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

May 23, 2012
June 26, 2014
July 2012
December 2013   (final data collection date for primary outcome measure)
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
Safety and tolerability of multiple oral doses of BMS-9333043 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 6 months ] [ Designated as safety issue: Yes ]
AEs = adverse events
Complete list of historical versions of study NCT01605994 on ClinicalTrials.gov Archive Site
  • 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 ]
  • Effect of BMS-933043 on ECG intervals and to explore the relationship between plasma exposure and ECG intervals [ Time Frame: Baseline (Day - 1), 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
  • Maximum observed plasma concentration (Cmax) of BMS-933043 and metabolites will be derived from plasma concentration versus time and urinary excretion data [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Observed plasma concentration at 6 hours (C6) of BMS-933043 and metabolites will be derived from plasma concentration versus time [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Trough observed plasma concentration between dose interval (Cmin) of BMS-933043 and metabolites will be derived from plasma concentration versus time and urinary excretion data [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Time of maximum observed plasma concentration (Tmax) of BMS-933043 and metabolites will be derived from plasma concentration versus time and urinary excretion data [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-933043 and metabolites will be derived from plasma concentration versus time and urinary excretion data [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Plasma half-life (T-HALF) of BMS-933043 and metabolites will be derived from plasma concentration versus time and urinary excretion data [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Accumulation index (AI): ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose of BMS-933043 and metabolites [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Volume of distribution at steady-state (VSS) of BMS-933043 and metabolites will be derived from plasma concentration versus time and urinary excretion data [ Time Frame: Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 ] [ Designated as safety issue: No ]
  • Cerebral Spinal Fluid (CSF) penetration of BMS-933043 [ Time Frame: Day 10 ] [ Designated as safety issue: No ]
    CSF will be analyzed for drug levels to confirm adequate CNS penetration (> 2nM is required) and to estimate the brain/plasma ratio in humans
Not Provided
Not Provided
 
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

Not Provided
Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Healthy Adult Normals
  • Drug: BMS-933043
  • Drug: Placebo matching with BMS-933043
  • Drug: Antacid Buffer Predose Solution
  • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • 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

    Interventions:
    • Drug: BMS-933043
    • Drug: Placebo matching with BMS-933043
    • Drug: Antacid Buffer Predose Solution
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
115
December 2013
December 2013   (final data collection date for primary outcome measure)

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
Both
18 Years to 55 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01605994
CN171-002
No
Bristol-Myers Squibb
Bristol-Myers Squibb
Not Provided
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
Bristol-Myers Squibb
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP