SRL (Sirolimus) Withdrawal

• Status: Completed
• Trial end date: 2020-07-01
• Target enrollment: 0
• Participant gender: All

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'.

• Phase: N/A
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Northwestern University
• Treatments: Everolimus; Immunosuppressive Agents; Sirolimus

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])