A Study of Daclatasvir and Sofosbuvir With Ribavirin in Subjects With Cirrhosis and Genotype 3 Hepatitis C Infection

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02673489
• Collaborator: (none)
• Enrollment: 106
• Locations: 19
• Arm: 1
• Actual Duration (Months): 14.4
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether 24 weeks of Daclatasvir and Sofosbuvir with Ribavirin is safe and effective in the treatment of genotype 3 hepatitis C infected patients with liver cirrhosis.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C	Drug: DCV; Drug: SOF; Drug: RBV	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Evaluation of Daclatasvir and Sofosbuvir With Ribavirin in Cirrhotic Subjects With Genotype 3 Chronic Hepatitis C Infection
• Actual Study Start Date: Mar 15, 2016
• Actual Primary Completion Date: Mar 2, 2017
• Actual Study Completion Date: May 26, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daclatasvir (DCV) + Sofosbuvir (SOF) + Ribavirin (RBV) Oral dosing of DCV 60 mg tablet once daily + SOF 400 mg tablet once daily + RBV 1000-1200 mg tablet per day (weight based) for 24 weeks.	Drug: DCV; Drug: SOF; Drug: RBV

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response (SVR12) [Week 12]

   SVR12 was defined as hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target detected or target not detected at follow-up Week 12. HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria and the Next Value Carried Backwards approach.

Secondary Outcome Measures

1. Percentage of Participants Who Achieve SVR12 in the Presence and Absence of Baseline NS5A (Non-structural Protein 5A) Resistance-associated Polymorphisms [Week 12 (Follow-up period)]

   SVR12 was defined as hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target detected or target not detected at follow-up Week 12. HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria and the Next Value Carried Backwards approach.

2. Percentage of Subjects Who Achieve HCV RNA < LLOQ, TD or TND Through Follow up Week 24 [At Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, End of Treatment (24 weeks), Follow Up Week 4 (28 weeks), Follow Up Week 12 (36 weeks), Follow Up Week 24 (48 weeks)]

   HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria. SVR12 is based on Next Value Carried Backwards approach.

3. Percentage of Subjects Who Achieve HCV RNA < LLOQ, TND Through Follow up Week 24 [At Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, End of Treatment, Follow Up Week 4, Follow Up Week 12, Follow Up Week 24]

   HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding Bristol-Myers Squibb (BMS) Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Genotype 3 HCV

• HCV RNA ≥10000 IU (International Unit)/mL

• Compensated Liver Cirrhosis

• BMI 18-40 kg/m2

• Previously treated for HCV or never treated for HCV

Exclusion Criteria:

• Infection with HCV other than Genotype 3. Mixed infection of any genotype

• Evidence of decompensated liver disease

• Previous exposure to NS5A inhibitors

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck Medical Center Of USC	Los Angeles	California	United States	90033
2	University Of California, San Francisco	San Francisco	California	United States	94143
3	Gastrointestinal Specialists of Georgia, PC	Marietta	Georgia	United States	30060
4	Ruth Rothstein Core Center	Chicago	Illinois	United States	60612
5	Digestive Disease Associates, PA	Catonsville	Maryland	United States	21228
6	Northeast Clinical Research Center	Bethlehem	Pennsylvania	United States	18017
7	University Gastroenterology	Providence	Rhode Island	United States	02905
8	Texas Clinical Research Institute	Arlington	Texas	United States	76012
9	Methodist Transplant Physicians	Dallas	Texas	United States	75203
10	The Texas Liver Institute	San Antonio	Texas	United States	78215
11	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
12	Bon Secours St. Mary's Hospital of Richmond, Inc	Richmond	Virginia	United States	23226
13	Local Institution	Calgary	Alberta	Canada	T2N 4Z6
14	Local Institution	Edmonton	Alberta	Canada	T6G 2P4
15	Local Institution	Vancouver	British Columbia	Canada	V6Z 2K5
16	Local Institution	Victoria	British Columbia	Canada	V8V 3P9
17	Local Institution	Toronto	Ontario	Canada	M5G 2C4
18	Local Institution	Montreal	Quebec	Canada	H3T 1E2
19	Local Institution	Regina	Saskatchewan	Canada	S4O 0W5

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 14, 2015
• Study Protocol - Dec 14, 2015

More Information

Additional Information:

• BMS Clinical Trial Patient Recruiting

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02673489
• Other Study ID Numbers: AI444-379; 2015-004331-12
• First Posted: Feb 4, 2016
• Last Update Posted: May 8, 2018
• Last Verified: Apr 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis

Study Results

Participant Flow

Pre-assignment Detail	Of the 106 subjects enrolled, 78 participants entered the treatment period and received study treatment; 28 participants were enrolled but did not enter the treatment period. 26 were due to no longer meeting study criteria; 1 was due to poor/non-compliance (missed Day 1 visit); and 1 was other (missed screening window).

Arm/Group Title	Treatment Naive	Treatment Experienced
Arm/Group Description	HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs	HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents
Period Title: Treatment Period
STARTED	54	24
COMPLETED	49	21
NOT COMPLETED	5	3
Period Title: Treatment Period
STARTED	50	23
COMPLETED	50	21
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Treatment Naive	Treatment Experienced	Total
Arm/Group Description	HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs	HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents	Total of all reporting groups
Overall Participants	54	24	78
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54 (7.97)	55.3 (4.90)	54.4 (7.16)
Sex: Female, Male (Count of Participants)
Female	14 25.9%	7 29.2%	21 26.9%
Male	40 74.1%	17 70.8%	57 73.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 13%	6 25%	13 16.7%
Not Hispanic or Latino	20 37%	8 33.3%	28 35.9%
Unknown or Not Reported	27 50%	10 41.7%	37 47.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 3.7%	0 0%	2 2.6%
Asian	4 7.4%	3 12.5%	7 9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	48 88.9%	21 87.5%	69 88.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response (SVR12)
Description	SVR12 was defined as hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target detected or target not detected at follow-up Week 12. HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria and the Next Value Carried Backwards approach.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	HCV Treatment Naive	HCV Treatment Experienced
Arm/Group Description	HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs	HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents
Measure Participants	54	24
Number (95% Confidence Interval) [Percentage of participants]	92.6 171.5%	75.0 312.5%

2. Secondary Outcome

Title	Percentage of Participants Who Achieve SVR12 in the Presence and Absence of Baseline NS5A (Non-structural Protein 5A) Resistance-associated Polymorphisms
Description	SVR12 was defined as hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target detected or target not detected at follow-up Week 12. HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria and the Next Value Carried Backwards approach.
Time Frame	Week 12 (Follow-up period)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	HCV Treatment Naive	HCV Treatment Experienced
Arm/Group Description	HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs	HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents
Measure Participants	54	24
NS5A-Y93 Polymorphism: YES	85.7 158.7%	0.0 0%
NS5A-Y93 Polymorphism: NO	93.6 173.3%	78.3 326.3%

3. Secondary Outcome

Title	Percentage of Subjects Who Achieve HCV RNA < LLOQ, TD or TND Through Follow up Week 24
Description	HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria. SVR12 is based on Next Value Carried Backwards approach.
Time Frame	At Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, End of Treatment (24 weeks), Follow Up Week 4 (28 weeks), Follow Up Week 12 (36 weeks), Follow Up Week 24 (48 weeks)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	HCV Treatment Naive	HCV Treatment Experienced
Arm/Group Description	HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs	HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents
Measure Participants	54	24
Week 1	14.8	12.5
Week 2	50.0	54.2
Week 4	92.6	75.0
Week 8	98.1	91.7
Week 12	92.6	87.5
Week 16	90.7	83.3
Week 20	94.4	83.3
Week 24	88.9	87.5
End of Treatment	100.0	91.7
Follow Up Week 4	88.9	79.2
Follow Up Week 12 (Imputed)	92.6	75.0
Follow Up Week 24	92.6	66.7

4. Secondary Outcome

Title	Percentage of Subjects Who Achieve HCV RNA < LLOQ, TND Through Follow up Week 24
Description	HCV RNA measurements are excluded after the start of non-study anti-HCV medication on treatment or during follow-up. Modified (mITT) approach is based on treated subjects. The numerator is based on subjects meeting the response criteria.
Time Frame	At Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, End of Treatment, Follow Up Week 4, Follow Up Week 12, Follow Up Week 24

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	HCV Treatment Naive	HCV Treatment Experienced
Arm/Group Description	HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs	HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents
Measure Participants	54	24
Week 1	1.9	0.0
Week 2	11.1	12.5
Week 4	64.8	62.5
Week 8	94.4	83.3
Week 12	90.7	83.3
Week 16	90.7	79.2
Week 20	94.4	83.3
Week 24	88.9	83.3
End of Treatment	100.0	87.5
Follow Up Week 4	88.9	79.2
Follow Up Week 12	90.7	75.0
Follow Up Week 24	90.7	66.7

Adverse Events

Time Frame	From first dose until last dose plus 7 days (assessed up to May 2017, approximately 14 months).
Arm/Group Title	Overall: Daclatasvir(DCV) + Sofosbuvir(SOF) + Ribavirin(RBV)		HCV Treatment Naive		HCV Treatment Experienced
Arm/Group Description	Oral dosing of DCV 60 mg tablet once daily + SOF 400 mg tablet once daily + RBV 1000-1200 mg tablet per day (weight based) for 24 weeks.		HCV treatment-naive: No previous exposure to any interferon (IFN) formulation (ie, IFN or peg-IFN), RBV, or any HCV DAAs		HCV treatment-experienced: Previous treatment with IFN/RBV, SOF + RBV, and other anti-HCV agents
All Cause Mortality
	Overall: Daclatasvir(DCV) + Sofosbuvir(SOF) + Ribavirin(RBV)		HCV Treatment Naive		HCV Treatment Experienced
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/78 (0%)		0/54 (0%)		0/24 (0%)
Serious Adverse Events
	Overall: Daclatasvir(DCV) + Sofosbuvir(SOF) + Ribavirin(RBV)		HCV Treatment Naive		HCV Treatment Experienced
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/78 (10.3%)		4/54 (7.4%)		4/24 (16.7%)
Gastrointestinal disorders
Ascites	1/78 (1.3%)		1/54 (1.9%)		0/24 (0%)
General disorders
Chest discomfort	1/78 (1.3%)		1/54 (1.9%)		0/24 (0%)
Hepatobiliary disorders
Cholecystitis	1/78 (1.3%)		0/54 (0%)		1/24 (4.2%)
Infections and infestations
Bronchiolitis	1/78 (1.3%)		1/54 (1.9%)		0/24 (0%)
Streptococcal bacteraemia	1/78 (1.3%)		0/54 (0%)		1/24 (4.2%)
Injury, poisoning and procedural complications
Accidental overdose	2/78 (2.6%)		1/54 (1.9%)		1/24 (4.2%)
Overdose	1/78 (1.3%)		1/54 (1.9%)		0/24 (0%)
Psychiatric disorders
Depression	1/78 (1.3%)		0/54 (0%)		1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Overall: Daclatasvir(DCV) + Sofosbuvir(SOF) + Ribavirin(RBV)		HCV Treatment Naive		HCV Treatment Experienced
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/78 (80.8%)		44/54 (81.5%)		19/24 (79.2%)
Blood and lymphatic system disorders
Anaemia	10/78 (12.8%)		6/54 (11.1%)		4/24 (16.7%)
Gastrointestinal disorders
Abdominal pain	4/78 (5.1%)		3/54 (5.6%)		1/24 (4.2%)
Dyspepsia	4/78 (5.1%)		3/54 (5.6%)		1/24 (4.2%)
Nausea	19/78 (24.4%)		13/54 (24.1%)		6/24 (25%)
Toothache	5/78 (6.4%)		3/54 (5.6%)		2/24 (8.3%)
Vomiting	4/78 (5.1%)		3/54 (5.6%)		1/24 (4.2%)
Constipation	3/78 (3.8%)		3/54 (5.6%)		0/24 (0%)
Gastroesophageal Reflux Disease	3/78 (3.8%)		1/54 (1.9%)		2/24 (8.3%)
General disorders
Fatigue	34/78 (43.6%)		21/54 (38.9%)		13/24 (54.2%)
Pyrexia	2/78 (2.6%)		0/54 (0%)		2/24 (8.3%)
Infections and infestations
Nasopharyngitis	4/78 (5.1%)		4/54 (7.4%)		0/24 (0%)
Oral Herpes	2/78 (2.6%)		0/54 (0%)		2/24 (8.3%)
Upper Respiratory Tract Infection	2/78 (2.6%)		0/54 (0%)		2/24 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/78 (6.4%)		3/54 (5.6%)		2/24 (8.3%)
Nervous system disorders
Dizziness	6/78 (7.7%)		3/54 (5.6%)		3/24 (12.5%)
Headache	22/78 (28.2%)		14/54 (25.9%)		8/24 (33.3%)
Psychiatric disorders
Anxiety	5/78 (6.4%)		3/54 (5.6%)		2/24 (8.3%)
Insomnia	14/78 (17.9%)		11/54 (20.4%)		3/24 (12.5%)
Irritability	7/78 (9%)		6/54 (11.1%)		1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/78 (5.1%)		2/54 (3.7%)		2/24 (8.3%)
Dyspnoea exertional	4/78 (5.1%)		2/54 (3.7%)		2/24 (8.3%)
Skin and subcutaneous tissue disorders
Pruritis Generalised	3/78 (3.8%)		3/54 (5.6%)		0/24 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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