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SRL (Sirolimus) Withdrawal (SRL)

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ClinicalTrials.gov Identifier: NCT02062944
Recruitment Status : Completed
First Posted : February 14, 2014
Results First Posted : July 14, 2022
Last Update Posted : July 14, 2022
Sponsor:
Information provided by (Responsible Party):
Josh Levitsky, Northwestern University

Brief Summary:
The significance of this clinical trial lies in its potential to increase the success of immunosuppression (IS) therapy withdrawal in liver transplant (LT) recipients, thus decreasing the negative impact of IS on their long-term outcomes. Lifetime immunosuppression (IS) with standard agents, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus (TAC), is currently required at clinically recommended doses and trough levels to prevent allograft rejection. However, this occurs at the significant expense of long-term CNI toxicity, i.e. chronic kidney disease (CKD), hypertension, hyperlipidemia, diabetes, infections and malignancy. With improvements in early graft and patient survival, long term adverse IS effects have become increasingly important in this rapidly expanding patient population. The strategies to reduce long term CNI toxicity include dose minimization that still leaves patients on CNI therapy, conversion to non-CNI therapy, or even complete IS withdrawal. The second approach, conversion to non-CNI IS therapy, is attractive in the potential to stabilize or improve renal function and other CNI toxicities. One such non-nephrotoxic IS agent, the mammalian target of rapamycin inhibitor (mTOR-I) SRL, has a different mechanism of IS action and studies have shown that CNI to SRL conversion can stabilize renal dysfunction with a low risk of rejection. Yet even with these possible benefits, patients on SRL are still subject to lifetime IS therapy with side effects and costs, highlighting the need to investigate the strategies that promote full IS withdrawal without rejection (3rd approach), also known as 'operational tolerance'.

Condition or disease Intervention/treatment Phase
Acute Rejection of Liver Transplant Effects of Immunosuppressant Therapy Drug: Sirolimus Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Liver Transplant Tolerance Enhanced By Sirolimus Therapy
Study Start Date : March 2013
Actual Primary Completion Date : July 2020
Actual Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arm Intervention/treatment
Experimental: Single-arm study Sirolimus Withdrawal
SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Drug: Sirolimus
SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Other Names:
  • Withdrawal from Immunosuppressant Therapy
  • Minimization of Immunosuppressant Therapy




Primary Outcome Measures :
  1. Proportion of Tolerant Patients Off SRL Therapy With Normal Liver Biochemistry and Graft Histology at 12 Months [ Time Frame: 12 months ]
    The primary outcome will be the proportion of patients off SRL therapy with normal liver biochemistry and graft histology at 12 months (i.e. tolerant). Thus, the incidence of graft dysfunction (acute rejection, immune mediated or autoimmune hepatitis, chronic rejection) or non-tolerance will be assessed in this SRL withdrawal group and compared to the historical CNI group (20% tolerant; 80% failure) as the primary endpoint.


Secondary Outcome Measures :
  1. Number of Subjects With TCMR Rejection [ Time Frame: 12 months ]
    Major secondary measures compared will be the predictive capacity of the blood and graft biomarker assays (immunophenotyping, genomic/proteomics) before and after minimization/withdrawal in the success vs. failure groups.


Other Outcome Measures:
  1. Number of Participants Resumed SRL After Minimization [ Time Frame: 12 months ]
    patient did not have rejection during withdrawal but was withdrawn from the trial due to an unexpected adrenal metastasis of hepatocellular carcinoma.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult male and female recipients of all races, ≥ 18-75 years of age
  2. Patients who underwent primary living or deceased donor liver transplantation ≥ 3 years (previous to screening ) and on ≥ 3 months of stable SRL monotherapy
  3. Recipient of single organ transplant only
  4. Liver transplant for non-immune, non-viral (no hepatitis B or hepatitis C virus unless currently non-viremic) causes
  5. Ability to provide informed consent and to comply with the study protocol of IS withdrawal.

Exclusion Criteria:

  1. Inability or unwillingness to provide informed consent
  2. Acute cellular rejection within 12 months prior to enrollment
  3. Viral (viremic hepatitis B virus [HBV] or hepatitis C virus [HCV]) or immune-mediated liver disease (Autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis) history
  4. Abnormal liver function tests: Direct bilirubin ≥ 1 mg/dL; ([ALT, AST, GGT] or alkaline phosphatase [AlkPhos] ≥ 2x [ULN]); 5) Abnormal graft histology at enrollment: a) ≥ Grade 2 inflammation or stage 2 fibrosis; b) Acute or Chronic Rejection; c) De-novo Autoimmune Hepatitis; d) inflammation of >50% of portal tracts; e) Other pathology not-specified but deemed high risk per the PI and pathologist; 6) Ongoing or recurrent substance abuse

7) Retransplantation or combined liver-other organ 8) Human Immunodeficiency Virus(HIV) co-infection 9) Glomerular Filtration Rate (GFR)<30 ml/min by estimated glomerular filtration rate ([eGFR]-[MDRD-4])


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02062944


Locations
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United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Northwestern University
Investigators
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Principal Investigator: Josh Levitsky, MD Northwestern University
  Study Documents (Full-Text)

Documents provided by Josh Levitsky, Northwestern University:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Josh Levitsky, Associate Professor, Northwestern University
ClinicalTrials.gov Identifier: NCT02062944    
Other Study ID Numbers: STU00072766
First Posted: February 14, 2014    Key Record Dates
Results First Posted: July 14, 2022
Last Update Posted: July 14, 2022
Last Verified: June 2022
Keywords provided by Josh Levitsky, Northwestern University:
Liver Transplant
Sirolimus
Rapamune
Immunosuppressant Therapy
Withdrawal
Additional relevant MeSH terms:
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Sirolimus
Immunosuppressive Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunologic Factors
Physiological Effects of Drugs