Open Label Study of the Efficacy and Safety of MBL-HCV1 in Combination With Oral Direct-Acting Antivirals in Patients Undergoing Liver Transplantation for Hepatitis C

Study Overview
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Brief Summary
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The purpose of this study is to assess efficacy of a human monoclonal antibody against Hepatitis C (MBL-HCV1) combined with telaprevir [part 1: an HCV protease inhibitor] or sofosbuvir [part 2: an Hepatitis C virus NS5B polymerase inhibitor] in a 56 day treatment duration in patients undergoing liver transplantation due to chronic HCV infection. There is an option for extended study treatment through 84 days if viral load is undetectable at day 56.

Detailed Description
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Administration of Intravenous infusions of MBL-HCV1 (50mg/kg) human monoclonal antibody during the first 14 days post-transplantation: three infusions on day 0 (1-4 hours prior to the anhepatic phase, during the anhepatic phase, and 4-12 hours post-reperfusion). Daily infusions on days 1 through 7, weekly infusions on day 14 ± 2, day 21 ± 3, and day 28 ± 3, followed by biweekly infusions on day 42 ± 3 and on day 56 ± 3 if criteria for the stopping rule are not met. For those subjects electing extended treatment, the administration of additional infusions on day 70 ± 3 and day 84 ± 3 will be performed. Subjects receive an oral direct-acting antiviral (telaprevir in Part 1 and sofosbuvir in Part 2) starting no earlier than day 3 post-transplant and no later than day 7; dosing continuing through day 56 unless criteria for the stopping rule are met. Subjects who elect to receive extended study treatment for a total of 12 weeks continue telaprevir in Part 1 or sofosbuvir in Part 2 through day 84 ± 3.

Official Title
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A Phase II Open-Label Study of the Clinical Effectiveness of a Human Monoclonal Antibody Against Hepatitis C Virus E2 Glycoprotein (MBL-HCV1) Combined With Oral Direct-Acting Antivirals in Hepatitis C Infected Patients Undergoing Liver Transplantation

Conditions
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Hepatitis C Infection

Intervention / Treatment
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* Biological: MBL-HCV1
* Drug: Telaprevir (Part 1)
* Drug: Sofosbuvir (Part 2)


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 1 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 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 Extrahepatic malignancy not currently in remission and/or receiving systemic chemotherapy and/or radiation within 90 days prior to enrollment. Exceptions include chemoembolization for hepatocellular carcinoma or cutaneous malignancies managed with local treatment Hepatocellular carcinoma with tumor burden outside of the Milan criteria Serum creatinine > 2.5 for > or = six months at the time of enrollment Personal or family history (first degree relative) 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 30 days prior to liver transplantation, unless patient has documented detectable HCV RNA during this 30 day period Previous receipt of an HCV protease inhibitor (for subjects enrolling in Part 1: telaprevir) Receipt of any other investigational study product within 30 days prior to enrollment Seizure disorder requiring anti-convulsant therapy Pulmonary arterial hypertension requiring sildenafil or tadalafil infusion (for subjects enrolling in Part 1: telaprevir) 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: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: MBL-HCV1 and Telaprevir<br> | Biological: MBL-HCV1<br>* 50 mg/kg MBL-HCV1, intravenous, up to 15 infusions over 56 days; option for extended treatment through 84 days if viral load undetectable at day 56<br>Drug: Telaprevir (Part 1)<br>* Two 375 mg tablets, 3 times a day up to 56 days; option for extended treatment through 84 days if viral load undetectable at day 56<br>* Other names: Incivek (telaprevir);|
| Experimental: Part 2: MBL-HCV1 and Sofosbuvir<br> | Biological: MBL-HCV1<br>* 50 mg/kg MBL-HCV1, intravenous, up to 15 infusions over 56 days; option for extended treatment through 84 days if viral load undetectable at day 56<br>Drug: Sofosbuvir (Part 2)<br>* One 400 mg tablet, 1 time per day up to 56 days; option for extended treatment through 84 days if viral load undetectable at day 56<br>* Other names: Sovaldi (sofosbuvir);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Undetectable HCV RNA at Day 56 Post Liver Transplantation | The primary outcome was to determine if MBL-HCV1 in combination with the oral direct-acting antiviral could reduce HCV viral RNA to undetectable at day 56 post transplant and prevent the new liver from becoming productively infected. Undetectable HCV RNA was defined as the level below the lower limit of detection (LLOD) of an FDA-approved polymerase chain reaction (PCR) assay. HCV RNA was quantified by PCR (e.g., COBAS®AmpliPrep/ COBAS® TaqMan® HCV Test manufactured by Roche or equivalent) at each study site | Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Study Treatment by Number of Adverse Events Reported | Adverse events were assessed by targeted medical history, physical examinations and laboratory testing. Abnormal laboratory values constituted adverse events only if they induced clinical signs or symptoms and/or required therapy that was new or enhanced from baseline. Solicited adverse reactions included the occurrence of the following during or immediately after the infusion: arthralgia, chills, dyspnea, fatigue, fever, headache, nausea, hives, or rash. The presence of any of these symptoms (new or worsening from baseline) was documented as an adverse event. In addition, subjects were asked at all scheduled study visits to report any other adverse events. Adverse events were summarized by System Organ Class (SOC) using MedDRA (version 14.1) | Day 0 start of first infusion through Day 56 or six weeks after last dose of study treatment whichever is later, up to approximately 126 days | 
| Number of Subjects With Undetectable Serum HCV RNA at Study Day 7, 10, 14, 28, 35, 42, 49, 70, 84 and 98 in Liver Transplant Recipients and for Those Subjects Receiving an Additional 4 Weeks of Treatment at Study Day 105, 112 and 126 | The number of subjects with undetectable HCV RNA by study visit day was analyzed utilizing a last value carried forward (LVCF) strategy so that each study visit day had data from (8 subjects in Part 1 and 2 subjects in Part 2), effectively imputing the information for the subjects who had missing data due to a missed study visit, HCV RNA measured with a non-FDA approved assay, or completion of all required post-treatment study visits. The last recorded HCV RNA status for a subject (detectable vs undetectable) was used for the next missing level (in ascending visit number order) until a new HCV RNA level was recorded at a later visit. Serum HCV RNA was measured by Quantitative RT-PCR using an FDA-approved quantitative assay | Day 7, 10, 14, 28, 35, 42, 49, 70, 84, 98, 105, 112 and 126 | 
| Change in Viral Load Between Baseline Pre-transplant HCV RNA Levels and Study Day 7, 10, 14, 28, 35, 42, 49, 56, 70, 84 and 98 in Liver Transplant Recipients | Serum HCV RNA was measured by quantitative RT-PCR. The change in log 10 IU/mL HCV viral load from baseline was compared with pre-transplant HCV RNA level and evaluated for each subject at each study visit. Change in the level of HCV RNA in serum, log10(IU/mL), is defined as the difference between the level measured at Baseline and the specified time point. If HCV RNA was not detected by the PCR assay, the lower level of detection of the PCR assay was used for the calculation | Baseline pre-transplant and study Day 7, 10, 14, 28, 35, 42, 49, 56, 70, 84 and 98 | 
| Number of Participants With HCV Resistance-associated Variants to MBL-HCV1 and Oral Direct-acting Antivirals Before and After Receipt of Study Treatment | Conventional sequencing was performed on HCV RNA isolated from a subset of serum samples obtained at baseline, at the time of viral rebound, and at the end of study in subjects who did not achieve a sustained virologic response. The targets of both the MBL-HCV1 antibody (E1/E2 glycoprotein) and telaprevir (NS3) were sequenced. The data displays the number of subjects with > 20% resistance associated variants (RAV) reported for the target MBL-HCV1 and/or Direct-acting Antiviral (DAA) | Pre-transplant, time of viral rebound (assessed from Day 7-Day 56 of treatment), end of study (up to day 126) in subjects who did not achieve a sustained virologic response (SVR) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Transplantation