Chronic Hepatitis C
Conditions
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
Interventions
DRUGDaclatasvir
Oral Solution, Oral, Single Dose
DRUGPlacebo
Oral Solution, Oral, Single Dose
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 49 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 7 centers in United States.
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Daclatasvir-1 mg 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. | 6 |
| Daclatasvir-10 mg 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. | 5 |
| Daclatasvir-100 mg 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. | 5 |
| Placebo Participants received single dose of placebo matched to daclatasvir daily, after fasting for at least 10 hours pre-dose and 4 hours post-dose. | 2 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Daclatasvir-1 mg | Daclatasvir-10 mg | Daclatasvir-100 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.5 years | 46 years | 44 years | 28 years | 44 years |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 1 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 6 | 3 / 5 | 1 / 5 | 0 / 2 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 | 0 / 5 | 0 / 2 |
Outcome results
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.
Time frame: Day 1 up to Day 7 or Discharge
Population: The analysis was performed in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daclatasvir-1 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Systolic blood pressure | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Diastolic blood pressure | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Pulse rate | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Respiration rate | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Temperature | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Weight | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Weight | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Respiration rate | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Systolic blood pressure | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Pulse rate | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Diastolic blood pressure | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Temperature | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Diastolic blood pressure | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Pulse rate | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Respiration rate | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Weight | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Temperature | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Systolic blood pressure | 0 participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Temperature | 0 participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Weight | 0 participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Diastolic blood pressure | 0 participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Respiration rate | 0 participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Systolic blood pressure | 0 participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Sign Measurements and Physical Examination Findings | Pulse rate | 0 participants |
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.
Time frame: Day 1 up to Day 7
Population: The analysis was performed in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine Kinase (High) | 1 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Bicarbonate (High) | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Total Protein (High) | 1 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Blood in Urine (High) | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Leukocytes (Low) | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Aspartate Aminotransferase (High) | 1 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Hematocrit (Low) | 1 participants |
| Daclatasvir-1 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine (High) | 1 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Aspartate Aminotransferase (High) | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine (High) | 1 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Hematocrit (Low) | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Total Protein (High) | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Leukocytes (Low) | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Blood in Urine (High) | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Bicarbonate (High) | 1 participants |
| Daclatasvir-10 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine Kinase (High) | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Blood in Urine (High) | 1 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Bicarbonate (High) | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Hematocrit (Low) | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Leukocytes (Low) | 1 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Aspartate Aminotransferase (High) | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine (High) | 1 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Total Protein (High) | 1 participants |
| Daclatasvir-100 mg | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine Kinase (High) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Total Protein (High) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Aspartate Aminotransferase (High) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Leukocytes (Low) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Blood in Urine (High) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine Kinase (High) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Hematocrit (Low) | 0 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Creatinine (High) | 1 participants |
| Placebo | Number of Participants With Marked Abnormalities in Laboratory Findings | Bicarbonate (High) | 0 participants |
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.
Time frame: Day 1 up to Day 7 for non-SAEs and Day 1 to 30 days after study discontinuation for SAEs
Population: Analysis was performed in safety population defined as all participants who received any study drug treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daclatasvir-1 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | SAEs | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Daclatasvir-1 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinuations due to AEs | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | SAEs | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Daclatasvir-10 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinuations due to AEs | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinuations due to AEs | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | SAEs | 0 participants |
| Daclatasvir-100 mg | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | SAEs | 0 participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinuations due to AEs | 0 participants |
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.
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
Population: The analysis was performed in the PK set population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Daclatasvir-1 mg | Apparent Total Body Clearance (CLT/F) | 129.1 mL/min | Geometric Coefficient of Variation 48 |
| Daclatasvir-10 mg | Apparent Total Body Clearance (CLT/F) | 116.5 mL/min | Geometric Coefficient of Variation 43 |
| Daclatasvir-100 mg | Apparent Total Body Clearance (CLT/F) | 57.0 mL/min | Geometric Coefficient of Variation 49 |
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 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
Population: The analysis was performed in the PK set population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Daclatasvir-1 mg | 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 | AUC(0-T) | 126.8 ng*h/mL | Geometric Coefficient of Variation 49 |
| Daclatasvir-1 mg | 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 | AUC(0-INF) | 129.1 ng*h/mL | Geometric Coefficient of Variation 49 |
| Daclatasvir-10 mg | 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 | AUC(0-T) | 1413.9 ng*h/mL | Geometric Coefficient of Variation 45 |
| Daclatasvir-10 mg | 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 | AUC(0-INF) | 1431.1 ng*h/mL | Geometric Coefficient of Variation 45 |
| Daclatasvir-100 mg | 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 | AUC(0-T) | 28239.1 ng*h/mL | Geometric Coefficient of Variation 48 |
| Daclatasvir-100 mg | 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 | AUC(0-INF) | 29256.1 ng*h/mL | Geometric Coefficient of Variation 53 |
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.
Time frame: Baseline (Day 1), Day 7 or Discharge
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daclatasvir-1 mg | Change From Baseline in Blood Pressure to Day 7 or Discharge | Diastolic blood pressure | 9.6 mmHg | Standard Deviation 7.3 |
| Daclatasvir-1 mg | Change From Baseline in Blood Pressure to Day 7 or Discharge | Systolic blood pressure | 14 mmHg | Standard Deviation 4.4 |
| Daclatasvir-10 mg | Change From Baseline in Blood Pressure to Day 7 or Discharge | Systolic blood pressure | 1 mmHg | Standard Deviation 15.7 |
| Daclatasvir-10 mg | Change From Baseline in Blood Pressure to Day 7 or Discharge | Diastolic blood pressure | 4.3 mmHg | Standard Deviation 5.9 |
| Daclatasvir-100 mg | Change From Baseline in Blood Pressure to Day 7 or Discharge | Diastolic blood pressure | 3.7 mmHg | Standard Deviation 12.7 |
| Daclatasvir-100 mg | Change From Baseline in Blood Pressure to Day 7 or Discharge | Systolic blood pressure | 6 mmHg | Standard Deviation 17.5 |
| Placebo | Change From Baseline in Blood Pressure to Day 7 or Discharge | Diastolic blood pressure | 1 mmHg | — |
| Placebo | Change From Baseline in Blood Pressure to Day 7 or Discharge | Systolic blood pressure | -2 mmHg | — |
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.
Time frame: Baseline (Day 1), Day 7 or Discharge
Population: The analysis was performed in the safety population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daclatasvir-1 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Fridericia Interval | -13.3 msec | Standard Deviation 10.5 |
| Daclatasvir-1 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QT Interval | -27.5 msec | Standard Deviation 32.7 |
| Daclatasvir-1 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Bazett Interval | -5.5 msec | Standard Deviation 21 |
| Daclatasvir-1 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | PR Interval | -6.7 msec | Standard Deviation 9.9 |
| Daclatasvir-1 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QRS Width | -2.3 msec | Standard Deviation 4.7 |
| Daclatasvir-10 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QRS Width | 1 msec | Standard Deviation 11.3 |
| Daclatasvir-10 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | PR Interval | 2.4 msec | Standard Deviation 10.3 |
| Daclatasvir-10 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QT Interval | -18.6 msec | Standard Deviation 29.2 |
| Daclatasvir-10 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Fridericia Interval | -5.6 msec | Standard Deviation 14.7 |
| Daclatasvir-10 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Bazett Interval | 1.2 msec | Standard Deviation 12.7 |
| Daclatasvir-100 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Fridericia Interval | 0.4 msec | Standard Deviation 11.4 |
| Daclatasvir-100 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QRS Width | -3.6 msec | Standard Deviation 8.2 |
| Daclatasvir-100 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | PR Interval | -4.4 msec | Standard Deviation 11.2 |
| Daclatasvir-100 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Bazett Interval | 1.8 msec | Standard Deviation 7.2 |
| Daclatasvir-100 mg | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QT Interval | -1.2 msec | Standard Deviation 27.8 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QRS Width | 0 msec | Standard Deviation 0 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Bazett Interval | 1 msec | Standard Deviation 21.2 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QTc Fridericia Interval | -12.5 msec | Standard Deviation 19.1 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | QT Interval | -36 msec | Standard Deviation 14.1 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameters (PR, QRS, QT, and QTc Intervals) to Day 7 or Discharge | PR Interval | -7 msec | Standard Deviation 7.1 |
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.
Time frame: Baseline (Day 1), Day 7 or Discharge
Population: The analysis was performed in the safety population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daclatasvir-1 mg | Change From Baseline in Heart Rate to Day 7 or Discharge | 7.3 bpm | Standard Deviation 16.2 |
| Daclatasvir-10 mg | Change From Baseline in Heart Rate to Day 7 or Discharge | 7.6 bpm | Standard Deviation 9.3 |
| Daclatasvir-100 mg | Change From Baseline in Heart Rate to Day 7 or Discharge | 1.6 bpm | Standard Deviation 8.5 |
| Placebo | Change From Baseline in Heart Rate to Day 7 or Discharge | 14 bpm | Standard Deviation 1.4 |
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.
Time frame: Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daclatasvir-1 mg | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Decline From Baseline to 24 hours | 2.12 log IU/mL | Standard Deviation 0.57 |
| Daclatasvir-1 mg | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Maximum Decline | 2.44 log IU/mL | Standard Deviation 0.8 |
| Daclatasvir-10 mg | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Maximum Decline | 3.12 log IU/mL | Standard Deviation 0.66 |
| Daclatasvir-10 mg | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Decline From Baseline to 24 hours | 3.24 log IU/mL | Standard Deviation 0.51 |
| Daclatasvir-100 mg | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Decline From Baseline to 24 hours | 3.28 log IU/mL | Standard Deviation 0.35 |
| Daclatasvir-100 mg | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Maximum Decline | 4.06 log IU/mL | Standard Deviation 0.53 |
| Placebo | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Decline From Baseline to 24 hours | -0.12 log IU/mL | Standard Deviation 0.29 |
| Placebo | Decline From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) | Maximum Decline | 0.06 log IU/mL | Standard Deviation 0.11 |
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.
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Daclatasvir-1 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | C-12 | 2.7 ng/mL | Geometric Coefficient of Variation 49 |
| Daclatasvir-1 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | Cmax | 15.7 ng/mL | Geometric Coefficient of Variation 56 |
| Daclatasvir-1 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | C-24 | 1.1 ng/mL | Geometric Coefficient of Variation 65 |
| Daclatasvir-10 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | Cmax | 177.6 ng/mL | Geometric Coefficient of Variation 52 |
| Daclatasvir-10 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | C-12 | 32.2 ng/mL | Geometric Coefficient of Variation 28 |
| Daclatasvir-10 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | C-24 | 14.2 ng/mL | Geometric Coefficient of Variation 44 |
| Daclatasvir-100 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | Cmax | 2416.5 ng/mL | Geometric Coefficient of Variation 27 |
| Daclatasvir-100 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | C-24 | 363.2 ng/mL | Geometric Coefficient of Variation 55 |
| Daclatasvir-100 mg | Maximum Observed Plasma Concentration (Cmax) and Observed Plasma Concentration at 12 Hours (C-12) and 24 Hours (C-24) | C-12 | 706.7 ng/mL | Geometric Coefficient of Variation 51 |
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.
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
Population: The analysis was performed in the PK set population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daclatasvir-1 mg | Plasma Half-life (T-half) | 9.7 hours | Standard Deviation 2.65 |
| Daclatasvir-10 mg | Plasma Half-life (T-half) | 12.1 hours | Standard Deviation 1.97 |
| Daclatasvir-100 mg | Plasma Half-life (T-half) | 14.0 hours | Standard Deviation 6.43 |
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.
Time frame: Pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 144 hours post-dose on Day 1
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daclatasvir-1 mg | Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline | 16.4 hours | Standard Deviation 7.8 |
| Daclatasvir-10 mg | Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline | 43.2 hours | Standard Deviation 56.74 |
| Daclatasvir-100 mg | Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline | 105.60 hours | Standard Deviation 55.25 |
| Placebo | Time to Reach Maximum Decline in Plasma Hepatitis C Virus RNA Levels From Baseline | 144 hours | Standard Deviation 0 |
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.
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
Population: The analysis was performed in the PK set population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daclatasvir-1 mg | Time to Reach Maximum Plasma Concentration (Tmax) | 1 hours |
| Daclatasvir-10 mg | Time to Reach Maximum Plasma Concentration (Tmax) | 1 hours |
| Daclatasvir-100 mg | Time to Reach Maximum Plasma Concentration (Tmax) | 1.5 hours |