitment and retention, Monitoring Services in Denmark","organisation_type":"Pharmaceutical company (CRO services)"}
• {"country":"Germany","full_name":"MARKEN Germany GmbH","duties_or_roles":"Site to Patient (STP)","organisation_type":"Pharmaceutical company (logistics)"}
• {"country":"Greece","full_name":"Excelya Greece CRO Single Member S.A.","duties_or_roles":"Monitoring services and submission activities in Greece","organisation_type":"Pharmaceutical company (CRO)"}
• {"country":"Canada","full_name":"Altasciences Compagnie Inc.","duties_or_roles":"Laboratory services","organisation_type":"Pharmaceutical company (laboratory)"}
• {"country":"United States","full_name":"The Brigham And Women’s Hospital Inc.","duties_or_roles":"Adjudication Committee","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Iqvia Laboratories Limited","duties_or_roles":"Laboratory services","organisation_type":"Non-Pharmaceutical company (laboratory)"}
• {"country":"United States","full_name":"Azenta US Inc.","duties_or_roles":"Sample logistics","organisation_type":"Pharmaceutical company (laboratory logistics)"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Bioanalytical laboratory services","organisation_type":"Pharmaceutical company (bioanalysis lab)"}