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

Chronic Hepatitis C Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00546715
• Other study ID #: AI444-002
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 17, 2007
• Last updated: October 20, 2015
• Start date: November 2007
• Est. completion date: May 2008

Study information

• Verified date: October 2015
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: May 2008
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 49 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

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

Locations

Country	Name	City	State
United States	Advanced Clinical Research Institute	Anaheim	California
United States	Parexel International Corporation	Baltimore	Maryland
United States	University Of Virginia Digestive Health Center Of Excellence	Charlottesville	Virginia
United States	Bristol-Myers Squibb Clinical Pharmacology Unit	Hamilton	New Jersey
United States	Orlando Clinical Research Center	Orlando	Florida
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died	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.	Day 1 up to Day 7 for non-SAEs and Day 1 to 30 days after study discontinuation for SAEs	Yes
Primary	Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings	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.	Day 1 up to Day 7 or Discharge	Yes
Primary	Number of Participants With Marked Abnormalities in Laboratory Findings	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.	Day 1 up to Day 7	Yes
Secondary	Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24)	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.	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	No
Secondary	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	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 ?, where ? 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.	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	No
Secondary	Time to Reach Maximum Plasma Concentration (Tmax)	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.	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	No
Secondary	Plasma Half-life (T-half)	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.	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	No
Secondary	Apparent Total Body Clearance (CLT/F)	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.	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	No
Secondary	Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA)	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.	Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1	No
Secondary	Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline	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.	Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1	No
Secondary	Change From Baseline in Heart Rate to 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.	Baseline (Day 1), Day 7 or Discharge	Yes
Secondary	Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to 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.	Baseline (Day 1), Day 7 or Discharge	Yes
Secondary	Change From Baseline in Blood Pressure to 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.	Baseline (Day 1), Day 7 or Discharge	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm