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

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00546715
• Collaborator: (none)
• Enrollment: 95
• Locations: 7
• Arms: 4
• Duration (Months): 6
• Patients Per Site: 13.6
• Patients Per Site Per Month: 2.3

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis C	Drug: Daclatasvir; Drug: Placebo	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, 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
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 49 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 ≥ 105 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

Locations

	Site	City	State	Country	Postal Code
1	Advanced Clinical Research Institute	Anaheim	California	United States	92801
2	Orlando Clinical Research Center	Orlando	Florida	United States	32809
3	Parexel International Corporation	Baltimore	Maryland	United States	21225
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Bristol-Myers Squibb Clinical Pharmacology Unit	Hamilton	New Jersey	United States	08690
6	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
7	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00546715
• Other Study ID Numbers: AI444-002
• First Posted: Oct 19, 2007
• Last Update Posted: Nov 18, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis

Study Results

Participant Flow

Recruitment Details	The study was conducted at 7 centers in United States.
Pre-assignment Detail	A total of 95 participants were enrolled, of which 18 received treatment. Remaining 77 participants were not randomized (participants either no longer met study criteria by the time of randomization or were no longer needed as an adequate number of study participants had already been dosed in each dose panel).

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Period Title: Overall Study
STARTED	6	5	5	2
COMPLETED	6	4	5	2
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo	Total
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Total of all reporting groups
Overall Participants	6	5	5	2	18
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	43.5	46	44	28	44
Sex: Female, Male (Count of Participants)
Female	1 16.7%	3 60%	4 80%	0 0%	8 44.4%
Male	5 83.3%	2 40%	1 20%	2 100%	10 55.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died
Description	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.
Time Frame	Day 1 up to Day 7 for non-SAEs and Day 1 to 30 days after study discontinuation for SAEs

Outcome Measure Data

Analysis Population Description

Analysis was performed in safety population defined as all participants who received any study drug treatment.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5	2
SAEs	0 0%	0 0%	0 0%	0 0%
Discontinuations due to AEs	0 0%	0 0%	0 0%	0 0%
Death	0 0%	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings
Description	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.
Time Frame	Day 1 up to Day 7 or Discharge

Outcome Measure Data

Analysis Population Description

The analysis was performed in the safety population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5	2
Systolic blood pressure	0 0%	0 0%	0 0%	0 0%
Diastolic blood pressure	0 0%	0 0%	0 0%	0 0%
Pulse rate	0 0%	0 0%	0 0%	0 0%
Respiration rate	0 0%	0 0%	0 0%	0 0%
Temperature	0 0%	0 0%	0 0%	0 0%
Weight	0 0%	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Number of Participants With Marked Abnormalities in Laboratory Findings
Description	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.
Time Frame	Day 1 up to Day 7

Outcome Measure Data

Analysis Population Description

The analysis was performed in the safety population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5	2
Hematocrit (Low)	1 16.7%	0 0%	0 0%	0 0%
Leukocytes (Low)	0 0%	0 0%	1 20%	0 0%
Aspartate Aminotransferase (High)	1 16.7%	0 0%	0 0%	0 0%
Creatinine (High)	1 16.7%	1 20%	1 20%	1 50%
Bicarbonate (High)	0 0%	1 20%	0 0%	0 0%
Total Protein (High)	1 16.7%	0 0%	1 20%	0 0%
Creatinine Kinase (High)	1 16.7%	0 0%	0 0%	0 0%
Blood in Urine (High)	0 0%	0 0%	1 20%	0 0%

4. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24)
Description	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 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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the pharmacokinetic (PK) set population defined as all participants who received at least single dose of daclatasvir with available valid data.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5
Cmax	15.7 (56)	177.6 (52)	2416.5 (27)
C-12	2.7 (49)	32.2 (28)	706.7 (51)
C-24	1.1 (65)	14.2 (44)	363.2 (55)

5. Secondary Outcome

Title	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
Description	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 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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK set population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5
AUC(0-T)	126.8 (49)	1413.9 (45)	28239.1 (48)
AUC(0-INF)	129.1 (49)	1431.1 (45)	29256.1 (53)

6. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax)
Description	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.
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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK set population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5
Median (Full Range) [hours]	1	1	1.5

7. Secondary Outcome

Title	Plasma Half-life (T-half)
Description	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.
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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK set population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5
Mean (Standard Deviation) [hours]	9.7 (2.65)	12.1 (1.97)	14.0 (6.43)

8. Secondary Outcome

Title	Apparent Total Body Clearance (CLT/F)
Description	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.
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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK set population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5
Geometric Mean (Geometric Coefficient of Variation) [mL/min]	129.1 (48)	116.5 (43)	57.0 (49)

9. Secondary Outcome

Title	Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA)
Description	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 Frame	Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The analysis was performed in the pharmacodynamic (PD) population defined as participants who received at least one dose of study medication with available valid data.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	5	5	5	2
Decline From Baseline to 24 hours	2.12 (0.57)	3.24 (0.51)	3.28 (0.35)	-0.12 (0.29)
Maximum Decline	2.44 (0.80)	3.12 (0.66)	4.06 (0.53)	0.06 (0.11)

10. Secondary Outcome

Title	Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline
Description	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.
Time Frame	Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PD population defined as participants who received at least one dose of study medication with available valid data.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	5	5	5	2
Mean (Standard Deviation) [hours]	16.4 (7.8)	43.2 (56.74)	105.60 (55.25)	144 (0)

11. Secondary Outcome

Title	Change From Baseline in Heart Rate to Day 7 or Discharge
Description	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.
Time Frame	Baseline (Day 1), Day 7 or Discharge

Outcome Measure Data

Analysis Population Description

The analysis was performed in the safety population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5	2
Mean (Standard Deviation) [bpm]	7.3 (16.2)	7.6 (9.3)	1.6 (8.5)	14 (1.4)

12. Secondary Outcome

Title	Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge
Description	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.
Time Frame	Baseline (Day 1), Day 7 or Discharge

Outcome Measure Data

Analysis Population Description

The analysis was performed in the safety population.

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	6	5	5	2
QT Interval	-27.5 (32.7)	-18.6 (29.2)	-1.2 (27.8)	-36 (14.1)
QTc Fridericia Interval	-13.3 (10.5)	-5.6 (14.7)	0.4 (11.4)	-12.5 (19.1)
QTc Bazett Interval	-5.5 (21.0)	1.2 (12.7)	1.8 (7.2)	1 (21.2)
QRS Width	-2.3 (4.7)	1 (11.3)	-3.6 (8.2)	0 (0)
PR Interval	-6.7 (9.9)	2.4 (10.3)	-4.4 (11.2)	-7 (7.1)

13. Secondary Outcome

Title	Change From Baseline in Blood Pressure to Day 7 or Discharge
Description	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.
Time Frame	Baseline (Day 1), Day 7 or Discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daclatasvir-1 mg	Daclatasvir-10 mg	Daclatasvir-100 mg	Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.	Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
Measure Participants	5	4	3	1
Diastolic blood pressure	9.6 (7.3)	4.3 (5.9)	3.7 (12.7)	1 (NA)
Systolic blood pressure	14 (4.4)	1 (15.7)	6 (17.5)	-2 (NA)

Adverse Events

Time Frame	Day 1 up to Day 7 (for non-SAEs), Day 1 to 30 days after study discontinuation (for SAEs)
Adverse Event Reporting Description	On-treatment period
Arm/Group Title	Daclatasvir-1 mg		Daclatasvir-10 mg		Daclatasvir-100 mg		Placebo
Arm/Group Description	Participants received single dose of daclatasvir 1 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.		Participants received single dose of daclatasvir 10 mg as oral solution at concentration of 1 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.		Participants received single dose of daclatasvir 100 mg as oral solution at concentration of 50 mg/mL daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.		Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose.
All Cause Mortality
	Daclatasvir-1 mg		Daclatasvir-10 mg		Daclatasvir-100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Daclatasvir-1 mg		Daclatasvir-10 mg		Daclatasvir-100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/5 (0%)		0/5 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Daclatasvir-1 mg		Daclatasvir-10 mg		Daclatasvir-100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		3/5 (60%)		1/5 (20%)		0/2 (0%)
Gastrointestinal disorders
Flatulence	0/6 (0%)		1/5 (20%)		0/5 (0%)		0/2 (0%)
Abdominal pain	1/6 (16.7%)		0/5 (0%)		0/5 (0%)		0/2 (0%)
Nausea	1/6 (16.7%)		0/5 (0%)		0/5 (0%)		0/2 (0%)
Diarrhoea	0/6 (0%)		1/5 (20%)		0/5 (0%)		0/2 (0%)
Investigations
Blood creatine phosphokinase increased	1/6 (16.7%)		0/5 (0%)		0/5 (0%)		0/2 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/6 (0%)		1/5 (20%)		0/5 (0%)		0/2 (0%)
Nervous system disorders
Headache	2/6 (33.3%)		2/5 (40%)		0/5 (0%)		0/2 (0%)
Paraesthesia	1/6 (16.7%)		0/5 (0%)		0/5 (0%)		0/2 (0%)
Memory impairment	1/6 (16.7%)		0/5 (0%)		0/5 (0%)		0/2 (0%)
Psychiatric disorders
Abnormal dreams	0/6 (0%)		1/5 (20%)		0/5 (0%)		0/2 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/6 (0%)		0/5 (0%)		1/5 (20%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.