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A Trial of IDN-6556 in Post Orthotopic Liver Transplant for Chronic HCV (POLT-HCV-SVR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02138253
Recruitment Status : Completed
First Posted : May 14, 2014
Results First Posted : December 11, 2019
Last Update Posted : December 11, 2019
Sponsor:
Information provided by (Responsible Party):
Conatus Pharmaceuticals Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Liver Fibrosis
Hepatic Fibrosis
Liver Cirrhosis
Hepatic Cirrhosis
Interventions Drug: IDN-6556
Drug: Placebo
Enrollment 64
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.

Pre-assignment Details  
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Period Title: Overall Study
Started 41 23
Completed 32 19
Not Completed 9 4
Reason Not Completed
Adverse Event             3             3
Lost to Follow-up             2             1
Physician Decision             2             0
Non compliance             1             0
Withdrawal by Subject             1             0
Arm/Group Title IDN-6556 Placebo Total
Hide Arm/Group Description

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Total of all reporting groups
Overall Number of Baseline Participants 41 23 64
Hide Baseline Analysis Population Description
Subjects who underwent orthotopic liver transplantation for chronic HCV, developed HCV-related liver fibrosis or cirrhosis, achieved a SVR with anti-viral treatment and had demonstrable fibrosis or cirrhosis on liver histology were enrolled.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 23 participants 64 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
29
  70.7%
17
  73.9%
46
  71.9%
>=65 years
12
  29.3%
6
  26.1%
18
  28.1%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 23 participants 64 participants
Female
9
  22.0%
5
  21.7%
14
  21.9%
Male
32
  78.0%
18
  78.3%
50
  78.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 23 participants 64 participants
Hispanic or Latino
10
  24.4%
6
  26.1%
16
  25.0%
Not Hispanic or Latino
31
  75.6%
17
  73.9%
48
  75.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 23 participants 64 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
7
  17.1%
2
   8.7%
9
  14.1%
White
30
  73.2%
20
  87.0%
50
  78.1%
More than one race
1
   2.4%
0
   0.0%
1
   1.6%
Unknown or Not Reported
3
   7.3%
1
   4.3%
4
   6.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 41 participants 23 participants 64 participants
41 23 64
Baseline Ishak Fibrosis Score   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 41 participants 23 participants 64 participants
Baseline Ishak Fibrosis Score F2 9 6 15
Baseline Ishak Fibrosis Score F3 20 7 27
Baseline Ishak Fibrosis Score F4 5 5 10
Baseline Ishak Fibrosis Score F5 2 2 4
Baseline Ishak Fibrosis Score F6 5 3 8
[1]
Measure Description: Ishak Fibrosis Score is a standard measure to classify the severity of fibrosis in patients. A score of 0 indicates no evidence of fibrosis and a score of 6 indicates the most severe evidence of fibrosis (i.e., cirrhosis).
1.Primary Outcome
Title Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized subjects who received at least 1 dose of study drug.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 41 23
Measure Type: Number
Unit of Measure: participants
25 14
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IDN-6556, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments For the primary efficacy analysis based on the Month 24 biopsy, subjects with a missing Month 24 biopsy had their Ishak fibrosis score imputed. Imputation of missing Ishak fibrosis scores was conducted using multiple imputation (MI). Results were imputed based on age, gender, baseline Ishak fibrosis score, and the Month 12 Ishak fibrosis score.
Statistical Test of Hypothesis P-Value 0.73
Comments Stratified by baseline Ishak Fibrosis Score strata (F2, F3+F4+F5, and F6).
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
-20.5 to 26.4
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only)
Hide Description 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
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 32 19
Measure Type: Count of Participants
Unit of Measure: Participants
25
  78.1%
14
  73.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IDN-6556, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.658
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 4.4
Confidence Interval (2-Sided) 95%
-20.0 to 28.9
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score
Hide Description 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
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, the # of subject analyzed included subjects with an observed Ishak Fibrosis Score at 12 months.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 35 20
Measure Type: Count of Participants
Unit of Measure: Participants
27
  77.1%
17
  85.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IDN-6556, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.421
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -7.9
Confidence Interval (2-Sided) 95%
-28.8 to 13.1
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Alanine Aminotransferase (ALT) - Change From Baseline
Hide Description Liver function laboratory parameter
Time Frame Baseline and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, the # of subject analyzed included subjects with an observed ALT at 24 months.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 36 21
Mean (Standard Deviation)
Unit of Measure: U/L
-3.7  (10) 43.7  (239.5)
5.Secondary Outcome
Title Aspartate Aminotransferase (AST) Change From Baseline
Hide Description Liver function laboratory parameter
Time Frame Baseline and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, the # of subject analyzed included subjects with an observed AST at 24 months.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 35 21
Mean (Standard Deviation)
Unit of Measure: U/L
-4.0  (8.5) 31.4  (161.8)
6.Secondary Outcome
Title Caspase 3/7 Change From Baseline
Hide Description Mechanistic biomarker of liver function
Time Frame Baseline and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, the # of subject analyzed included subjects with an observed Caspase 3/7 at 24 months.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 32 19
Mean (Standard Deviation)
Unit of Measure: Raw RLU
-296.1  (830.3) 2081.2  (10116.4)
7.Secondary Outcome
Title cCK18/M30 Change From Baseline
Hide Description Mechanistic biomarker of liver function.
Time Frame Baseline and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, the # of subject analyzed included subjects with an observed cCK18/M30 at 24 months.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 31 18
Mean (Standard Deviation)
Unit of Measure: U/L
-104.7  (193.2) -66.1  (176.9)
8.Secondary Outcome
Title flCK18/M65 Change From Baseline
Hide Description Mechanistic biomarker of liver function
Time Frame Baseline and 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, the # of subject analyzed included subjects with an observed flCK18/M65 at 24 months.
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 32 18
Mean (Standard Deviation)
Unit of Measure: U/L
-70.2  (189.0) -98.6  (311.7)
9.Secondary Outcome
Title Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis
Hide Description

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)
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 41 23
Measure Type: Count of Participants
Unit of Measure: Participants
Interface Hepatitis Score of 0
6
  14.6%
5
  21.7%
Interface Hepatitis Score of 1
14
  34.1%
4
  17.4%
Interface Hepatitis Score of 2
8
  19.5%
6
  26.1%
Interface Hepatitis Score of 3
3
   7.3%
1
   4.3%
Interface Hepatitis Score of 4
1
   2.4%
3
  13.0%
Missing Interface Hepatitis Score
9
  22.0%
4
  17.4%
10.Secondary Outcome
Title Ishak Modification of Knodell Histological Index - Confluent Necrosis
Hide Description

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
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 41 23
Measure Type: Count of Participants
Unit of Measure: Participants
Confluent necrosis score of 0
32
  78.0%
19
  82.6%
Missing confluent necrosis score
9
  22.0%
4
  17.4%
11.Secondary Outcome
Title Ishak Modification of Knodell Histological Index - Parenchymal Injury
Hide Description

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
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 41 23
Measure Type: Count of Participants
Unit of Measure: Participants
Parenchymal Injury Score of 0
1
   2.4%
2
   8.7%
Parenchymal Injury Score of 1
22
  53.7%
9
  39.1%
Parenchymal Injury Score of 2
5
  12.2%
7
  30.4%
Parenchymal Injury Score of 3
4
   9.8%
1
   4.3%
Missing Parenchymal Injury Score
9
  22.0%
4
  17.4%
12.Secondary Outcome
Title Ishak Modification of Knodell Histological Index - Portal Inflammation
Hide Description

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
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description:

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

Overall Number of Participants Analyzed 41 23
Measure Type: Count of Participants
Unit of Measure: Participants
Portal Inflammation Score of 1
11
  26.8%
4
  17.4%
Portal Inflammation Score of 2
19
  46.3%
8
  34.8%
Portal Inflammation Score of 3
2
   4.9%
6
  26.1%
Portal Inflammation Score of 4
0
   0.0%
1
   4.3%
Missing Portal Inflammation Score
9
  22.0%
4
  17.4%
Time Frame Treatment emergent adverse events were collected from the first day of study drug administration until the subject's last study follow-up visit. All treatment emergent adverse events were collected up to the subsequent follow-up visit of the month 24 month visit.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title IDN-6556 Placebo
Hide Arm/Group Description

IDN-6556 25 mg BID

IDN-6556

Placebo BID

Placebo: Placebo control

All-Cause Mortality
IDN-6556 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/41 (0.00%)      1/23 (4.35%)    
Hide Serious Adverse Events
IDN-6556 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/41 (0.00%)      1/23 (4.35%)    
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Death * 1  0/41 (0.00%)  0 1/23 (4.35%)  1
1
Term from vocabulary, MedDRA (17.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
IDN-6556 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   37/41 (90.24%)      20/23 (86.96%)    
Gastrointestinal disorders     
Diarrhea * 1  9/41 (21.95%)  10 5/23 (21.74%)  6
Nausea * 1  7/41 (17.07%)  10 5/23 (21.74%)  11
Abdominal pain * 1  4/41 (9.76%)  6 2/23 (8.70%)  2
General disorders     
Fatigue * 1  8/41 (19.51%)  8 6/23 (26.09%)  7
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  6/41 (14.63%)  10 2/23 (8.70%)  7
Vascular disorders     
Hypertension * 1  6/41 (14.63%)  7 4/23 (17.39%)  9
1
Term from vocabulary, MedDRA (17.0)
*
Indicates events were collected by non-systematic assessment
The broad range of fibrosis stages included in the study and the high placebo response rates especially in the F2 and F6 fibrosis stages impacted the primary endpoint of improvement in fibrosis score from baseline.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Sponsor has the right to publish the results before the PI.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Steven Mento, Ph.D., CEO
Organization: Conatus Pharmaceuticals, Inc.
Phone: 858-376-2622
EMail: smento@conatuspharma.com
Layout table for additonal information
Responsible Party: Conatus Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02138253    
Other Study ID Numbers: IDN-6556-07
First Submitted: May 12, 2014
First Posted: May 14, 2014
Results First Submitted: May 2, 2019
Results First Posted: December 11, 2019
Last Update Posted: December 11, 2019