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

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ClinicalTrials.gov Identifier: NCT02115113
Recruitment Status : Completed
First Posted : April 15, 2014
Results First Posted : February 28, 2019
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Liver Transplantation Drug: Everolimus Drug: Tacrolimus Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 28, 2014
Actual Primary Completion Date : September 30, 2016
Actual Study Completion Date : September 30, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A (Tacrolimus Elimination Arm)
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
Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.

Drug: 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.

Active Comparator: Group B (Tacrolimus Minimization Arm)
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
Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.

Drug: 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.




Primary Outcome Measures :
  1. Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR) [ Time Frame: At 12 months post-transplant ]

    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.



Secondary Outcome Measures :
  1. Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) [ Time Frame: At 12 and 18 months post-transplant ]
    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.

  2. Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant [ Time Frame: baseline, 12 months post-transplant ]
    Blood samples were collected to assess serum creatinine.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02115113


Locations
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Italy
Novartis Investigative Site
Ancona, AN, Italy, 60126
Novartis Investigative Site
Bari, BA, Italy, 70124
Novartis Investigative Site
Bergamo, BG, Italy, 24127
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Milano, MI, Italy, 20122
Novartis Investigative Site
Modena, MO, Italy, 41124
Novartis Investigative Site
Padova, PD, Italy, 35128
Novartis Investigative Site
Pisa, PI, Italy, 56124
Novartis Investigative Site
Roma, RM, Italy, 00144
Novartis Investigative Site
Roma, RM, Italy, 00168
Novartis Investigative Site
Torino, TO, Italy, 10126
Novartis Investigative Site
Udine, UD, Italy, 33100
Novartis Investigative Site
Verona, VR, Italy, 37126
Novartis Investigative Site
Napoli, Italy, 80132
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02115113     History of Changes
Other Study ID Numbers: CRAD001HIT34
2013-004325-91 ( EudraCT Number )
First Posted: April 15, 2014    Key Record Dates
Results First Posted: February 28, 2019
Last Update Posted: February 28, 2019
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Liver transplantation, everolimus, CNI-minimization, CNI-elimination, renal function

Additional relevant MeSH terms:
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Tacrolimus
Everolimus
Sirolimus
Calcineurin Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents