Safety, Pharmacokinetics and Efficacy of Bimagrumab in Overweight and Obese Patients With Type 2 Diabetes

A Randomized, Subject- and Investigator-blinded, Placebo Controlled Study to Assess the Safety, Pharmacokinetics and Efficacy of Intravenous Bimagrumab in Overweight and Obese Patients With Type 2 Diabetes

This study assessed the safety, pharmacokinetics and efficacy of bimagrumab when administered in overweight and obese patients with type 2 diabetes

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: BYM338 10 mg/kg; Other: Placebo

Detailed Description

A non-confirmatory, randomized, subject and investigator blinded, placebo controlled, parallel-arm study, investigating a 48-week treatment period with i.v. bimagrumab 10 mg/kg in overweight and obese subjects with type 2 diabetes.

Participants were randomized and assigned to one of the following 2 treatment arms in a ratio of 1:1:

Arm 1: Bimagrumab 10 mg/kg up to maximum 1200 mg, every 4 weeks (12 doses) until week 44.

Arm 2: Placebo, every 4 weeks (12 doses) until week 44.

The study consisted of a screening baseline period of 3 weeks, treatment period of 48 weeks and then a follow-up period of 8 weeks.

Treatment period visits were scheduled every 4 weeks until week 44. Administration of bimagrumab or placebo was done via an i.v. infusion over 30 minutes followed by flushing for 15 minutes. Subjects were asked to return to the Investigator site for dosing approximately every 4 weeks during the treatment period. During those visits, subjects were evaluated for safety, tolerability, PK and efficacy. The treatment period ended approximately 4 weeks after the last dose administration.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Mid Glamorgan
    • Merthyr Tydfil, Mid Glamorgan, United Kingdom, CF484DR
      • Novartis Investigative Site
• United States
  • California
    • Anaheim, California, United States, 92801
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33126
      • Novartis Investigative Site
    • Miami, Florida, United States, 33143
      • Novartis Investigative Site
    • Miami Lakes, Florida, United States, 33014
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32804
      • Novartis Investigative Site
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Novartis Investigative Site
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Novartis Investigative Site
    • Eatontown, New Jersey, United States, 07724
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes with HbA1c between 6.5% and 10% at screening with stable treatment for 3 months prior to randomization
• On one of the following anti-diabetes regimens with stable treatment for approximately 3 months prior to randomization: 1) metformin monotherapy; 2) DPP4 inhibitor agent monotherapy; 3) combination therapy of metformin and DPP4 inhibitor agent; 4) no anti-diabetes therapy.
• Body Mass Index of 28 to 40 kg/m2 at screening
• Body weight between 65 and 140 kg at screening

Exclusion Criteria:

• Women of child-bearing potential unless they are using highly effective methods of contraception
• Diabetes other than Type 2 such as Type 1 diabetes, surgically induced diabetes, "brittle" type 2 diabetes as per investigator judgement, history of severe hypoglycemic episodes in the year preceding screening or hypoglycemic unawareness
• History of clinically significant arrythmias, heart failure, unstable angina, myocardial infarction or stroke, coronary artery bypass graft surgery, or percutaneous coronary intervention, deep vein thrombosis/pulmonary embolism, valve disorders or defects, pulmonary hypertension within 6 months of screening or 1 year for drug-eluting stents
• Tachycardia
• Use of anti-obesity medications, nutritional supplements or over the counter products for weight loss within 3 months of screening
• Use of medications known to induce weight gain such as some anti-convulsant and psychotropic medications within 3 months of screening
• Any chronic active infection (e.g., HIV, Hepatitis B or C, tuberculosis, etc) or has received anti-HCV treatments within the previous 6 months.
• Uncontrolled thyroid disease. Stable euthyroid patients on stable thyroid replacement therapy for at least 3 months of screening are allowed.
• Abnormal liver function tests such as SGOT, SGPT, alkaline phosphatase, or serum bilirubin, or abnormal lipase and/or amylase.
• Known history or presence of severe active acute or chronic liver disease (e.g., cirrhosis).
• Uncontrolled depression
• Use of skeletal muscle anabolic agents in any form for 3 months prior to screening
• Chronic kidney disease [estimated glomerular filtration rate (GFR) < 30 mL/min];

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BYM338 10 mg/kg; Bimagrumab (BYM338) 10 mg/kg up to maximum 1200 mg, every 4 weeks until week 44 (12 doses)	Drug: BYM338 10 mg/kg; intravenous infusion every four weeks; Other Names: Bimagrumab
PLACEBO_COMPARATOR: Placebo; Placebo, every 4 weeks until week 44 (12 doses)	Other: Placebo; intravenous infusion every four weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Body Fat Mass by Dual Energy X-ray Absorptiometry (DXA) at Week 48	Dual energy X-ray absorptiometry (DXA) was used to assess changes in body composition, including total fat and lean body mass (FM and LBM) and appendicular skeletal fat and muscle mass (aFM and aLBM). DXA instruments had a source that generated x-rays split into two energies which measured bone mineral mass and soft tissue from which fat and fat-free mass (or lean body mass) were estimated.	Baseline, Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Body Fat Mass by Dual Energy X-ray Absorptiometry (DXA) at Week 24	Dual energy X-ray absorptiometry (DXA) was used to assess changes in body composition, including total fat and lean body mass (FM and LBM) and appendicular skeletal fat and muscle mass (aFM and aLBM). DXA instruments had a source that generated x-rays split into two energies which measured bone mineral mass and soft tissue from which fat and fat-free mass (or lean body mass) were estimated.	Baseline, Week 24
Change From Baseline in HbA1c at Week 24 and 48	HbA1c reflects average glucose concentrations over the past 3 months and therefore provides a useful index of the glycemic control of bimagrumab over that time period. It is a standard endpoint used to assess the glycemic efficacy of any anti-diabetic medication. HbA1c is a key glycemic parameter which correlates with reduction of risk of diabetic complications.	Baseline, Week 24, Week 48
The Trough Observed Analyte Concentration (Ctrough) of Repeat Doses of BYM338 10 mg/kg on Day 84, 168, 252, 308 and 336	The trough observed analyte concentration (Ctrough) is the concentration that is just prior to the beginning of, or at the end of, a dosing interval (μg/mL).	Day 84, 252, 336 at pre-dose only. Day 168, 308 at pre-dose and 45 mins post-dose
Maximum Observed Serum Concentration(Cmax) Derived on Day 1, 168 and 308	Cmax is the observed maximum plasma concentration following administration (μg/mL).	Day 1, 168, 308 at pre-dose and 45 mins post-dose
Time to Reach the Maximum Concentration After Drug Administration (Tmax) Derived on Day 168 and 308	Tmax is the time to reach peak or maximum concentration (h) after the drug administration.	Day 1, 168, 308 at pre-dose and 45 mins post-dose
Change From Baseline in Body Mass Index (BMI)	Body Mass Index (BMI) was determined by height and weight measurements at week 24 and 48. A negative change from baseline indicates improvement. BMI was calculated as (Body weight (kg)/ [Height (m)]^2)	Baseline, Week 24, Week 48
Change From Baseline in Weight	Body weight was measured to the nearest 0.1 kilogram (kg) in indoor clothing without shoes. A negative change from baseline indicates improvement.	Baseline, Week 24, Week 48
Change From Baseline in Lean Body Mass (LBM) Measured by DXA	Lean body mass (LBM) is a part of body composition defined as the difference between total body weight and body fat weight. This means that it counts the mass of all organs except body fat, including bones, muscles, blood, skin, and everything else. Dual energy X-ray absorptiometry (DXA) was used to assess changes in body composition, including total fat and lean body mass (FM and LBM) and appendicular skeletal fat and muscle mass (aFM and aLBM). DXA instruments had a source that generated x-rays split into two energies which measured bone mineral mass and soft tissue from which fat and fat-free mass (or lean body mass) were estimated.	Baseline, Week 24, Week 48
Change From Baseline in Waist Circumference	Waist circumference is the length in cm of the circumference to the nearest 0.1 cm at the level of the umbilicus with the subject in the upright position. A negative change indicates improvement.	Baseline, Week 24, Week 52
Change From Baseline in Waist to Hip Ratio	Hip circumference was measured at the greatest protrusion of the buttocks. Combined with waist circumference, the waist-to-hip ratio was derived during data analysis.	Baseline, Week 24, Week 52
Change From Baseline in Insulin Resistance (HOMA2-IR)	Blood samples were collected to analyze insulin resistance. The homeostasis model assessment computational method was used to estimate insulin resistance (HOMA2-IR) from fasting plasma glucose and insulin. The HOMA2-IR is the reciprocal of insulin sensitivity (%S), as a percentage of a normal reference population (normal young adult). Higher numbers indicate higher insulin resistance. No established cutoffs are indicating impaired resistance. HOMA2-IR was calculated using an online calculator [https://www.dtu.ox.ac.uk/homacalculator/].	Baseline. Week 12, Week 36
Immunogenicity Assessed by the Number of Participants Developing Anti-BYM338 Antibodies During the Trial	Describes the number of participants tested positive for anti-BYM338 antibodies after the start of bimagrumab (BYM338) treatment. A validated bridging enzyme-linked immunosorbent assay (ELISA) was used for the confirmation of the presence of anti-BYM338 antibodies in human serum.	392 days

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Heymsfield SB, Coleman LA, Miller R, Rooks DS, Laurent D, Petricoul O, Praestgaard J, Swan T, Wade T, Perry RG, Goodpaster BH, Roubenoff R. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021 Jan 4;4(1):e2033457. doi: 10.1001/jamanetworkopen.2020.33457. Erratum In: JAMA Netw Open. 2021 Feb 1;4(2):e211376. JAMA Netw Open. 2021 Mar 1;4(3):e212581.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2017
• Primary Completion (ACTUAL): March 21, 2019
• Study Completion (ACTUAL): May 8, 2019

Study Registration Dates

• First Submitted: December 24, 2016
• First Submitted That Met QC Criteria: December 28, 2016
• First Posted (ESTIMATE): December 29, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: MRI; obesity; type 2 diabetes; DXA
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight
• Other Study ID Numbers: CBYM338X2211

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No