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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IDN-6556 | Experimental | IDN-6556 25 mg BID |
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| Placebo | Placebo Comparator | Placebo BID |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IDN-6556 | Drug |
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| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only) | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David Hagerty, MD | Conatus Pharmaceuticals Inc. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Southern California Research Center | Coronado | California | 92118 | United States | ||
| Scripps Clinic |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | IDN-6556 | IDN-6556 25 mg BID IDN-6556 |
| FG001 | Placebo | Placebo BID Placebo: Placebo control |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 3, 2015 | May 2, 2019 |
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| Drug |
Placebo control |
|
| 24 months |
| 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 | 12 months |
| Alanine Aminotransferase (ALT) - Change From Baseline | Liver function laboratory parameter | Baseline and 24 months |
| Aspartate Aminotransferase (AST) Change From Baseline | Liver function laboratory parameter | Baseline and 24 months |
| Caspase 3/7 Change From Baseline | Mechanistic biomarker of liver function | Baseline and 24 months |
| cCK18/M30 Change From Baseline | Mechanistic biomarker of liver function. | Baseline and 24 months |
| flCK18/M65 Change From Baseline | Mechanistic biomarker of liver function | Baseline and 24 months |
| Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis | The Ishak modification of Knodell histological activity index was determined by liver biopsy. Interface hepatitis
| 24 months |
| Ishak Modification of Knodell Histological Index - Confluent Necrosis | The Ishak modification of Knodell histological activity index will be determined by liver biopsy. The four items and their categorizations scores include: • confluent necrosis
| 24 months |
| Ishak Modification of Knodell Histological Index - Parenchymal Injury | The Ishak modification of Knodell histological activity index will be determined by liver biopsy. • parenchymal injury (focal lytic necrosis, apoptosis and focal inflammation)
| 24 months |
| Ishak Modification of Knodell Histological Index - Portal Inflammation | Portal inflammation
| 24 months |
| La Jolla |
| California |
| 92037 |
| United States |
| Loma Linda University Medical Center | Loma Linda | California | 92354 | United States |
| UCLA Pfleger Liver Institute | Los Angeles | California | 90095 | United States |
| Georgetown University Hospital | Washington D.C. | District of Columbia | 20007 | United States |
| Johns Hopkins Sibley Memorial Hospital | Washington D.C. | District of Columbia | 21287 | United States |
| University of Florida | Gainesville | Florida | 32610 | United States |
| University of Miami | Miami | Florida | 33136 | United States |
| Piedmont Atlanta Hospital | Atlanta | Georgia | 30309 | United States |
| Rush University Medical Center | Chicago | Illinois | 60612 | United States |
| University of Chicago Medicine | Chicago | Illinois | 60637 | United States |
| Indiana University | Indianapolis | Indiana | 46202 | United States |
| University of Kansas Medical Center | Kansas City | Kansas | 66160 | United States |
| University of Louisville | Louisville | Kentucky | 40202 | United States |
| Tulane Health Science Center | New Orleans | Louisiana | 70112 | United States |
| Ochsner Clinic | New Orleans | Louisiana | 70121 | United States |
| John Hopkins Hospital | Baltimore | Maryland | 21287 | United States |
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| Henery Ford Health System | Detroit | Michigan | 48202 | United States |
| Saint Louis University | St Louis | Missouri | 63104 | United States |
| Rutgers New Jersey Medical School | Newark | New Jersey | 07103 | United States |
| Columbia University Medical Center | New York | New York | 10032 | United States |
| University of Cincinnati Physicians Company | Cincinnati | Ohio | 45267 | United States |
| University of Pennsylvania Milton Hershey Hospital | Philadelphia | Pennsylvania | 19104 | United States |
| Temple University Hospital | Philadelphia | Pennsylvania | 19140 | United States |
| Albert Einstein Medical Center | Philadelphia | Pennsylvania | 19141 | United States |
| Baylor All Saints Medical Center | Fort Worth | Texas | 76104 | United States |
| Liver Associates of Texas, PA | Houston | Texas | 77030 | United States |
| University of Texas Health Science Center at Houston | Houston | Texas | 77030 | United States |
| VAMC/Baylor College of Medicine | Houston | Texas | 77030 | United States |
| University of Utah | Salt Lake City | Utah | 84132 | United States |
| Bon Secours Mary Immaculate Hospital | Newport News | Virginia | 23602 | United States |
| Bon Secours St. Mary's Hospital of Richmond | Richmond | Virginia | 23226 | United States |
| McGuire DVAMC | Richmond | Virginia | 23249 | United States |
| University of Washington Harborview Medical Center | Seattle | Washington | 98104 | United States |
| COMPLETED |
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| NOT COMPLETED |
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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.
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| ID | Title | Description |
|---|---|---|
| BG000 | IDN-6556 | IDN-6556 25 mg BID IDN-6556 |
| BG001 | Placebo | Placebo BID Placebo: Placebo control |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Baseline Ishak Fibrosis Score | 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). | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The Full Analysis Set (FAS) consisted of all randomized subjects who received at least 1 dose of study drug. | Posted | Number | participants | 24 months |
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| Secondary | Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only) | 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 | Full analysis set | Posted | Count of Participants | Participants | 24 months |
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| Secondary | 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 | Full analysis set, the # of subject analyzed included subjects with an observed Ishak Fibrosis Score at 12 months. | Posted | Count of Participants | Participants | 12 months |
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| Secondary | Alanine Aminotransferase (ALT) - Change From Baseline | Liver function laboratory parameter | Full analysis set, the # of subject analyzed included subjects with an observed ALT at 24 months. | Posted | Mean | Standard Deviation | U/L | Baseline and 24 months |
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| Secondary | Aspartate Aminotransferase (AST) Change From Baseline | Liver function laboratory parameter | Full analysis set, the # of subject analyzed included subjects with an observed AST at 24 months. | Posted | Mean | Standard Deviation | U/L | Baseline and 24 months |
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| Secondary | Caspase 3/7 Change From Baseline | Mechanistic biomarker of liver function | Full analysis set, the # of subject analyzed included subjects with an observed Caspase 3/7 at 24 months. | Posted | Mean | Standard Deviation | Raw RLU | Baseline and 24 months |
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| Secondary | cCK18/M30 Change From Baseline | Mechanistic biomarker of liver function. | Full analysis set, the # of subject analyzed included subjects with an observed cCK18/M30 at 24 months. | Posted | Mean | Standard Deviation | U/L | Baseline and 24 months |
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| Secondary | flCK18/M65 Change From Baseline | Mechanistic biomarker of liver function | Full analysis set, the # of subject analyzed included subjects with an observed flCK18/M65 at 24 months. | Posted | Mean | Standard Deviation | U/L | Baseline and 24 months |
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| Secondary | Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis | The Ishak modification of Knodell histological activity index was determined by liver biopsy. Interface hepatitis
| Full analysis set | Posted | Count of Participants | Participants | 24 months |
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| Secondary | Ishak Modification of Knodell Histological Index - Confluent Necrosis | The Ishak modification of Knodell histological activity index will be determined by liver biopsy. The four items and their categorizations scores include: • confluent necrosis
| Full analysis set | Posted | Count of Participants | Participants | 24 months |
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| Secondary | Ishak Modification of Knodell Histological Index - Parenchymal Injury | The Ishak modification of Knodell histological activity index will be determined by liver biopsy. • parenchymal injury (focal lytic necrosis, apoptosis and focal inflammation)
| Full analysis set | Posted | Count of Participants | Participants | 24 months |
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| Secondary | Ishak Modification of Knodell Histological Index - Portal Inflammation | Portal inflammation
| Full analysis set | Posted | Count of Participants | Participants | 24 months |
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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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | IDN-6556 | IDN-6556 25 mg BID IDN-6556 | 0 | 41 | 0 | 41 | 37 | 41 |
| EG001 | Placebo | Placebo BID Placebo: Placebo control | 1 | 23 | 1 | 23 | 20 | 23 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (17.0) | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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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.
Sponsor has the right to publish the results before the PI.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Steven Mento, Ph.D., CEO | Conatus Pharmaceuticals, Inc. | 858-376-2622 | smento@conatuspharma.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 18, 2018 | May 2, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D008103 | Liver Cirrhosis |
| D006526 | Hepatitis C |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D005355 | Fibrosis |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D006525 | Hepatitis, Viral, Human |
| D014777 | Virus Diseases |
| D018178 | Flaviviridae Infections |
| D012327 | RNA Virus Infections |
| D006505 | Hepatitis |
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| ID | Term |
|---|---|
| C487112 | 3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Baseline Ishak Fibrosis Score F3 |
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| Baseline Ishak Fibrosis Score F4 |
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| Baseline Ishak Fibrosis Score F5 |
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| Baseline Ishak Fibrosis Score F6 |
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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. |
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