Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00135798
Status:
COMPLETED
Last Update Posted:
2013-04-23
First Post:
2005-08-24
Brief Title:
Pre-Transplant Treatment to Prevent Recurrence of Hepatitis C After Liver Transplantation
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Study Overview
Official Title:
The Adult-to-adult Living Donor Liver Transplantation Cohort Study A2ALL Low Accelerated Dosing Regimen LADR Protocol Pre-Transplant Treatment to Prevent Recurrence of Hepatitis C Virus HCV After Liver Transplantation
Status:
COMPLETED
Status Verified Date:
2013-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
LADR
Brief Summary:
The purpose of this study is to learn if pre-liver transplant treatment using peginterferon plus ribavirin will clear hepatitis C virus HCV RNA from the blood in HCV-infected recipients and reduce the risk of recurrent HCV and allograft hepatitis following liver transplant
Detailed Description:
Patients awaiting deceased donor liver transplant will be asked to enroll in this protocol at the time of identification of a potential living liver donor see note note at end of description Patients randomized to treatment arm will be encouraged to delay living donor liver transplant 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 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 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 21 to either treatment or control no treatment Randomization will be web-based to avoid prior knowledge of treatment assignment at any site 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 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 deceased donor liver transplant 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 Child-Turcotte-Pugh CTP and Model for End-stage Liver Disease MELD scores These patients should lack uncontrolled or ongoing bleeding from portal hypertension ascites systolic blood pressure 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 the researchers 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 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 The following details the schedule of visits and the testsprocedures to be performed at each visit
Baseline
History and Physical Examination
Vital signs Weight blood pressure BP heart rate HR Temperature
Fundoscopic exam in all patients In patients with hypertension or diabetes exam should be performed with pupils dilated
Quality of Life and Depression Assessment SF-36V2 Beck Depression Inventory
Functional status evaluation
Symptom assessment
HCV RNA
HCV Genotype
Urinalysis
Pregnancy Test
HIV Test
Other blood tests including complete blood count CBC International Normalized Ratio INR Liver Panel Creatine Sodium Alpha-fetoprotein triglycerides iron studies uric acid thyroid stimulating hormone TSH antinuclear antibody ANA
Ultrasound US computed tomography CT andor magnetic resonance imaging MRI some or all are probably done in LDLT evaluation
Week 0 Randomization andor Treatment Start
Confirm eligibility
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
Weeks 4 and 8 Focused physical exam signs and symptoms of liver disease vital signs urinalysis and symptom assessment
Every 4 weeks from 12 to 48 weeks Full physical exam and vital signs urinalysis and symptom assessment CBC chemistries
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 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 Medications adverse events AE
Blood samples will be collected at Treatment Weeks 4 8 12 24 48 and at time of transplantation for subsequent HCV RNA testing in a central lab
Quality of life QOL assessment at week 12 24 and 48 Beck Depression Inventory 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
Week 12 TSH and urine or serum pregnancy test treated subjects of childbearing capacity only
Week 12 24 and 52 QOL Assessment BDI and SF-36V2
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 and 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
NOTE As a result of LADR Protocol Amendment III patients with hepatocellular carcinoma HCC and tumor stage T2 awaiting DDLT are now eligible to participate in the LADR study The following inclusion criteria was added
Candidates for DDLT who are listed for transplantation and meet United Network for Organ Sharing UNOS criteria for MELD upgrade for HCC
HCC DDLT candidates will not have their transplant delayed if a liver becomes available even if they have not completed 12 weeks of Rx
Treatment is continued up to the time of LDLT or deceased donor liver transplant 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 Child-Turcotte-Pugh CTP and Model for End-stage Liver Disease MELD scores These patients should lack uncontrolled or ongoing bleeding from portal hypertension ascites systolic blood pressure 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 the researchers 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 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 The following details the schedule of visits and the testsprocedures to be performed at each visit
Baseline
History and Physical Examination
Vital signs Weight blood pressure BP heart rate HR Temperature
Fundoscopic exam in all patients In patients with hypertension or diabetes exam should be performed with pupils dilated
Quality of Life and Depression Assessment SF-36V2 Beck Depression Inventory
Functional status evaluation
Symptom assessment
HCV RNA
HCV Genotype
Urinalysis
Pregnancy Test
HIV Test
Other blood tests including complete blood count CBC International Normalized Ratio INR Liver Panel Creatine Sodium Alpha-fetoprotein triglycerides iron studies uric acid thyroid stimulating hormone TSH antinuclear antibody ANA
Ultrasound US computed tomography CT andor magnetic resonance imaging MRI some or all are probably done in LDLT evaluation
Week 0 Randomization andor Treatment Start
Confirm eligibility
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
Weeks 4 and 8 Focused physical exam signs and symptoms of liver disease vital signs urinalysis and symptom assessment
Every 4 weeks from 12 to 48 weeks Full physical exam and vital signs urinalysis and symptom assessment CBC chemistries
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 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 Medications adverse events AE
Blood samples will be collected at Treatment Weeks 4 8 12 24 48 and at time of transplantation for subsequent HCV RNA testing in a central lab
Quality of life QOL assessment at week 12 24 and 48 Beck Depression Inventory 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
Week 12 TSH and urine or serum pregnancy test treated subjects of childbearing capacity only
Week 12 24 and 52 QOL Assessment BDI and SF-36V2
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 and 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
NOTE As a result of LADR Protocol Amendment III patients with hepatocellular carcinoma HCC and tumor stage T2 awaiting DDLT are now eligible to participate in the LADR study The following inclusion criteria was added
Candidates for DDLT who are listed for transplantation and meet United Network for Organ Sharing UNOS criteria for MELD upgrade for HCC
HCC DDLT candidates will not have their transplant delayed if a liver becomes available even if they have not completed 12 weeks of Rx
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| U01DK062498 | NIH | None | None |
| U01DK062536 | NIH | None | None |
| U01DK062444 | NIH | None | None |
| U01DK062467 | NIH | None | None |
| U01DK062483 | NIH | None | None |
| U01DK062484 | NIH | None | None |
| U01DK062494 | NIH | None | None |
| U01DK062496 | NIH | None | None |
| U01DK062505 | NIH | None | None |
| U01DK062531 | NIH | None | None |
| CRADA through NIH-NIDDK | OTHER | None | None |
| CTA through NIH-NIDDK | OTHER | None | None |
| HRSA | OTHER | None | None |
| ASTS | OTHER | American Society of Transplant Surgeons | httpsreporternihgovquickSearchU01DK062531 |