Hepatitis C
Conditions
Brief summary
The purpose of this study is to determine whether multiple doses of darunavir/ritonavir or lopinavir/ritonavir affect the pharmacokinetics of daclatasvir in healthy participants.
Interventions
DRUGDaclatasvir
DRUGDarunavir
DRUGRitonavir
DRUGLopinavir/Ritonavir
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Key Inclusion Criteria: * Healthy male and female participants, aged 18 to 49, as determined by medical history, physical examination, 12 lead electrocardiogram, vital signs, and clinical laboratory evaluations Key
Exclusion criteria
* Any significant acute or chronic medical illness; donation of blood to a blood bank or in a clinical study (except a screening visit) within 4 weeks of study drug administration (within 2 weeks for plasma only); or blood screen findings positive for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 and HIV-2 antibodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) for Daclatasvir | Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2) | Cmax was obtained from concentration-time plot using a noncompartmental method and a validated pharmacokinetic analysis program. |
| Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir | Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2) | AUC(TAU) was the area under the curve from time zero to end of dosing interval. AUC(TAU) was obtained from concentration-time plot of daclatasvir using noncompartmental method and a validated pharmacokinetic analysis program. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2) | Cmax/D and C24/D are obtained from concentration-time plot of daclatasvir by using noncompartmental method by a validated pharmacokinetic analysis program. |
| Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir | Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2) | AUC(TAU)/D was obtained from concentration-time plot of daclatasvir by using noncompartmental method by a validated pharmacokinetic analysis program. |
| Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | From start of study treatment (Day 1) to study discharge for AEs (up to 15 days); Day 1 to 30 days after last dose of study treatment for SAEs (up to 44 days) | AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization. |
| Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2) | Tmax was obtained from concentration-time plot of daclatasvir by using non-compartmental method by a validated pharmacokinetic analysis program. |
| Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | From start of study treatment (Day 1) to study discharge (up to 15 days) | Abnormalities in ECG findings included: PR ≥210 msec, QRS ≥120 msec, QT ≥500 msec, QTcF ≥450 msec, and second- or third-degree heart block. |
| Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | From start of study treatment (Day 1) to study discharge (up to 15 days) | Criteria for marked abnormalities in test results: Platelet count \>1.5\*upper limits of normal (ULN) value, \>1.5\*ULN if pretreatment (PreRx) value is missing, \<0.85\*lower limit of normal (LLN) if PreRx ≥LLN, \<0.85\*LLN if PreRx is missing, \<0.85\*PreRx if PreRx \<LLN. Leukocytes \>1.2\*ULN if LLN ≤PreRx ≤ULN, \>1.2\*ULN if PreRx is missing, \>1.5\*PreRx if PreRx \>ULN, \>ULN if PreRx \<LLN, \<0.85\*PreRx if PreRx \<LLN, \<0.9\*LLN if LLN ≤PreRx ≤ULN, \<0.9\*LLN if PreRx is missing and \<LLN if PreRx \>ULN. Lymphocytes \>7.5\*10\^3 c/uL and \<0.75\*10\^3 c/uL. Neutrophils \<0.85\*PreRx if PreRx \<1.5\*ULN, \<1.5\*ULN if PreRx ≥1.5\*ULN and \<1.5\*ULN if PreRx is missing. |
| Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | From start of study treatment (Day 1) to study discharge (up to 15 days) | Criteria for marked abnormalities on laboratory test results: urinary dipstick blood: ≥2 if pretreatment (PreRx) \<1, ≥2 if PreRx is missing or ≥2\*PreRx if PreRx ≥1. Urinary microscopic red blood cell (RBC): ≥2 if PreRx \<2, ≥2 if PreRx is missing or ≥4 if PreRx ≥2. Urinary microscopic white blood cell (WBC): ≥2 if PreRx \<2, ≥2 if PreRx is missing or ≥4 if PreRx ≥2. Lactate dehydrogenase \>1.25\*upper limit of normal (ULN) if PreRx ≤ULN, \>1.25\*ULN if PreRx is missing and \>1.5\*PreRx if PreRx \>ULN. |
| Number of Participants With Abnormalities in Vital Sign Measurements | From start of study treatment (Day 1) to study discharge (up to 15 days) | Criteria for abnormalities in vital sign measurements: Diastolic blood pressure: Value \>90 and change from baseline \> 0 or value \< 55 and change from baseline \<-10. Systolic blood pressure: Value \>140 and change from baseline \>20 or value \<90 and change from baseline \<-20. Heart rate: Value \>100 and change from baseline \>30 or value \<55 and change from baseline \<-15. Respiration: Value \>16 or change from baseline \>10. Temperature: Value \>38.3°C or change from baseline \>1.6°C. |
| Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir | Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2) | C24 was obtained from concentration time plot of daclatasvir by using noncompartmental method by a validated pharmacokinetic analysis program. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 1 site in the United States of America.
Pre-assignment details
Of 49 participants enrolled, 28 were randomized to receive treatment. Of the 21 who were not randomized, 16 no longer met study criteria and 5 discontinued due to other reasons.
Participants by arm
| Arm | Count |
|---|---|
| Daclatasvir + Darunavir/Ritonavir Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4 and a 30-mg daclatasvir tablet once daily, along with an 800-mg darunavir tablet and a 100-mg ritonavir capsule once daily on Days 5 through 14. | 14 |
| Daclatasvir + Lopinavir/Ritonavir Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4 and a 30-mg daclatasvir tablet once daily, along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily on Days 5 through 14. | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Daclatasvir + Darunavir/Ritonavir | Daclatasvir + Lopinavir/Ritonavir | Total |
|---|---|---|---|
| Age, Customized Between 18 and 65 years | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 14 | 1 / 14 | 6 / 14 | 8 / 14 | 3 / 14 | 8 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir
AUC(TAU) was the area under the curve from time zero to end of dosing interval. AUC(TAU) was obtained from concentration-time plot of daclatasvir using noncompartmental method and a validated pharmacokinetic analysis program.
Time frame: Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2)
Population: All treated participants with adequate pharmacokinetic profiles. Number of participants analyzed (N) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir | 12677 ng*h/mL | Geometric Coefficient of Variation 41 |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir | 8295 ng*h/mL | Geometric Coefficient of Variation 39 |
| Group 2: Daclatasvir (60 mg) | Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir | 13799 ng*h/mL | Geometric Coefficient of Variation 26 |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir | 7855 ng*h/mL | Geometric Coefficient of Variation 23 |
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed AUC(TAU).90% CI: [0.658, 0.75]
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed AUC(TAU).90% CI: [0.535, 0.622]
Primary
Maximum Observed Plasma Concentration (Cmax) for Daclatasvir
Cmax was obtained from concentration-time plot using a noncompartmental method and a validated pharmacokinetic analysis program.
Time frame: Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2)
Population: All treated participants with adequate pharmacokinetic profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Maximum Observed Plasma Concentration (Cmax) for Daclatasvir | 1335 ng/mL | Geometric Coefficient of Variation 38 |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Maximum Observed Plasma Concentration (Cmax) for Daclatasvir | 493 ng/mL | Geometric Coefficient of Variation 36 |
| Group 2: Daclatasvir (60 mg) | Maximum Observed Plasma Concentration (Cmax) for Daclatasvir | 1412 ng/mL | Geometric Coefficient of Variation 28 |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Maximum Observed Plasma Concentration (Cmax) for Daclatasvir | 476 ng/mL | Geometric Coefficient of Variation 21 |
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed Cmax.90% CI: [0.348, 0.423]
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed Cmax.90% CI: [0.306, 0.371]
Secondary
Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir
AUC(TAU)/D was obtained from concentration-time plot of daclatasvir by using noncompartmental method by a validated pharmacokinetic analysis program.
Time frame: Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2)
Population: All treated participants with adequate pharmacokinetic profile. Here, N signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir | 211 (ng*h/mL)/mg | Geometric Coefficient of Variation 41 |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir | 276 (ng*h/mL)/mg | Geometric Coefficient of Variation 39 |
| Group 2: Daclatasvir (60 mg) | Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir | 230 (ng*h/mL)/mg | Geometric Coefficient of Variation 26 |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir | 262 (ng*h/mL)/mg | Geometric Coefficient of Variation 23 |
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed (AUC(TAU)/D).90% CI: [1.317, 1.501]
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed (AUC(TAU)/D).90% CI: [1.07, 1.244]
Secondary
Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir
Cmax/D and C24/D are obtained from concentration-time plot of daclatasvir by using noncompartmental method by a validated pharmacokinetic analysis program.
Time frame: Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2)
Population: All treated participants with adequate pharmacokinetic profile.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | Cmax/D | 22.2 ng/mL/mg | Geometric Coefficient of Variation 38 |
| Group 1: Daclatasvir (60 mg) | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | C24/D | 3.75 ng/mL/mg | Geometric Coefficient of Variation 54 |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | C24/D | 8.34 ng/mL/mg | Geometric Coefficient of Variation 45 |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | Cmax/D | 16.4 ng/mL/mg | Geometric Coefficient of Variation 36 |
| Group 2: Daclatasvir (60 mg) | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | Cmax/D | 23.5 ng/mL/mg | Geometric Coefficient of Variation 28 |
| Group 2: Daclatasvir (60 mg) | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | C24/D | 3.76 ng/mL/mg | Geometric Coefficient of Variation 36 |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | Cmax/D | 15.9 ng/mL/mg | Geometric Coefficient of Variation 21 |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir | C24/D | 9.33 ng/mL/mg | Geometric Coefficient of Variation 29 |
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed Cmax/D.90% CI: [0.697, 0.846]
Comparison: A general linear mixed effect model (restricted maximum likelihood) with treatment as fixed effect and measurements within each participant as repeated measures was fitted to the log-transformed Cmax/D.90% CI: [0.611, 0.742]
Secondary
Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings
Abnormalities in ECG findings included: PR ≥210 msec, QRS ≥120 msec, QT ≥500 msec, QTcF ≥450 msec, and second- or third-degree heart block.
Time frame: From start of study treatment (Day 1) to study discharge (up to 15 days)
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QTcF >450 | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QT >500 | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QRS >120 | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | PR >210 | 2 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | PR >210 | 4 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QRS >120 | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QT >500 | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QTcF >450 | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | PR >210 | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QRS >120 | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QTcF >450 | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QT >500 | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QTcF >450 | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QRS >120 | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | QT >500 | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings | PR >210 | 1 participants |
Secondary
Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results
Criteria for marked abnormalities on laboratory test results: urinary dipstick blood: ≥2 if pretreatment (PreRx) \<1, ≥2 if PreRx is missing or ≥2\*PreRx if PreRx ≥1. Urinary microscopic red blood cell (RBC): ≥2 if PreRx \<2, ≥2 if PreRx is missing or ≥4 if PreRx ≥2. Urinary microscopic white blood cell (WBC): ≥2 if PreRx \<2, ≥2 if PreRx is missing or ≥4 if PreRx ≥2. Lactate dehydrogenase \>1.25\*upper limit of normal (ULN) if PreRx ≤ULN, \>1.25\*ULN if PreRx is missing and \>1.5\*PreRx if PreRx \>ULN.
Time frame: From start of study treatment (Day 1) to study discharge (up to 15 days)
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Blood, urine | 2 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | WBC, urine | 1 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Lactate dehydrogenase | 2 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | RBC, urine | 1 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Lactate dehydrogenase | 2 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Blood, urine | 1 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | WBC, urine | 3 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | RBC, urine | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | RBC, urine | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Lactate dehydrogenase | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Blood, urine | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | WBC, urine | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Blood, urine | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | RBC, urine | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | WBC, urine | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results | Lactate dehydrogenase | 1 participants |
Secondary
Number of Participants With Abnormalities in Vital Sign Measurements
Criteria for abnormalities in vital sign measurements: Diastolic blood pressure: Value \>90 and change from baseline \> 0 or value \< 55 and change from baseline \<-10. Systolic blood pressure: Value \>140 and change from baseline \>20 or value \<90 and change from baseline \<-20. Heart rate: Value \>100 and change from baseline \>30 or value \<55 and change from baseline \<-15. Respiration: Value \>16 or change from baseline \>10. Temperature: Value \>38.3°C or change from baseline \>1.6°C.
Time frame: From start of study treatment (Day 1) to study discharge (up to 15 days)
Population: Participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Daclatasvir (60 mg) | Number of Participants With Abnormalities in Vital Sign Measurements | 3 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Abnormalities in Vital Sign Measurements | 2 participants |
Secondary
Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results
Criteria for marked abnormalities in test results: Platelet count \>1.5\*upper limits of normal (ULN) value, \>1.5\*ULN if pretreatment (PreRx) value is missing, \<0.85\*lower limit of normal (LLN) if PreRx ≥LLN, \<0.85\*LLN if PreRx is missing, \<0.85\*PreRx if PreRx \<LLN. Leukocytes \>1.2\*ULN if LLN ≤PreRx ≤ULN, \>1.2\*ULN if PreRx is missing, \>1.5\*PreRx if PreRx \>ULN, \>ULN if PreRx \<LLN, \<0.85\*PreRx if PreRx \<LLN, \<0.9\*LLN if LLN ≤PreRx ≤ULN, \<0.9\*LLN if PreRx is missing and \<LLN if PreRx \>ULN. Lymphocytes \>7.5\*10\^3 c/uL and \<0.75\*10\^3 c/uL. Neutrophils \<0.85\*PreRx if PreRx \<1.5\*ULN, \<1.5\*ULN if PreRx ≥1.5\*ULN and \<1.5\*ULN if PreRx is missing.
Time frame: From start of study treatment (Day 1) to study discharge (up to 15 days)
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Platelet Count | 1 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Lymphocytes (absolute) | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Neutrophils (absolute) | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Leukocytes | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Platelet Count | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Leukocytes | 1 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Neutrophils (absolute) | 2 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Lymphocytes (absolute) | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Neutrophils (absolute) | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Lymphocytes (absolute) | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Leukocytes | 1 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Platelet Count | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Neutrophils (absolute) | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Platelet Count | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Leukocytes | 1 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results | Lymphocytes (absolute) | 0 participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died
AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization.
Time frame: From start of study treatment (Day 1) to study discharge for AEs (up to 15 days); Day 1 to 30 days after last dose of study treatment for SAEs (up to 44 days)
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | SAE | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Group 1: Daclatasvir (60 mg) | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinued due to AEs | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | SAE | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinued due to AEs | 3 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinued due to AEs | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | SAE | 0 participants |
| Group 2: Daclatasvir (60 mg) | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | SAE | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Death | 0 participants |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | Discontinued due to AEs | 1 participants |
Secondary
Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir
C24 was obtained from concentration time plot of daclatasvir by using noncompartmental method by a validated pharmacokinetic analysis program.
Time frame: Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2)
Population: All treated participants with adequate pharmacokinetic profile. Here, N signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Daclatasvir (60 mg) | Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir | 225 ng/mL | Geometric Coefficient of Variation 54 |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir | 250 ng/mL | Geometric Coefficient of Variation 45 |
| Group 2: Daclatasvir (60 mg) | Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir | 225 ng/mL | Geometric Coefficient of Variation 36 |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir | 280 ng/mL | Geometric Coefficient of Variation 29 |
Secondary
Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir
Tmax was obtained from concentration-time plot of daclatasvir by using non-compartmental method by a validated pharmacokinetic analysis program.
Time frame: Predose (0 hour) on Day 2, 3 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 4 (Period 1); Predose (0 hour) on Day 12, 13 and 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hour on Day 14 (Period 2)
Population: All treated participants with adequate pharmacokinetic profile. Here, N signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Daclatasvir (60 mg) | Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 2.00 hours |
| Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir | Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 3.00 hours |
| Group 2: Daclatasvir (60 mg) | Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 2.00 hours |
| Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir | Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 2.00 hours |