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

NCT02115113 | Completed Phase 3 Results DMC

• 2 other identifiers: CRAD001HIT342013-004325-91
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 14

Brief 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.

Conditions

Liver Transplantation

Keywords

Liver transplantation, everolimus, CNI-minimization, CNI-elimination, renal function

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D)

  At 12 and 18 months post-transplant

• Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant

  baseline, 12 months post-transplant

Study Arms (2)

Group A (Tacrolimus Elimination Arm)

EXPERIMENTAL

At study start, participants received an Everolimus starting dose of 1.0 mg twice daily in combination with Tacrolimus. Tacrolimus was administered as per center practice. Thereafter, Everolimus doses were adjusted to achieve Everolimus C-0h blood trough levels between 3-8 ng/mL by week 1 after drug initiation until 5 months after transplant. At 5 months after transplant, Everolimus doses were adjusted to achieve C-0h blood trough level target ranges 6-10 ng/mL. Tacrolimus withdrawal was completed by 6 months after transplant.

Drug: Everolimus; Drug: Tacrolimus

Group B (Tacrolimus Minimization Arm)

ACTIVE COMPARATOR

At study start, participants received an Everolimus starting dose of 1.0 mg twice daily in combination with Tacrolimus. Tacrolimus was administered as per center practice. Thereafter, Everolimus doses were adjusted to achieve Everolimus C-0h blood trough levels between 3-8 ng/mL by week 1 after drug initiation until 5 months after transplant. At 5 months after transplant, Everolimus doses continued to be adjusted to achieve C-0h blood trough level target ranges 3-8 ng/mL and Tacorlimus doses were adjusted to achieve C-0h blood trough level target ranges 3-5 ng/mL.

Drug: Everolimus; Drug: Tacrolimus

Interventions

Everolimus DRUG

Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.

Group A (Tacrolimus Elimination Arm); Group B (Tacrolimus Minimization Arm)

Tacrolimus DRUG

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.

Group A (Tacrolimus Elimination Arm); Group B (Tacrolimus Minimization Arm)

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (14)

Novartis Investigative Site

Ancona, AN, 60126, Italy

Location

Novartis Investigative Site

Bari, BA, 70124, Italy

Location

Novartis Investigative Site

Bergamo, BG, 24127, Italy

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Milan, MI, 20122, Italy

Location

Novartis Investigative Site

Modena, MO, 41124, Italy

Location

Novartis Investigative Site

Padua, PD, 35128, Italy

Location

Novartis Investigative Site

Pisa, PI, 56124, Italy

Location

Novartis Investigative Site

Roma, RM, 00144, Italy

Location

Novartis Investigative Site

Roma, RM, 00168, Italy

Location

Novartis Investigative Site

Torino, TO, 10126, Italy

Location

Novartis Investigative Site

Udine, UD, 33100, Italy

Location

Novartis Investigative Site

Verona, VR, 37126, Italy

Location

Novartis Investigative Site

Napoli, 80132, Italy

Location

MeSH Terms

Interventions

Everolimus; Tacrolimus

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2014
• First Posted: April 15, 2014
• Study Start: March 28, 2014
• Primary Completion: September 30, 2016
• Study Completion: September 30, 2016
• Last Updated: February 28, 2019
• Results First Posted: February 28, 2019

Record last verified: 2018-10

Locations

IT (14)