Study of the Anti-HCV Drug (BMS-790052) Combined With Peginterferon and Ribavirin in Patients Who Failed Prior Treatment

A Phase 2B Study of BMS-790052 in Combination With Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C Genotype 1 Infected Subjects Who Are Null or Partial Responders to Prior Treatment With Peginterferon Alfa Plus Ribavirin Therapy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01170962

Acronym

HEPCAT

Enrollment

512

Registered

2010-07-28

Start date

2010-08-31

Completion date

2012-12-31

Last updated

2015-10-12

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

The purpose of this study is to determine whether BMS-790052 added to Peginterferon Alfa-2a and ribavirin can result in higher cure rates in patients who previously failed therapy and may have limited response to retreatment with Peginterferon Alfa-2a and ribavirin alone.

Interventions

DRUGBMS-790052

Film coated tablet, Oral, 20 mg, once daily, 24 weeks

DRUGPlacebo

Film coated tablet, Oral, 0mg, Once daily, 24 weeks

DRUGpeginterferon alfa-2a

Solution for injection, Subcutaneous injection, 180 µg, weekly, 24 or 48 weeks

DRUGribavirin

Film coated tablet, Oral, 1,000 or 1,200 mg based on weight, divided dose taken twice a day (BID), 48 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Subjects chronically infected with HCV genotype 1 * Non-responder to prior therapy with peginterferon alfa and ribavirin * HCV RNA viral load of 100,00 IU/mL * Results of a liver biopsy ≤ 24 months prior to randomization consistent with chronic HCV infection; for compensated cirrhotics can be any time prior to randomization (compensated cirrhotics biopsy enrollment will be capped at 25% of randomized study population) * Ultrasound, CT scan or MRI results 12 months prior to randomization that do not demonstrate hepatocellular carcinoma * Body Mass Index (BMI) of 18 to 35 kg/m2

Exclusion criteria

* Positive for Hepatitis B infection (HBsAg) or HIV-1/HIV-2 antibody at screening * Evidence of 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 Participants With Extended Rapid Virologic Response (eRVR)	Week 4, Week 12	eRVR was defined as undetectable Hepatitis C virus RNA at both Weeks 4 and 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.
Percentage of Participants With 24-week Sustained Virologic Response (SVR24)	Follow-up Week 24	SVR24 was defined as undetectable RNA (Hepatitis C Virus \[HCV\] RNA \<lower limit of quantitation \[LLOQ\], target not detected \[TND\]) at follow-up Week 24. 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 On-treatment	From first dose to last dose plus 7 days, up to 49 weeks	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. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity; or was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization.
Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	From day 8 post last dose of treatment up-to Week 72	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. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or; 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 Participants With Rapid Virologic Response (RVR)	Week 4	RVR was defined as undetectable RNA ie., Hepatitis C virus (HCV) RNA \<lower limit of quantitation \[LLOQ\], target not detected (TND) at Week 4. 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 Genotypic-1B Substitution at Baseline, On-treatment and During Follow-up Associated With Virologic Failures	Baseline to follow-up Week 48	Non-structural protein 5A of HCV resistance associated polymorphisms in GT-1b samples, included L28M/V, R30H/Q, L31M, Q54H/N/Y, P58A/Q/S, Q62E/K/N/R/S, A92T/V and Y93F/H.
Percentage of Participants With Complete Early Virologic Response (cEVR)	Week 12	cEVR was defined as undetectable RNA ie., Hepatitis C virus (HCV) RNA \<lower limit of quantitation \[LLOQ\], target not detected (TND) at Week 12. TND was 10 IU/mL. HCV RNA levels were measured by the Roche Cobas® TaqMan® HCV Test version 2.0 from the central laboratory.
Percentage of Participants With Sustained Virologic Response at Week 12 (SVR12)	Follow-up Week 12	SVR12 was defined as undetectable RNA ie., Hepatitis C virus (HCV) RNA \<lower limit of quantitation (LLOQ), target not detected (TND) at follow-up Week 12. 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 Genotypic-1A Substitution at Baseline, On-treatment and During Follow-up Associated With Virologic Failures	Baseline to follow-up Week 48	Non-structural protein 5A of HCV resistance associated polymorphism in GT-1a samples included M28L/T/V, Q30H, L31M, H54Y, H58C/D/N/P/Q, E62D and Y93C.

Countries

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

Participant flow

Recruitment details

Participants were enrolled at 69 sites in 11 countries.

Pre-assignment details

A total of 512 participants were enrolled and 421 participants were randomized (2 randomized participants were not treated: 1 due to positive pregnancy test and 1 no longer met criteria). Remaining 91 participants were not randomized as; 73 no longer met study criteria, 15 withdrew consent, 1 due to administrative reason and 2 for other reasons.

Participants by arm

Arm	Count
Daclastavir (20mg): Prior Null and Partial Responders Participants (prior null or partial responders) received daclatasvir tablets 60 mg orally once daily, pegylated-interferon alfa-2a (pegIFNα-2a) injection 180 µg/0.5 mL subcutaneously once weekly, ribavirin tablets 1000-1200 mg orally twice daily for 24 weeks. At Week 24, participants with a protocol defined response (PDR: HCV RNA \<LOQ at Week 4, undetectable HCV RNA at Week 12) were randomized (1:1) to either a follow-up period of 48 weeks or received pegIFNα-2a and ribavirin for 24 weeks and then followed for 24 weeks. Participants with no PDR continued to receive pegIFNα-2a and ribavirin, for an additional 24 weeks and followed up for 24 weeks. Prior null responders: \<1 log10 HCV RNA decrease from baseline at or after 4 weeks, or \<2 log10 decrease from baseline in HCV RNA at or after Week 12 of IFN-based therapy. Prior Partial responders: \>2 log10 decrease in HCV RNA from baseline at Week 12 of IFN-based therapy but detectable HCV RNA when therapy was discontinued.	203
Daclastavir (60mg): Prior Null and Partial Responders Participants (prior null or partial responders) received daclatasvir tablets 20 mg orally once daily, pegylated-interferon alfa-2a (pegIFNα-2a) injection 180 µg/0.5 mL subcutaneously once weekly, ribavirin tablets 1000-1200 mg orally twice daily for 24 weeks. At Week 24, participants with a protocol defined response (PDR: HCV RNA \<LOQ at Week 4, undetectable HCV RNA at Week 12) were randomized (1:1) to either a follow-up period of 48 weeks or received pegIFNα-2a and ribavirin for 24 weeks and then followed for 24 weeks. Participants with no PDR continued to receive pegIFNα-2a and ribavirin, for an additional 24 weeks and followed up for 24 weeks. Prior null responders: \<1 log10 HCV RNA decrease from baseline at or after 4 weeks, or \<2 log10 decrease from baseline in HCV RNA at or after Week 12 of IFN-based therapy. Prior Partial responders: \>2 log10 decrease in HCV RNA from baseline at Week 12 of IFN-based therapy but detectable HCV RNA when therapy was discontinued.	199
Placebo: Prior Partial Responders Participants who were prior partial responders received placebo matched with daclatasvir tablets orally, once daily for 24 weeks. Participants received pegIFNα-2a 180 µg/0.5 mL subcutaneously, once weekly, and ribavirin tablets 1000-1200 mg orally, twice daily for 48 weeks and followed post treatment for 24 weeks. Prior partial responders: \>2 log10 decrease in HCV RNA from baseline at Week 12 of IFN-based therapy but detectable HCV RNA when therapy was discontinued.	17
Total	419

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Follow up Period	Death	2	2	0
Follow up Period	Lost to Follow-up	13	8	1
Follow up Period	Others	10	7	3
Follow up Period	Withdrawal by Subject	14	10	2
Treatment Period	Adverse Event	11	12	3
Treatment Period	Completed 24 Week treatment period only	10	2	0
Treatment Period	Lack of Efficacy	96	91	7
Treatment Period	Lost to Follow-up	1	1	1
Treatment Period	Participant no longer meets criteria	0	1	0
Treatment Period	Request to discontinue treatment	7	3	1
Treatment Period	Withdrawal by Subject	2	1	0

Baseline characteristics

Characteristic	Daclastavir (20mg): Prior Null and Partial Responders	Daclastavir (60mg): Prior Null and Partial Responders	Placebo: Prior Partial Responders	Total
Age, Customized 21-65 years	192 participants	189 participants	15 participants	396 participants
Age, Customized >=65 years	11 participants	10 participants	2 participants	23 participants
Sex: Female, Male Female	70 Participants	72 Participants	4 Participants	146 Participants
Sex: Female, Male Male	133 Participants	127 Participants	13 Participants	273 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	190 / 203	195 / 199	15 / 17
serious Total, serious adverse events	14 / 203	11 / 199	3 / 17

Outcome results

Primary

Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period

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. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization.

Time frame: From day 8 post last dose of treatment up-to Week 72

Population: Safety population included all treated participants.

Arm	Measure	Group	Value (NUMBER)
Daclatasvir (20 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	SAEs	6 participants
Daclatasvir (20 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	Death	2 participants
Daclatasvir (60 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	SAEs	7 participants
Daclatasvir (60 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	Death	2 participants
Daclatasvir (20 mg): Prior Partial Responders	Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	SAEs	0 participants
Daclatasvir (20 mg): Prior Partial Responders	Number of Participants With Serious Adverse Events (SAEs) and Who Died During Follow-up Period	Death	0 participants

Primary

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

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. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity; or was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization.

Time frame: From first dose to last dose plus 7 days, up to 49 weeks

Population: Safety population included all treated participants.

Arm	Measure	Group	Value (NUMBER)
Daclatasvir (20 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	AEs Leading to Discontinuation of Treatment	11 participants
Daclatasvir (20 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	SAEs	14 participants
Daclatasvir (20 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	Death	0 participants
Daclatasvir (60 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	AEs Leading to Discontinuation of Treatment	12 participants
Daclatasvir (60 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	SAEs	11 participants
Daclatasvir (60 mg): Prior Null Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	Death	0 participants
Daclatasvir (20 mg): Prior Partial Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	SAEs	3 participants
Daclatasvir (20 mg): Prior Partial Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	Death	1 participants
Daclatasvir (20 mg): Prior Partial Responders	Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died On-treatment	AEs Leading to Discontinuation of Treatment	3 participants

Primary

Percentage of Participants With 24-week Sustained Virologic Response (SVR24)

SVR24 was defined as undetectable RNA (Hepatitis C Virus \[HCV\] RNA \<lower limit of quantitation \[LLOQ\], target not detected \[TND\]) at follow-up Week 24. 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