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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03005288
• Collaborator: (none)
• Enrollment: 78
• Locations: 9
• Arms: 2
• Actual Duration (Months): 27.1
• Patients Per Site: 8.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: BYM338 10 mg/kg; Other: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Feb 1, 2017
• Actual Primary Completion Date: Mar 21, 2019
• Actual Study Completion Date: May 8, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Total Body Fat Mass by Dual Energy X-ray Absorptiometry (DXA) at Week 48 [Baseline, 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.

Secondary Outcome Measures

1. Change From Baseline in Total Body Fat Mass by Dual Energy X-ray Absorptiometry (DXA) at Week 24 [Baseline, 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.

2. Change From Baseline in HbA1c at Week 24 and 48 [Baseline, Week 24, Week 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.

3. The Trough Observed Analyte Concentration (Ctrough) of Repeat Doses of BYM338 10 mg/kg on Day 84, 168, 252, 308 and 336 [Day 84, 252, 336 at pre-dose only. Day 168, 308 at pre-dose and 45 mins post-dose]

   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).

4. Maximum Observed Serum Concentration(Cmax) Derived on Day 1, 168 and 308 [Day 1, 168, 308 at pre-dose and 45 mins post-dose]

   Cmax is the observed maximum plasma concentration following administration (μg/mL).

5. Time to Reach the Maximum Concentration After Drug Administration (Tmax) Derived on Day 168 and 308 [Day 1, 168, 308 at pre-dose and 45 mins post-dose]

   Tmax is the time to reach peak or maximum concentration (h) after the drug administration.

6. Change From Baseline in Body Mass Index (BMI) [Baseline, Week 24, Week 48]

   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)

7. Change From Baseline in Weight [Baseline, Week 24, Week 48]

   Body weight was measured to the nearest 0.1 kilogram (kg) in indoor clothing without shoes. A negative change from baseline indicates improvement.

8. Change From Baseline in Lean Body Mass (LBM) Measured by DXA [Baseline, Week 24, Week 48]

   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.

9. Change From Baseline in Waist Circumference [Baseline, Week 24, Week 52]

   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.

10. Change From Baseline in Waist to Hip Ratio [Baseline, Week 24, Week 52]

    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.

11. Change From Baseline in Insulin Resistance (HOMA2-IR) [Baseline. Week 12, Week 36]

    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/].

12. Immunogenicity Assessed by the Number of Participants Developing Anti-BYM338 Antibodies During the Trial [392 days]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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];

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Anaheim	California	United States	92801
2	Novartis Investigative Site	Miami Lakes	Florida	United States	33014
3	Novartis Investigative Site	Miami	Florida	United States	33126
4	Novartis Investigative Site	Miami	Florida	United States	33143
5	Novartis Investigative Site	Orlando	Florida	United States	32804
6	Novartis Investigative Site	Baton Rouge	Louisiana	United States	70808
7	Novartis Investigative Site	Berlin	New Jersey	United States	08009
8	Novartis Investigative Site	Eatontown	New Jersey	United States	07724
9	Novartis Investigative Site	Merthyr Tydfil	Mid Glamorgan	United Kingdom	CF484DR

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jan 17, 2019
• Statistical Analysis Plan - Mar 18, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03005288
• Other Study ID Numbers: CBYM338X2211
• First Posted: Dec 29, 2016
• Last Update Posted: Jan 5, 2021
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: type 2 diabetes; obesity; DXA; MRI
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight

Study Results

Participant Flow

Recruitment Details	The study was completed as planned.
Pre-assignment Detail	Participants were randomized to the study at 1:1 ratio to receive BYM338 10 mg/kg or placebo.

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Period Title: Overall Study
STARTED	39	39
Safety Analysis Set	37	38
Pharmacokinetics (PK) Analysis Set	36	0
Pharmacodynamics (PD) Analysis Set	36	36
COMPLETED	27	31
NOT COMPLETED	12	8

Baseline Characteristics

Arm/Group Title	BYM338 10 mg/kg	Placebo	Total
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks	Total of all reporting groups
Overall Participants	37	38	75
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.7 (7.50)	60.2 (8.02)	60.4 (7.72)
Sex: Female, Male (Count of Participants)
Female	23 62.2%	12 31.6%	35 46.7%
Male	14 37.8%	26 68.4%	40 53.3%
Race/Ethnicity, Customized (Count of Participants)
Black Or African American	6 16.2%	9 23.7%	15 20%
Other	1 2.7%	0 0%	1 1.3%
White	30 81.1%	27 71.1%	57 76%
Asian	0 0%	1 2.6%	1 1.3%
Unknown	0 0%	1 2.6%	1 1.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic Or Latino	27 73%	25 65.8%	52 69.3%
Not Hispanic Or Latino	9 24.3%	12 31.6%	21 28%
Not Reported	1 2.7%	1 2.6%	2 2.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Total Body Fat Mass by Dual Energy X-ray Absorptiometry (DXA) at Week 48
Description	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.
Time Frame	Baseline, Week 48

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
Least Squares Mean (80% Confidence Interval) [kg]	-7.49	-0.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.31
	Confidence Interval	(2-Sided) 80%; -8.48 to -6.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Total Body Fat Mass by Dual Energy X-ray Absorptiometry (DXA) at Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
Least Squares Mean (80% Confidence Interval) [kg]	-5.37	-0.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.19
	Confidence Interval	(2-Sided) 80%; -6.01 to -4.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in HbA1c at Week 24 and 48
Description	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.
Time Frame	Baseline, Week 24, Week 48

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 24	-0.85	0.28
week 48	-0.76	0.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.13
	Confidence Interval	(2-Sided) 80%; -1.42 to -0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.80
	Confidence Interval	(2-Sided) 80%; -1.20 to -0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	The Trough Observed Analyte Concentration (Ctrough) of Repeat Doses of BYM338 10 mg/kg on Day 84, 168, 252, 308 and 336
Description	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).
Time Frame	Day 84, 252, 336 at pre-dose only. Day 168, 308 at pre-dose and 45 mins post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set - PK samples were only obtained and evaluated for subjects treated with BYM338

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	0
Day 84	25.3 (6.20)
Day 168	27.5 (8.37)
Day 252	31.0 (11.2)
Day 308	29.9 (11.0)
Day 336	27.8 (10.9)

5. Secondary Outcome

Title	Maximum Observed Serum Concentration(Cmax) Derived on Day 1, 168 and 308
Description	Cmax is the observed maximum plasma concentration following administration (μg/mL).
Time Frame	Day 1, 168, 308 at pre-dose and 45 mins post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set - PK samples were only obtained and evaluated for subjects treated with BYM338

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	0
Day 1	283 (32.0)
Day 168	292 (45.3)
Day 308	271 (31.1)

6. Secondary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax) Derived on Day 168 and 308
Description	Tmax is the time to reach peak or maximum concentration (h) after the drug administration.
Time Frame	Day 1, 168, 308 at pre-dose and 45 mins post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set - PK samples were only obtained and evaluated for subjects treated with BYM338

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	0
Day 1	0.750
Day 168	0.750
Day 308	0.750

7. Secondary Outcome

Title	Change From Baseline in Body Mass Index (BMI)
Description	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)
Time Frame	Baseline, Week 24, Week 48

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 24	-1.50	-0.17
week 48	-2.19	-0.28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.33
	Confidence Interval	(2-Sided) 80%; -1.71 to -0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.91
	Confidence Interval	(2-Sided) 80%; -2.48 to -1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Weight
Description	Body weight was measured to the nearest 0.1 kilogram (kg) in indoor clothing without shoes. A negative change from baseline indicates improvement.
Time Frame	Baseline, Week 24, Week 48

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 24	-3.99	-0.57
week 48	-5.90	-0.79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.43
	Confidence Interval	(2-Sided) 80%; -4.54 to -2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.10
	Confidence Interval	(2-Sided) 80%; -6.74 to -3.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Lean Body Mass (LBM) Measured by DXA
Description	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.
Time Frame	Baseline, Week 24, Week 48

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 24	1.72	0.23
week 48	1.70	-0.44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 80%; 0.82 to 2.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.14
	Confidence Interval	(2-Sided) 80%; 1.36 to 2.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Waist Circumference
Description	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.
Time Frame	Baseline, Week 24, Week 52

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 24	-5.04	-0.95
week 52	-9.00	0.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.09
	Confidence Interval	(2-Sided) 80%; -5.26 to -2.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.46
	Confidence Interval	(2-Sided) 80%; -11.3 to -7.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in Waist to Hip Ratio
Description	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.
Time Frame	Baseline, Week 24, Week 52

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 24	-0.02	-0.01
week 52	-0.05	0.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 80%; -0.03 to -0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 52
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 80%; -0.08 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in Insulin Resistance (HOMA2-IR)
Description	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/].
Time Frame	Baseline. Week 12, Week 36

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	36	36
week 12	0.10	0.76
week 36	-0.09	0.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 80%; -1.03 to -0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BYM338 10 mg/kg, Placebo
	Comments	week 36
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.081
	Comments
	Method	Mixed-Effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.66
	Confidence Interval	(2-Sided) 80%; -1.14 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Immunogenicity Assessed by the Number of Participants Developing Anti-BYM338 Antibodies During the Trial
Description	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.
Time Frame	392 days

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	BYM338 10 mg/kg	Placebo
Arm/Group Description	intravenous infusion every four weeks	intravenous infusion every four weeks
Measure Participants	37	38
Confirmed with positive immunogenicity	2 5.4%	4 10.5%

Adverse Events

Time Frame	Adverse events were collected throughout the study for 56 weeks which includes the treatment period of 48 weeks and the follow-up period of 8 weeks.
Arm/Group Title	BYM338 10 mg/kg		Placebo
Arm/Group Description	intravenous infusion every four weeks		intravenous infusion every four weeks
All Cause Mortality
	BYM338 10 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/38 (0%)
Serious Adverse Events
	BYM338 10 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/37 (8.1%)		3/38 (7.9%)
Cardiac disorders
Acute coronary syndrome	0/37 (0%)		1/38 (2.6%)
Acute myocardial infarction	0/37 (0%)		1/38 (2.6%)
Gastrointestinal disorders
Abdominal pain upper	1/37 (2.7%)		0/38 (0%)
Impaired gastric emptying	0/37 (0%)		1/38 (2.6%)
Pancreatitis	1/37 (2.7%)		0/38 (0%)
Infections and infestations
Cellulitis	0/37 (0%)		1/38 (2.6%)
Pneumonia	1/37 (2.7%)		0/38 (0%)
Injury, poisoning and procedural complications
Thermal burn	0/37 (0%)		1/38 (2.6%)
Investigations
Lipase increased	1/37 (2.7%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	BYM338 10 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/37 (83.8%)		31/38 (81.6%)
Blood and lymphatic system disorders
Anaemia	3/37 (8.1%)		0/38 (0%)
Cardiac disorders
Bundle branch block right	0/37 (0%)		1/38 (2.6%)
Congenital, familial and genetic disorders
Type V hyperlipidaemia	1/37 (2.7%)		0/38 (0%)
Ear and labyrinth disorders
Vertigo positional	0/37 (0%)		1/38 (2.6%)
Endocrine disorders
Thyroid cyst	1/37 (2.7%)		0/38 (0%)
Thyroid mass	1/37 (2.7%)		0/38 (0%)
Eye disorders
Cataract	1/37 (2.7%)		0/38 (0%)
Diabetic retinopathy	1/37 (2.7%)		0/38 (0%)
Macular oedema	1/37 (2.7%)		0/38 (0%)
Gastrointestinal disorders
Abdominal pain	2/37 (5.4%)		1/38 (2.6%)
Abdominal pain upper	0/37 (0%)		2/38 (5.3%)
Diarrhoea	15/37 (40.5%)		4/38 (10.5%)
Dyspepsia	1/37 (2.7%)		0/38 (0%)
Frequent bowel movements	1/37 (2.7%)		0/38 (0%)
Nausea	4/37 (10.8%)		0/38 (0%)
Tooth impacted	1/37 (2.7%)		0/38 (0%)
Toothache	0/37 (0%)		2/38 (5.3%)
Vomiting	2/37 (5.4%)		1/38 (2.6%)
General disorders
Asthenia	0/37 (0%)		1/38 (2.6%)
Chest pain	1/37 (2.7%)		0/38 (0%)
Early satiety	1/37 (2.7%)		0/38 (0%)
Fatigue	1/37 (2.7%)		1/38 (2.6%)
Influenza like illness	0/37 (0%)		1/38 (2.6%)
Infusion site extravasation	0/37 (0%)		1/38 (2.6%)
Non-cardiac chest pain	0/37 (0%)		1/38 (2.6%)
Pain	1/37 (2.7%)		0/38 (0%)
Peripheral swelling	0/37 (0%)		1/38 (2.6%)
Hepatobiliary disorders
Cholelithiasis	1/37 (2.7%)		0/38 (0%)
Hepatic steatosis	0/37 (0%)		1/38 (2.6%)
Hepatomegaly	1/37 (2.7%)		0/38 (0%)
Immune system disorders
Allergy to arthropod bite	0/37 (0%)		1/38 (2.6%)
Food allergy	0/37 (0%)		1/38 (2.6%)
Infections and infestations
Bronchitis	1/37 (2.7%)		0/38 (0%)
Folliculitis	0/37 (0%)		1/38 (2.6%)
Gastroenteritis	0/37 (0%)		1/38 (2.6%)
Helicobacter infection	1/37 (2.7%)		0/38 (0%)
Hordeolum	1/37 (2.7%)		0/38 (0%)
Influenza	2/37 (5.4%)		0/38 (0%)
Pharyngitis	1/37 (2.7%)		0/38 (0%)
Pneumonia	0/37 (0%)		1/38 (2.6%)
Rhinitis	0/37 (0%)		2/38 (5.3%)
Sialoadenitis	1/37 (2.7%)		0/38 (0%)
Sinusitis	1/37 (2.7%)		1/38 (2.6%)
Tooth abscess	0/37 (0%)		1/38 (2.6%)
Tooth infection	0/37 (0%)		1/38 (2.6%)
Upper respiratory tract infection	6/37 (16.2%)		5/38 (13.2%)
Urinary tract infection	1/37 (2.7%)		0/38 (0%)
Urinary tract infection fungal	0/37 (0%)		1/38 (2.6%)
Viral infection	0/37 (0%)		1/38 (2.6%)
Viral upper respiratory tract infection	1/37 (2.7%)		0/38 (0%)
Injury, poisoning and procedural complications
Contusion	1/37 (2.7%)		0/38 (0%)
Craniocerebral injury	1/37 (2.7%)		0/38 (0%)
Ligament sprain	0/37 (0%)		1/38 (2.6%)
Rib fracture	0/37 (0%)		1/38 (2.6%)
Skin laceration	0/37 (0%)		2/38 (5.3%)
Investigations
Alanine aminotransferase increased	1/37 (2.7%)		0/38 (0%)
Amylase increased	2/37 (5.4%)		0/38 (0%)
Aspartate aminotransferase increased	1/37 (2.7%)		0/38 (0%)
Blood alkaline phosphatase increased	1/37 (2.7%)		0/38 (0%)
Blood creatine phosphokinase MB increased	0/37 (0%)		1/38 (2.6%)
Blood creatine phosphokinase increased	1/37 (2.7%)		1/38 (2.6%)
Blood creatinine increased	0/37 (0%)		1/38 (2.6%)
Gamma-glutamyltransferase increased	1/37 (2.7%)		0/38 (0%)
Lipase increased	4/37 (10.8%)		2/38 (5.3%)
Pancreatic enzymes increased	1/37 (2.7%)		0/38 (0%)
Weight decreased	0/37 (0%)		1/38 (2.6%)
Weight increased	1/37 (2.7%)		1/38 (2.6%)
Metabolism and nutrition disorders
Decreased appetite	2/37 (5.4%)		1/38 (2.6%)
Dehydration	1/37 (2.7%)		0/38 (0%)
Diabetes mellitus	1/37 (2.7%)		1/38 (2.6%)
Hyperglycaemia	1/37 (2.7%)		2/38 (5.3%)
Hypoglycaemia	0/37 (0%)		1/38 (2.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/37 (2.7%)		2/38 (5.3%)
Back pain	0/37 (0%)		1/38 (2.6%)
Coccydynia	0/37 (0%)		1/38 (2.6%)
Muscle fatigue	1/37 (2.7%)		0/38 (0%)
Muscle spasms	15/37 (40.5%)		1/38 (2.6%)
Muscle twitching	0/37 (0%)		1/38 (2.6%)
Musculoskeletal stiffness	1/37 (2.7%)		0/38 (0%)
Myalgia	0/37 (0%)		3/38 (7.9%)
Neck mass	1/37 (2.7%)		0/38 (0%)
Pain in extremity	0/37 (0%)		2/38 (5.3%)
Plantar fasciitis	1/37 (2.7%)		0/38 (0%)
Tendonitis	0/37 (0%)		1/38 (2.6%)
Nervous system disorders
Cognitive disorder	0/37 (0%)		1/38 (2.6%)
Dizziness	0/37 (0%)		2/38 (5.3%)
Dysgeusia	1/37 (2.7%)		0/38 (0%)
Headache	0/37 (0%)		5/38 (13.2%)
Paraesthesia	0/37 (0%)		1/38 (2.6%)
Sciatica	1/37 (2.7%)		0/38 (0%)
Syncope	2/37 (5.4%)		0/38 (0%)
Psychiatric disorders
Anxiety	0/37 (0%)		1/38 (2.6%)
Insomnia	0/37 (0%)		1/38 (2.6%)
Nervousness	0/37 (0%)		1/38 (2.6%)
Renal and urinary disorders
Acute kidney injury	1/37 (2.7%)		0/38 (0%)
Chromaturia	0/37 (0%)		1/38 (2.6%)
Dysuria	0/37 (0%)		1/38 (2.6%)
Nephrolithiasis	1/37 (2.7%)		0/38 (0%)
Proteinuria	1/37 (2.7%)		0/38 (0%)
Renal cyst	0/37 (0%)		1/38 (2.6%)
Reproductive system and breast disorders
Menorrhagia	1/37 (2.7%)		0/38 (0%)
Postmenopausal haemorrhage	1/37 (2.7%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/37 (0%)		2/38 (5.3%)
Dyspnoea exertional	0/37 (0%)		1/38 (2.6%)
Epistaxis	1/37 (2.7%)		0/38 (0%)
Sinus congestion	1/37 (2.7%)		0/38 (0%)
Skin and subcutaneous tissue disorders
Acne	1/37 (2.7%)		0/38 (0%)
Alopecia	0/37 (0%)		2/38 (5.3%)
Blister	1/37 (2.7%)		0/38 (0%)
Dermatitis	0/37 (0%)		1/38 (2.6%)
Ecchymosis	0/37 (0%)		1/38 (2.6%)
Rash	2/37 (5.4%)		2/38 (5.3%)
Skin ulcer	0/37 (0%)		1/38 (2.6%)
Vascular disorders
Aortic stenosis	0/37 (0%)		1/38 (2.6%)
Hypertension	3/37 (8.1%)		1/38 (2.6%)
Phlebitis	0/37 (0%)		1/38 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.