Simtuzumab (GS-6624) in the Prevention of Progression of Liver Fibrosis in Adults With Primary Sclerosing Cholangitis (PSC)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether simtuzumab (GS-6624) is effective at preventing the progression of liver fibrosis in adults with primary sclerosing cholangitis (PSC).

Official Title
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A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase Like 2 (LOXL2) in Subjects With Primary Sclerosing Cholangitis (PSC)

Conditions
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Primary Sclerosing Cholangitis (PSC)

Intervention / Treatment
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* Biological: Simtuzumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adult Individuals (aged 18-70) with chronic cholestatic liver disease of at least 6 months. Liver biopsy consistent with PSC: If a liver biopsy has been performed within 3 months of the screening visit, tissue from that biopsy may be used as the screening biopsy. Slides would be re-cut from the existing tissue block and submitted for central reader assessment. Some individuals with PSC may have a normal liver biopsy, in the event of a normal liver biopsy, the individual must have an abnormal magnetic resonance cholangiopancreatography (MRCP). MRCP consistent with PSC: Some individuals with PSC may have a normal MRCP; in the event of a normal MRCP, the individual must have an abnormal liver biopsy. Exclusion of other causes of liver disease including viral hepatitis ,alcoholic liver disease,primary biliary cirrhosis and secondary sclerosing cholangitis Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 10 x the Central Laboratory Upper Limit of Normal (clULN) Must have serum creatinine < 2.0 mg/dL A negative serum pregnancy test is required for female individuals of childbearing potential All sexually active female individuals of childbearing potential must agree to use a protocol recommended method of contraception during heterosexual intercourse throughout the study and for 90 days following the last dose of study medication Lactating females must agree to discontinue nursing before starting study treatment Males if not vasectomized, are required to use barrier contraception (condom plus spermicide) during intercourse from the screening through the study completion and for 90 days following the last dose of study drug Key Exclusion Criteria: Pregnant or breast feeding Evidence of hepatic decompensation present, including ascites, episodes of hepatic encephalopathy, variceal bleeding or a prolonged prothrombin time/international normalized ratio (PT/INR) Positive for hepatitis C virus (HCV) RNA Positive for HBsAg Positive for anti-mitochondrial antibody Alcohol consumption greater than 21oz/week for males or 14oz/week for females Moderately active ulcerative colitis (UC) defined as either a partial Mayo score of > 4, bleeding score of >1, or current use of oral corticosteroid therapy and/or any inhibitor of Tumor necrosis factor-α (TNF-α) or α4β7 integrin antagonist Positive urine screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at screening. Individuals on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Individuals with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator Clinically significant cardiac disease History of cholangiocarcinoma History of other cancers,other than non-melanomatous skin cancer, within 5 years prior to screening Ascending cholangitis within 60 days of screening Presence of a percutaneous drain or bile duct stent Known hypersensitivity to the investigation product or any of its formulation excipients History of bleeding diathesis within 6 months of screening Unavailable for follow-up assessment or concern for individual's compliance with the protocol procedures; Participation in an investigational trial of a drug or device within 30 days prior to screening Major surgical procedure within 30 days prior to screening or the presence of an open wound Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm A<br>Simtuzumab 75 mg for 96 weeks | Biological: Simtuzumab<br>* Subcutaneous injections weekly for a total of 96 injections<br>* Other names: GS-6624;|
| Experimental: Treatment Arm B<br>Simtuzumab 125 mg for 96 weeks | Biological: Simtuzumab<br>* Subcutaneous injections weekly for a total of 96 injections<br>* Other names: GS-6624;|
| Placebo Comparator: Treatment Arm C<br>Placebo for 96 weeks | Biological: Placebo<br>* Subcutaneous injections weekly for a total of 96 injections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in MQC on Liver Biopsy at Week 96 |  | Baseline; Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event |  | First dose date up to Week 96 | 
| Study Drug Exposure | The average SIM exposure was summarized. | First dose date up to Week 96 | 
| Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment and occurring after the predose visit and on or before the date of the administration of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening)]. | First dose date up to Week 96 plus 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSC, Sclerosis, Monoclonal antibody, LOXL2, Simtuzumab, Primary sclerosing cholangitis, Liver fibrosis, Liver disease, MRCP, MRE, Liver biopsy