Single Ascending Dose Safety Study of BMS-962476 in Healthy Subjects and Patients With Elevated Cholesterol on Statins

Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BMS-962476 in Healthy Subjects and in Patients With Hypercholesterolemia on Statin Therapy

To obtain safety and tolerability information in healthy subjects is administered as a single dose

Study Overview

• Status: Completed
• Conditions: Atherosclerosis
• Intervention / Treatment: Biological: BMS-962476; Biological: Placebo matching with BMS-962476

Detailed Description

• Study Classification: Pharmacokinetics and Pharmacodynamics
• Intervention Model: Single Ascending Dose (SAD) study
• Allocation: Randomized Non-Stratified

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Metabolic And Atherosclerosis Research Center/ Medpace Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy population

  • Untreated low density lipoprotein cholesterol (LDL-c) ≥ 130 and ≤ 190 mg/dL and triglycerides ≤ 200 mg/dL
  • Body Mass Index (BMI) of 18 to 35 kg/m2 inclusive
  • Men and women, ages 18 to 65 years, inclusive

• Statin population

  • Patients with hypercholesterolemia on stable statin therapy for 6 weeks prior to enrollment
  • At enrollment, LDL-c ≥ 100mg/dL and triglycerides ≤ 200 mg/dL
  • Patients with controlled hypertension on a stable dose of no more than two antihypertensive drugs
  • BMI of 18 to 37 kg/m2 inclusive
  • Men and women, ages 18 to 75 years inclusive

Exclusion Criteria:

• Healthy Population

  • Subjects with fasting LDL-c < 130 or > 190 mg/dL, or fasting triglycerides > 200 mg/dL
  • Subjects at increased 10-year cardiovascular risk of ≥ 20% based on Framingham risk score
  • Subjects with any significant acute or chronic medical illness at the time of screening, including history of cancer, known history of sickle cell disease or trait, and known history of thalassemia

• Statin population

  • Patients with fasting LDL-c < 100mg/dL, or fasting triglycerides > 200 mg/dL on statin therapy
  • Patients on prescription or over the counter lipid-lowering therapy other than statin therapy
  • Patients with established atherosclerotic vascular disease
  • Patients with diabetes who are requiring oral or injectable anti-diabetic drug therapy
  • Patients with uncontrolled hypertension or controlled hypertension requiring more than two antihypertensive drugs
  • Patients with any significant acute or chronic medical illness that is severe, progressive or uncontrolled at the time of screening
• Use of any lipid lowering medication including over the counter products (eg, niacin > 500 mg; omega-3 fatty acids > 1000 mg; red rice yeast; phytosterols or stanol esters) for lipid lowering within 30 days prior to screening visit (42 days for fibrates) with the exception of stable statin therapy in the target disease population
• Prior treatment with any monoclonal antibody or investigational protein biologic within the preceding one year before study drug administration
• Concurrent or use within 3 months of study drug administration of marketed or investigational systemic or inhaled corticosteroids or other immunosuppressant drugs, and within 6 weeks for topical corticosteroids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panel 1: BMS-962476 SC (0.01 mg/Kg) or Placebo; BMS-962476 0.01 mg/kg or Placebo matching with BMS-962476 0 mg liquid subcutaneously (SC), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 2: BMS-962476 SC (0.03 mg/Kg) or Placebo; BMS-962476 0.03 mg/kg or Placebo matching with BMS-962476 0 mg liquid subcutaneously (SC), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 3: BMS-962476 SC (0.1 mg/Kg) or Placebo; BMS-962476 0.1 mg/kg or Placebo matching with BMS-962476 0 mg liquid subcutaneously (SC), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 4: BMS-962476 SC (0.3 mg/Kg) or Placebo; BMS-962476 0.3 mg/kg or Placebo matching with BMS-962476 0 mg liquid subcutaneously (SC), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 5: BMS-962476 IV (0.3 mg/Kg) or Placebo; BMS-962476 0.3 mg/kg or Placebo matching with BMS-962476 0 mg liquid intravenously (IV), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 6: BMS-962476 IV (1.0 mg/Kg) or Placebo; BMS-962476 1.0 mg/kg or Placebo matching with BMS-962476 0 mg liquid intravenously (IV), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 7: Statin + BMS-962476 SC (0.1 mg/Kg) or Placebo; BMS-962476 0.1 mg/kg or Placebo matching with BMS-962476 0 mg liquid subcutaneously (SC), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476
Experimental: Panel 8: Statin + BMS-962476 SC (0.3 mg/Kg) or Placebo; BMS-962476 0.3 mg/kg or Placebo matching with BMS-962476 0 mg liquid subcutaneously (SC), Single Dose, 1 day	Biological: BMS-962476; Biological: Placebo matching with BMS-962476

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of BMS-962476 as measured by the number of subjects with serious adverse events, deaths or discontinuations due to adverse events (AEs), AEs of injection site reactions, or potentially clinically significant changes in vital signs	Up to Day 43

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic effects of single subcutaneous (SC) and intravenous (IV) doses of BMS-962476	Pharmacodynamic effects will be measured by fasting lipid panel	Up to Day 43
Maximum observed plasma concentration (Cmax) of single dose pharmacokinetics (PK) and dose proportionality of BMS-962476 following SC and IV administration		17 time points up to Day 43
Time of maximum observed plasma concentration (Tmax) of single dose pharmacokinetics (PK) and dose proportionality of BMS-962476 following SC and IV administration		17 time points up to Day 43
Area under the plasma concentration-time curve from time zero to the time of last quantifiable plasma concentration [AUC(0-T)] of single dose pharmacokinetics (PK) and dose proportionality of BMS-962476 following SC and IV administration		17 time points up to Day 43
Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of single dose pharmacokinetics (PK) and dose proportionality of BMS-962476 following SC and IV administration		17 time points up to Day 43
Plasma elimination half-life (T-HALF) of single dose pharmacokinetics (PK) and dose proportionality of BMS-962476 following SC and IV administration		17 time points up to Day 43
Total body clearance (CL/F) of BMS-962476 SC Dosing		15 time points up to Day 43
Total body clearance (CL) of BMS-962476 IV Dosing		17 time points up to Day 43
Volume of distribution at steady state (Vss/F) of BMS-962476 SC Dosing		15 time points up to Day 43
Volume of distribution at steady state (Vss) of BMS-962476 IV Dosing		15 time points up to Day 43
Absolute bioavailability (F) of total and free BMS-962476		15 time points up to Day 43
Frequency of anti-BMS-962476 antibodies (immunogenicity) following single SC and IV doses of BMS-962476		Up to Day 43

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: April 26, 2012
• First Submitted That Met QC Criteria: April 27, 2012
• First Posted (Estimate): April 30, 2012

Study Record Updates

• Last Update Posted (Estimate): September 4, 2013
• Last Update Submitted That Met QC Criteria: September 2, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: CV206-001