Study to Investigate the Effect of BMS-986142 on the Pharmacokinetics (PK) of Methotrexate and Probe Substrate Cocktail in Healthy Patients

Effects of BMS-986142 on the Single-dose Pharmacokinetics of Methotrexate and Probe Substrates Montelukast (CYP2C8), Flurbiprofen (CYP2C9), Midazolam (CYP3A4), Digoxin (P-gp), and Pravastatin (OATP1B1) in Healthy Subjects

To study the Pharmacokinetics (PK) parameters of montelukast, flurbiprofen, midazolam, digoxin, pravastatin, and MTX when coadministered with BMS-986142.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Montelukast, Flurbiprofen, Midazolam, Digoxin, Pravastatin and BMS-986142; Drug: Methotrexate, Leucovorin and BMS-986142

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Groups 1 and 2:

1. Written informed consent from all subjects.
2. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive
3. Non-smokers.
4. Normal renal function at screening as evidenced by an estimated glomerular filtration rate (GFR) of > 90 mL/min/1.73 m2 .
5. Subject reenrollment.
6. Males who are sexually active with women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of BMS-986142.
7. Male subjects must be willing to refrain from sperm donation during the entire study plus 5 half-lives of BMS-986142.

Group 1 only:

1. Healthy male and female (not of childbearing potential) subjects as determined by medical history, and clinical assessments.
2. Women must have documented proof that they are not of childbearing potential and must not be breast feeding.

Group 2 only:

1. Healthy male subjects as determined by medical history, and clinical assessments.

Exclusion Criteria:

1. Administration of live vaccine including polio vaccine during the course of the study, 12 weeks prior to the first dose of study drug, or 30 days after the last dose of study drug.
2. Active tuberculosis (TB) requiring treatment within the previous 3 years.
3. History of herpes zoster.
4. Subjects who have experienced recent infection, upper respiratory infection,.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Montelukast, Flurbiprofen, Midazolam, Digoxin, Pravastatin and BMS-986142	Drug: Montelukast, Flurbiprofen, Midazolam, Digoxin, Pravastatin and BMS-986142; Montelukast 10-mg tablet: On Days 1 and 8,Single oral dose; Flurbiprofen 50-mg tablet: On Days 1 and 8,Single oral dose; Midazolam syrup 2.5 mL × 2 mg/mL (5 mg): On Days 1 and 8,Single oral dose; Digoxin (Lanoxin®) 0.25 mg tablet: On Days 1 and 8,Single oral dose; Pravastatin 40-mg tablet: On Days 1 and 8,Single oral dose; BMS-986142: On Days 6 through 12.
Experimental: Group 2; Methotrexate,Leucovorin and BMS-986142	Drug: Methotrexate, Leucovorin and BMS-986142; Methotrexate (MTX) single oral dose of 3 × 2.5-mg tablet (Days 1 and 8); Leucovorin single oral dose of 15-mg tablet (Days 2 and 9; 24 hours after MTX administration); BMS-986142 on Days 6 through 10.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum observed plasma concentration (Cmax)	Days 1 through 10
Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration, AUC(0-T)	Days 1 through 10
Area under the plasma concentration-time curve from time zero extrapolated to infinite time, AUC(INF)	Days 1 through 10

Secondary Outcome Measures

Outcome Measure	Time Frame
Time of maximum observed plasma concentration (Tmax)	Days 1 through 10
Terminal plasma half-life (T-half)	Days 1 through 10
Apparent total body clearance (parents only), CLT/F	Days 1 through 10
Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight	Days 1 through 10
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for molecular weight	Days 1 through 10
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular weight	Days 1 through 10
Trough observed plasma concentration (For BMS-986142 only)	Days 1 through 10

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Investigators: Principal Investigator: Thomas L Hunt, MD PhD, PPD

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: May 27, 2015
• First Submitted That Met QC Criteria: May 27, 2015
• First Posted (Estimate): May 29, 2015

Study Record Updates

• Last Update Posted (Estimate): February 1, 2016
• Last Update Submitted That Met QC Criteria: January 29, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Cardiotonic Agents; Dermatologic Agents; Micronutrients; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Digoxin; Midazolam; Montelukast; Leucovorin; Methotrexate; Pravastatin; Flurbiprofen
• Other Study ID Numbers: IM006-003