Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-986120 in Healthy Subjects and the Effects of Co-Administration of Midazolam and BMS-986120

Randomized, Double-Blind, Placebo-Controlled Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Multiple Oral Doses of BMS-986120 in Healthy Subjects and the Effect of BMS-986120 on the Pharmacokinetics of Midazolam in Healthy Subjects

The purpose of this study is to assess the safety, tolerability and effect on Midazolam pharmacokinetics of multiple oral doses of BMS-986120 in healthy subjects.

Study Overview

• Status: Completed
• Conditions: Healthy Adult Volunteers
• Intervention / Treatment: Drug: Placebo; Drug: Midazolam; Drug: BMS-986120

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744
      • PPD Development, LP

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

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

1. Healthy male and female subjects as determined by no clinically significant deviation from normal in medical history, physical examination, ECGs, and clinical laboratory determinations
2. Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive. BMI=Weight (kg)/[Height(m)]2
3. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and men, ages 18 to 75, inclusive

Exclusion Criteria:

1. Concurrent, or use within 2-weeks of study drug administration, of marketed or investigational, non-steroidal anti-inflammatory compounds (NSAIDS), aspirin or other antiplatelet agents, oral or parenteral anticoagulants

2. Subjects at screening or prior to first dose with the following abnormal laboratory values upon repeat testing are excluded:

   • i) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >upper limit of normal (ULN)
   • ii) Total bilirubin >ULN, thyroid-stimulating hormone (TSH) >1.5 x ULN with T4 within normal limits (Subjects with mild unconjugated hyperbilirubinemia due to Gilbert's syndrome are excluded)
   • iii) CK >3 x ULN (unless exercise related and CK-MB within normal limits)
   • iv) Activated partial thromboplastin (aPTT) or Prothrombin Time (PT)/International Normalized Ratio (INR) >ULN
   • v) Blood urea nitrogen (BUN) or creatinine (Cr) >ULN
3. Hemoglobin or hematocrit or platelet count <lower limit of normal (LLN)
4. Bleeding time exceeding 8 minutes at pre-dose on Day -1
5. Subjects with micro- or macro-hematuria and/or fecal occult blood detected during screening, baseline or documented during other recent medical assessment, unless deemed not clinically significant by the Investigator and Medical Monitor
6. Any significant acute or chronic medical illness
7. Current or recent (within 3 months of study drug administration) gastrointestinal disease
8. Any major surgery within 12 weeks of study drug administration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panel 1: BMS-986120 or Placebo; BMS-986120 or Placebo multiple dose by mouth as specified	Drug: Placebo; Drug: BMS-986120
Experimental: Panel 2: BMS-986120 or Placebo; BMS-986120 or Placebo multiple dose by mouth as specified	Drug: Placebo; Drug: BMS-986120
Experimental: Panel 3: BMS-986120 or Placebo + Midazolam; BMS-986120 or Placebo (multiple dose) + Midazolam (single dose) by mouth as specified	Drug: Placebo; Drug: Midazolam; Drug: BMS-986120
Experimental: Panel 4: BMS-986120 or Placebo; BMS-986120 or Placebo multiple dose by mouth as specified	Drug: Placebo; Drug: BMS-986120

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability measured by number of subjects experience serious adverse events, deaths, adverse events leading to discontinuation, and potential clinically significant changes in electrocardiogram (ECG) parameters	Up to 168 days
Safety and tolerability measured by percent of subjects experience serious adverse events, deaths, adverse events leading to discontinuation, and potential clinically significant changes in electrocardiogram (ECG) parameters	Up to 168 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum observed plasma concentration (Cmax) of BMS-986120, BMT-141464, Midazolam, and 1'hydroxymidazolam	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Time of maximum observed plasma concentration (Tmax) of BMS-986120, BMT-141464, Midazolam, and 1'hydroxymidazolam	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Area under the concentration-time curve from time zero to 24h [AUC(TAU)] of BMS-986120 and BMT-141464	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Concentration at the end of the dosing Interval (Ctau) of BMS-986120 and BMT-141464	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Half-life (T-HALF) of BMS-986120 and BMT-141464	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Apparent total body clearance (CLT/F) of BMS-986120, Midazolam, and 1'hydroxymidazolam	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
AUC accumulation index (AI_AUC) of BMS-986120 and BMT-141464	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Effective elimination half-life that explains the degree of AUC accumulation observed (T-HALFeff_AUC) of BMS-986120	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR_AUC(TAU)] of BMT-141464	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight (MR_Cmax) of BMT-141464	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-T)] of Midazolam and 1'hydroxymidazolam	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of Midazolam and 1'hydroxymidazolam	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular weight [MR_AUC(INF)] of 1'hydroxymidazolam	Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
Change from baseline in protease-activated receptor-4 - agonist peptide (PAR4-AP) induced platelet aggregation of BMS-986120	Part A (Days 1-3) & Part B/C (Days 1-19)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Merali S, Wang Z, Frost C, Callejo M, Hedrick M, Hui L, Meadows Shropshire S, Xu K, Bouvier M, DeSouza MM, Yang J. New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans. Platelets. 2022 Oct 3;33(7):969-978. doi: 10.1080/09537104.2022.2088719. Epub 2022 Jun 26.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: August 4, 2014
• First Submitted That Met QC Criteria: August 4, 2014
• First Posted (Estimate): August 5, 2014

Study Record Updates

• Last Update Posted (Estimate): July 7, 2015
• Last Update Submitted That Met QC Criteria: July 3, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Platelet Aggregation Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; BMS-986120
• Other Study ID Numbers: CV004-006