REnal Function in Liver Transplantation: Everolimus With Calcineurin Inhibitor (CNI)-Sparing sTrategy

Liver Transplantation Clinical Trial

— REFLECT  

Official title:

Multicenter, Prospective, Open-label, Controlled, Randomized, Parallel Groups Study to Evaluate the Renal Function of Adult Liver Transplant Recipients Treated With Two Everolimus-based Immunosuppressive Regimens (Tacrolimus Withdrawal vs. Minimization) Until 12 Months Post-transplant, With a 6-months Follow-up

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02115113
• Other study ID #: CRAD001HIT34
• Secondary ID: 2013-004325-91
• Status: Completed
• Phase: Phase 3
• Start date: March 28, 2014
• Est. completion date: September 30, 2016

Study information

• Verified date: October 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was, starting from the Italian clinical practice in liver transplantation, to optimize the immunosuppressive therapy, considering specific patient characteristics as alcoholic cirrhosis, hepatitis C virus (HCV), hepatocellular carcinoma (HCC), and short/long-term implications. Then efficacy and safety of a calcineurin inhibitor (CNI)-withdrawal regimen was evaluated in comparison with a CNI-minimization regimen.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: September 30, 2016
• Est. primary completion date: September 30, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria at Baseline:

• Male and female liver transplant recipients who are = 18 years of age, treated with a tacrolimus-based immunosuppressive regimen, who have received an induction therapy or i.v. steroids as per local clinical practice.

• Recipients of a full-size or technically modified liver allograft will be eligible at 4 weeks (± 7 days) after liver transplantation.

• Allograft is functioning at an acceptable level by the time of Baseline as defined by the AST, ALT, total bilirubin levels = 3 times ULN and INR < 1.5 times ULN.

• Abbreviated MDRD-4 eGFR = 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Baseline are acceptable.

Inclusion criteria at Randomization:

• Effective tacrolimus minimization, confirmed by stable blood trough levels in the two months prior to randomization, i.e. verification of last two tacrolimus blood trough level = 5 ng/mL in the two months prior to randomization. Investigators should make adjustments in tacrolimus dosing to continue to target trough levels = 5 ng/mL prior to randomization.

• Abbreviated MDRD-4 eGFR = 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Visit 5 are acceptable.

Exclusion criteria at Baseline:

• Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an AB0 incompatible transplant.

• Patients who experienced more than one episode of treated biopsy proven acute rejection (BANFF = 3 or RAI = 7) or one steroid-resistant acute rejection.

• Patients who require renal replacement therapy.

• Patients with a confirmed spot urine protein/creatinine ratio that indicates =1.0 g/24 hrs of proteinuria.

• History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC.

Exclusion criteria at Randomization:

• Patients who experienced more than two episodes of treated biopsy proven acute rejection (BANFF = 3 or RAI = 7) since transplantation or one steroid-resistant acute rejection during the run-in period.

• Patients with a confirmed spot urine protein/creatinine ratio that indicates = 3.0 g/24 hrs of proteinuria.

Related Conditions & MeSH terms

• Liver Transplantation

Intervention

Drug:
• Everolimus
Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.
• Tacrolimus
Commercial product labeled according to local requirements will be provided as 0.5 mg, 1.0 mg and 5.0 mg capsules for oral administration.

Locations

Country	Name	City	State
Italy	Novartis Investigative Site	Ancona	AN
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Udine	UD
Italy	Novartis Investigative Site	Verona	VR

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR)	Renal function was assessed by eGFR using the MDRD-4 formula at 12 months after transplant: eGFR = 186.3 * (serum creatinine)-1.154 * age-0.203 * (0.742 for women) * (1.21 if African American) where serum creatinine was in mg/dL and age in years.	At 12 months post-transplant
Secondary	Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D)	Participants were assessed for tBPAR, AR, GL or death. For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, a liver biopsy was to be performed preferably within 24 hours, latest within 48 hours whenever clinically possible. A treated biopsy proven acute rejection was considered an episode of acute rejection when demonstrated by local pathology reading with a rejection activity index of at least 3 or greater of acute rejection index and when treated with anti-rejection therapy. The allograft was considered lost on the day the subject was re-transplanted or died due to liver failure.	At 12 and 18 months post-transplant
Secondary	Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant	Blood samples were collected to assess serum creatinine.	baseline, 12 months post-transplant