Clinical trial NCT02208882: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Adult Volunteers
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2014-08-05
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Up to 168 days
measure: 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
timeFrame: Up to 168 days
Secondary outcomes:
measure: Maximum observed plasma concentration (Cmax) of BMS-986120, BMT-141464, Midazolam, and 1'hydroxymidazolam
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Time of maximum observed plasma concentration (Tmax) of BMS-986120, BMT-141464, Midazolam, and 1'hydroxymidazolam
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Area under the concentration-time curve from time zero to 24h [AUC(TAU)] of BMS-986120 and BMT-141464
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Concentration at the end of the dosing Interval (Ctau) of BMS-986120 and BMT-141464
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Half-life (T-HALF) of BMS-986120 and BMT-141464
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Apparent total body clearance (CLT/F) of BMS-986120, Midazolam, and 1'hydroxymidazolam
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: AUC accumulation index (AI_AUC) of BMS-986120 and BMT-141464
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Effective elimination half-life that explains the degree of AUC accumulation observed (T-HALFeff_AUC) of BMS-986120
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR_AUC(TAU)] of BMT-141464
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight (MR_Cmax) of BMT-141464
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: 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
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of Midazolam and 1'hydroxymidazolam
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular weight [MR_AUC(INF)] of 1'hydroxymidazolam
timeFrame: Part A (Days 1-8), Part B/C (Days 1-19), & Part D (Days 1-22)
measure: Change from baseline in protease-activated receptor-4 - agonist peptide (PAR4-AP) induced platelet aggregation of BMS-986120
timeFrame: Part A (Days 1-3) & Part B/C (Days 1-19)
Other outcomes:
Locations:
city: Austin
country: United States
facility: Ppd Development, Lp
state: Texas
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.