Study in Hepatitis C Virus (HCV) Infected Patients Undergoing Liver Transplantation to Evaluate a Human Monoclonal Antibody Against Hepatitis C

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a human monoclonal antibody against Hepatitis C (MBL-HCV1) is effective in preventing detectable levels of Hepatitis C virus in patients undergoing liver transplantation due to chronic HCV infection. The study will also determine if MBL-HCV1 is effective in delaying or reducing the amount of detectable HCV in patients after transplant.

Detailed Description
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This is a Phase 2, randomized, double-blind, placebo controlled study in Hepatitis C (HCV) infected patients undergoing liver transplantation. Chronically infected patients with HCV genotype 1a scheduled to receive a liver transplant from either a deceased or living donor who satisfy all study inclusion or exclusion criteria will be approached to participate. The study will be conducted in two parts to test a human monoclonal antibody against Hepatitis C (MBL-HCV1). In Part 1, sixteen eligible patients will be randomized 1:1 to receive 50 mg/kg MBL-HCV1 or 0.9% sodium chloride placebo intravenously. Eleven doses will be given during the first 14 days post transplantation. Patients will be evaluated through day 56 for safety and clinical outcomes that include measurement of anti-HCV antibodies, anti-drug antibody and HCV viral load. On study visit day 42, a liver biopsy will be performed for evaluation of hepatitis. Physical examination, vital sign measurements, emergence of adverse events and concomitant medication usage will be assessed at scheduled visits and as needed during the 56 day study period. The Data Safety and Monitoring Board will perform a futility analysis after the first 16 patients have been enrolled and completed study follow-up through study visit day 42 post transplant. Based on the results of the interim analysis, the dose of MBL-HCV1 for part 2 of the study will be determined. Part 2 of the study will be conducted in the same manner as Part 1.

Official Title
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A Phase II Randomized, Double-Blind, Placebo Controlled Study of the Clinical Effectiveness of a Human Monoclonal Antibody Against Hepatitis C Virus E2 Glycoprotein (MBL-HCV1) in Hepatitis C Infected Patients Undergoing Liver Transplantation

Conditions
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HCV Infection, Liver Transplantation

Intervention / Treatment
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* Biological: MBL-HCV1
* Other: 0.9% Sodium chloride Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient ≥ 18 years of age with documented chronic hepatitis C virus infection of genotype 1a undergoing liver transplantation from either a deceased donor or living donor. Patient or legal guardian/health care proxy must have read, understood and provided written informed consent and HIPAA authorization after the nature of the study has been fully explained. Exclusion Criteria: Positive serology for Hepatitis B surface Antigen Positive serology for HIV Pregnancy or breastfeeding Previous history of any organ transplant Planned receipt of combined organ transplant (e.g. liver and kidney) Receipt or planned receipt of immune globulin (IVIG) within 90 days of enrollment History of extrahepatic malignancy and/or receiving chemotherapy within 90 days prior to enrollment with the exception of chemoembolization for hepatocellular carcinoma Hepatocellular carcinoma with tumor burden outside of the Milan criteria History of chronic renal insufficiency or creatinine > 2.5 for ≥ six months Personal or family history of deep venous thrombosis or pulmonary embolism Receipt of liver allograft from HCV positive donor or Hepatitis B core antibody positive donor Receipt of liver allograft donated after cardiac death of donor Receipt of any antiviral agents, licensed or investigational for hepatitis C virus within 90 days prior to enrollment Receipt of any other investigational study product within 30 days prior to enrollment Any other condition that in the opinion of the investigator would jeopardize the safety or rights of the patient participating in the study or make it unlikely that the patient could complete the study

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBL-HCV1<br> | Biological: MBL-HCV1<br>* 50 mg/kg MBL-HCV1, intravenous<br>|
| Placebo Comparator: 0.9% sodium chloride<br> | Other: 0.9% Sodium chloride Placebo<br>* 0.9% sodium chloride, intravenous<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects With Detectable Serum HCV RNA at Day 42 Post-Transplantation | Serum HCV RNA was measured by Quantitative RT-PCR | At Day 42 post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence of Adverse Events and Treatment-Emergent Adverse Events Determined Through Medical History, Physical Examination and Laboratory Evaluation | Adverse events were assessed by targeted medical history, physical examinations and laboratory testing. Subjects were asked at scheduled study visits through day 42 whether they experienced solicited adverse reactions (fever, chills, nausea, rash, joint pain or swelling, shortness of breath, headache, fatigue, and hives). In addition to these solicited adverse events, subjects were asked at all scheduled study visits through day 56 to report any other adverse events, regardless of whether the event was thought to be related to the study infusions. Adverse events were summarized by System Organ Class (SOC) using MedDRA (version 12.0) | Through Day 56 | 
| Change in Serum HCV RNA Between Baseline and Day 3, 14, 28 and 42 Post-Transplantation | Serum HCV RNA was measured by quantitative RT-PCR. The change in HCV RNA from baseline was obtained by calculating the difference between the baseline pre-transplantation HCV RNA level and the HCV RNA level measured at each study visit. | Baseline and Day 3, 14, 28 and 42 Post-Transplantation | 
| Histologic Evidence of Hepatitis by Histologic Activity Index (HAI) Score at Baseline and Day 42 | Liver biopsies obtained at baseline (day 0) and day 42 post-transplantation were assessed for histologic evidence of hepatitis by a pathologist blinded to treatment assignment using the Ishak modification of the Knodell histologic grading system to assign a histologic activity index (HAI) score. The HAI score consists of a sum of four components: 1) periportal or periseptal interface hepatitis; 2) confluent necrosis; 3) focal lytic necrosis, apoptosis and focal inflammation; 4) portal inflammation. The total HAI score can range from a minimum of 0 to a maximum of 18, with higher scores indicating more severe hepatic inflammation. | Baseline Day 0 and Day 42 | 
| Graft Function Assessed by Measurement of Biochemical and Synthetic Function at Multiple Time Points / International Normalized Ratio (INR) | Biochemical function was assessed by measurement of alanine aminotransferase (ALT) and total bilirubin and synthetic function was assessment by measurement of the pro-thrombin time (reported as the international normalized ratio, INR) at multiple time-points during the 56-day study period. The table below displays the INR at each time-point. The INR is the ratio of a patient's prothrombin time to a control sample, raised to the power of the ISI value (International Sensitivity Index) for the batch of tissue factor being used for the assay. | Through Day 56 | 
| Graft Function Assessed by Measurement of Biochemical and Synthetic Function at Multiple Time Points / Alanine Aminotransferase (ALT) | Biochemical function was assessed by measurement of alanine aminotransferase (ALT) and total bilirubin and synthetic function was assessment by measurement of the pro-thrombin time (reported as the international normalized ratio, INR) at multiple time-points during the 56-day study period. The table below displays the ALT at each time-point. | Through Day 56 | 
| Graft Function Assessed by Measurement of Biochemical and Synthetic Function at Multiple Time Points / Total Bilirubin | Biochemical function was assessed by measurement of alanine aminotransferase (ALT) and total bilirubin and synthetic function was assessment by measurement of the pro-thrombin time (reported as the international normalized ratio, INR) at multiple time-points during the 56-day study period. The table below displays the total bilirubin at each time-point. | Through Day 56 | 
| Time to Onset of Recurrence of Detectable HCV RNA Post-Transplantation | Serum HCV RNA was measured by Quantitative RT-PCR | Through Day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C virus (HCV), Liver transplantation, Human Monoclonal Antibody