SRL (Sirolimus) Withdrawal

NCT02062944 | Completed Results

• 1 other identifier: STU00072766
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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'.

Conditions

Acute Rejection of Liver Transplant; Effects of Immunosuppressant Therapy

Keywords

Liver Transplant; Sirolimus; Rapamune; Immunosuppressant Therapy; Withdrawal

Outcome Measures

Primary Outcomes (1)

• Proportion of Tolerant Patients Off SRL Therapy With Normal Liver Biochemistry and Graft Histology at 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.

  12 months

Secondary Outcomes (1)

• Number of Subjects With TCMR Rejection

  12 months

Other Outcomes (1)

• Number of Participants Resumed SRL After Minimization

  12 months

Study Arms (1)

Single-arm study Sirolimus Withdrawal

EXPERIMENTAL

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

Interventions

Sirolimus DRUG

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.

Also known as: Withdrawal from Immunosuppressant Therapy, Minimization of Immunosuppressant Therapy

Single-arm study Sirolimus Withdrawal

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Inability or unwillingness to provide informed consent
• Acute cellular rejection within 12 months prior to enrollment
• 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
• 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
• \) 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 (\[eGFR\]-\[MDRD-4\])

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Related Publications (1)

• Levitsky J, Burrell BE, Kanaparthi S, Turka LA, Kurian S, Sanchez-Fueyo A, Lozano JJ, Demetris A, Lesniak A, Kirk AD, Stempora L, Yang GY, Mathew JM. Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus. Hepatology. 2020 Aug;72(2):569-583. doi: 10.1002/hep.31036. Epub 2020 Jun 8.

  PMID: 31721246 DERIVED

MeSH Terms

Interventions

Sirolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Josh Levitsky
• Organization: Northwestern University

josh.levitsky@nm.org

312 695 4413

Study Officials

• Josh Levitsky, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 3, 2014
• First Posted: February 14, 2014
• Study Start: March 1, 2013
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: July 14, 2022
• Results First Posted: July 14, 2022

Record last verified: 2022-06

Locations

US (1)