Back to resultsOpen 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 (MBL-HCV1)
Primary Purpose
Hepatitis C Infection
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
MBL-HCV1
Telaprevir (Part 1)
Sofosbuvir (Part 2)
Sponsored by
About this trial
This is an interventional treatment trial for Hepatitis C Infection focused on measuring Liver Transplantation
Eligibility Criteria
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
Sites / Locations
- Massachusetts General Hospital
- Beth Israel Deaconess Medical Center
- Washington University School of Medicine
- Mount Sinai Hospital
- The Liver Institute at Methodist Dallas Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Part 1: MBL-HCV1 and Telaprevir
Part 2: MBL-HCV1 and Sofosbuvir
Arm Description
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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)
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
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
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)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01532908
Brief Title
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
Acronym
MBL-HCV1
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated due to funding constraints
Study Start Date
November 21, 2012 (Actual)
Primary Completion Date
August 27, 2015 (Actual)
Study Completion Date
August 27, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
MassBiologics
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C Infection
Keywords
Liver Transplantation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part 1: MBL-HCV1 and Telaprevir
Arm Type
Experimental
Arm Title
Part 2: MBL-HCV1 and Sofosbuvir
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
MBL-HCV1
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Telaprevir (Part 1)
Other Intervention Name(s)
Incivek (telaprevir)
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Sofosbuvir (Part 2)
Other Intervention Name(s)
Sovaldi (sofosbuvir)
Intervention Description
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
Primary Outcome Measure Information:
Title
Number of Subjects With Undetectable HCV RNA at Day 56 Post Liver Transplantation
Description
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
Time Frame
Day 56
Secondary Outcome Measure Information:
Title
Safety and Tolerability of Study Treatment by Number of Adverse Events Reported
Description
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)
Time Frame
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
Title
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
Description
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
Time Frame
Day 7, 10, 14, 28, 35, 42, 49, 70, 84, 98, 105, 112 and 126
Title
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
Description
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
Time Frame
Baseline pre-transplant and study Day 7, 10, 14, 28, 35, 42, 49, 56, 70, 84 and 98
Title
Number of Participants With HCV Resistance-associated Variants to MBL-HCV1 and Oral Direct-acting Antivirals Before and After Receipt of Study Treatment
Description
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)
Time Frame
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)
Other Pre-specified Outcome Measures:
Title
Number of Subjects With Sustained Virologic Response (SVR) at Week 12 and Week 24
Description
Number of subjects with sustained virologic response (defined as HCV RNA concentration below the limit of detection) at 12 and 24 weeks post-treatment was examined as an exploratory endpoint in subjects whose HCV RNA remained undetectable at the 6 week post-treatment safety follow-up visit.
Those subjects that had detectable HCV RNA at the end of safety follow-up period were not assessed for SVR 12 and SVR 24. Those subjects achieving an SVR12 were assessed for the durability of the response at 24 weeks after the end of treatment
Time Frame
12 weeks after the end of treatment (SVR12) and 24 weeks after the end of treatment 12 weeks and 24 weeks post-treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Mount Sinai Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
The Liver Institute at Methodist Dallas Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75203
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
28127942
Citation
Smith HL, Chung RT, Mantry P, Chapman W, Curry MP, Schiano TD, Boucher E, Cheslock P, Wang Y, Molrine DC. Prevention of allograft HCV recurrence with peri-transplant human monoclonal antibody MBL-HCV1 combined with a single oral direct-acting antiviral: A proof-of-concept study. J Viral Hepat. 2017 Mar;24(3):197-206. doi: 10.1111/jvh.12632. Epub 2016 Nov 7.
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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
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