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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01605994
First received: May 23, 2012
Last updated: June 26, 2014
Last verified: June 2014
  Purpose

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


Condition Intervention Phase
Healthy Adult Normals
Drug: BMS-933043
Drug: Placebo matching with BMS-933043
Drug: Antacid Buffer Predose Solution
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Placebo-Controlled, Multiple Ascending-Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-933043

Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • 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 [ Time Frame: Up to Day 26 of Follow-up ] [ Designated as safety issue: Yes ]
    AEs = Adverse Events


Secondary Outcome Measures:
  • Maximum observed plasma concentration (Cmax) [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Time of maximum observed plasma concentration (Tmax) [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Area under the concentration-time curve in one dosing interval [AUC(TAU)] [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Plasma half-life (T-HALF) [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Trough observed plasma concentration (Cmin) between dose interval [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Volume of distribution at steady-state (VSS/F) of BMS-933043 [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043 will be derived from plasma concentration versus time and urinary excretion data

  • Accumulation index (AI): ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR AUC(tau)] [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight [MR Cmax] [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
    PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data

  • CSF penetration of BMS-933043 [ Time Frame: Day 8 ] [ Designated as safety issue: No ]
    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

  • Effect of BMS-933043 on ECG intervals and to explore the relationship between plasma exposure and ECG intervals [ Time Frame: Baseline (Day -2), Day 1, Day 6 and Day 10 ] [ Designated as safety issue: No ]
    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

  • 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 [ Time Frame: Up to 6 months ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]

Enrollment: 115
Study Start Date: July 2012
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01605994

Locations
United States, New York
Clinilabs, Inc.
New York, New York, United States, 10019
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01605994     History of Changes
Other Study ID Numbers: CN171-002
Study First Received: May 23, 2012
Last Updated: June 26, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Antacids
Anti-Ulcer Agents
Pharmaceutical Solutions
Gastrointestinal Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014