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

Study Overview
=================
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.

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

Conditions
-----------------
Healthy Adult Volunteers

Intervention / Treatment
-----------------
* Drug: BMS-986120
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Healthy male and female subjects as determined by no clinically significant deviation from normal in medical history, physical examination, ECGs, and clinical laboratory determinations Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive. BMI=Weight (kg)/[Height(m)]2 Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and men, ages 18 to 75, inclusive Exclusion Criteria: 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 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 Hemoglobin or hematocrit or platelet count <lower limit of normal (LLN) Bleeding time exceeding 8 minutes at pre-dose on Day -1 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 Any significant acute or chronic medical illness Current or recent (within 3 months of study drug administration) gastrointestinal disease Any major surgery within 12 weeks of study drug administration

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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) |