Protocol Calcineurin Inhibitor (CNI) Weaning

Prospective, Multicenter, Randomized, Double-blind, Controlled Parallel Group Study Designed to Assess the Risk-benefit Balance of the Gradual Withdrawal of a Calcineurin Inhibitor (Tacrolimus) in Renal Transplant Patients Over 4 Years and Clinically Selected

The main objective of this study is to demonstrate the benefit of the withdrawal of Tacrolimus (Prograf®) on renal function in patients one year after the end of the weaning period. The secondary objectives will focus on assessing the risks and consequences of withdrawal of Tacrolimus (Prograf®).

Study Overview

• Status: Terminated
• Conditions: Function of Renal Transplant
• Intervention / Treatment: Drug: Tacrolimus; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Nantes, France, 44093
    • Nantes University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Pre-inclusion criteria :

• Male or female aged between 18 and 80 years (inclusive),
• Having received a deceased donor transplant or living with ABO compatibility,
• First renal allograft for at least 4 years and under 10 years,
• Presenting a stable renal function : serum creatinine with a variation of ± 25% of the average of the year before inclusion,
• Treated with tacrolimus (Prograf®) in combination with MPA (Cellcept® and Myfortic®) + / - steroids (between 5 and 10 mg per day),
• Patient has given informed consent,
• Patient insured,
• Patient (of childbearing age) with effective contraception.

Inclusion Criteria:

• Glomerular Filtration Rate (GFR), defined by the dosage of cystatin C ≥ 40 ml/min/1, 73m²,
• Proteinuria ≤ 0,5 g / day,
• Patient with serum levels of Tacrolimus between 5 to 10 ng / ml on average during the last 6 months (inclusive). It is accepted that 25% of the assays performed during the last 6 months, serum levels of tacrolimus are outside the limits mentioned above (5-10 ng / ml). They must nevertheless be between 3.5 to 12.5 ng / ml (inclusive).
• Patient with serum levels of MPA (Cellcept® and Myfortic®) higher ≥ 30 mg / ml,
• No anti-HLA antibodies at the time of inclusion, verified using highly sensitive techniques (Luminex HD),
• Lack of histological evidence of cellular or humoral acute or chronic or subclinical rejection on renal graft according to the latest classification of Banff 2009.

Exclusion Criteria:

• Patients under age 18 or over 80 years,
• Transplanted from less than 4 years and over 10 years,
• Patients re-transplanted,
• Transplantation of several organs,
• Patient not treated with tacrolimus as maintenance therapy,
• Serum levels of Tacrolimus patient <5 or >10 ng / ml,
• Serum levels of MPA of the patient <30 mg / ml,
• Patients treated with other immunosuppressive drugs that Tacrolimus (Prograf®), MPA (Cellcept® and Myfortic®) and steroids,
• Patient not having a stable graft function at baseline (change in serum creatinine > 25% of the average of the year before inclusion in the study), with a GFR defined by the dosage of cystatin C <40 ml/min/1, 73m² at the time of inclusion,- Patients with proteinuria > 0.5 g at study entry,
• Patient with HLA antibodies at study entry,
• Patient non-compliant,
• Presence of histological evidence of cellular or humoral acute or chronic or subclinical rejection on renal graft according to the latest classification of Banff 2009,
• History of lymphoproliferative disorders,
• Diagnosis of a malignancy within 5 years before enrollment,
• Significantly abnormal hematologic data of a clinical standpoint, as determined by the investigator for hematocrit, hemoglobin, white blood cell count or platelets,
• Data significantly abnormal blood biochemistry of a clinical standpoint, as determined by the investigator,
• Abuse of significant drug or alcohol at the time of inclusion, determined by the investigator,
• Patient positive for antibodies to hepatitis C or hepatitis B surface antigen of hepatitis B (HBsAg) or HIV infection,
• Participation in a clinical study within 3 months,
• Pregnancy, Breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus	Drug: Tacrolimus; A control group continued conventional therapy, Tacrolimus (Prograf®) ("control" group) and will be followed in parallel group "withdrawal" that will stop treatment with Tacrolimus (Prograf®).
Experimental: Withdrawal of Tacrolimus	Drug: Placebo; Patients randomized to the "withdrawal"group will begin the protocol with their usual dose of Tacrolimus (Prograf®) (initial dose). The initial dose of tacrolimus (Prograf®) will be reduced by one third at visit 3 (day 0) and again a third visit 5 (J60). The complete withdrawal Tacrolimus (Prograf®) begins to visit 7 (J120). The withdrawal of Tacrolimus (Prograf®) will be obtained in four months. Monitoring of all patients lasted 17 months in total from the screening visit, which corresponds to 12 months after complete withdrawal of Tacrolimus (Prograf®) for patients in the "withdrawal" group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function	The primary endpoint will be the improvement of renal function one year after complete withdrawal of Tacrolimus (Prograf®) assessed by measuring the glomerular filtration rate (GFR) calculated by the dosage of cystatin C according to the equation Bricon. The DFG will be compared between times J-30 and J480 (1 year after the withdrawal).	one year after complete withdrawal of Tacrolimus

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function	Improvement of renal function by measuring serum creatinine, using the original MDRD equation,	one year after complete withdrawal
Acute rejection	Rate of histologically proven acute rejection by biopsy according to Banff classification 2009,	one year after complete withdrawal
Chronic rejection	Rate of chronic rejection histologically proven by biopsy according to Banff classification 2009,	One year after complete withdrawal
Steroid-resistant rejection	Rates of steroid-resistant rejection	One year after complete withdrawal
Graft survival	Rate of return to dialysis (graft survival)	One year after complete withdrawal
Cancer and infections	Incidence of cancer and infections	one year after complete withdrawal
Patients survival	Survival rate of patients	One year after complete withdrawal
Anti-HLA antibodies	Appearance of anti-HLA donor specific and non-donor specific antibodies measured by the technique Luminex	One year after complete withdrawal
Histological lesions of rejection	The appearance of histological lesions of cellular or humoral acute or chronic or subclinical rejection on the biopsy protocol	One year after complete withdrawal
Histological lesions of fibrosis	Onset or worsening of histological lesions of interstitial fibrosis and tubular atrophy on biopsy inflammatory	One year after complete withdrawal
Hypertension, hyperglycemia and hyperlipidemia	Incidence of hypertension, hyperglycemia and hyperlipidemia	One year after complete withdrawal
Quality of life	Determination of the benefits of withdrawal of Tacrolimus on the quality of life of patients, defined by the scale of quality of life validated SF-36 used at the beginning (J-15) and at the end of the weaning period (J120) at 6 months (J300) and one year after complete withdrawal of Tacrolimus (J480)	One year after complete withdrawal

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Investigators: Study Chair: Emmanuel MORELON, Profesor, CHU de Lyon; Principal Investigator: Magali GIRAL, Profesor, CHU de Nantes; Study Chair: Jean-Paul SOULILLOU, Profesor, CHU de Nantes; Study Chair: Christophe LEGENDRE, Profesor, Hôpital Necker - AP-HP; Study Chair: Georges MOURAD, Profesor, CHU de Montpellier

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: February 8, 2011
• First Submitted That Met QC Criteria: February 8, 2011
• First Posted (Estimate): February 9, 2011

Study Record Updates

• Last Update Posted (Estimate): March 23, 2016
• Last Update Submitted That Met QC Criteria: March 22, 2016
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: renal allograft; Withdrawal of Tacrolimus and renal graft; stable renal function
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 09/7-D; 2010-019574-33 (EudraCT Number)