Filibuvir In Treatment Naive Hepatitis C Virus (HCV) Genotype 1 Subjects

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study To Evaluate The Safety And Efficacy Of Filibuvir Plus Pegylated Interferon Alfa-2a And Ribavirin In Treatment-Naive, HCV Genotype 1 Infected Subjects

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00987337

Acronym

FITNESS

Enrollment

288

Registered

2009-09-30

Start date

2009-11-30

Completion date

2012-01-31

Last updated

2014-01-27

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

Conditions

Hepatitis, Hepatitis C

Keywords

Hepatitis C Polymerase Inhibitor PF-00868554 Filibuvir

Brief summary

The primary objective for this study is to determine if the addition of filibuvir to a standard regimen of peginterferon/ribavirin (pegIFN/RBV) significantly increases the proportion of subjects who achieve a sustained viral response (SVR) compared to peginterferon/ribavirin (pegIFN/RBV) therapy alone.

Interventions

DRUGFilibuvir

300 mg BID

DRUGPlacebo

BID

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Male or female subjects at least 18 years of age. * HCV seropositive. * HCV RNA \>10,000 IU/mL at screening. * HCV Genotype 1. Subjects infected with a non-genotype 1 strain or mixed genotypes are not eligible. * Treatment naïve (no prior treatment with IFN alfa +/ RBV regimens or investigational anti-HCV agents). * Liver biopsy within two years (24 months) of Screening with non-cirrhotic fibrosis classification. For those subjects with liver biopsy outside of the time window or for those subjects with no history of liver biopsy, a biopsy must be performed prior to randomization. * Ultrasound within 6 months of Screening for 1) those subjects with bridging fibrosis or 2) those subjects with AFP \>50 and \<100 ng/mL with no evidence of hepatocellular carcinoma. For those subjects with an ultrasound conducted outside the 6-month time window, an ultrasound must be performed prior to randomization.

Exclusion criteria

* Co-infection with either HIV or HBV. * Evidence of severe or decompensated liver disease. * Subjects with liver disease unrelated to HCV infection. * Pre-existing medical condition that makes the subject unsuitable for treatment with pegIFN/RBV therapy per product labeling. * Laboratory abnormality at Screening that makes the subject unsuitable for treatment with pegIFN/RBV therapy per product labeling. * Abnormal ECG suggestive of clinically significant cardiac disease or QTc\>450msec. * History of organ transplant. * Contraindicated medications being taken by the subject at the time of randomization that must be continued during the study period, including potent CYP3A4 inhibitors, sensitive CYP3A4 substrates, CYP3A4 substrates with narrow therapeutic range and CYP3A4 inducers. * Active alcohol or substance abuse sufficient, in the Investigator's judgment, to prevent adherence to study medication and/or follow up. * Pregnant or nursing females. * Males whose female partner is pregnant.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Sustained Viral Response (SVR) at Week 72	Week 72	For participants who received filibuvir, had undetectable HCV RNA from Week 4 through 24 and discontinued therapy at Week 24, SVR was defined as undetectable plasma HCV RNA levels (\<15 IU/mL) at both Week 24 (End of Treatment \[EOT\]) and Week 72, regardless of the HCV RNA levels between Week 24 and 72. For participants who received filibuvir, had detectable HCV RNA at Week 4 or later and discontinued therapy at Week 48 or who received placebo, SVR was defined as undetectable plasma HCV RNA levels (\<15 IU/mL) at both Week 48 (EOT) and Week 72, regardless of the HCV RNA levels between Week 48 and 72.

Secondary

Measure	Time frame	Description
Percentage of Participants With Sustained Viral Response at 12 Weeks Following Completion of Therapy (SVR12)	12 weeks after completion of therapy (Week 36 or 60)	A participant was considered to have achieved SVR12 if the plasma HCV RNA levels were \<15 IU/mL at both the end of treatment (Week 24 or 48, depending on the time of therapy discontinuation based on HCV RNA levels during therapy) and 12 weeks following the completion of therapy (Week 36 for participants who ended therapy at Week 24; Week 60 for participants who ended therapy at Week 48). Overall percentage of participants with SVR12 was summarized.
Percentage of Participants With Sustained Viral Response at 24 Weeks Following Completion of Therapy (SVR24)	24 weeks after completion of therapy (Week 48 or 72)	SVR24 was summarized only for those participants who received filibuvir, had undetectable HCV RNA from Week 4 through 24 and discontinued therapy at Week 24 and all participants who received placebo for 48 weeks. A participant was considered to have achieved SVR24 if the plasma HCV RNA levels were \<15 IU/mL at both the end of treatment (Week 24 for filibuvir participants who ended therapy at Week 24 and Week 48 for participants who received placebo) and 24 weeks following the completion of therapy (Week 48 for filibuvir participants who ended therapy at Week 24; Week 72 for placebo participants who ended therapy at Week 48).
Percentage of Participants With Breakthrough Viremia	Baseline up to Week 48	A participant was considered to have breakthrough viremia if there was a \>2 log10 increase from nadir in HCV RNA concentration while on treatment or HCV RNA that became undetectable with treatment but then became persistently detectable (2 or more consecutive viral RNA measurements \>1000 IU/mL) again during treatment. Overall percentage of participants with breakthrough viremia was summarized.
Percentage of Participants With Relapsed Response	Week 24 or Week 48 up to Week 72	A participant was considered to have relapsed response if the plasma HCV RNA levels were undetectable at end of treatment (Week 24 or 48, depending on the time of therapy discontinuation based on HCV RNA levels during therapy) but detectable (\>=15 IU/mL) during the off-treatment follow-up period up to Week 72. Overall percentage of participants with relapsed response was summarized.
Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Baseline, Week 4, 12, 24	Plasma HCV RNA levels were measured using the Roche COBAS TaqMan assay (limit of detection: 15 IU/mL). Baseline value calculated as the average of the screening and Day 1 pre-dose measurements.
Percentage of Participants With Undetectable Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12, 24 and 48	Week 4, 12, 24, 48	Percentage of participants with undetectable HCV RNA at Week 4 (rapid viral response \[RVR\]), Week 12 (early viral response \[EVR\]), Week 24 and Week 48 were summarized. Undetectable HCV RNA was defined as plasma HCV RNA levels \<15 IU/mL.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Relationship to Study Drug (Any Therapy)	Baseline up to Week 72	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Week 72 that were absent before treatment or that worsened relative to pretreatment state. All causality AEs included SAEs as well as non-serious AEs, without regard to relationship to the study drug, which occurred during the trial. Treatment-related were events considered related to study drug by the investigator. Number of participants with treatment related TEAEs and all causality TEAEs were summarized.
Number of Participants Who Discontinued Study Due to Adverse Events (AEs)	Baseline up to Week 72	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Number of Participants With Dose Reduction or Temporary Discontinuation Due to Adverse Events (AEs)	Baseline up to Week 72	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Number of Participants With Laboratory Test Abnormalities by Severity	Baseline up to Week 72	Number of participants with laboratory abnormalities by Division of Auto Immune Disease Syndrome (DAIDS) grade of 4; 3 or 4; 2, 3 or 4 was summarized. Abnormal laboratory values refers to a DAIDS grade greater than 0, where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4 = potentially life-threatening.
Plasma Concentration of Filibuvir, Pegylated Interferon and Ribavirin	Week 0 (pre-dose), Week 2, 4, 8, 12, 16, 20, 24, 48 (only for those participants who received treatment till Week 48) post-dose	—
Number of Adverse Events (AEs) by Severity (All Causality)	Baseline up to Week 72	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Adverse events were graded as mild (did not interfere with participant's usual function), moderate (interfered to some extent with participant's usual function) or severe (interfered significantly with participant's usual function). The most severe grade was used in case of multiple occurrences of the same event.

Countries

Belgium, Canada, France, Germany, Hungary, Puerto Rico, South Korea, Spain, United States

Participant flow

Participants by arm

Arm	Count
Filibuvir 300 mg Plus pegIFN/RBV Filibuvir 300 mg tablet orally twice daily as blinded therapy along with pegIFN alpha-2a 180 mcg subcutaneously once weekly and RBV 1000 mg/day to participants weighing \<=75 kg or RBV 1200 mg/day to participants weighing \>75 kg orally in 2 divided doses up to Week 24. Participants with undetectable HCV RNA (plasma HCV RNA \<15 IU/mL) from Week 4 through 24 were discontinued from therapy and followed through Week 72. Participants with detectable HCV RNA (\>=15 IU/mL) at Week 4 or later but undetectable at Week 24 received open-label pegIFN alpha-2a 180 mcg subcutaneously once weekly and RBV 1000 mg/day if participant weighed \<=75 kg or RBV 1200 mg/day if participant weighed \> 75 kg, orally in 2 divided doses up to Week 48 and then followed through Week 72.	96
Filibuvir 600 mg Plus pegIFN/RBV Filibuvir 600 mg tablet orally twice daily as blinded therapy along with pegIFN alpha-2a 180 mcg subcutaneously once weekly and RBV 1000 mg/day to participants weighing \<=75 kg or RBV 1200 mg/day to participants weighing \>75 kg orally in 2 divided doses up to Week 24. Participants with undetectable HCV RNA (plasma HCV RNA \<15 IU/mL) from Week 4 through 24 were discontinued from therapy and followed through Week 72. Participants with detectable HCV RNA (\>=15 IU/mL) at Week 4 or later but undetectable at Week 24 received open-label pegIFN alpha-2a 180 mcg subcutaneously once weekly and RBV 1000 mg/day if participant weighed \<=75 kg or RBV 1200 mg/day if participant weighed \> 75 kg, orally in 2 divided doses up to Week 48 and then followed through Week 72.	96
Placebo Plus pegIFN/RBV Placebo matched to filibuvir tablet orally twice daily as blinded therapy in combination with pegIFN alpha-2a 180 mcg subcutaneously once weekly and RBV 1000 mg/day to participants weighing \<=75 kg or RBV 1200 mg/day to participants weighing \>75 kg, orally in 2 divided doses up to Week 24 followed by open-label pegIFN alpha-2a 180 mcg subcutaneously once weekly and RBV 1000 mg/day to participants weighing \<=75 kg or RBV 1200 mg/day to participants weighing \>75 kg orally in 2 divided doses up to Week 48. Participants were then followed through Week 72.	96
Total	288

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	10	9	8
Overall Study	Insufficient Virologic Response	10	7	12
Overall Study	Lost to Follow-up	10	6	2
Overall Study	Other	0	2	5
Overall Study	Participant Relapsed	18	20	5
Overall Study	Protocol Violation	1	0	2
Overall Study	Virologic Breakthrough	2	2	8
Overall Study	Withdrawal by Subject	6	9	9

Baseline characteristics

Characteristic	Filibuvir 300 mg Plus pegIFN/RBV	Filibuvir 600 mg Plus pegIFN/RBV	Placebo Plus pegIFN/RBV	Total
Age, Customized 18 to 44 years	36 participants	25 participants	31 participants	92 participants
Age, Customized 45 to 64 years	56 participants	68 participants	61 participants	185 participants
Age, Customized >=65 years	4 participants	3 participants	4 participants	11 participants
Sex: Female, Male Female	44 Participants	47 Participants	44 Participants	135 Participants
Sex: Female, Male Male	52 Participants	49 Participants	52 Participants	153 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	85 / 96	89 / 96	90 / 96
serious Total, serious adverse events	14 / 96	6 / 96	6 / 96

Outcome results

Primary

Percentage of Participants With Sustained Viral Response (SVR) at Week 72

For participants who received filibuvir, had undetectable HCV RNA from Week 4 through 24 and discontinued therapy at Week 24, SVR was defined as undetectable plasma HCV RNA levels (\<15 IU/mL) at both Week 24 (End of Treatment \[EOT\]) and Week 72, regardless of the HCV RNA levels between Week 24 and 72. For participants who received filibuvir, had detectable HCV RNA at Week 4 or later and discontinued therapy at Week 48 or who received placebo, SVR was defined as undetectable plasma HCV RNA levels (\<15 IU/mL) at both Week 48 (EOT) and Week 72, regardless of the HCV RNA levels between Week 48 and 72.

Time frame: Week 72

Population: ITT population included all randomized participants who took at least 1 dose of study drug. If a participant had a missing value at Week 72, participant was considered a failure; if a participant had achieved SVR but died or discontinued within same time period, the participant was considered a success.

Arm	Measure	Value (NUMBER)
Filibuvir 300 mg Plus pegIFN/RBV	Percentage of Participants With Sustained Viral Response (SVR) at Week 72	41.7 percentage of participants
Filibuvir 600 mg Plus pegIFN/RBV	Percentage of Participants With Sustained Viral Response (SVR) at Week 72	39.6 percentage of participants
Placebo Plus pegIFN/RBV	Percentage of Participants With Sustained Viral Response (SVR) at Week 72	45.8 percentage of participants

Secondary

Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24

Plasma HCV RNA levels were measured using the Roche COBAS TaqMan assay (limit of detection: 15 IU/mL). Baseline value calculated as the average of the screening and Day 1 pre-dose measurements.

Time frame: Baseline, Week 4, 12, 24

Population: ITT population included all randomized participants who took at least 1 dose of study drug. LOCF method was used for imputing missing values for participants who did not discontinue from study. Final value was imputed as baseline for participants who discontinued before the time point of interest.

Arm	Measure	Group	Value (MEAN)	Dispersion
Filibuvir 300 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 24	-3.7 log10 IU/mL	Standard Deviation 2.2
Filibuvir 300 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 4	-4.0 log10 IU/mL	Standard Deviation 1.6
Filibuvir 300 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Baseline	6.1 log10 IU/mL	Standard Deviation 0.7
Filibuvir 300 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 12	-4.1 log10 IU/mL	Standard Deviation 1.8
Filibuvir 600 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Baseline	6.0 log10 IU/mL	Standard Deviation 0.6
Filibuvir 600 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 24	-3.8 log10 IU/mL	Standard Deviation 2.1
Filibuvir 600 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 12	-4.2 log10 IU/mL	Standard Deviation 1.6
Filibuvir 600 mg Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 4	-4.2 log10 IU/mL	Standard Deviation 1.2
Placebo Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 24	-3.9 log10 IU/mL	Standard Deviation 2
Placebo Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 12	-3.9 log10 IU/mL	Standard Deviation 1.7
Placebo Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Change at Week 4	-3.0 log10 IU/mL	Standard Deviation 1.6
Placebo Plus pegIFN/RBV	Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4, 12 and 24	Baseline	6.1 log10 IU/mL	Standard Deviation 0.7

Secondary

Number of Adverse Events (AEs) by Severity (All Causality)

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Adverse events were graded as mild (did not interfere with participant's usual function), moderate (interfered to some extent with participant's usual function) or severe (interfered significantly with participant's usual function). The most severe grade was used in case of multiple occurrences of the same event.