Multiple Ascending-Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-933043 in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
Includes a placebo-controlled sequential, ascending multiple-dose panels (10 panels, 8 ascending doses, and 2 fixed Japanese Panels exploring safety, tolerability, and Pharmacokinetic (PK) measures

Official Title
-----------------
Placebo-Controlled, Multiple Ascending-Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-933043

Conditions
-----------------
Healthy Adult Normals

Intervention / Treatment
-----------------
* Drug: BMS-933043
* Drug: Placebo matching with BMS-933043
* Drug: Antacid Buffer Predose Solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy subjects as determined by no clinically significant deviation from normal medical history, physical examination, ECGs and clinical laboratory determinations Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive. BMI = weight (kg)/ [height (m)]2 Normal Neurological Exam (LP subjects only: to rule out focal CNS lesions that would render LP unsafe) Men and women, ages 18 to 55 years, inclusive. Women who are not of childbearing potential (WOCBP) [ie, who are postmenopausal or surgically sterile] and men Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product. Women must not be breastfeeding Sexually active fertile men must use effective birth control if their partners are WOCBP throughout the study and for 90 days after last dose Exclusion Criteria: Any significant acute or chronic medical illness Current or recent (within 3 months of study drug administration) gastrointestinal disease Any major surgery within 4 weeks of study drug administration Any gastrointestinal surgery that could impact upon the absorption of study drug Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within 4 weeks of study drug administration Blood transfusion within 4 weeks of study drug administration Inability to tolerate oral medication Inability to be venipunctured and/or tolerate venous access Smoking more than 1 cigarette/cigar per week, within 3 months prior to screening Regular daily use of nicotine products or Varenicline (Chantix® or Champix®) within 3 months prior to screening Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders (4th Edition) [DSM IV], Diagnostic Criteria for Drug and Alcohol Abuse History of cardiac arrhythmias, or palpitations associated with presyncope or syncope or history of unexplained syncope

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel 1:BMS-933043(2mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 2 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 2:BMS-933043(5mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 5 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 3:BMS-933043(10mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 10 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 4:BMS-933043(25mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 25 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 5:BMS-933043(50mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 50 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days CSF sampling required | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 6:BMS-933043(100mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 100 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 7:BMS-933043(200mg)/Placebo+Antacid Buffer Solution<br>BMS-933043 200 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 8:BMS-933043(25mg)/Placebo+Antacid Buffer Predose<br>MAD Phase: Japanese Subjects. Cerebrospinal fluid (CSF) sampling not required BMS-933043 25 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 9:BMS-933043(200mg)/Placebo+Antacid Buffer Predose<br>Japanese Subjects. CSF sampling not required. BMS-933043 200 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: Panel 10:BMS-933043(350mg)/Placebo+Antacid Buffer Predose<br>BMS-933043 350 mg solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |
| Experimental: CSF Panel:BMS-933043(MTD)/Placebo+Antacid Buffer Predose<br>If Panel 5 does not run. CSF Sampling at steady state BMS-933043 maximum tolerated dose (MTD), solution by mouth twice daily for 10 days OR Placebo matching with BMS-933043 0 mg solution by mouth twice daily for 10 days Antacid Buffer Predose 150 mL solution by mouth twice daily for 10 days | Drug: BMS-933043<br> <br> Drug: Placebo matching with BMS-933043<br> <br> Drug: Antacid Buffer Predose Solution<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of multiple oral doses of BMS-933043 in healthy subjects measured by AEs, Vital signs, clinical laboratory test results, physical examination findings, neurological examination findings and electrocardiogram (ECG) parameters | AEs = Adverse Events | Up to Day 26 of Follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Time of maximum observed plasma concentration (Tmax) | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Area under the concentration-time curve in one dosing interval [AUC(TAU)] | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Plasma half-life (T-HALF) | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Trough observed plasma concentration (Cmin) between dose interval | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Volume of distribution at steady-state (VSS/F) of BMS-933043 | PK of BMS-933043 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Accumulation index (AI): ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR AUC(tau)] | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight [MR Cmax] | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 
| CSF penetration of BMS-933043 | Cerebral Spinal Fluid (CSF) will be analyzed for drug levels to confirm adequate central nervous system (CNS) penetration (>2 nM is required) and to estimate the brain/plasma ratio in humans | Day 8 | 
| Effect of BMS-933043 on ECG intervals and to explore the relationship between plasma exposure and ECG intervals | The effects of BMS-933043 on ECG parameters (heart rate, QTcF, PR, and QRS) will be explored graphically and by summary statistics. Absolute levels, as well as changes from baseline, will be summarized and plotted versus time by treatment and day for each ECG parameter. Frequency distributions for subjects' maximum values will be provided by treatment. The relationships between ECG parameters and BMS-933043 concentrations may be explored using scatter plots and the relationship between the change from baseline in QTcF and the BMS-933043 concentration may be estimated | Baseline (Day -2), Day 1, Day 6 and Day 10 | 
| Safety and tolerability of multiple oral doses of BMS-9333043 in Japanese healthy subjects is measured by AEs, Vital signs, clinical laboratory test results, physical examination findings, neurological examination findings and ECG parameters |  | Up to 6 months | 
| Effect of ethnicity (Japanese versus non-Japanese) on PK of BMS-933043 will be assessed graphically and by point estimates and 90% confidence intervals for geometric mean ratio for Cmax using data from subjects receiving the same dose of BMS-933043 |  | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 |