Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination (FDC) With and Without Ribavirin for the Treatment of HCV

A Phase 3, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/GS-5885 Fixed-Dose Combination (FDC) +/- Ribavirin for 12 and 24 Weeks in Treatment-Naive Subjects With Chronic Genotype 1 HCV Infection.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01701401

Enrollment

870

Registered

2012-10-05

Start date

2012-09-30

Completion date

2014-04-30

Last updated

2018-11-16

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

Conditions

Chronic Hepatitis C Virus

Keywords

HCV genotype 1 (GT-1), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, GS-7977, GS-5885, Ribavirin, Open Label, Sofosbuvir, Additional relevant MeSH terms:, Hepatitis, Hepatitis, Chronic, Hepatitis C, Hepatitis C, Chronic, Liver Diseases, Digestive System Diseases, Hepatitis, Viral, Human, Virus Diseases, Enterovirus Infections, Picornaviridae Infections, RNA Virus Infections, Flaviviridae Infections, Antiviral Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions, Antimetabolites, Molecular Mechanisms of Pharmacological Action

Brief summary

The purpose of this study is to evaluate the safety, tolerability, and antiviral efficacy of ledipasvir (LDV)/sofosbuvir (SOF) fixed-dose combination (FDC) tablets with or without ribavirin (RBV) administered for 12 and 24 weeks in treatment-naive subjects with chronic genotype 1 HCV infection.

Interventions

DRUGLDV/SOF

LDV/SOF 90/400 mg FDC tablet administered orally once daily

DRUGRBV

RBV tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

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

* Age ≥ 18, with chronic genotype 1 HCV infection * HCV treatment-naive * HCV RNA \> 10,000 IU/mL at screening * Cirrhosis determination; a liver biopsy may be required * Screening laboratory values within defined thresholds * Use of two effective contraception methods if female of childbearing potential or sexually active male

Exclusion criteria

* Pregnant or nursing female or male with pregnant female partner * Co-infection with HIV or hepatitis B virus (HBV) * Current or prior history of clinical hepatic decompensation * Hepatocellular carcinoma (HCC) or other malignancy (with exception of certain resolved skin cancers) * Chronic use of systemic immunosuppressive agents * History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12)	Posttreatment Week 12	SVR12 was defined as HCV RNA level \< the lower limit of quantification (LLOQ, ie, \< 25 copies/mL) 12 weeks after last dose of study drug.
Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug	Up to 24 weeks	The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized.

Secondary

Measure	Time frame	Description
Percentage of Participants With HCV RNA < LLOQ at Week 8	Week 8	—
Change From Baseline in HCV RNA at Week 2	Baseline; Week 2	—
Change From Baseline in HCV RNA at Week 4	Baseline; Week 4	—
Percentage of Participants With HCV RNA < LLOQ at Week 2	Week 2	—
Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Study Drug	Posttreatment Weeks 4 and 24	SVR4 and SVR24 were defined as HCV RNA level \< LLOQ at 4 and 24 weeks after discontinuation of study drug, respectively.
Percentage of Participants With Virologic Failure	Baseline to posttreatment Week 24	On-treatment virologic failure was defined as: * Breakthrough: HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ, while on treatment, confirmed with 2 consecutive values (second confirmation value could have been posttreatment), or last available on-treatment measurement with no subsequent follow- up values, OR * Rebound: \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 2 consecutive values (second confirmation value could have been posttreatment), or last available on-treatment measurement with no subsequent follow-up values, OR * Nonresponse: HCV RNA persistently ≥ LLOQ through 8 weeks of treatment Virologic relapse was defined as HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement
Change From Baseline in HCV RNA at Week 8	Baseline; Week 8	—
Percentage of Participants With HCV RNA < LLOQ at Week 4	Week 4	—

Countries

France, Germany, Italy, Puerto Rico, Spain, United Kingdom, United States

Participant flow

Recruitment details

Participants were enrolled at a total of 100 study sites in the United States and Europe. The first participant was screened on 26 September 2012. The last study visit occurred on 30 April 2014.

Pre-assignment details

1015 participants were screened.

Participants by arm

Arm	Count
LDV/SOF 12 Weeks LDV/SOF 90/400 mg FDC tablet once daily for 12 weeks	214
LDV/SOF+RBV 12 Weeks LDV/SOF 90/400 mg FDC tablet once daily plus RBV tablets (1000 to 1200 mg daily based on weight) in a divided daily dose for 12 weeks	217
LDV/SOF 24 Weeks LDV/SOF 90/400 mg FDC tablet once daily for 24 weeks	217
LDV/SOF+RBV 24 Weeks LDV/SOF 90/400 mg FDC tablet once daily plus RBV tablets (1000 to 1200 mg daily based on weight) in a divided daily dose for 24 weeks	217
Total	865

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	1	0	0	0
Overall Study	Lack of Efficacy	1	0	2	0
Overall Study	Lost to Follow-up	5	5	1	3
Overall Study	Protocol Violation	0	0	1	0
Overall Study	Randomized But Not Treated	3	1	0	1
Overall Study	Withdrew Consent	0	3	1	2

Baseline characteristics

Characteristic	LDV/SOF 24 Weeks	LDV/SOF+RBV 24 Weeks	Total	LDV/SOF+RBV 12 Weeks	LDV/SOF 12 Weeks
Age, Continuous	53 years STANDARD_DEVIATION 10.3	53 years STANDARD_DEVIATION 9.9	52 years STANDARD_DEVIATION 10.6	52 years STANDARD_DEVIATION 11.5	52 years STANDARD_DEVIATION 10.7
HCV Genotype Genotype 1a	146 participants	143 participants	581 participants	148 participants	144 participants
HCV Genotype Genotype 1b	68 participants	71 participants	273 participants	68 participants	66 participants
HCV Genotype Genotype 1 (no confirmed subtype)	1 participants	1 participants	4 participants	1 participants	1 participants
HCV Genotype Genotype 4	0 participants	1 participants	2 participants	0 participants	1 participants
HCV Genotype Missing	2 participants	1 participants	5 participants	0 participants	2 participants
HCV RNA Category < 800,000 IU/mL	49 participants	44 participants	182 participants	44 participants	45 participants
HCV RNA Category ≥ 800,000 IU/mL	168 participants	173 participants	683 participants	173 participants	169 participants
Hepatitis C Virus (HCV) RNA	6.3 log10 IU/mL STANDARD_DEVIATION 0.68	6.3 log10 IU/mL STANDARD_DEVIATION 0.65	6.4 log10 IU/mL STANDARD_DEVIATION 0.66	6.4 log10 IU/mL STANDARD_DEVIATION 0.64	6.4 log10 IU/mL STANDARD_DEVIATION 0.69
IL28b Status CC	52 participants	73 participants	256 participants	76 participants	55 participants
IL28b Status CT	119 participants	112 participants	451 participants	107 participants	113 participants
IL28b Status TT	46 participants	32 participants	158 participants	34 participants	46 participants
Race/Ethnicity, Customized American Indian/Alaska Native	0 participants	1 participants	2 participants	1 participants	0 participants
Race/Ethnicity, Customized Asian	5 participants	5 participants	11 participants	0 participants	1 participants
Race/Ethnicity, Customized Black or African American	32 participants	26 participants	108 participants	26 participants	24 participants
Race/Ethnicity, Customized Hawaiian or Pacific Islander	1 participants	0 participants	1 participants	0 participants	0 participants
Race/Ethnicity, Customized Hispanic or Latino	29 participants	26 participants	101 participants	20 participants	26 participants
Race/Ethnicity, Customized Not Disclosed	0 participants	1 participants	2 participants	0 participants	1 participants
Race/Ethnicity, Customized Not Hispanic or Latino	188 participants	190 participants	762 participants	197 participants	187 participants
Race/Ethnicity, Customized Other	2 participants	1 participants	6 participants	1 participants	2 participants
Race/Ethnicity, Customized White	177 participants	183 participants	735 participants	188 participants	187 participants
Region of Enrollment France	18 participants	10 participants	63 participants	24 participants	11 participants
Region of Enrollment Germany	22 participants	18 participants	84 participants	20 participants	24 participants
Region of Enrollment Italy	23 participants	23 participants	96 participants	23 participants	27 participants
Region of Enrollment Spain	12 participants	14 participants	55 participants	15 participants	14 participants
Region of Enrollment United Kingdom	10 participants	15 participants	55 participants	17 participants	13 participants
Region of Enrollment United States	132 participants	137 participants	512 participants	118 participants	125 participants
Sex: Female, Male Female	78 Participants	98 Participants	352 Participants	89 Participants	87 Participants
Sex: Female, Male Male	139 Participants	119 Participants	513 Participants	128 Participants	127 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	140 / 214	168 / 217	149 / 217	189 / 217
serious Total, serious adverse events	1 / 214	7 / 217	18 / 217	7 / 217

Outcome results

Primary

Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug

The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized.

Time frame: Up to 24 weeks

Population: Safety Analysis Set: participants were randomized and received at least 1 dose of study drug.

Arm	Measure	Value (NUMBER)
LDV/SOF 12 Weeks	Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug	0 percentage of participants
LDV/SOF+RBV 12 Weeks	Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug	0.5 percentage of participants
LDV/SOF 24 Weeks	Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug	1.8 percentage of participants
LDV/SOF+RBV 24 Weeks	Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug	3.7 percentage of participants

Primary

Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12)

SVR12 was defined as HCV RNA level \< the lower limit of quantification (LLOQ, ie, \< 25 copies/mL) 12 weeks after last dose of study drug.

Time frame: Posttreatment Week 12

Population: Full Analysis Set: participants were randomized and received at least 1 dose of study drug.

Arm	Measure	Value (NUMBER)
LDV/SOF 12 Weeks	Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12)	98.6 percentage of participants
LDV/SOF+RBV 12 Weeks	Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12)	97.2 percentage of participants
LDV/SOF 24 Weeks	Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12)	98.2 percentage of participants
LDV/SOF+RBV 24 Weeks	Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12)	99.1 percentage of participants

p-value: <0.001Binomial test

Secondary