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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy Adult Normals
• Intervention / Treatment: Drug: BMS-933043; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution

• Study Type: Interventional
• Enrollment (Actual): 115
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10019
      • Clinilabs, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panel 1:BMS-933043(2mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 2:BMS-933043(5mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 3:BMS-933043(10mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 4:BMS-933043(25mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 5:BMS-933043(50mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 6:BMS-933043(100mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 7:BMS-933043(200mg)/Placebo+Antacid Buffer Solution; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 8:BMS-933043(25mg)/Placebo+Antacid Buffer Predose; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 9:BMS-933043(200mg)/Placebo+Antacid Buffer Predose; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: Panel 10:BMS-933043(350mg)/Placebo+Antacid Buffer Predose; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution
Experimental: CSF Panel:BMS-933043(MTD)/Placebo+Antacid Buffer Predose; 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; Drug: Placebo matching with BMS-933043; Drug: Antacid Buffer Predose Solution

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: May 23, 2012
• First Submitted That Met QC Criteria: May 24, 2012
• First Posted (Estimate): May 25, 2012

Study Record Updates

• Last Update Posted (Estimate): June 27, 2014
• Last Update Submitted That Met QC Criteria: June 26, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Antacids
• Other Study ID Numbers: CN171-002