Hepatitis CPhase 2A-WISHNCT00135694
Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant
A Phase 2 study testing calcineurin inhibitor-based immunosuppression, liver transplant and corticosteroids in people with Hepatitis C and Hepatitis C, Chronic, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in United States.
Trial summary
In order to prevent organ rejection, patients receiving liver transplants currently require life-long treatment with immune system-suppressing medications to prevent the rejection of the transplanted liver. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatitis C, Hepatitis C, Chronic, Nonimmune Nonviral Causes of Liver Failure
- What is being tested?
- calcineurin inhibitor-based immunosuppression, liver transplant and corticosteroids
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 275 participants
- Where
- 8 sitesUnited States
- Study dates
- Oct 2005to Sep 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female 18 years of age or older.
- Necessity for liver transplant.
- For females of childbearing potential: a negative pregnancy test at study entry and agreement to use approved methods of birth control for the duration of their participation.
- Ability to provide informed consent.
- Availability of donor specimen(s).
- For individuals with hepatitis C infection, presence of hepatitis genomes in blood.
Who cannot join
- Previous transplant.
- Multiorgan or split liver transplant other than with a right trisegment.
- Living donor transplant.
- Donor liver from a donor positive for antibody against hepatitis C.
- Donor liver from a non-heart-beating donor.
- Liver failure due to autoimmune disease.
Show all 17Show fewer
- Fulminant liver failure.
- Hepatitis B infection as defined by the presence of HbSAg or hepatitis-C infection with a genome other than genome 1.
- Stage III or higher hepatocellular cancer.
- History of malignancy except hepatocellular cancer, adequately treated in situ cervical carcinoma,adequately treated basal or squamous cell carcinoma of skin, or other cancer judged to have a 5-year risk of recurrence less than 10%.
- Active systemic infection at the time of transplantation.
- Clinically significant chronic renal disease.
- Clinically significant cardiovascular or cerebrovascular disease.
- Infection with human immunodeficiency virus.
- Any investigational drug received within 6 weeks of study entry or any investigational vaccine received at any time.
- Hypersensitivity to tacrolimus.
- Unwillingness or inability to comply with study requirements.
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
University of Michigan
Ann Arbor, Michigan, 48109
Northwestern University
Chicago, Illinois, 60208
Cleveland Clinic
Cleveland, Ohio, 44195
Baylor University
Dallas, Texas, 76798
University of Colorado
Denver, Colorado, 80262
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of California, San Francisco
San Francisco, California, 94143
University of Washington
Seattle, Washington, 98195
About this study
Official title: A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients
In order to prevent organ rejection, patients receiving liver transplants currently require life-long treatment with immune system-suppressing medications to prevent the rejection of the transplanted liver. However, these medications can cause long-term side effects, such as infection, kidney problems, diabetes, and cancer. In patients infected with hepatitis C virus (HCV), these medications may increase the risk of HCV infection in the transplanted liver. The purpose of this study is to determine whether a slow withdrawal of immune system-suppressing medications is safe in two groups of subjects: those who receive a liver transplant due to HCV, and those who receive a liver transplant due to non-immune, non-viral causes of liver failure. The study will also look at whether slow withdrawal will help reduce the long-term side effects of immune system-suppressing medications and decrease the chance for HCV infection of the new liver in transplant patients with HCV.
Read the detailed description
This is a prospective multicenter, open-label, randomized trial in which individuals with liver failure due to hepatitis C or to nonimmune nonviral causes undergo liver transplantation and receive immunosuppression with a calcineurin inhibitor and corticosteroids. Corticosteroids are tapered in the 3 months after transplantation and the calcineurin inhibitor is continued. Participants are regularly assessed for evidence of allograft rejection. One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance. Participants assigned to withdrawal undergo a scheduled taper over approximately 1 year.
- Being tested
- calcineurin inhibitor-based immunosuppression, liver transplant, corticosteroids, immunosuppression withdrawal
- Keywords
- hepatitis, hepatitis C, HCV, liver, liver disease, liver transplant, liver transplantation, transplant, hepatic, hepatic transplantation, immunosuppression, rejection
- Medical subject headings
- Hepatitis C, Hepatitis C, Chronic, Hepatitis, Liver Diseases, Rejection, Psychology
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
calcineurin inhibitor-based immunosuppressionDrug
May be cyclosporine, mycophenolate mofetil, or tacrolimus
liver transplantProcedure or surgery
Also called liver transplantation
Occurs at study entry
corticosteroidsDrug
Also called prednisone
3-month course of corticosteroids
immunosuppression withdrawalOther
One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.
| Study group | Role | What they receive |
|---|---|---|
| Immunosuppression Withdrawal | Experimental | Subjects may randomize to this group at 12 to 24 months after transplantation. This is followed by tapered withdrawal of calcineurin inhibitor-based immunosuppression therapy over the course of 1 year. Receives: Drug: calcineurin inhibitor-based immunosuppression; Procedure: liver transplant; Drug: corticosteroids; Other: immunosuppression withdrawal |
| Immunosuppression Maintenance | Active comparator | Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy. Receives: Drug: calcineurin inhibitor-based immunosuppression; Procedure: liver transplant; Drug: corticosteroids |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
This is a composite endpoint comprising clinical complications related to immunosuppression and is defined as the occurrence of any of the following: death or graft loss, grade 4 secondary malignancy (graded by Common Terminology Criteria for Adverse Events [CTCAE] version 3.0), grade 4 opportunistic infection (graded by CTCAE version 3.0), stage 3 or higher fibrosis, or decrease in renal function. Decrease in renal function is defined as: a) the estimated glomerular filtration rate (eGFR) using creatinine obtained prior to and closest to randomization will be considered the baseline and will be compared to the eGFR using creatinine obtained at 24 months +/- 3 months after randomization; b) for those with a baseline eGFR 30-90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR; c) for those with a baseline eGFR greater than 90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR and a decrease in eGFR to less than 90 ml per min per 1.73 meter-squared.
Measured: Randomization to 2 years post-randomization
Secondary outcomes (7)
Number of Participants Who Qualify for Random Assignment
Measured: One to two years post-transplantation
Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months
Measured: Randomization until study completion or participant termination (up to six years post-transplant)
Immunosuppression-free Duration
Time (in days) from withdrawing off of all immunosuppressive drugs to re-starting immunosuppression or study termination/completion.
Measured: Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years
Number of Hepatitis C Infected Participants With Progression of Hepatitis C Related Liver Disease, Defined as Stage 4 or Higher Fibrosis on the Ishak Scale
Number of subjects with a biopsy showing stage 4 fibrosis or higher on the Ishak scale. Stage 4 represents at least 13.7% fibrosis measurement with a description of fibrous expansion of portal areas with marked bridging (P-P) as well as portal to central (P-C). Stage 5 is marked bridging (P-P and/or P-C), with occasional nodules (incomplete cirrhosis) and stage 6 is cirrhosis, probable or definite.
Measured: Randomization to 2 years post-randomization.
Number of Participants Experiencing Graft Loss or Death
Number of participants with graft loss or death. Graft loss is defined as subject death or re-transplantation.
Measured: Randomization to 2 years post-randomization.
Total Immunosuppression From Month 21 to Month 24 Post-randomization
Daily immunosuppression score in units per day averaged over the 3-month period from Month 21 to Month 24 post-randomization. Daily doses were assigned a score of 1 unit as follows: tacrolimus 1 mg, cyclosporine 100 mg, Sirolimus 1 mg, mycophenolate mofetil 1000 mg, Mycophenolic acid 720 mg, azathioprine 50 mg, and prednisone 5 mg. Any antibody use equaled 20 units. Unit scores based on Vasudev (Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005; 8(4):1834-1839.)
Measured: Month 21 to Month 24 post-randomization
Total Burden of Immunosuppression From Random Assignment to Month 24
Total immunosuppression score in units taken as the sum of units per day over the 2-year period from randomization to Month 24 post-randomization. Daily doses were assigned a score of 1 unit as follows: tacrolimus 1 mg, cyclosporine 100 mg, Sirolimus 1 mg, mycophenolate mofetil 1000 mg, Mycophenolic acid 720 mg, azathioprine 50 mg, and prednisone 5 mg. Any antibody use equaled 20 units. Unit scores based on Vasudev (Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005; 8(4):1834-1839.).
Measured: Randomization to Month 24 post-randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2005 (estimated)
- Study startOct 2005
- Primary completionSep 2015
- Study completionSep 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hepatitis CStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 275 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- Immune Tolerance Network (ITN)
- Responsible party
- Sponsor
- Investigators
- Abraham Shaked, MD, PhD, Study chair, University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00135694
- Sponsor's protocol ID
- DAIT ITN030ST
- Acronym
- A-WISH
- Status last verified
- Jan 2019
- First submitted
- 25 Aug 2005
- Last updated
- 4 Feb 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, Reyes J, Klintmalm GB, Demetris AJ, Burrell BE, Priore A, Bridges ND, Sayre PH. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019 May;19(5):1397-1409. doi: 10.1111/ajt.15205. Epub 2018 Dec 31.
PubMed 30506630Muthukumar T, Akat KM, Yang H, Schwartz JE, Li C, Bang H, Ben-Dov IZ, Lee JR, Ikle D, Demetris AJ, Tuschl T, Suthanthiran M. Serum MicroRNA Transcriptomics and Acute Rejection or Recurrent Hepatitis C Virus in Human Liver Allograft Recipients: A Pilot Study. Transplantation. 2022 Apr 1;106(4):806-820. doi: 10.1097/TP.0000000000003815.
PubMed 33979314
Study at a glance
From the registry record, last updated by the sponsor on 4 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients
- ClinicalTrials.gov ID
- NCT00135694
- Acronym / sponsor ID
- A-WISH / DAIT ITN030ST
- Keywords
- hepatitis, hepatitis C, HCV, liver, liver disease, liver transplant, liver transplantation, transplant
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 275 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Collaborators
- Immune Tolerance Network (ITN)
- Study start
- Oct 2005
- Primary completion
- Sep 2015 (actual)
- Study completion
- Sep 2015 (actual)
- First posted
- 26 Aug 2005 (estimated)
- Results
- Posted 8 Dec 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In order to prevent organ rejection, patients receiving liver transplants currently require life-long treatment with immune system-suppressing medications to prevent the rejection of the transplanted liver. However, these medications can cause long-term side effects, such as infection, kidney problems, diabetes, and cancer. In patients infected with hepatitis C virus (HCV), these medications may increase the risk of HCV infection in the transplanted liver. The purpose of this study is to determine whether a slow withdrawal of immune system-suppressing medications is safe in two groups of subjects: those who receive a liver transplant due to HCV, and those who receive a liver transplant due to non-immune, non-viral causes of liver failure. The study will also look at whether slow withdrawal will help reduce the long-term side effects of immune system-suppressing medications and decrease the chance for HCV infection of the new liver in transplant patients with HCV.
Detailed description
This is a prospective multicenter, open-label, randomized trial in which individuals with liver failure due to hepatitis C or to nonimmune nonviral causes undergo liver transplantation and receive immunosuppression with a calcineurin inhibitor and corticosteroids. Corticosteroids are tapered in the 3 months after transplantation and the calcineurin inhibitor is continued. Participants are regularly assessed for evidence of allograft rejection. One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance. Participants assigned to withdrawal undergo a scheduled taper over approximately 1 year.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Immunosuppression Withdrawal | Experimental | Drug: calcineurin inhibitor-based immunosuppression, Procedure: liver transplant, Drug: corticosteroids, Other: immunosuppression withdrawalSubjects may randomize to this group at 12 to 24 months after transplantation. This is followed by tapered withdrawal of calcineurin inhibitor-based immunosuppression therapy over the course of 1 year. |
| Immunosuppression Maintenance | Active comparator | Drug: calcineurin inhibitor-based immunosuppression, Procedure: liver transplant, Drug: corticosteroidsLiver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male or female 18 years of age or older.
- Necessity for liver transplant.
- For females of childbearing potential: a negative pregnancy test at study entry and agreement to use approved methods of birth control for the duration of their participation.
- Ability to provide informed consent.
- Availability of donor specimen(s).
Key exclusion criteria (17 listed)
- Previous transplant.
- Multiorgan or split liver transplant other than with a right trisegment.
- Living donor transplant.
- Donor liver from a donor positive for antibody against hepatitis C.
- Donor liver from a non-heart-beating donor.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| calcineurin inhibitor-based immunosuppressionMay be cyclosporine, mycophenolate mofetil, or tacrolimus | Drug | Immunosuppression Maintenance, Immunosuppression Withdrawal |
| liver transplantAlso: liver transplantationOccurs at study entry | Procedure or surgery | Immunosuppression Maintenance, Immunosuppression Withdrawal |
| corticosteroidsAlso: prednisone3-month course of corticosteroids | Drug | Immunosuppression Maintenance, Immunosuppression Withdrawal |
| immunosuppression withdrawalOne year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance. | Other | Immunosuppression Withdrawal |
Primary outcome
Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
Time frame: Randomization to 2 years post-randomization
This is a composite endpoint comprising clinical complications related to immunosuppression and is defined as the occurrence of any of the following: death or graft loss, grade 4 secondary malignancy (graded by Common Terminology Criteria for Adverse Events [CTCAE] version 3.0), grade 4 opportunistic infection (graded by CTCAE version 3.0), stage 3 or higher fibrosis, or decrease in renal function. Decrease in renal function is defined as: a) the estimated glomerular filtration rate (eGFR) using creatinine obtained prior to and closest to randomization will be considered the baseline and will be compared to the eGFR using creatinine obtained at 24 months +/- 3 months after randomization; b) for those with a baseline eGFR 30-90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR; c) for those with a baseline eGFR greater than 90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR and a decrease in eGFR to less than 90 ml per min per 1.73 meter-squared.
7 secondary outcomes
Number of Participants Who Qualify for Random Assignment
Time frame: One to two years post-transplantation
Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months
Time frame: Randomization until study completion or participant termination (up to six years post-transplant)
Immunosuppression-free Duration
Time frame: Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years
Number of Hepatitis C Infected Participants With Progression of Hepatitis C Related Liver Disease, Defined as Stage 4 or Higher Fibrosis on the Ishak Scale
Time frame: Randomization to 2 years post-randomization.
Number of Participants Experiencing Graft Loss or Death
Time frame: Randomization to 2 years post-randomization.
Total Immunosuppression From Month 21 to Month 24 Post-randomization
Time frame: Month 21 to Month 24 post-randomization
Total Burden of Immunosuppression From Random Assignment to Month 24
Time frame: Randomization to Month 24 post-randomization
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Feb 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 30506630Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, Reyes J, Klintmalm GB, Demetris AJ, Burrell BE, Priore A, Bridges ND, Sayre PH. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019 May;19(5):1397-1409. doi: 10.1111/ajt.15205. Epub 2018 Dec 31.
- Derived from this study: PubMed 33979314Muthukumar T, Akat KM, Yang H, Schwartz JE, Li C, Bang H, Ben-Dov IZ, Lee JR, Ikle D, Demetris AJ, Tuschl T, Suthanthiran M. Serum MicroRNA Transcriptomics and Acute Rejection or Recurrent Hepatitis C Virus in Human Liver Allograft Recipients: A Pilot Study. Transplantation. 2022 Apr 1;106(4):806-820. doi: 10.1097/TP.0000000000003815.
- National Institute of Allergy and Infectious Diseases websiteLink provided by the sponsor.
- Click here for the Immune Tolerance Network websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Abraham Shaked, MD, PhD study chair
University of Pennsylvania
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing calcineurin inhibitor-based immunosuppression, liver transplant and corticosteroids in people with Hepatitis C and Hepatitis C, Chronic, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Dec 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Clinical Complications Usually Attributed to Immunosuppression (time frame: Randomization to 2 years post-randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00135694, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Feb 2019.