Pre-transplant treatment, using peginterferon plus ribavirin, will clear HCV RNA from the blood in HCV-infected recipients and reduce the risk of recurrent HCV and allograft hepatitis.

A low, accelerating dose regimen (LADR) of peginterferon plus ribavirin will be used. Treatment is initiated with half-doses of peginterferon alfa-2b and 600 mg/d of liquid formulation of ribavirin. CBC is monitored weekly during the first 4 weeks. After 1 week, if the CBC is stable, peginterferon is increased to full dose and ribavirin is increased to 800 mg/d. Further increases in ribavirin, to achieve full dose [target 10.6 mg/kg/d, maximum 13.2 mg/kg/d] is done at weekly intervals. The goal of this regimen is to achieve full doses of both peginterferon and ribavirin within 3 weeks of initiation of therapy and to continue therapy for at least 12 weeks prior to performance of LT.

Condition	Intervention
Hepatitis C	Drug: PEG-Intron (peginterferon alfa-2b) Powder for injection and Rebetol (ribavirin, USP) oral solution

Further Study Details: 

Primary Outcomes: • Percentage of patients who are negative for HCV RNA at 3 months post-transplant
Secondary Outcomes: • Post-Transplant;  Percentage of patients who are negative for HCV RNA at 6 and 12 months post-transplant;  AST, ALT, alkaline phosphatase, bilirubin, albumin, and prothrombin time at 3, 6, and 12 months;  Percentage of patients with histologic recurrence of hepatitis C at 3 and 12 months;  Probability of 1 year Graft Survival;  Probability of 1 year Patient Survival;  Percentage of patients with treated episodes of histologically confirmed rejection;  Percentage of patients with treated infections; • Pre-Transplant;  Percentage of patients who are negative for HCV RNA on the day of transplantation;  CBC, AST, ALT, alkaline phosphatase, bilirubin, albumin, prothrombin time every 3 months up to the time of transplant or completion of 48 weeks of therapy;  Cumulative doses of peginterferon and ribavirin;  Percentage of patients who discontinue either or both antiviral drugs;  Percentage of patients who require erythropoietin analogue, G-CSF, or both.;  Percentage of patients experiencing cytopenias, adverse events, serious adverse events, or death
Expected Total Enrollment:  150

Patients will be asked to enroll in this protocol at the time of identification of a potential living donor as defined above. Patients randomized to treatment arm will be encouraged to delay LDLT until they have received 12 weeks of treatment to allow for a treatment response, if any, to occur. The pros and cons of immediate versus delayed LDLT will be discussed with each patient; the timing of LDLT for patients randomized to no treatment will be determined by clinical need. There will be separate treatment strategies depending upon HCV genotype (see Flow Diagram, Appendix C). Preliminary data and experience strongly suggests that interferon-based treatment clears HCV RNA in the majority of patients with genotypes 2 and 3, even at lower than standard doses (79% on-treatment response and 50% SVR). In contrast, clearance rates for genotype 1 patients with advanced cirrhosis may only be 28% on-treatment with an 11% SVR (16). In addition, treatment may be associated with significant side effects, intolerance, and increased risk of complications of liver disease. The HCV Committee for A2ALL strongly agreed that monitoring safety of pre-transplant antiviral therapy was essential and advised inclusion of an untreated control group. For these reasons, all patients with HCV, genotypes 1, 4, 5, & 6 infection will be randomized 2:1 to either treatment or control (no treatment). Randomization will be web-based to avoid prior knowledge of treatment assignment at any site. Stratification by clinical center will be performed using the method of minimization (27). This method will assure 2:1 balance of treatments within strata using an algorithm that assigns each successive patient to the treatment that minimizes the treatment imbalance; it is often used when multiple stratification factors are desired. For example, balance by clinical center would assure that the treatment proportions at each center are approximately 2:1, the treatment group ratio in the overall study. With a single stratification factor, clinical center, it will be necessary to add a random component to the balancing algorithm to avoid a predictable pattern. We will employ an algorithm that moves toward balance with 70% probability, and provides a random assignment with 30% probability. In contrast to the randomized design for patients with genotypes 1, 4, 5, and 6, all patients with genotypes 2 and 3 HCV will receive treatment.

After enrollment (all 150 patients) and randomization (120 patients with genotypes 1, 4, 5, & 6), current data suggest that only 50% will ultimately undergo LDLT. We estimate that an additional 20% will undergo DDLT and 30% will not be transplanted. Reasons for failure to undergo transplantation will include an SVR with stabilization or improvement in liver function (N = 5), failed donor evaluation and still wait-listed (N=20), and death or delisting for disease progression, intercurrent illness, or untreatable hepatocellular carcinoma (N=20). The follow-up and data analysis in those undergoing DDLT will be similar to those who undergo LDLT, and results will be included in some of the pre- and post-transplant secondary endpoints. All genotypes will be included in the analyses of efficacy of pre-transplant antiviral therapy in preventing post-transplant HCV recurrence and allograft hepatitis. All genotypes will be included in the analysis of safety, tolerance, and complications occurring during pre-transplant treatment.

Treatment is continued up to the time of LDLT or DDLT, or to a maximum of 48 weeks of continuous treatment. Both peginterferon and ribavirin will be stopped if transplantation is expected to occur within 24 hours. Patients whose liver disease stabilize and are no longer in need of a liver transplant will complete a full 48 weeks of treatment with the aim of achieving SVR. These patients will be followed by measurement of HCV RNA, biochemical tests, hematology, and clinical evaluation at 3, 6, and 12 months post-treatment. If relapse occurs when treatment is discontinued after 48 weeks of therapy, institution of retreatment will be at the discretion of the investigator.

Deferral of LDLT while antiviral therapy is continued will be considered in patients who have undetectable HCV RNA, tolerate treatment well, lack evidence of HCC or ongoing hepatic decompensation, and have had stabilization or improvement in clinical or biochemical measures of liver disease (CTP and MELD scores). These patients should lack uncontrolled or ongoing bleeding from portal hypertension, ascites, SBP, or encephalopathy. The decision to defer transplantation and to continue antiviral therapy will be made at the transplant center by the clinical investigator in consultation with the patient.

Based upon the kinetics of early virologic response in the peginterferon + ribavirin clinical trials, we anticipate that a minimum of 12 weeks treatment is necessary to achieve a virologic response. However, the optimum duration of pre-transplant antiviral therapy that yields the highest rates of prevention of post-transplant HCV recurrence is unknown. Prolongation of antiviral therapy beyond 12 weeks may be advantageous in this regard, but prolonged therapy may also increase the risk of development of intercurrent complications of liver disease or side effects of treatment. In addition, patients with stable liver disease who achieve virologic remission may experience hepatic improvement and avoid transplantation.

All patients, treated and untreated controls will be followed and tested at the same intervals unless specified (Appendices E-H). Unscheduled visits and additional tests may be performed if clinically indicated, the findings at these visits and results of additional tests will be recorded in the database. Windows for baseline tests are indicated in [ ].

• Baseline • History and Physical Examination • Vital signs (Weight, BP, HR, Temp) • Fundoscopic exam in all patients. In patients with hypertension or diabetes exam should be performed with pupils dilated [6 months]. FYI – these exams will only be repeated if clinically indicated.

• SF-36V2, Beck Depression Inventory (Appendix G) • Functional status evaluation • Symptom assessment • HCV RNA  Genotype, determined at each site’s clinical laboratory [6 months]  Quantitative level (IU/ml), measured at each site’s clinical laboratory [1 month] • Biochemistry and Hematology  CBC, INR [must be performed at baseline]  Chemistries (Liver Panel, Cr, Na) [must be performed at baseline]  Alpha-fetoprotein [1 month]  Pregnancy Test [must be performed at baseline]  Urinalysis [must be performed at baseline]  Triglycerides, iron studies, uric acid, TSH, ANA [6 months]  HIV [6 months] • Child-Turcotte-Pugh (CTP) Score • MELD Score • Imaging (within preceding 6 months)  US, CT, and/or MRI (some or all are probably done in LDLT eval)  HCC diagnosis (confirmed, probable, possible) • Record results from prior liver biopsy • Capture all prior complications of chronic liver disease (SBP, variceal bleeding, etc) Week 0 • Confirm eligibility • Randomize if genotype 1,4,5 or 6 • Initiate treatment for all genotype 2,3 patients and genotype 1,4,5 or 6 patients randomized to treatment group • Repeat CBC, chemistries, INR After randomization • Week 1 and 3: CBC (for treated patients only, may be performed in local labs) • Every 2 weeks up to 12 weeks: CBC, chemistries, Meds, AEs • Weeks 4 and 8: Focused physical exam (signs and symptoms of liver disease) vital signs, urinalysis and symptom assessment • Monthly from 12 to 48 weeks: Full physical exam and vital signs, urinalysis and symptom assessment (This is every 12 weeks not monthly) • Monthly from 12 to 48 weeks: CBC, chemistries, Meds, AEs • Every 12 weeks up to 48 weeks: INR, TSH, urine or serum pregnancy test female (treated subjects of childbearing capacity only) • At 12 Weeks: HCV RNA is measured by quantitative test and reflexed to qualitative testing if HCV RNA negative on quantitative test. Patients without a 2-log or more drop in HCV RNA level are declared nonresponders and treatment is discontinued.

• After 12 weeks: HCV RNA is measured every 12 weeks on treatment by quantitative tests.

• At the time of LDLT or DDLT: CBC, INR, chemistries, quantitative and qualitative HCV RNA, Meds, AEs • Blood samples will be collected at TW 4, 8, 12, 24, 48 and at time of transplantation for subsequent HCV RNA testing in a central lab • QOL assessment at week 12, 24 and 48 (BDI and SF-36V2) • Patients who discontinue treatment early due to adverse events will be followed according to the study schedule until 12 months after transplant or 48 weeks after randomization.

Post-LT (LDLT or DDLT) Follow-up • Week 12, 24 and 52: CBC, INR, chemistries, HCV RNA by quantitative testing (part of A2ALL prospective study) • Week 12, 24 and 52: Full physical exam and vital signs, urinalysis and symptom assessment Are we continuing this post-txp when they are simply Cohort pts? • Week 12: TSH • Week 12 and 24: Urine or serum pregnancy test (treated subjects of childbearing capacity only) (Why continue for 6 months after treatment?) • Week 12, 24 and 52: QOL Assessment (BDI, and SF-36V2) BDI continues in after Txp? • Week 12 and 52: Liver Biopsy (part of A2ALL prospective study). Pathologists reading the 3 and 12 month biopsies will be blinded to the patients’ clinical course and treatment.

• Blood samples will be collected at Week 12, 24 and 52 for subsequent HCV RNA testing in a central laboratory

Follow-up of Patients completing 48 weeks of Treatment without Transplantation • Week 12, 24 and 48: CBC, INR, chemistries, HCV RNA by quantitative testing • Week 12, 24 and 48: Full physical exam and vital signs, urinalysis and symptom assessment • Week 12: TSH • Week 12 and 24: Urine or serum pregnancy test (treated subjects of childbearing capacity only) • Week 12, 24 and 48: QOL Assessment (BDI, and SF-36V2) • Blood samples will be collected at Week 12, 24 and 48 for subsequent HCV RNA testing in a central laboratory

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Adult (18 or older) • LDLT candidate • HCV RNA positive • Expected time on treatment is at least 12 weeks -

Exclusion Criteria:

• Severe Cytopenia,

• PMN < 750, OR
• Hgb < 10 g/dL, OR
• Platelet count < 35,000/mm3 • Uncontrolled depression or psychiatric disease characterized by current symptoms of major depression or other psychiatric disease or increase in medication for major depression or other psychiatric disease within the past three months.

• Uncontrolled cardiopulmonary disease characterized by myocardial infarction, coronary artery bypass graft surgery, Percutaneous coronary intervention, or unstable angina within the past three months.

• Uncontrolled autoimmune disease characterized by current symptoms of autoimmune disease or increase in medications within the last three months.

• Autoimmune hepatitis • Active substance abuse within 6 months of initiation of treatment • Known intolerance or serious adverse event during prior therapy with interferon or ribavirin • Prior nonresponse after at least 24 weeks of full dose treatment with peginterferon plus ribavirin • Laboratory MELD score >20. Patients with laboratory MELD score 21-25 may be enrolled if deemed appropriate by the site investigator • Serum creatinine >2.2 mg/dL

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Please refer to this study by ClinicalTrials.gov identifier  NCT00135798

California
      University of California Los Angeles, Los Angeles,  California,  90095-7054,  United States
      University of California San Francisco, San Francisco,  California,  94143-0538,  United States
Colorado
      University of Colorado, Denver,  Colorado,  80262,  United States
Illinois
      Northwestern University Division of Transplantation, Chicago,  Illinois,  60611,  United States
New York
      Columbia University, New York,  New York,  10032,  United States
North Carolina
      University of North Carloina, Chapel Hill,  North Carolina,  27599-7080,  United States
Pennsylvania
      University of Pennsylvania, Philadelphia,  Pennsylvania,  19104,  United States
Virginia
      Virginia Commonwealth University, Richmond,  Virginia,  23219,  United States
      University of Virginia, Charlottesville,  Virginia,  22908,  United States

Study chairs or principal investigators

Gregory T. Everson, MD,  Study Chair,  University of Colorado   
James Everhart, MD,  Study Director,  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)   

Study ID Numbers:  The A2ALL LADR Protocol
Last Updated:  August 29, 2005
Record first received:  August 24, 2005
ClinicalTrials.gov Identifier:  NCT00135798
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-08-30