Study of Daclatasvir (BMS-790052) Add-on to Standard of Care in Treatment- naïve Patients

A Phase 2b Study of Daclatasvir in Combination With Peg-Interferon Alfa-2a and Ribavirin in Treatment Naive Subjects With Chronic Hepatitis C Genotype 1 and 4 Infection

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01125189

Acronym

HEPCAT

Enrollment

558

Registered

2010-05-18

Start date

2010-07-31

Completion date

2012-08-31

Last updated

2015-10-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hepatitis C Virus

Brief summary

To establish that at least 1 dose of daclatasvir combined with standard of care (pegylated interferon and ribavirin) is safe and well tolerated and demonstrates extended rapid virologic response rates at least 35% greater than those with placebo.

Interventions

DRUGDaclatasvir

Tablets, oral, 20 mg, once daily, 12-24 weeks, depending on response

DRUGPlacebo

Tablets, oral, 0 mg, once daily, 24 weeks

DRUGpeg-interferon alfa-2a

Syringe, subcutaneous Injection, 180 µg, once weekly, 24 or 48 weeks depending on response

DRUGribavirin

Tablets, oral, 1000 or 1200 mg based on weight, once daily, 24 or 48 weeks depending on response

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Patients chronically infected with hepatitis C virus (HCV) genotype 1 or 4 * HCV RNA viral load of ≥100,000 IU/mL * No previous exposure to interferon, pegIFNα, or RBV * Results of a liver biopsy demonstrating absence of cirrhosis obtained ≤24 months prior to randomization. Compensated cirrhotics with Hepatitis C virus genotype 1 infection are eligible, but will be capped at 10% of the randomized study population (biopsy can be from any time period prior to randomization) * Findings on ultrasound, computed tomography scan, or magnetic resonance imaging 12 months prior to randomization that do not demonstrate evidence of hepatocellular carcinoma * Body mass index of 18 to 35 kg/m\^2

Exclusion criteria

* Positive for hepatitis B or HIV-1/HIV-2 antibody at screening * Evidence of a medical condition associated with chronic liver disease other than HCV * Evidence of decompensated cirrhosis based on radiologic criteria or biopsy

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Extended Rapid Virologic Response (eRVR)	Weeks 4 and 12	eRVR was defined as HCV RNA \<lower limit of quantitation and target not detected at both Weeks 4 and 12 on treatment.
Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Sustained Virologic Response (SVR24)	Follow-up Week 24	SVR24 was defined as HCV \<lower limit of quantitation (LLOQ) and target not detected (TND) at follow-up Week 24. The LLOQ was 25 IU/mL, and \<LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.
Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	From start of study treatment (day 1) up to follow-up Week 48	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.

Secondary

Measure	Time frame	Description
Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Rapid Virologic Response (RVR)	Week 4	RVR was defined as undetectable RNA (HCV RNA \<lower limit of quantitation \[LLOQ\], target not detected \[TND\]) at Week 4. The LLOQ was 25 IU/mL, and \<LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome.
Percentage of Resistant Variants Associated With Virologic Failure	Follow-up Week 48	Virologic failure was defined as: 1. Virologic breakthrough: confirmed \>1 log10 increase in hepatitis C virus (HCV) RNA over nadir or confirmed RNA ≥lower limit of quantitation (LLOQ) after confirmed HCV RNA \<LLOQ, target not detected (TND) while on treatment 2. \<1 log10 decrease in HCV RNA from baseline at Week 4 of treatment 3. Failure to achieve early virologic response: \<2 log10 decrease in HCV RNA from baseline and HCV RNA ≥LLOQ at Week 12 of treatment 4. HCV RNA \< LLOQ, TD or ≥ LLOQ at Week 12 and ≥ LLOQ at Week 24 5. HCV RNA ≥LLOQ or \<LLOQ, target detected (TD) at the end of treatment (EOT) (including early discontinuation) 6. Relapse, defined as HCV RNA ≥LLOQ or \<LLOQ, TD during follow-up, after HCV RNA \< LLOQ, TND at EOT. The LLOQ was 25 IU/mL, and \<LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome.
Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Complete Early Virologic Response (cEVR)	Week 12	cEVR was defined as undetectable RNA (HCV RNA \<lower limit of quantitation \[LLOQ\], target not detected \[TND\]) at Week 12. The LLOQ was 25 IU/mL, and \<LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome.
Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With 12-week Sustained Virologic Response (SVR12)	Follow-up Week 12	SVR12 was defined as undetectable RNA (HCV RNA \< lower limit of quantitation (LLOQ), target not detected (TND) at follow-up Week 12. The LLOQ was 25 IU/mL, and \<LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome.

Countries

Australia, Canada, Denmark, Egypt, France, Germany, Italy, Mexico, Puerto Rico, Sweden, United States

Participant flow

Recruitment details

Participants were enrolled at 64 sites in 11 countries.

Pre-assignment details

A total of 558 participants were enrolled in this study, and 395 participants were randomized and treated.

Participants by arm

Arm	Count
Daclatasvir (20 mg) + Peg-interferon Alfa-2a + Ribavirin Participants received daclatasvir tablets 20 mg orally, once daily with pegylated-interferon alfa-2a solution for injection 180 µg per 0.5 mL subcutaneously, once weekly, and ribavirin tablets 1000-1200 mg orally, twice daily for a total duration of 12 weeks. After Week 12, additional treatment was provided with interferon and ribavirin for a total of 24 or 48 weeks of therapy depending on whether or not the participant achieved an on-treatment response as defined in protocol.	159
Daclatasvir (60 mg) + Peg-interferon Alfa-2a + Ribavirin Participants received daclatasvir tablets 60 mg orally, once daily with pegylated-interferon alfa-2a solution for injection 180 µg per 0.5 mL subcutaneously, once weekly, and ribavirin tablets 1000-1200 mg orally, twice daily for a total duration of 12 weeks. After Week 12, additional treatment was provided with interferon and ribavirin for a total of 24 or 48 weeks of therapy depending on whether or not the participant achieved an on-treatment response as defined in protocol.	158
Placebo + Peg-interferon Alfa-2a + Ribavirin Participants received placebo matched with daclatasvir tablets orally, once daily with pegylated-interferon alfa-2a solution for injection 180 µg per 0.5 mL subcutaneously, once weekly, and ribavirin tablets 1000-1200 mg orally, twice daily, for a total duration of 24 weeks and pegylated-interferon alfa-2a and ribavirin, for a total duration of 48 weeks.	78
Total	395

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Follow up Period	Death	1	0	0
Follow up Period	Lost to Follow-up	12	9	6
Follow up Period	Other reasons	4	4	5
Follow up Period	Withdrawal by Subject	3	2	5
Treatment Period	Adverse Event	7	8	8
Treatment Period	Completed 24 week treatment period only	2	1	2
Treatment Period	Death	1	0	0
Treatment Period	Lack of Efficacy	15	18	25
Treatment Period	Lost to Follow-up	1	2	1
Treatment Period	Other reasons	1	1	0
Treatment Period	Participants requested to discontinue	1	3	4
Treatment Period	Poor compliance/noncompliance	0	1	0
Treatment Period	Withdrawal by Subject	3	1	1

Baseline characteristics

Characteristic	Daclatasvir (20 mg) + Peg-interferon Alfa-2a + Ribavirin	Daclatasvir (60 mg) + Peg-interferon Alfa-2a + Ribavirin	Placebo + Peg-interferon Alfa-2a + Ribavirin	Total
Age, Customized <65 years	154 participants	154 participants	77 participants	385 participants
Age, Customized ≥65 years	5 participants	4 participants	1 participants	10 participants
Hepatitis C Virus RNA Distribution <800,000 IU/mL	26 participants	35 participants	17 participants	78 participants
Hepatitis C Virus RNA Distribution ≥800,000 IU/mL	133 participants	123 participants	61 participants	317 participants
IL-28B Genotype CC genotype	53 participants	44 participants	23 participants	120 participants
IL-28B Genotype CT genotype	82 participants	86 participants	38 participants	206 participants
IL-28B Genotype Missing	7 participants	10 participants	6 participants	23 participants
IL-28B Genotype TT genotype	17 participants	18 participants	11 participants	46 participants
Sex: Female, Male Female	52 Participants	55 Participants	23 Participants	130 Participants
Sex: Female, Male Male	107 Participants	103 Participants	55 Participants	265 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	156 / 159	155 / 158	76 / 78
serious Total, serious adverse events	12 / 159	13 / 158	6 / 78

Outcome results

Primary

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

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) up to follow-up Week 48

Population: All treated participants.

Arm	Measure	Group	Value (NUMBER)
Daclatasvir (20 mg) + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	Death	2 participants
Daclatasvir (20 mg) + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	Discontinuations Due to AEs	7 participants
Daclatasvir (20 mg) + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	SAEs	12 participants
Daclatasvir (60 mg) + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	Discontinuations Due to AEs	7 participants
Daclatasvir (60 mg) + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	SAEs	13 participants
Daclatasvir (60 mg) + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	Death	0 participants
Placebo + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	SAEs	6 participants
Placebo + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	Death	0 participants
Placebo + Peg-interferon Alfa-2a + Ribavirin	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died	Discontinuations Due to AEs	8 participants

Primary

Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Extended Rapid Virologic Response (eRVR)

eRVR was defined as HCV RNA \<lower limit of quantitation and target not detected at both Weeks 4 and 12 on treatment.

Time frame: Weeks 4 and 12

Population: All treated participants. Here, 'number of participants' analyzed (N) signifies number of participants evaluable for this outcome measure.

Arm	Measure	Value (NUMBER)
Daclatasvir (20 mg) + Peg-interferon Alfa-2a + Ribavirin	Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Extended Rapid Virologic Response (eRVR)	54.4 percentage of participants
Daclatasvir (60 mg) + Peg-interferon Alfa-2a + Ribavirin	Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Extended Rapid Virologic Response (eRVR)	54.1 percentage of participants
Placebo + Peg-interferon Alfa-2a + Ribavirin	Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Extended Rapid Virologic Response (eRVR)	13.9 percentage of participants

Primary

Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Sustained Virologic Response (SVR24)

SVR24 was defined as HCV \<lower limit of quantitation (LLOQ) and target not detected (TND) at follow-up Week 24. The LLOQ was 25 IU/mL, and \<LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.

Time frame: Follow-up Week 24