A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-986104 in Healthy Male Subjects

Study Overview
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Brief Summary
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The primary objective in this study is to assess if single doses of BMS-986104 that are safe, tolerable, and result in sufficient lymphopenia (50% to 70% reduction in absolute lymphocyte count) can be achieved without bradycardia or other adverse events in healthy male subjects.

Official Title
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A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-986104 in Healthy Male Subjects

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: BMS-986104
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: Healthy male subjects as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory evaluations will be eligible to participate in the study Men ages 18 to 49 years, inclusive Exclusion Criteria: Any acute or chronic medical illness judged to be clinically-significant by the Investigator and/or Sponsor medical monitor Presence of fecal occult blood at screening History of prolonged occupational exposure to organic solvents or pesticides History of vitamin B12 deficiency and/or achlorhydria; or a vitamin B12 level at screening <lower limit of normal (LLN), confirmed by repeat test History of Guillain-Barré Syndrome Past or current history of central or peripheral neuropathies, or past or current symptoms of sustained or recurrent paresthesias (tingling), numbness, or neuropathic pain (burning, aching or stabbing) in any extremities. Note: Experiencing an extremity falling asleep occasionally is not be exclusionary Clinically significant abnormality in the neurological exam at baseline (predose) Clinically significant nerve electrophysiology abnormalities at baseline (predose) Any history of testicular or epididymal disease/disorder Clinically significant abnormality on ophthalmologic exam or any findings suggesting an increased risk of macular edema at baseline (predose) History of hypothyroidism or carpal tunnel syndrome Subjects with history of diabetes mellitus Subjects with history of any type of heart disease, including ischemia, infarction, arrhythmias, hypertension, atrioventricular block of any degree, bradycardia, syncope, clinically significant ECG abnormalities, or any congenital heart disease Subjects with any acute or chronic bacterial, fungal or viral infection within the last 3 months prior to screening, as well as any febrile illness of unknown origin within 14 days of screening Subjects who have received any live vaccines within 1 month of study drug administration or who plan to have a live vaccine at any time during the study Positive test for tuberculosis at screening (QuantiFERON® GOLD)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel 1: BMS-986104 or Placebo<br>BMS-986104 or Placebo single dose by mouth as specified | Drug: BMS-986104<br> <br> Drug: Placebo<br> <br> |
| Experimental: Panel 2: BMS-986104 or Placebo<br>BMS-986104 or Placebo single dose by mouth as specified | Drug: BMS-986104<br> <br> Drug: Placebo<br> <br> |
| Experimental: Panel 3: BMS-986104 or Placebo<br>BMS-986104 or Placebo single dose by mouth as specified | Drug: BMS-986104<br> <br> Drug: Placebo<br> <br> |
| Experimental: Panel 4: BMS-986104 or Placebo<br>BMS-986104 or Placebo single dose by mouth as specified | Drug: BMS-986104<br> <br> Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of all adverse events (AEs) / serious adverse events (SAEs) |  | Up to 1 month post discharge | 
| Mean difference in ECG heart rate (HR) nadir values |  | Up to 4 days postdose | 
| Nadir absolute lymphocyte count (ALC) defined as the lowest ALC measured at any time after the dose |  | Up to 4 days postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability based on severity, investigator causality assessment and outcomes of all AEs (regardless of seriousness criteria), association between AEs and study drug exposure parameters, and physical examination |  | Up to 1 month post discharge | 
| Mean difference in ECG HR values in BMS-986104-treated versus placebo-treated healthy male subjects, identifying nadir ECG HR |  | Day -1 up to 24h and Days 1-5 | 
| Percent reduction in ECG HR |  | Day -1 up to 24h and Days 1-5 | 
| Time to nadir ECG HR |  | Day -1 up to 24h and Days 1-5 | 
| Maximum observed blood concentration (Cmax) of BMS-986104 |  | Up to Day 56 | 
| Time of maximum observed blood concentration (Tmax) of BMS-986104 |  | Up to Day 56 | 
| Terminal half-life (T-HALF) of BMS-986104 |  | Up to Day 56 | 
| Area under the blood concentration-time curve from time zero to time of last quantifiable concentration [AUC(0-T)] of BMS-986104 |  | Up to Day 56 | 
| Area under the blood concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of BMS-986104 |  | Up to Day 56 | 
| Apparent total clearance (CLT/F) of BMS-986104 |  | Up to Day 56 | 
| Apparent volume of distribution of terminal phase (Vz/F) of BMS-986104 |  | Up to Day 56 | 
| Metabolite to parent AUC(INF) ratio [MR_AUC(INF)] for both BMS-986104 and BMT-019434 |  | Up to Day 56 | 
| Effects of single oral doses of BMS-986104 on the following ALC | Time to nadir ALC from time 0h (predose) Percent reduction in ALC from baseline to nadir | Up to 4 days postdose |