Effect of Bimagrumab on Body Composition, Insulin Sensitivity, and Bone in Adults With Obesity

Study Overview
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Brief Summary
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In adults with obesity seeking treatment, weight loss would ideally be composed almost exclusively of fat mass. However, loss of muscle mass and bone are unintentional consequences of weight loss, which has detrimental effects on health by lessening improvements in glucose and insulin levels, contributing to weight regain by reducing basal metabolic rate, and increasing the risk of falls, and fractures. Data in animals and humans suggest that bimagrumab, an investigational new drug for obesity that inhibits the activin type II receptor (ActRII) inhibitor, may build muscle and bone while resulting in a loss of fat mass. Semaglutide, which is FDA-approved for the treatment of obesity, results in loss of fat mass, but its effects on muscle and bone are less clear. The investigators hypothesize that in a randomized, placebo-controlled trial of 65 adults with obesity randomized to IV bimagrumab, identical IV placebo plus semaglutide, or identical IV placebo alone, bimagrumab will result in improvements in muscle, fat, and bone compared to semaglutide or placebo when given in addition to a lifestyle intervention for weight loss over 52 weeks.

Official Title
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Effect of Bimagrumab on Body Composition, Insulin Sensitivity, and Bone in Adults With Obesity

Conditions
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Obesity

Intervention / Treatment
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* Drug: IV bimagrumab
* Drug: IV placebo
* Drug: Semaglutide
* Dietary Supplement: Calcium/Vitamin D
* Behavioral: Lifestyle and nutrition counseling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI ≥30 kg/m2 or ≥27kg/m2 with at least one weight-related medical condition Have a history of at least one self-reported unsuccessful behavioral effort to lose body weight Exclusion Criteria: Current or prior history of diabetes mellitus based on self-report, use of diabetes medications, HbA1c ≥6.5%, or fasting glucose ≥126 mg/dL Any single serum transaminase level (i.e., ALT, AST, alk phos, GGT) ≥3x the upper limit of normal (ULN) Serum lipase and/or amylase levels ≥2x ULN Serum bilirubin level >1.5x ULN (except for cases of known Gilbert syndrome) Significantly impaired renal function as indicated by eGFR < 45, BUN ≥ 25, or proteinuria >2+ on urine dipstick or urinalysis Total WBC <3000/μL, neutrophils <1500/μL, hemoglobin <12 g/dL, or platelet count <100,000/μL Significant coagulopathy, e.g., PT/INR >1.5 Serum fasting triglyceride >500 mg/dL Uncontrolled thyroid disease, defined as abnormal TSH with abnormal fT4 Any chronic active infection (e.g., HIV, hepatitis B or C) or hepatitis C treatment within the previous 6 months Known history or presence of severe active acute or chronic liver disease (e.g., cirrhosis) or conditions with hepatotoxic potential (e.g., gallbladder or bile duct disease, acute or chronic pancreatitis, exocrine pancreatic insufficiency) History of clinically significant arrhythmias, unstable angina, myocardial infarction, stroke, coronary artery bypass graft surgery, percutaneous coronary intervention, heart failure, valve disorders or defect, pulmonary hypertension, chronic hypotension (<100/50), or chronic uncontrolled hypertension (>160/100) Tachycardia, defined as heart rate >100 bpm after 5 minutes resting in a sitting position History of malignancy of any organ system (other than localized squamous or basal cell carcinoma of the skin), treated or untreated, within the previous 5 years Confirmed diagnosis of current, significant psychiatric disease (e.g., dementia, Alzheimer's disease, schizophrenia, or bipolar disorder). Individuals with adequately treated depression on stable treatment for at least 3 months are eligible. Personal or family history of multiple endocrine neoplasia 2A or 2B or medullary thyroid cancer Active alcohol, drug, or tobacco abuse History of weight loss surgery or planned weight loss surgery during the trial period Use of any anti-obesity medication, nutritional supplement, or over the counter (OTC) product for weight loss within the previous 3 months or during study participation Any new dietary intervention or exercise regimen for weight loss started within the previous 3 months Weight instability of >5kg within the previous 3 months Weight > 150kg due to limitations of radiology imaging machines Use of medications known or suspected to induce weight gain within the previous 3 months or during study participation (e.g., anti-androgens, gonadotropin releasing hormone (GnRH) analogs, some anticonvulsant and psychotropic medications (excluding anti-depressant medication) and oral glucocorticoids) Use of skeletal muscle anabolic agents within the previous 3 months or during study participation (e.g., hormones such as growth hormone or testosterone, nutritional supplements (other than protein) and over-the-counter products labeled as muscle anabolic agents) History of hypersensitivity to monoclonal antibodies or drugs in the same compound class as the study drugs Bone fracture within the previous 3 months Use of osteoporosis medications within the previous 12 months or during study participation Not able or willing to comply with dietary and lifestyle intervention for weight loss, including history of clinically significant condition that precludes regular walking for exercise or contraindication to following a 500-calorie daily deficit, high protein diet Women who are pregnant or breastfeeding Women of child-bearing potential, defined as women physiologically capable of becoming pregnant, unless they are using an intrauterine device (IUD) from at least 3 months before the baseline visit through at least 4 months after the last dose of bimagrumab or placebo IV and an additional contraceptive (barrier) method from screening through at least 4 months after the last dose of bimagrumab or placebo IV. The following groups of women are eligible to participate: (a) women who are s/p surgical bilateral oophorectomy or total hysterectomy at least 6 weeks before taking study treatment, (b) women who have an IUD (see additional criteria above), (c) women who are s/p tubal ligation provided that they use an additional barrier form of contraception during the trial, and (d) women who are post-menopausal defined as ≥12 months of spontaneous amenorrhea with appropriate clinical and hormonal profile (e.g., age-appropriate, history of vasomotor symptoms, and/or FSH >40 IU/L). Male participants (and their female partners) must also use contraception for the duration of the study. Concurrently enrolled in any other type of medical research judged to be scientifically or medically incompatible with this study Plans to move out of the study area within 12 months, or be out of the study area for >12 weeks, continuously Routine MRI exclusion Previous significant radiation exposure Donation or loss of 400 mL or more of blood within past 2 months or plasma donation (> 250 mL) within past 2 weeks Any disorder, unwillingness, or inability not covered by any of the other exclusion criteria, which in the Investigator's opinion, might jeopardize the subject's safety or compliance with the protocol

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV bimagrumab<br> | Drug: IV bimagrumab<br>* IV bimagrumab (30mg/kg IV administered at 0, 4, 16, 28, and 40 weeks)<br>Dietary Supplement: Calcium/Vitamin D<br>* Elemental calcium 1200 mg + vitamin D3 800 IU PO daily<br>Behavioral: Lifestyle and nutrition counseling<br>* Lifestyle and nutrition counseling consistent with current guidelines for weight management<br>|
| Active Comparator: IV placebo plus semaglutide<br> | Drug: IV placebo<br>* IV placebo (administered at 0, 4, 16, 28, and 40 weeks)<br>Drug: Semaglutide<br>* Semaglutide 2.4mg SQ qweek<br>Dietary Supplement: Calcium/Vitamin D<br>* Elemental calcium 1200 mg + vitamin D3 800 IU PO daily<br>Behavioral: Lifestyle and nutrition counseling<br>* Lifestyle and nutrition counseling consistent with current guidelines for weight management<br>|
| Placebo Comparator: IV placebo alone<br> | Drug: IV placebo<br>* IV placebo (administered at 0, 4, 16, 28, and 40 weeks)<br>Dietary Supplement: Calcium/Vitamin D<br>* Elemental calcium 1200 mg + vitamin D3 800 IU PO daily<br>Behavioral: Lifestyle and nutrition counseling<br>* Lifestyle and nutrition counseling consistent with current guidelines for weight management<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in number of kilograms of lean mass by dual-energy x-ray absorptiometry |  | 52 weeks | 
| Change in visceral adipose tissue volume by magnetic resonance imaging |  | 52 weeks | 
| Change in hip bone mineral density by dual-energy x-ray absorptiometry |  | 52 weeks |