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

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02159352
• Collaborator: (none)
• Enrollment: 49
• Location: 1
• Arms: 2
• Duration (Days): 30
• Patients Per Site Per Month: 49.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C	Drug: Daclatasvir; Drug: Darunavir; Drug: Ritonavir; Drug: Lopinavir/Ritonavir	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: A Phase 1 Clinical Study to Assess the Effect of Darunavir/Ritonavir or Lopinavir/Ritonavir on the Pharmacokinetics of Daclatasvir in Healthy Subjects
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 49 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Healthcare Discoveries, Llc D/B/A Icon Development Solutions	San Antonio	Texas	United States	78209

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02159352
• Other Study ID Numbers: AI444-093
• First Posted: Jun 9, 2014
• Last Update Posted: Nov 30, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Hepatitis C; Ritonavir; Lopinavir; Darunavir

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 1 site in the United States of America.
Pre-assignment Detail	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.

Arm/Group Title	Daclatasvir + Darunavir/Ritonavir	Daclatasvir + Lopinavir/Ritonavir
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	14	14
Phase 1 (Day 1- 4)	14	14
Phase 2 (Day 5-14)	11	12
COMPLETED	11	12
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Daclatasvir + Darunavir/Ritonavir	Daclatasvir + Lopinavir/Ritonavir	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	14	14	28
Age, Customized (participants) [Number]
Between 18 and 65 years	14 100%	14 100%	28 100%
Sex: Female, Male (Count of Participants)
Female	5 35.7%	4 28.6%	9 32.1%
Male	9 64.3%	10 71.4%	19 67.9%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) for Daclatasvir
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants with adequate pharmacokinetic profiles.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 5 through 14.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily Days 5 through 14.
Measure Participants	14	11	14	13
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1335 (38)	493 (36)	1412 (28)	476 (21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Daclatasvir (60 mg), Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	0.384
	Confidence Interval	(2-Sided) 90%; 0.348 to 0.423
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 2: Daclatasvir (60 mg), Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	0.337
	Confidence Interval	(2-Sided) 90%; 0.306 to 0.371
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]) for Daclatasvir
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants with adequate pharmacokinetic profiles. Number of participants analyzed (N) signifies number of participants evaluable for this outcome measure.

Arm/Group Title	Daclatasvir (60 mg) Days 1-4	Daclatasvir (30 mg) + Darunavir/Ritonavir Days 5-14	Daclatasvir (60 mg) Days 5-14	Daclatasvir (30 mg) + Lopinavir/Ritonavir Days 5-14
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 5 through 14.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily Days 5 through 14.
Measure Participants	14	11	14	12
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	12677 (41)	8295 (39)	13799 (26)	7855 (23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Daclatasvir (60 mg), Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	0.703
	Confidence Interval	(2-Sided) 90%; 0.658 to 0.750
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 2: Daclatasvir (60 mg), Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	0.577
	Confidence Interval	(2-Sided) 90%; 0.535 to 0.622
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants with adequate pharmacokinetic profile. Here, N signifies number of participants evaluable for this outcome measure.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	11	14	13
Median (Full Range) [hours]	2.00	3.00	2.00	2.00

4. Secondary Outcome

Title	Plasma Concentration Observed at 24 Hours Postdose (C24) of Daclatasvir
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants with adequate pharmacokinetic profile. Here, N signifies number of participants evaluable for this outcome measure.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received 60 mg of daclatasvir tablet once daily from Day 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	11	14	12
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	225 (54)	250 (45)	225 (36)	280 (29)

5. Secondary Outcome

Title	Dose-normalized Maximum Observed Plasma Concentration (Cmax/D) and Dose-normalized Plasma Concentration Observed at 24 Hours Postdose (C24/D) of Daclatasvir
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants with adequate pharmacokinetic profile.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received 60 mg of daclatasvir tablet once daily from Day 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/ 50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	11	14	13
Cmax/D	22.2 (38)	16.4 (36)	23.5 (28)	15.9 (21)
C24/D	3.75 (54)	8.34 (45)	3.76 (36)	9.33 (29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Daclatasvir (60 mg), Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	0.768
	Confidence Interval	(2-Sided) 90%; 0.697 to 0.846
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 2: Daclatasvir (60 mg), Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	0.673
	Confidence Interval	(2-Sided) 90%; 0.611 to 0.742
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Dose-normalized Area Under the Concentration-Time Curve in 1 Dosing Interval (AUC[TAU]/D) of Daclatasvir
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants with adequate pharmacokinetic profile. Here, N signifies number of participants evaluable for this outcome measure.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	11	14	12
Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/mg]	211 (41)	276 (39)	230 (26)	262 (23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Daclatasvir (60 mg), Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	1.406
	Confidence Interval	(2-Sided) 90%; 1.317 to 1.501
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 2: Daclatasvir (60 mg), Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric Mean Ratio
	Estimated Value	1.154
	Confidence Interval	(2-Sided) 90%; 1.070 to 1.244
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died
Description	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)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 -mg lopinavir/50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	14	14	14
SAE	0 0%	0 0%	0 0%	0 NaN
Discontinued due to AEs	0 0%	3 21.4%	0 0%	1 NaN
Death	0 0%	0 0%	0 0%	0 NaN

8. Secondary Outcome

Title	Number of Participants With Abnormalities in Vital Sign Measurements
Description	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)

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of study drug

Arm/Group Title	Group 1: Daclatasvir + Darunavir/Ritonavir	Group 2: Daclatasvir + Lopinavir/Ritonavir
Arm/Group Description	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.	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.
Measure Participants	14	14
Number [participants]	3 21.4%	2 14.3%

9. Secondary Outcome

Title	Number of Participants With Abnormalities in Electrocardiogram (ECG) Findings
Description	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)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with an 800-mg darunavir tablet and 100-mg ritonavir capsule once daily on Days 5 through 14.	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/ 50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	14	14	14
PR >210	2 14.3%	4 28.6%	0 0%	1 NaN
QRS >120	0 0%	0 0%	0 0%	0 NaN
QT >500	0 0%	0 0%	0 0%	0 NaN
QTcF >450	0 0%	1 7.1%	0 0%	0 NaN

10. Secondary Outcome

Title	Number of Participants With Marked Abnormalities in Hematology Laboratory Test Results
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/ 50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	14	14	14
Platelet Count	1 7.1%	0 0%	0 0%	0 NaN
Leukocytes	0 0%	1 7.1%	1 3.6%	1 NaN
Neutrophils (absolute)	0 0%	2 14.3%	1 3.6%	0 NaN
Lymphocytes (absolute)	0 0%	1 7.1%	0 0%	0 NaN

11. Secondary Outcome

Title	Number of Participants With Abnormalities in Urinalysis and Other Chemistry Testing Results
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants.

Arm/Group Title	Group 1: Daclatasvir (60 mg)	Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir	Group 2: Daclatasvir (60 mg)	Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received 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.	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.	Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/50-mg ritonavir tablets twice daily on Days 5 through 14.
Measure Participants	14	14	14	14
Blood, urine	2 14.3%	1 7.1%	1 3.6%	0 NaN
RBC, urine	1 7.1%	1 7.1%	0 0%	0 NaN
WBC, urine	1 7.1%	3 21.4%	0 0%	0 NaN
Lactate dehydrogenase	2 14.3%	2 14.3%	1 3.6%	1 NaN

Adverse Events

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)
Arm/Group Title	Group 1: Total		Group 1: Daclatasvir (60 mg)		Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir		Group 2: Total		Group 2: Daclatasvir (60 mg)		Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
Arm/Group Description	Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4 and 30 mg daclatasvir tablet once daily along with an 800-mg darunavir tablet and a 100-mg of ritonavir capsule once daily on Days 5 through 14.		Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.		Participants received a 30-mg daclatasvir tablet once daily along with an 800-mg darunavir tablet and a 100-mg of ritonavir capsule once daily on Days 5 through 14.		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.		Participants received a 60-mg daclatasvir tablet once daily on Days 1 through 4.		Participants received a 30-mg daclatasvir tablet once daily along with 2 200-mg lopinavir/ 50-mg ritonavir tablets twice daily on Days 5 through 14.
All Cause Mortality
	Group 1: Total		Group 1: Daclatasvir (60 mg)		Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir		Group 2: Total		Group 2: Daclatasvir (60 mg)		Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1: Total		Group 1: Daclatasvir (60 mg)		Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir		Group 2: Total		Group 2: Daclatasvir (60 mg)		Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Group 1: Total		Group 1: Daclatasvir (60 mg)		Group 1: Daclatasvir (30 mg) + Darunavir/Ritonavir		Group 2: Total		Group 2: Daclatasvir (60 mg)		Group 2: Daclatasvir (30 mg) + Lopinavir/Ritonavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/14 (42.9%)		1/14 (7.1%)		6/14 (42.9%)		8/14 (57.1%)		3/14 (21.4%)		8/14 (57.1%)
Eye disorders
Vitreous floaters	1/14 (7.1%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Gastrointestinal disorders
Diarrhoea	2/14 (14.3%)		0/14 (0%)		2/14 (14.3%)		5/14 (35.7%)		0/14 (0%)		5/14 (35.7%)
Constipation	0/14 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)
Nausea	0/14 (0%)		0/14 (0%)		0/14 (0%)		4/14 (28.6%)		2/14 (14.3%)		2/14 (14.3%)
Dyspepsia	0/14 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)
General disorders
Chest discomfort	0/14 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)
Injury, poisoning and procedural complications
Soft tissue injury	0/14 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)
Investigations
Electrocardiogram PR prolongation	1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/14 (0%)		0/14 (0%)		0/14 (0%)		2/14 (14.3%)		1/14 (7.1%)		1/14 (7.1%)
Nervous system disorders
Presyncope	0/14 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)
Headache	1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)		3/14 (21.4%)		2/14 (14.3%)		1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	0/14 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)		1/14 (7.1%)		0/14 (0%)
Skin and subcutaneous tissue disorders
Rash	1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Drug eruption	2/14 (14.3%)		0/14 (0%)		2/14 (14.3%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)

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.