Study Assessing the Effects of Darunavir/Ritonavir or Lopinavir/Ritonavir on the Pharmacokinetics of Daclatasvir in Healthy Participants

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Clinical Study to Assess the Effect of Darunavir/Ritonavir or Lopinavir/Ritonavir on the Pharmacokinetics of Daclatasvir in Healthy Subjects

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Daclatasvir
* Drug: Darunavir
* Drug: Ritonavir
* Drug: Lopinavir/Ritonavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Daclatasvir and Darunavir/Ritonavir<br>Treatment A: Daclatasvir oral tablet on specific days Treatment B: Daclatasvir tablet and Darunavir Tablet/Ritonavir capsule orally on specific days | Drug: Daclatasvir<br> <br> * Other names: BMS-790052;Drug: Darunavir<br> <br> * Other names: Prezista;Drug: Ritonavir<br> <br> * Other names: Norvir;|
| Experimental: Group 2: Daclatasvir and Lopinavir/Ritonavir<br>Treatment C: Daclatasvir oral tablet on specific days Treatment D: Daclatasvir tablet and Lopinavir/Ritonavir tablet orally on specific days | Drug: Daclatasvir<br> <br> * Other names: BMS-790052;Drug: Ritonavir<br> <br> * Other names: Norvir;Drug: Lopinavir/Ritonavir<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) for Daclatasvir | Cmax was obtained from concentration-time plot using a noncompartmental method and a validated pharmacokinetic analysis program. | 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) | 
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | From start of study treatment (Day 1) to study discharge (up to 15 days) | 
| 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. | From start of study treatment (Day 1) to study discharge (up to 15 days) | 
| 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. | From start of study treatment (Day 1) to study discharge (up to 15 days) | 
| 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. | From start of study treatment (Day 1) to study discharge (up to 15 days) |