A Trial of IDN-6556 in Post Orthotopic Liver Transplant for Chronic HCV

A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects Who Had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis Following Orthotopic Liver Transplantation for Chronic HCV Infection and Who Subsequently Achieved a Sustained Virologic Response Following Anti-HCV Therapy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02138253

Acronym

POLT-HCV-SVR

Enrollment

Registered

2014-05-14

Start date

2014-05-31

Completion date

2018-03-09

Last updated

2019-12-11

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

Conditions

Hepatic Cirrhosis, Hepatic Fibrosis, Liver Cirrhosis, Liver Fibrosis

Keywords

liver transplant, hepatitis C, liver fibrosis, hepatic fibrosis, liver cirrhosis, hepatic cirrhosis

Brief summary

This is a double-blind, multicenter study involving patients with chronic HCV infection who had a liver transplantation; developed HCV-related liver fibrosis and/or incomplete cirrhosis; achieved a sustained virologic response (SVR) following anti-HCV therapy; but still have fibrosis and/or incomplete cirrhosis on liver biopsy to see if treatment with IDN-6556 is better than placebo in reversing or stopping the progression of the damage to the new liver caused by HCV.

Detailed description

There are data to suggest that with eradication of the HCV virus, improvements in liver fibrosis can be seen in the post-transplant population. However, amelioration of inflammatory activity, and deceleration of fibrosis progression is a gradual process over the course of many years. This placebo-controlled study is designed to evaluate the effects of IDN-6556, compared to placebo, on markers of apoptosis and inflammation, and liver histology.

Interventions

DRUGIDN-6556

DRUGPlacebo

Placebo control

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 No maximum

Healthy volunteers

Inclusion criteria

* Male or female subjects of minimum adult legal age (according to local laws for signing the informed consent document), able to provide written informed consent, and able to understand and willing to comply with the requirements of the study * History of orthotopic liver transplantation for HCV-induced liver disease * Diagnosis of HCV infection (HCV-RNA detectable in serum) and liver fibrosis and/or incomplete cirrhosis status post liver transplantation, and achieved a sustained virologic response (SVR) with anti-viral HCV treatment within 18 months of Day 1 * Liver fibrosis on liver histology as read by central histopathologist of Ishak F2 to F6 within three months of Day 1 (Up to 15 subjects with an Ishak score of F6 can be enrolled) * Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from Screening to one month after the last dose of study drug

Exclusion criteria

* Known infection with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) * History of renal transplant and/or severe renal impairment defined as eGFR (estimated glomerular filtration rate) of less than 30 mL/min/1.73 m2 * Evidence of tumor burden \>Milan criteria, or evidence of micro- or macrovascular invasion in explanted liver * Hepatocellular carcinoma (HCC) at entry into the study * Concurrent sirolimus (rapamycin) use * History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of \> 480 milliseconds (msec) * Subjects with diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA) * If female: known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score	24 months	At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite Since the primary analysis used multiple imputation methodology, the numerator and denominator varied across 20 imputations.

Secondary

Measure	Time frame	Description
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score	12 months	At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite
Alanine Aminotransferase (ALT) - Change From Baseline	Baseline and 24 months	Liver function laboratory parameter
Aspartate Aminotransferase (AST) Change From Baseline	Baseline and 24 months	Liver function laboratory parameter
Caspase 3/7 Change From Baseline	Baseline and 24 months	Mechanistic biomarker of liver function
cCK18/M30 Change From Baseline	Baseline and 24 months	Mechanistic biomarker of liver function.
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only)	24 months	At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite
Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis	24 months	The Ishak modification of Knodell histological activity index was determined by liver biopsy. Interface hepatitis * 0 = None * 1 = Mild (local, few portal areas) * 2 = Mild/moderate (focal, most portal areas) * 3 = Moderate (continuous around \<50% of tracts or septa) * 4 = Severe (continuous around \>50% of tracts or septa)
Ishak Modification of Knodell Histological Index - Confluent Necrosis	24 months	The Ishak modification of Knodell histological activity index will be determined by liver biopsy. The four items and their categorizations scores include: • confluent necrosis * 0 = None * 1 = Focal confluent necrosis * 2 = Zone 3 necrosis in some areas * 3 = Zone 3 necrosis in most areas * 4 = Zone 3 necrosis + occasional portal-central bridging * 5 = Zone 3 necrosis + multiple portal-central bridging * 6 = Panacinar or multiacinar necrosis
Ishak Modification of Knodell Histological Index - Parenchymal Injury	24 months	The Ishak modification of Knodell histological activity index will be determined by liver biopsy. • parenchymal injury (focal lytic necrosis, apoptosis and focal inflammation) * 0 = None * 1 = One focus or less per 10× objective * 2 = Two to four foci per 10× objective * 3 = Five to ten foci per 10× objective * 4 = More than ten foci per 10× objective
Ishak Modification of Knodell Histological Index - Portal Inflammation	24 months	Portal inflammation * 0 = None * 1 = Mild, some or all portal areas * 2 = Moderate, some or all portal areas * 3 = Moderate/marked, all portal areas * 4 = Marked, all portal areas
flCK18/M65 Change From Baseline	Baseline and 24 months	Mechanistic biomarker of liver function

Countries

United States

Participant flow

Recruitment details

Subjects were enrolled from 20 of 35 US sites that obtained IRB approval. First subject randomized Sep 2014, last subject last visit was 15 Feb 2018. A total of 114 subjects were screened, 64 subjects randomized with 41 subjects randomized to emricasan and 23 subjects randomized to placebo. Thirteen subjects discontinued the study.

Participants by arm

Arm	Count
IDN-6556 IDN-6556 25 mg BID IDN-6556	41
Placebo Placebo BID Placebo: Placebo control	23
Total	64

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	3
Overall Study	Lost to Follow-up	2	1
Overall Study	Non compliance	1	0
Overall Study	Physician Decision	2	0
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	IDN-6556	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	12 Participants	6 Participants	18 Participants
Age, Categorical Between 18 and 65 years	29 Participants	17 Participants	46 Participants
Baseline Ishak Fibrosis Score Baseline Ishak Fibrosis Score F2	9 participants	6 participants	15 participants
Baseline Ishak Fibrosis Score Baseline Ishak Fibrosis Score F3	20 participants	7 participants	27 participants
Baseline Ishak Fibrosis Score Baseline Ishak Fibrosis Score F4	5 participants	5 participants	10 participants
Baseline Ishak Fibrosis Score Baseline Ishak Fibrosis Score F5	2 participants	2 participants	4 participants
Baseline Ishak Fibrosis Score Baseline Ishak Fibrosis Score F6	5 participants	3 participants	8 participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants	6 Participants	16 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	31 Participants	17 Participants	48 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	7 Participants	2 Participants	9 Participants
Race (NIH/OMB) More than one race	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants	1 Participants	4 Participants
Race (NIH/OMB) White	30 Participants	20 Participants	50 Participants
Region of Enrollment United States	41 participants	23 participants	64 participants
Sex: Female, Male Female	9 Participants	5 Participants	14 Participants
Sex: Female, Male Male	32 Participants	18 Participants	50 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 41	1 / 23
other Total, other adverse events	37 / 41	20 / 23
serious Total, serious adverse events	0 / 41	1 / 23

Outcome results

Primary

Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score

At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite Since the primary analysis used multiple imputation methodology, the numerator and denominator varied across 20 imputations.

Time frame: 24 months

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least 1 dose of study drug.

Arm	Measure	Value (NUMBER)
IDN-6556	Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score	25 participants
Placebo	Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score	14 participants

Comparison: All screening and post-baseline biopsy data collected were used in the primary analysis, irrespective of the defined protocol visit window. Classification of the Ishak fibrosis score was summarized descriptively by treatment group at baseline, Month 12, and Month 24. Response at Months 12 and 24 were summarized descriptively by treatment group, along with exact (Clopper-Pearson) 95% confidence intervals (CIs). The risk difference between groups was also was provided with its 95% CI.p-value: 0.7395% CI: [-20.5, 26.4]Cochran-Mantel-Haenszel

Secondary