Pilot Study of Simtuzumab in the Treatment of Liver Fibrosis

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability of simtuzumab (GS-6624) in patients with fibrosis of the liver. Up to 20 participants will be enrolled into two sequential cohorts. Cohort 1 will consist of 10 participants who will receive simtuzumab every other week for a total of 3 infusions. Participants in Cohort 2 (10 subjects) will also receive simtuzumab every other week for a total of 3 infusions; the dose will depend on the safety and tolerability of simtuzumab seen in Cohort 1. Participants from both cohorts who have completed the main study will be allowed to continue on simtuzumab treatment for an additional extension period, and will receive up to 13 additional infusions of simtuzumab at a fixed dose of 700 mg for an additional 24 weeks.

Official Title
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A Phase 2a, Pilot, Open-Label Trial Evaluating the Safety, Tolerability and Pharmacodynamic Effects of GS-6624 in Subjects With Fibrosis of the Liver

Conditions
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Liver Fibrosis

Intervention / Treatment
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* Biological: Simtuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females 18 - 65 years of age Chronic liver disease of any etiology Stage 1-3 fibrosis by Metavir score on a liver biopsy. Body mass index <36 kg/m2 Exclusion Criteria: Any evidence of hepatic decompensation past or present Subjects currently abusing amphetamines, cocaine, opiates, or alcohol Clinically significant cardiac disease History of cancer, other than non-melanomatous skin cancer, within 5 years prior to Screening Systemic fungal, bacterial, viral, or other infection that is not controlled Use of systemic immunosuppressants within 28 days of the Pre-treatment Phase Use of approved therapy for hepatitis C or hepatitis B virus within 28 days of the Pre-treatment Phase Pregnant or lactating History of bleeding diathesis within the last 6 months of study Day 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Participants will receive simtuzumab at a dose of 10 mg/kg by intravenous (IV) infusion every other week for a total of 3 infusions. | Biological: Simtuzumab<br> <br> * Other names: GS-6624;|
| Experimental: Cohort 2<br>Participants will receive simtuzumab IV every other week for a total of 3 infusions. The dose will depend on the safety and tolerability of simtuzumab seen in Cohort 1 but will not exceed 20 mg/kg. | Biological: Simtuzumab<br> <br> * Other names: GS-6624;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events on multiple, escalating IV doses of simtuzumab | The endpoints to be evaluated will include graded Adverse Events, laboratory abnormalities, and vital sign measurements | Through Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of serum concentration of simtuzumab | Trough concentrations will be summarized by day, treatment and dose. | Through Week 14 | 
| Antibody formation to simtuzumab (anti-simtuzumab Abs) | Immunogenicity endpoints will be geometric mean titer (GMT) and geometric mean fold rate (GMFR) for a select set of antibodies. | Through Week 14 | 
| Measurement of pharmacodynamic (PD) markers after administration of simtuzumab | Pharmacodynamic markers include: Tissue PD markers through mRNA expression, LOXL2, LOX, Other LOXL proteins, αSMA, Collagen 1A1, NFKB1, Caspase 1, SMAD, and NOD; Serum and plasma PD markers include: APRI, LOXL2, Osteopontin, Hyaluronic Acid, CXCL 9, 10 and 11, MMP1, MMP3, MMP9, TIMP1, CD40L, TGF-β1, ET-1, VEGF, GAL3, IL-6 / IL-8 / TNFα / IFNγ, α2-macroglobulin, Apolipoprotein A1. | Through Week 14 | 
| Assessing the effects of chronic dosing of simtuzumab on liver structure and fibrotic markers | Measuring the effect of an additional 24 weeks of simtuzumab dosing on liver histology, LOXL2 and mRNA expression in the liver and serum markers of liver fibrosis | Up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSI, Gilead, Gilead Sciences, Liver Fibrosis, Liver, Fibrosis