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Phase III BMS-790052 Add-On to Peg-Interferon Alfa-2a and Ribavirin in Naive Hepatitis C

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ClinicalTrials.gov Identifier: NCT01448044
Recruitment Status : Completed
First Posted : October 7, 2011
Results First Posted : September 7, 2015
Last Update Posted : October 12, 2015
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hepatitis C
Interventions Drug: BMS-790052 (NS5A Replication Complex Inhibitor)
Drug: Placebo matching BMS-790052
Drug: Pegylated-interferon alfa 2a
Drug: Ribavirin
Enrollment 152
Recruitment Details  
Pre-assignment Details A total of 152 participants were enrolled in the study, of which 125 were randomized and 27 participants were not randomized due to 23 no longer met criteria, 1 withdrew consent, 1 due to administrative reason, and 2 other reasons. Of 125 randomized, 124 were treated and 1 was not treated due to withdrawal of consent.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response. Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
Period Title: Treatment Period
Started 82 42
Completed 59 26
Not Completed 23 16
Reason Not Completed
Adverse Event             4             3
Lack of Efficacy             5             12
Subject requested discontinue study drug             1             0
Completed 24 weeks treatment period only             8             0
Participant does not meet study criteria             1             0
Lost to Follow-up             2             1
Other reason             2             0
Period Title: Follow Up Period
Started 77 [1] 40 [2]
Completed 65 26
Not Completed 12 14
Reason Not Completed
Withdrawal by Subject             1             1
Lost to Follow-up             6             2
not specified             5             11
[1]
Out of 82 participants who entered the treatment period, 77 continued in the follow-up period.
[2]
Out of 42 participants who entered the treatment period, 40 continued in the follow-up period.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin Total
Hide Arm/Group Description Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response. Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks. Total of all reporting groups
Overall Number of Baseline Participants 82 42 124
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 82 participants 42 participants 124 participants
47.7  (10.23) 48.4  (8.09) 48.0  (9.53)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 82 participants 42 participants 124 participants
< 21 years 1 0 1
21 to < 65 years 78 42 120
>= 65 years 3 0 3
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 82 participants 42 participants 124 participants
Female
21
  25.6%
13
  31.0%
34
  27.4%
Male
61
  74.4%
29
  69.0%
90
  72.6%
1.Primary Outcome
Title Percentage of Participants With 12 Week Sustained Virologic Response (SVR12)
Hide Description Participants were assessed for sustained virologic response 12 weeks post treatment (SVR12) defined as hepatitis C virus (HCV) RNA levels < lower limit of quantitation (LLOQ was 25 IU/mL), target detected (TD) or target not detected (TND) at post-treatment Week 12.
Time Frame Week 12 (Follow-up period)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in modified Intent to treat population (ITT), defined as the proportions of participants meeting the response criteria in numerator and denominator based on all treated participants. Missing values were imputed using backward imputation technique.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description:
Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
Overall Number of Participants Analyzed 82 42
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
81.7
(73.3 to 90.1)
42.9
(27.9 to 57.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Daclatasvir + PegIFNα2a + Ribavirin, Placebo + PegIFNα2a + Ribavirin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The pvalue was based on the CochranMantelHaenszel (CMH) test, stratified by IL28B host genotype, geography, and baseline cirrhosis status.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentages
Estimated Value 38.850
Confidence Interval (2-Sided) 95%
21.703 to 55.997
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants Who Achieve HCV Ribonucleic Acid (RNA) < Limit of Quantification (LLOQ)
Hide Description Participants who achieved HCV RNA levels below LLOQ ie, 25 international unit per milliliter (IU/mL). Participants in the placebo arm did not have visits beyond post treatment Week 24.
Time Frame Treatment Weeks 1, 2, 4, 6, 8 and 12; Weeks 4 and 12; End of treatment (EOT); Post treatment Week 24; Post treatment Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in modified ITT population.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description:
Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
Overall Number of Participants Analyzed 82 42
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
Week 1
53.7
(42.9 to 64.5)
4.8
(0.0 to 11.2)
Week 2
89.0
(82.3 to 95.8)
11.9
(2.1 to 21.7)
Week 4
91.5
(85.4 to 97.5)
19.0
(7.2 to 30.9)
Week 6
84.1
(76.2 to 92.1)
40.5
(25.6 to 55.3)
Week 8
87.8
(80.7 to 94.9)
47.6
(32.5 to 62.7)
Week 12
85.4
(77.7 to 93.0)
59.5
(44.7 to 74.4)
Weeks 4 and 12
84.1
(76.2 to 92.1)
19.0
(7.2 to 30.9)
End of Treatment
92.7
(87.0 to 98.3)
64.3
(49.8 to 78.8)
Post treatment Week 24
80.5
(71.9 to 89.1)
40.5
(25.6 to 55.3)
Post treatment Week 48
83.6
(73.9 to 93.4)
NA [1] 
(NA to NA)
[1]
No visit on post treatment Week 48 was planned for this arm.
3.Secondary Outcome
Title Percentage of Participants With Undetectable Hepatitis C Virus (HCV) RNA Levels
Hide Description Participants who achieved HCV RNA undetectable ie, 10 international units per milliliter (IU/mL). Participants in the placebo arm did not have visits beyond post treatment Week 24.
Time Frame Treatment Weeks 1, 2, 4, 6, 8 and 12; Weeks 4 and 12, End of treatment (EOT), Post treatment Week 24, Post treatment Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in modified ITT population.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description:
Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
Overall Number of Participants Analyzed 82 42
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
Week 1
14.6
(7.0 to 22.3)
0.0
(0.0 to 0.0)
Week 2
45.1
(34.4 to 55.9)
9.5
(0.6 to 18.4)
Week 4
85.4
(77.7 to 93.0)
11.9
(2.1 to 21.7)
Week 6
80.5
(71.9 to 89.1)
16.7
(5.4 to 27.9)
Week 8
87.8
(80.7 to 94.9)
38.1
(23.4 to 52.8)
Week 12
84.1
(76.2 to 92.1)
47.6
(32.5 to 62.7)
Weeks 4 and 12 (VR 4 & 12)
79.3
(70.5 to 88.0)
11.9
(2.1 to 21.7)
EOT
90.2
(83.8 to 96.7)
64.3
(49.8 to 78.8)
Post treatment Week 24
78.0
(69.1 to 87.0)
40.5
(25.6 to 55.3)
Post treatment Week 48
81.8
(71.6 to 92.0)
NA [1] 
(NA to NA)
[1]
No visits planned for post treatment Week 48 for this arm.
4.Secondary Outcome
Title Percentage of Participants With Sustained Virologic Response at Follow-up Week 12 (SVR12) or Sustained Virologic Response at Follow-up Week 24 (SVR24) by rs12979860 Single Nucleotide Polymorphism (SNP) in the IL28B Gene
Hide Description Participants categorized into three genotypes based on SNPs in the IL28B gene were assessed for SVR12 and SVR24, defined as response in which hepatitis C virus RNA levels below lower limit of quantitation or below target detected or target not detected at follow-up Week 12 and Week 24 respectively.
Time Frame Post Treatment Weeks 12, 24
Hide Outcome Measure Data
Hide Analysis Population Description
For SVR12; analysis was performed by backward imputation method, For SVR24: analysis was performed in Modified ITT population.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description:
Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
Overall Number of Participants Analyzed 82 42
Measure Type: Number
Unit of Measure: Percentage of participants
IL28B Genotype CC (SVR12) (n=22, 9) 95.5 100.0
IL28B Genotype CT (SVR12) (n=40, 27) 75.0 33.3
IL28B Genotype TT (SVR12) (n=20, 6) 80.0 0.0
IL28B Genotype CC (SVR24) (n=22, 9) 95.5 88.9
IL28B Genotype CT (SVR24) (n=40, 27) 72.5 33.3
IL28B Genotype TT (SVR24) (n=20, 6) 80.0 0.0
5.Secondary Outcome
Title Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died
Hide Description AE was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing 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, was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalisation.
Time Frame From Day 1 (start of study treatment) up to Follow-up Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all treated participants.
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description:
Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
Overall Number of Participants Analyzed 82 42
Measure Type: Number
Unit of Measure: participants
AEs leading to discontinuation of study drug 4 3
SAEs 8 2
Death 0 0
Time Frame From first dose to last dose plus 7 days (baseline up to 49 weeks)
Adverse Event Reporting Description on-treatment
 
Arm/Group Title Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Hide Arm/Group Description Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response. Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. Peginterferon alfa-2a (PegIFNα2a) 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for participants <75 kg) or 600 mg (3 tablets for participants >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
All-Cause Mortality
Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Affected / at Risk (%) Affected / at Risk (%)
Total   8/82 (9.76%)   2/42 (4.76%) 
Blood and lymphatic system disorders     
Anaemia  1  2/82 (2.44%)  0/42 (0.00%) 
Iron deficiency anaemia  1  1/82 (1.22%)  0/42 (0.00%) 
Endocrine disorders     
Basedow's disease  1  0/82 (0.00%)  1/42 (2.38%) 
Gastrointestinal disorders     
Gastritis  1  1/82 (1.22%)  0/42 (0.00%) 
Hepatobiliary disorders     
Bile duct stone  1  0/82 (0.00%)  1/42 (2.38%) 
Metabolism and nutrition disorders     
Diabetes mellitus  1  1/82 (1.22%)  0/42 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Thyroid cancer metastatic  1  1/82 (1.22%)  0/42 (0.00%) 
Nervous system disorders     
Cerebrovascular accident  1  1/82 (1.22%)  0/42 (0.00%) 
Cluster headache  1  1/82 (1.22%)  0/42 (0.00%) 
Skin and subcutaneous tissue disorders     
Erythema multiforme  1  1/82 (1.22%)  0/42 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Daclatasvir + PegIFNα2a + Ribavirin Placebo + PegIFNα2a + Ribavirin
Affected / at Risk (%) Affected / at Risk (%)
Total   80/82 (97.56%)   39/42 (92.86%) 
Blood and lymphatic system disorders     
Anaemia  1  20/82 (24.39%)  12/42 (28.57%) 
Neutropenia  1  12/82 (14.63%)  11/42 (26.19%) 
Eye disorders     
Dry eye  1  3/82 (3.66%)  4/42 (9.52%) 
Gastrointestinal disorders     
Abdominal pain upper  1  7/82 (8.54%)  5/42 (11.90%) 
Dry mouth  1  3/82 (3.66%)  3/42 (7.14%) 
Diarrhoea  1  7/82 (8.54%)  4/42 (9.52%) 
Dyspepsia  1  3/82 (3.66%)  3/42 (7.14%) 
Constipation  1  2/82 (2.44%)  3/42 (7.14%) 
Nausea  1  10/82 (12.20%)  5/42 (11.90%) 
General disorders     
Influenza like illness  1  23/82 (28.05%)  13/42 (30.95%) 
Irritability  1  11/82 (13.41%)  9/42 (21.43%) 
Pyrexia  1  13/82 (15.85%)  8/42 (19.05%) 
Asthenia  1  47/82 (57.32%)  25/42 (59.52%) 
Fatigue  1  6/82 (7.32%)  7/42 (16.67%) 
Metabolism and nutrition disorders     
Decreased appetite  1  20/82 (24.39%)  5/42 (11.90%) 
Abnormal loss of weight  1  5/82 (6.10%)  1/42 (2.38%) 
Musculoskeletal and connective tissue disorders     
Myalgia  1  15/82 (18.29%)  11/42 (26.19%) 
Back pain  1  11/82 (13.41%)  6/42 (14.29%) 
Arthralgia  1  9/82 (10.98%)  6/42 (14.29%) 
Nervous system disorders     
Headache  1  28/82 (34.15%)  11/42 (26.19%) 
Psychiatric disorders     
Anxiety  1  3/82 (3.66%)  4/42 (9.52%) 
Insomnia  1  18/82 (21.95%)  6/42 (14.29%) 
Depression  1  3/82 (3.66%)  3/42 (7.14%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  10/82 (12.20%)  8/42 (19.05%) 
Dyspnoea  1  5/82 (6.10%)  8/42 (19.05%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  12/82 (14.63%)  7/42 (16.67%) 
Eczema  1  3/82 (3.66%)  4/42 (9.52%) 
Rash  1  15/82 (18.29%)  8/42 (19.05%) 
Erythema  1  2/82 (2.44%)  5/42 (11.90%) 
Pruritus  1  25/82 (30.49%)  13/42 (30.95%) 
Alopecia  1  7/82 (8.54%)  2/42 (4.76%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01448044     History of Changes
Other Study ID Numbers: AI444-042
2011-002793-23 ( EudraCT Number )
First Submitted: October 5, 2011
First Posted: October 7, 2011
Results First Submitted: August 7, 2015
Results First Posted: September 7, 2015
Last Update Posted: October 12, 2015