Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus

A Phase 2, Open-Label Study of Daclatasvir (BMS-790052) and TMC435 in Combination With or Without Ribavirin (RBV) For Treatment-Naive Subjects or Null Responders to Prior Peginterferon Alfa (PegIFN)/RBV Therapy With Genotype 1 Chronic Hepatitis C

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01628692

Enrollment

230

Registered

2012-06-27

Start date

2012-07-31

Completion date

2013-11-30

Last updated

2017-02-23

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

The purpose of this study is to assess the safety and efficacy of daclatasvir and simeprevir with and without ribavirin for genotype 1 chronic hepatitis C virus infection in patients who are treatment-naive or null responders to previous pegylated interferon/ribavirin therapy.

Interventions

DRUGDaclatasvir

Tablets, oral, 30 mg, once daily

DRUGSimeprevir

Capsule, oral, 150 mg, once daily

DRUGRibavirin

Tablets, oral, 500-600 mg, twice daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * Hepatitis C virus (HCV) genotype 1a or 1b * Males and females, ≥18 years of age * HCV RNA ≥10,000 IU/mL * Participants with compensated cirrhosis are permitted * Advanced fibrosis (F3/F4) is capped at approximately 35% of the total treated population with a minimum of 20% F4 patients * If no cirrhosis, a liver biopsy within 3 years prior to enrollment * If cirrhosis is present, any prior liver biopsy Key

Exclusion criteria

* Liver or any other transplant (other than cornea and hair) * Evidence of a medical condition contributing to chronic liver disease other than HCV infection * Current or known history of cancer, (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment * Evidence of decompensated liver disease including, but not limited to, radiologic criteria, a history or presence of ascites, bleeding varices, or hepatic encephalopathy * Patients infected with HIV or hepatitis B virus * Gastrointestinal disease impacting absorption of study drug * Uncontrolled diabetes or hypertension * Prior exposure to an HCV direct-acting agent * Any criteria that would exclude the patient from receiving ribavirin * Absolute neutrophil count \<1.5\*1,000,000,000 cells/L (\<1.2\*1,000,000,000 cells/L for Black/African Americans) * Platelets \<90\*1,000,000,000 cells/L * Hemoglobin \<12 g/dL for females, \<13 g/dL for males * Alanine aminotransferase ≥5\*upper limit of normal * In patients without cirrhosis, total bilirubin ≥2 mg/dL unless patient has a documented history of Gilbert's disease * In patients with cirrhosis, total bilirubin o ≥1.5 mg/dL * International normalized ratio ≥1.7 * QTcF or QTcB \>500 mSec * Creatinine clearance ≤50 mL/min * Alpha fetoprotein (AFP) \>100 ng/mL OR * AFP ≥50 ng/mL and ≤100 ng/mL requiring liver ultrasound * Albumin \<3.5 g/dL

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	Post Treatment Week 12 (Follow-up period)	SVR12 rate was defined as hepatitis C virus (HCV) RNA levels to be \<lower limit of quantitation, target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.

Secondary

Measure	Time frame	Description
Percentage of Participants With Rapid Virologic Response (RVR) at Week 4	Week 4	RVR was defined as hepatitis C virus (HCV) RNA levels to be \<lower limit of quantitation, target not detected at Week 4. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.
Percentage of Participants With Complete Early Virologic Response (cEVR)	Week 12	cEVR was defined as hepatitis C virus (HCV) RNA levels to be \<lower limit of quantitation, target not detected at Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.
Percentage of Participants With Extended Rapid Virologic Response (eRVR)	Week 4 and Week 12	eRVR were defined as hepatitis C virus (HCV) RNA levels to be \<lower limit of quantitation, target not detected at both Week 4 and Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.
Percentage of Participants With End of Treatment Response (EOTR)	End of treatment (Week 24)	EOTR were defined as hepatitis C virus (HCV) RNA levels \<lower limit of quantitation, target not detected at end of treatment. 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) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories	Baseline, post-treatment Week 12 (Follow-up period)	Participants were categorized into 3 genotypes based on single nucleotide polymorphisms in the IL28B gene. SVR12 was defined as hepatitis C virus (HCV) RNA levels below lower limit of quantitation, target detected or target not detected at follow-up Week 12. 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) and Discontinuations Due to Adverse Events (AEs) and Who Died	From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24)	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. Based on the severity, AEs were categorized as Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.

Countries

Argentina, France, Germany, Hungary, Spain, United States

Participant flow

Recruitment details

The study was conducted at 25 centers in 6 countries.

Pre-assignment details

Of the 230 participants enrolled, 168 received treatment.

Participants by arm

Arm	Count
Genotype 1b: Daclatasvir + Simeprevir (Naive) Participants with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.	53
Genotype 1b: Daclatasvir + Simeprevir (Null) Participants with hepatitis C virus genotype 1b, and who never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal QD, for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.	23
Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Participants with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing \<75/\>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.	51
Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Participants with hepatitis C virus genotype 1b, who never attained ≥2 log10 decline in hepatitis C virus RNA level after 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing \<75/\>=75 kg, respectively) ribavirin BID were continued to receive treatment for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up period.	20
Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Participants with no prior treatment of hepatitis C virus genotype 1a. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing \<75/\>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.	12
Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null) Participants with hepatitis C virus genotype 1a, who never attained ≥2 log10 decline in hepatitis C virus genotype RNA level after 12 weeks of prior therapy. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing \<75/\>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.	9
Total	168

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Administrative reason by sponsor	0	0	0	0	0	1
Overall Study	Adverse Event	2	0	2	0	0	0
Overall Study	Completed 12 Week only	0	0	0	0	0	1
Overall Study	Death	0	1	0	0	0	0
Overall Study	Lack of Efficacy	4	4	5	1	4	7
Overall Study	Poor compliance/noncompliance	1	0	0	0	0	0
Overall Study	Withdrawal by Subject	0	1	1	0	0	0

Baseline characteristics

Characteristic	Total	Genotype 1b: Daclatasvir + Simeprevir (Naive)	Genotype 1b: Daclatasvir + Simeprevir (Null)	Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)	Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)	Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)	Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
Age, Customized 21-<65 years	133 participants	41 participants	19 participants	42 participants	11 participants	11 participants	9 participants
Age, Customized <21 years	2 participants	0 participants	0 participants	0 participants	1 participants	1 participants	0 participants
Age, Customized >=65 years	33 participants	12 participants	4 participants	9 participants	8 participants	0 participants	0 participants
Gender Female	86 Participants	31 Participants	11 Participants	26 Participants	11 Participants	5 Participants	2 Participants
Gender Male	82 Participants	22 Participants	12 Participants	25 Participants	9 Participants	7 Participants	7 Participants
Hepatitis C Virus RNA Distribution <800,000 IU/mL	35 participants	12 participants	3 participants	11 participants	4 participants	5 participants	0 participants
Hepatitis C Virus RNA Distribution ≥800,000 IU/mL	133 participants	41 participants	20 participants	40 participants	16 participants	7 participants	9 participants
Randomization Stratum Hepatitis C Virus Genotype 1a	21 participants	0 participants	0 participants	0 participants	0 participants	12 participants	9 participants
Randomization Stratum Hepatitis C Virus Genotype 1b	147 participants	53 participants	23 participants	51 participants	20 participants	0 participants	0 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	49 / 76	63 / 71	21 / 21
serious Total, serious adverse events	7 / 76	3 / 71	1 / 21

Outcome results

Primary

Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)

SVR12 rate was defined as hepatitis C virus (HCV) RNA levels to be \<lower limit of quantitation, target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.

Time frame: Post Treatment Week 12 (Follow-up period)

Population: All participants who were randomized and received at least 1 dose of active study therapy (daclatasvir, simeprevir, ribavirin).

Arm	Measure	Value (NUMBER)
Genotype 1b: Daclatasvir + Simeprevir (Naive)	Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	84.9 Percentage of participants
Genotype 1b: Daclatasvir + Simeprevir (Null)	Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	69.6 Percentage of participants
Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)	Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	74.5 Percentage of participants
Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)	Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	95 Percentage of participants
Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)	Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	66.7 Percentage of participants
Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)	Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	0 Percentage of participants

Secondary

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

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. Based on the severity, AEs were categorized as Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.

Time frame: From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24)