Healthy Adult Normals
Conditions
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
Interventions
DRUGBMS-933043
DRUGPlacebo matching with BMS-933043
DRUGAntacid Buffer Predose Solution
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to Day 26 of Follow-up | AEs = Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of maximum observed plasma concentration (Tmax) | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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)] | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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) | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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 | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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 | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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 | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data |
| Maximum observed plasma concentration (Cmax) | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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] | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | 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 | Day 8 | 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 | Baseline (Day -2), Day 1, Day 6 and Day 10 | 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 | 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 | — |
| Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR AUC(tau)] | Day 1, Day 3, Day 6, Day 9, Day 10, Day 11 and Day 12 | PK of BMS-933043, BMS-941651, BMS-972869 and BMS-610999 will be derived from plasma concentration versus time and urinary excretion data |
Countries
United States
Outcome results
None listed