Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

A Single Ascending Dose Study of Daclatasvir (BMS-790052) in Hepatitis C Virus Infected Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00546715
First received: October 17, 2007
Last updated: October 20, 2015
Last verified: October 2015
  Purpose
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

Condition Intervention Phase
Chronic Hepatitis C
Drug: Daclatasvir
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Placebo-Controlled Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of BMS-790052 in Subjects Chronically Infected With Hepatitis C Virus Genotype 1

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died [ Time Frame: Day 1 up to Day 7 for non-SAEs and Day 1 to 30 days after study discontinuation for SAEs ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 up to Day 7 or Discharge ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 up to Day 7 ] [ Designated as safety issue: Yes ]
    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:
  • Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Time to Reach Maximum Plasma Concentration (Tmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Apparent Total Body Clearance (CLT/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1 ] [ Designated as safety issue: No ]
    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 Heart Rate to Day 7 or Discharge [ Time Frame: Baseline (Day 1), Day 7 or Discharge ] [ Designated as safety issue: Yes ]
    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.

  • Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge [ Time Frame: Baseline (Day 1), Day 7 or Discharge ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline (Day 1), Day 7 or Discharge ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 95
Study Start Date: November 2007
Study Completion Date: May 2008
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Dose Panel A

Daclatasvir - 1 mg

Placebo - 0 mg

Drug: Daclatasvir
Oral Solution, Oral, Single Dose
Drug: Placebo
Oral Solution, Oral, Single Dose
Active Comparator: Dose Panel B

Daclatasvir - 10 mg

Placebo - 0 mg

Drug: Daclatasvir
Oral Solution, Oral, Single Dose
Drug: Placebo
Oral Solution, Oral, Single Dose
Active Comparator: Dose Panel C

Daclatasvir - 100 mg

Placebo - 0 mg

Drug: Daclatasvir
Oral Solution, Oral, Single Dose
Drug: Placebo
Oral Solution, Oral, Single Dose
Active Comparator: Dose Panel D

Daclatasvir - 0.5 - 200 mg (to be determined)

Placebo - 0 mg

Drug: Daclatasvir
Oral Solution, Oral, Single Dose
Drug: Placebo
Oral Solution, Oral, Single Dose

  Eligibility

Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • 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 Exclusion Criteria:

  • 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
  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: NCT00546715

Locations
United States, California
Advanced Clinical Research Institute
Anaheim, California, United States, 92801
United States, Florida
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
United States, Maryland
Parexel International Corporation
Baltimore, Maryland, United States, 21225
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New Jersey
Bristol-Myers Squibb Clinical Pharmacology Unit
Hamilton, New Jersey, United States, 08690
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
United States, Virginia
University Of Virginia Digestive Health Center Of Excellence
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00546715     History of Changes
Other Study ID Numbers: AI444-002 
Study First Received: October 17, 2007
Results First Received: August 10, 2015
Last Updated: October 20, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections

ClinicalTrials.gov processed this record on September 28, 2016