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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03005288
• Other study ID #: CBYM338X2211
• Status: Completed
• Phase: Phase 2
• Start date: February 1, 2017
• Est. completion date: May 8, 2019

Study information

• Verified date: June 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: May 8, 2019
• Est. primary completion date: March 21, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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];

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Overweight

Intervention

Drug:
• BYM338 10 mg/kg
intravenous infusion every four weeks

Other:
• Placebo
intravenous infusion every four weeks

Locations

Country	Name	City	State
United Kingdom	Novartis Investigative Site	Merthyr Tydfil	Mid Glamorgan
United States	Novartis Investigative Site	Anaheim	California
United States	Novartis Investigative Site	Baton Rouge	Louisiana
United States	Novartis Investigative Site	Berlin	New Jersey
United States	Novartis Investigative Site	Eatontown	New Jersey
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami Lakes	Florida
United States	Novartis Investigative Site	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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