Evaluation of Maridebart Cafraglutide Efficacy and Safety in Adults with Type 2 Diabetes Mellitus and Obesity or Overweight: A Phase 3 Randomized, Double-blind Study
- Trial ID
- 2024-515523-11-00
- Protocol
- 20210184
- Sponsor
- Amgen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that **maridebart cafraglutide** is superior to placebo in achieving a percent change in body weight in adult participants with Type 2 Diabetes Mellitus who have obesity or are overweight. This is clinically relevant as effective weight management is crucial in reducing the risk of complications associated with Type 2 Diabetes Mellitus, such as cardiovascular disease and metabolic syndrome.
Secondary objectives include demonstrating the superiority of maridebart cafraglutide over placebo in:
- Reduction in central adiposity and body weight
- Reduction in systolic blood pressure and triglycerides
- Improvement in glycemic control, functional health, and well-being
- Improvement in cardiovascular risk factors and lipid parameters
- Reduction in diastolic blood pressure
- Characterization of the safety, tolerability, and pharmacokinetics of maridebart cafraglutide
Participants
The clinical trial for **chronic weight management** involves a total of 595 participants. The study population includes both male and female subjects aged 18 years and older, with a **body mass index (BMI)** of 27 kg/m² or higher. Participants are required to have a history of at least one self-reported unsuccessful attempt at weight loss through diet and exercise. Additionally, individuals with a diagnosis of type 2 diabetes mellitus (T2DM) for at least 180 days prior to screening are included, provided their **hemoglobin A1c** levels are between 7.0% and 10.0%. The trial population was selected based on these criteria, ensuring that participants are well-motivated and willing to adhere to study procedures, including lifestyle advice and self-monitoring of blood glucose. The study does not involve a vulnerable population, and both genders are equally represented.
Plans and Procedures
The clinical trial is a **Phase 3 randomized, double-blind, placebo-controlled study** designed to evaluate the efficacy, safety, and tolerability of **maridebart cafraglutide** in adult participants with **Type 2 Diabetes Mellitus** who are either obese or overweight. The primary objective is to demonstrate the superiority of maridebart cafraglutide over placebo in terms of percent change in body weight. The trial is expected to last for approximately 72 weeks, with the estimated recruitment start date being May 27, 2025, and the estimated end date being April 16, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, **Body Mass Index (BMI)**, and a history of unsuccessful weight loss attempts. Following successful screening, participants will be randomized to receive either maridebart cafraglutide or a placebo, both administered as a **solution for injection** via subcutaneous use. The study will include regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. These visits will involve assessments such as changes in body weight, waist circumference, **systolic blood pressure (SBP)**, fasting triglycerides, fasting plasma glucose, and **hemoglobin A1c (HbA1c)** levels. The end-of-study visit will conclude the trial, with a final evaluation of the primary and secondary endpoints.
Participant involvement is expected to last the full duration of the trial, approximately 72 weeks, unless early termination is warranted. Conditions that may lead to early termination include non-compliance with study procedures, adverse events, or withdrawal of consent. The trial aims to provide comprehensive data on the impact of maridebart cafraglutide on chronic weight management in the specified population, contributing valuable insights into its potential therapeutic benefits.
Treatment
The clinical trial involves the administration of **AMG 133**, an investigational medication, which is a **solution for injection**. The active substance in AMG 133 is **maridebart cafraglutide**, a protein-based compound classified as a human IgG1 monoclonal antibody against the gastric inhibitory polypeptide receptor, fused to a glucagon-like peptide 1 analog. The pharmaceutical form of AMG 133 is a solution intended for **subcutaneous use**. The dosing regimen for AMG 133 is determined by the study protocol, with a maximum daily dose and total dose amounting to 9999 mg, and the treatment period extending up to 72 weeks. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
The study also includes a **placebo** comparator, which is designed to match the experimental treatment in appearance and administration route but does not contain the active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered via the same subcutaneous route as AMG 133, following the same dosing schedule to provide a consistent basis for evaluating the efficacy and safety of maridebart cafraglutide in participants with **Type 2 Diabetes Mellitus** who are either obese or overweight.
Efficacy
The efficacy of maridebart cafraglutide in the treatment of **Type 2 Diabetes Mellitus** in adults with obesity or overweight will be assessed through a Phase 3 randomized, double-blind, placebo-controlled study. The primary endpoint for evaluating efficacy is the percent change from baseline in body weight at week 72. Secondary endpoints include changes from baseline in waist circumference, systolic blood pressure (SBP), fasting triglycerides, fasting plasma glucose, and hemoglobin A1c (HbA1c) levels at week 72. Additionally, the study will assess the achievement of ≥5%, ≥10%, and ≥15% reductions in body weight from baseline, as well as achieving HbA1c levels of less than 7% at week 72. The change from baseline in the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function Composite Score will also be evaluated at week 72.
Data collection will occur at specified timepoints, with the primary and secondary endpoints measured at week 72. The study will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The analysis will focus on comparing the efficacy of maridebart cafraglutide against a placebo, with the primary objective being to demonstrate the superiority of maridebart cafraglutide in achieving significant weight reduction. The study is designed to provide comprehensive insights into the efficacy of maridebart cafraglutide in managing weight and related metabolic parameters in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant has provided informed consent before initiation of any study-specific activities/procedures.
- Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
- BMI ≥ 27 kg/m2 at screening
- History of at least 1 self-reported unsuccessful attempt at weight loss by diet and exercise,History of at least 1 self-reported unsuccessful attempt at weight loss by diet and exercise,
- Diagnosis of T2DM at least 180 days before screening, based on the World Health Organization (WHO) classification.
- Hemogloblin A1c ≥ 7.0% (53 mmol/mol) and ≤ 10.0% (86 mmol/mol) at screening.
- Treatment of T2DM with diet and exercise alone and/or with a stable treatment of up to 3 oral glucose-lowering medications (as per local labeling), for at least 90 days before screening, except dipeptidyl peptidase 4 (DPP-4) inhibitors, and GLP-1RAs.
- In the opinion of the investigator, well-motivated and willing to: Follow study procedures for the duration of the study, including, but not limited to, following lifestyle advice, maintaining a study log(s)/diary(ies), and completing required study visits and, questionnaires. Perform self-monitoring of blood glucose (SMBG) per protocol
Exclusion Criteria
- Obesity induced by other endocrinologic disorders (including, but not limited to Cushing’s syndrome), or monogenetic or syndromic forms of obesity (including, but not limited to Prader Willi syndrome and melanocortin-4 receptor deficiency).
- One or more episode of severe hypoglycemia (Level 3 hypoglycemia) within 180 days before screening, as defined by the occurrence of neuroglycopenic symptoms requiring the assistance of another person for recovery. Refer to Section 11.9 (Appendix 9) for additional information.
- History of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms.
- History of a hematological condition (such as hemolytic anemia, sickle cell disease) that may interfere with HbA1c measurement.
- Fasting plasma glucose > 270 mg/dL (15.0 mmol/L) at screening.
- Use within 90 days before randomization of medications, supplements, or alternative remedies for weight loss (eg, GLP-1RA, GIP agonists, phentermine/topiramate, naltrexone/bupropion, orlistat, and sympathomimetic drugs).
- Use within 90 days before randomization or likely in the opinion of the investigator to require use during the study of medications that may cause significant weight gain (including, but not limited to chronic systemic glucocorticoid therapy, tricyclic antidepressants, atypical antipsychotics, valproic acid, and lithium). Note: Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) are permitted.
- Currently receiving treatment in another investigational device or drug study, or less than 90 days (or 5 half-lives, whichever is longer) since ending treatment on another investigational device or drug study(ies). This does not apply to other investigational procedures or participation in observational research studies.
- Previous participation in a study that includes maridebart cafraglutide (AMG 133) or AMG 598.
- Estimated glomerular filtration rate < 30 mL/min/1.73 m2 according to the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation or receiving dialysis at screening.
- Calcitonin ≥ 50 ng/L (pg/mL) at screening.
- History of organ transplant (except for corneal transplant) or on transplant list.
- Thyroid-stimulating hormone (TSH) < 0.4 mIU/L or TSH > 6.0 mIU/L with free thyroxine below the lower limit of normal at screening. Participants who receive treatment for hypothyroidism are permitted in the study, if their thyroid hormone replacement dose has been stable for at least 90 days before randomization and their TSH at screening is not exclusionary.
- Acute or chronic hepatitis, signs, and symptoms of any liver disease other than MASLD, alanine aminotransferase (ALT) > 3.0 x the upper limit of normal (ULN), or total bilirubin (TBL) > 1.2 x ULN (except for known diagnosis of Gilbert syndrome, which is not exclusionary).
- Systolic blood pressure > 180 mmHg and/or DBP >120 mmHg at screening.
- History of malignancy within the last 5 years before screening (except nonmelanoma skin cancers, cervical carcinoma in situ, or prostate cancer in situ).
- Patient Health Questionnaire-9 (PHQ-9) score of > 15 on day 1 before randomization
- Any suicidal ideation of category 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline version at screening, or on the C-SSRS Since Last Visit version on day 1 before randomization
- Lifetime history of suicide attempt evaluated through C-SSRS Baseline version at screening or any suicidal behavior on the C-SSRS Since Last Visit version on day 1 before randomization.
- History of chronic pancreatitis.
- History of acute pancreatitis within 180 days before screening.
- Family (first-degree relative(s) or personal history of MTC or multiple endocrine neoplasia syndrome type 2.
- History of any other condition (including, but not limited to known drug or alcohol abuse and eating disorders) that, in the opinion of the investigator, may preclude the participant from following the protocol and completing the study.
- History of any of the following within 60 days before screening: myocardial infarction, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack.
- New York Heart Association Class IV heart failure.
- History of unstable major depressive disorder (MDD) or other severe psychiatric disorder within 2 years before screening. Participants with MDD or other psychiatric disorder whose disease state is considered stable for the past 2 years before screening and is expected to remain stable throughout the study, in the opinion of the investigator, may be eligible.
- Participants of childbearing potential unwilling to use protocol-specified method of contraception during treatment and for an additional 16 weeks after the last dose of investigational product. Refer to Section 11.5 (Appendix 5) for additional contraceptive information
- Participants who are breastfeeding or who plan to breastfeed while on study through 16 weeks after the last dose of investigational product.
- Participants planning to become pregnant while on study through 16 weeks after the last dose of investigational product.
- Participants of childbearing potential with a positive pregnancy test assessed at screening and/or day 1 before randomization
- Any disorder, unwillingness, or inability, not covered by any of the other exclusion criteria, which in the investigator’s opinion, might jeopardize the participant’s safety or compliance with the protocol.
- Major surgical procedure planned during the study. Participants with minor surgical procedures (not requiring general anesthesia or deep sedation) planned during the study may be eligible at the discretion of the investigator
- Investigative site personnel directly affiliated with the study and/or their immediate family (ie, spouse, parent, child, or sibling, whether biological or legally adopted).
- Self-reported change in body weight > 5 kg within 90 days before screening.
- Participant has known sensitivity to any of the products or components to be administered during dosing.
- Clinically significant gastric-emptying abnormality (including, but not limited to gastroparesis and gastric outlet obstruction).
- Previous or planned (during the study) surgical, endoscopic, or device-based treatment for obesity. The following are allowed: liposuction and/or abdominoplasty that was performed > 1 year before screening; laparoscopic adjustable gastric banding, intragastric balloon, and/or duodenal-jejunal bypass liner or sleeves if removed > 1 year before screening.
- Type 1 diabetes mellitus, or any other types of diabetes mellitus (except T2DM or history of gestational diabetes).
- Current or prior treatment (within 90 days before screening) with DPP-4 inhibitors, oral GLP-1RAs, or any injectable therapy for T2DM.
- Proliferative diabetic retinopathy OR diabetic macular edema OR non-proliferative diabetic retinopathy that requires acute treatment. Note: A dilated fundoscopic examination or digital fundus photography with specified camera for non-dilated examination, performed by an ophthalmologist or another suitably qualified healthcare provider (eg, optometrist) within the past 90 days before screening or in the period between screening and randomization is required to verify eligibility criteria.
- Are currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema (for example, laser photocoagulation or intravitreal injections of anti-vascular endothelial growth factor [VEGF] inhibitors). History of proliferative diabetic retinopathy, diabetic maculopathy OR severe non-proliferative diabetic retinopathy. Note: A dilated fundoscopic examination or digital fundus photography with specified camera for non-dilated examination, performed by an ophthalmologist or another suitably qualified healthcare provider (eg, optometrist) within the past 90 days before screening or in the period between screening and randomization is required to verify eligibility criteria.
- Use within 90 days before randomization or likely in the opinion of the investigator to require use during the trial of medications that may cause significant weight gain (including, but not limited to chronic (>14 days) systemic glucocorticoid therapy (topical, intraocular, intranasal, intraarticular, or inhaled preparations are allowed), atypical tricyclic antidepressants, atypical antipsychotics, llithium and all formulations of valproic acid). Note: Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) are permitted.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 27 May 2025 | 30 |
 Czechia | Not Recruiting | 27 May 2025 | 49 |
 Germany | Not Recruiting | 27 May 2025 | 80 |
 Hungary | Not Recruiting | 27 May 2025 | 97 |
 Italy | Not Recruiting | 27 May 2025 | 8 |
 Poland | Not Recruiting | 27 May 2025 | 156 |
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 |
|---|---|---|---|---|---|---|
AMG 133 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 9999 | 72 | PRD10000277 |
Placebo for AMG 133maridebart cafraglutide | Placebo | N/A | — | — | — | N/A |