A Single Ascending Dose Study of Daclatasvir (BMS-790052) in Hepatitis C Virus Infected Subjects
- Registration Number
- NCT00546715
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The primary purpose of this study is to evaluate the safety profile and tolerability of single oral doses of daclatasvir in subjects with chronic hepatitis C infection
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 95
- Chronically infected with hepatitis C virus genotype 1
- Treatment naive or treatment non-responders or treatment intolerant; and not co-infected with HIV or hepatitis B virus
- Hepatitis C virus RNA viral load of ≥ 10*5* IU/mL
- BMI 18 to 35 kg/m²
Key
- Any significant acute or chronic medical illness which is not stable or is not controlled with medication and not consistent with hepatitis C virus infection
- Major surgery within 4 weeks of study drug administration and any gastrointestinal surgery that could impact the absorption of study drug
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose Panel B Daclatasvir Daclatasvir - 10 mg Placebo - 0 mg Dose Panel D Placebo Daclatasvir - 0.5 - 200 mg (to be determined) Placebo - 0 mg Dose Panel B Placebo Daclatasvir - 10 mg Placebo - 0 mg Dose Panel C Placebo Daclatasvir - 100 mg Placebo - 0 mg Dose Panel C Daclatasvir Daclatasvir - 100 mg Placebo - 0 mg Dose Panel A Placebo Daclatasvir - 1 mg Placebo - 0 mg Dose Panel D Daclatasvir Daclatasvir - 0.5 - 200 mg (to be determined) Placebo - 0 mg Dose Panel A Daclatasvir Daclatasvir - 1 mg Placebo - 0 mg
- Primary Outcome Measures
Name Time Method Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died Day 1 up to Day 7 for non-SAEs and Day 1 to 30 days after study discontinuation for SAEs AEs were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding) or disease which either occurs during study, whether or not related to the study drug. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings Day 1 up to Day 7 or Discharge Participants were assessed by investigator for any clinically significant changes in vital parameters like body temperature, respiratory rate, blood pressure, heart rate and weight. The assessment was performed by a calibrated sphygmomanometer and thermometer for blood pressure and temperature, respectively. Blood pressure and heart rate were measured after at least 5 minutes quiet seating of the subject. Weight was measured at the discharge. The criteria for clinically significant change was as per the investigators discretion.
Number of Participants With Marked Abnormalities in Laboratory Findings Day 1 up to Day 7 Laboratory marked abnormalities were defined as Hematocrit (low) as \<0.85\*pre-treatment value, Leukocytes (low) as \<0.9\*lower limit of normal, Aspartate Aminotransferase (high) as \>1.25\*upper limit of normal, Creatinine (high) as \>1.33\*pre-treatment value, Bicarbonate (high) as \>1.2\*upper limit of normal, Total Protein (high) as \>1.1\*upper limit of normal, Creatinine Kinase (high) as \>1.5\*upper limit of normal, Blood in Urine (high) as ≥ 2\*upper limit of normal. Participants were fasted for at least 10 hours prior to the collection of blood specimens for clinical laboratory tests.
- Secondary Outcome Measures
Name Time Method Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and 72 hours post-dosing on Day 1 Maximum observed plasma concentration following drug administration from the raw plasma concentration-time data. C-12 and C-24 were defined as observed plasma concentration of daclatasvir at 12 hours and 24 hours, respectively. The plasma samples were analyzed for daclatasvir using a validated liquid chromatography-tandem mass spectrometric assay.
Time to Reach Maximum Plasma Concentration (Tmax) Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and 72 hours post-dosing on Day 1 Tmax was defined as the time required to reach maximum observed plasma concentration. The plasma samples were analyzed for daclatasvir using a validated liquid chromatography-tandem mass spectrometric assay.
Plasma Half-life (T-half) Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and 72 hours post-dosing on Day 1 Plasma half-life was defined as the time required for one half of the total amount of administered drug eliminated from the body. The plasma samples were analyzed for daclatasvir using a validated liquid chromatography-tandem mass spectrometric assay.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-T]), Area Under the Plasma Concentration-time Curve From Time Zero (AUC[INF]) Extrapolated to Infinite Time Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and 72 hours post-dosing on Day 1 Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. It was calculated as the sum of linear trapezoids using non-compartmental analysis. Area under the plasma concentration-time curve from time zero extrapolated to infinite time was estimated as sum of AUC(0-T) and the extrapolated area, computed by the quotient of the last observable concentration and λ, where λ was the slopes of the terminal phases of the plasma concentration-time profiles. The plasma samples were analyzed for daclatasvir using a validated liquid chromatography-tandem mass spectrometric assay.
Change From Baseline in Heart Rate to Day 7 or Discharge Baseline (Day 1), Day 7 or Discharge Changes in heart rate from baseline were measured after the participants were supine for at least 5 minutes. Baseline was defined as the Day 1 pre-dose measurement. The normal heart rate lies between 60-90 beats per minute (bpm), below 60 bpm and above 90 bpm were considered as bradycardia and tachycardia, respectively.
Apparent Total Body Clearance (CLT/F) Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and 72 hours post-dosing on Day 1 Apparent total body clearance (CLT/F) was calculated as Dose/AUC(INF), where CLT was the clearance of the drug and F was the absolute oral bioavailability. The plasma samples were analyzed for daclatasvir using a validated liquid chromatography-tandem mass spectrometric assay.
Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1 The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Positive value indicated reduction from baseline in HCV RNA while negative value indicated an increase from baseline in HCV RNA. Baseline HCV RNA was defined as the pre-dose value on Day 1 log10 HCV RNA.
Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1 Participants were assessed for time to reach maximum decrease in log10 hepatitis C virus RNA level. Baseline HCV RNA was defined as the pre-dose value on Day 1 log10 HCV RNA.
Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge Baseline (Day 1), Day 7 or Discharge The ECG was recorded after the participant was in a supine position for at least 5 minutes. Baseline was defined as the Day 1 pre-dose measurement. The PR interval was defined as the beginning of the P wave to the beginning of the QRS complex, and represents the time taken by electrical impulse to travel from the sinus node through the atrioventricular (AV) node. The QRS complex represented the rapid depolarization of the right and left ventricles. The QT interval was defined as the time from the start of the Q wave to the end of the T wave, and represents the time taken for ventricular depolarization and repolarization. QTc was defined as corrected QT interval at a heart rate of 60 bpm. QTc was estimated using Bazett's formula and Fredericia's formula.
Change From Baseline in Blood Pressure to Day 7 or Discharge Baseline (Day 1), Day 7 or Discharge Changes in blood pressure from baseline were measured after the participants were supine for at least 5 minutes. Baseline was defined as the Day 1 pre-dose measurement.
Trial Locations
- Locations (7)
Bristol-Myers Squibb Clinical Pharmacology Unit
🇺🇸Hamilton, New Jersey, United States
Advanced Clinical Research Institute
🇺🇸Anaheim, California, United States
University Of Virginia Digestive Health Center Of Excellence
🇺🇸Charlottesville, Virginia, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Parexel International Corporation
🇺🇸Baltimore, Maryland, United States
Orlando Clinical Research Center
🇺🇸Orlando, Florida, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States