Myfortic in High MELD Liver Transplantation

Prospective Evaluation of the Efficacy and Safety of Zortress (Everolimus)/Myfortic (Enteric Coated Mycophenolate Sodium) Conversion in High MELD Liver Transplantation

The objective of the study is to determine the efficacy and safety of Everolimus conversion in liver transplantation. Most large US liver centers transplant patients with high Model for End-Stage Liver Disease (MELD) scores. However, many of the sponsored liver transplant trials in the US do not include patients with high MELD scores making it difficult to extrapolate these trial data to the patients cared for at larger liver transplant centers. The greatest potential benefit of mammalian target of rapamycin (mTOR) inhibitors is the avoidance of the side-effects of calcineurin-inhibitors, namely, renal insufficiency, diabetes and hypertension. Therefore, this protocol is designed to study the efficacy and safety of everolimus and Myfortic in liver transplant patients with high MELD scores at two large centers with a vast experience in the administration of mTOR inhibitors.

Study Overview

• Status: Withdrawn
• Conditions: High Model for End-Stage Liver Disease (MELD) Score
• Intervention / Treatment: Drug: Everolimus, Myfortic and Tacrolimus; Drug: Myfortic and Tacrolimus

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients must give written informed consent before any assessment is performed.

1. MELD ≥ 25.
2. Recipients who are 18-70 years of age of a primary or secondary liver transplant from a deceased donor.
3. Allograft is functioning at an acceptable level by the time of randomization as defined by the Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Total Bilirubin levels ≤3 times Upper Limit of Normal (ULN), and Alkaline Phosphatase (AlkP) levels ≤ 5 times ULN.
4. Ability and willingness to provide written informed consent and adhere to study regimen.
5. Patients who are able to take oral medication at time of randomization. Glomerular Filtration Rate (GFR) ≥ 30 ml/min.

Exclusion Criteria:

1. Patients receiving 3rd transplants
2. Fulminant hepatic failure
3. Living donor transplants
4. Donation after Cardiac Death (DCD) donors or split grafts
5. Active infection or hemodynamic instability at the time of transplant
6. Renal replacement therapy for clearance within 7 days prior to randomization
7. Presence of thrombosis via Doppler ultrasound of the major hepatic arteries, major hepatic veins, portal vein and inferior vena cava.
8. An episode of acute rejection that required antibody therapy or more than one steroid sensitive episode of acute rejection prior to randomization. This includes patients who have not completed steroid treatment for acute rejection within 7 days prior to randomization.
9. Spot urine protein/creatinine ratio > 1g/24h at time of randomization
10. Combined liver/kidney transplant
11. Patients who have severe hypercholesterolemia (>350 mg/dL) or Patients with platelet count < 50,000 at time of randomization
12. Patients with an Absolute neutrophil count (ANC) of < 1,000 or White Blood Count (WBC) of <2,000 at time of randomization
13. Patients with hemoglobin <6g/dL
14. Patients who are unable to take oral medication at time of randomization
15. Patients with clinically significant systemic infection requiring active use of IV antibiotics, anti-virals, or anti-fungals
16. Patients who are in a critical care setting at the time of randomization requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents
17. Known intolerance to tacrolimus or everolimus or Myfortic.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Everolimus, Myfortic and Tacrolimus; Tacrolimus discontinued (within 8 weeks of initiation of everolimus conversion). Everolimus 1mg BID started (targeted trough 6-12ng/mL). Patients must have an everolimus concentration between 6-12ng/mL before tacrolimus is discontinued. Myfortic 360-720 mg BID	Drug: Everolimus, Myfortic and Tacrolimus; Tacrolimus discontinued (within 8 weeks of initiation of everolimus conversion). Everolimus 1mg BID started (targeted trough 6-12ng/mL). Patients must have an everolimus concentration between 6-12ng/mL before tacrolimus is discontinued. Myfortic 360-720 mg BID; Other Names: Everolimus: Zortress, Certican, Afinitor; Myfortic: CellCept; Tacrolimus: FK-506, fujimycin, Prograf, Advagraf, Protopic
OTHER: Myfortic and Tacrolimus; Normal Care: Myfortic BID 360-720 mg Tacrolimus (5-12ng/mL)	Drug: Myfortic and Tacrolimus; Myfortic BID 360-720 mg Tacrolimus (5-12ng/mL); Other Names: Myfortic: CellCept; Tacrolimus: FK-506, fujimycin, Prograf, Advagraf, Protopic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proven acute rejection	1. To evaluate the use of a calcineurin-free immunosuppressive regimen utilizing concentration-controlled everolimus and mycophenolic acid (Myfortic) (Arm #12), in order to compare rates of the composite efficacy endpoint (biopsy proven-acute rejection, graft loss, and death) to the rates in the CNI-containing control arm (Arm #21) at 12 months post conversion to everolimus.	12 months

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Michael Zimmerman, MD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (ACTUAL): July 1, 2015
• Study Completion (ACTUAL): August 1, 2015

Study Registration Dates

• First Submitted: March 6, 2013
• First Submitted That Met QC Criteria: March 6, 2013
• First Posted (ESTIMATE): March 8, 2013

Study Record Updates

• Last Update Posted (ACTUAL): October 21, 2019
• Last Update Submitted That Met QC Criteria: October 17, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Liver Diseases; End Stage Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus
• Other Study ID Numbers: 12-0457; CRAD001HUS63T