Pharmacodynamics, Efficacy and Safety of Basiliximab 40 or 80 mg in Combination With Ciclosporine Microemulsion or Everolimus, in Adult Low Risk de Novo Renal Transplant Recipients (IDEALE Study) (IDEALE)

Prospective, Multicenter, Randomized, Open-label, Phase 2, Lasting 12 Weeks, Evaluating the Pharmacodynamics, Efficacy and Safety of Basiliximab in de Novo Adult Renal Transplant Patients at Low Risk Receiving Either a Cumulative Dose of Basiliximab of 40 or 80 mg in Combination With Cyclosporine Microemulsion, or a Cumulative Dose of 80 mg of Basiliximab Without Calcineurin Inhibitor, With Additional Follow-up of 12 Weeks

The aims of this study are to extensively study the levels of CD25-Receptors saturation and expression obtained with 2 different doses of Simulect® in combination with Neoral® (i.e to demonstrate that saturation and expression vary according to the dose of Simulect® given), and to study the levels of CD25-Receptors saturation without Neoral® and compare them to the data with Neoral®.

It will be conducted in low risk de novo adult renal transplant recipients until 12 weeks post-transplant, receiving either a cumulative dose of 40 or 80 mg of Simulect® in combination with Neoral®, or a cumulative dose of 80 mg of Simulect® in a calcineurin inhibitor free immunosuppressant therapy.

Study Overview

• Status: Completed
• Conditions: Renal Transplantation
• Intervention / Treatment: Drug: Simulect®; Drug: Neoral®; Drug: Myfortic®; Drug: Corticosteroids; Drug: Certican®

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux Cedex, France, 33076
    • Novartis Investigative Site
  • Paris cedex 15, France, 75015
    • Novartis Investigative Site
  • Tours Cedex, France, 37044
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients receiving a primary renal graft from a deceased or living, related or unrelated donor and who require basiliximab induction therapy
• Cold ischemia time < 30 hours

Exclusion (Non inclusion) criteria:

• Patients undergoing multi-organ transplantation, including both kidneys, or who have previously undergone organ transplantation, including renal transplantation
• Patients receiving a graft from a non-heart-beating donor
• A-B-O incompatible graft or positive T cell crossmatch
• Patients receiving a graft from an expanded criteria donor according to the UNOS definition (donor older than 60 years or donor aged between 50 and 60 years and presence of at least 2 of the following factors: hypertension, serum creatinine concentration ≥ 132 µmol/mL, cardiovascular cause of death)
• Positive anti-HLA antibodies (Luminex) prior to transplantation
• Patients whose original renal disease was primary focal and segmental hyalinosis or was related to atypical hemolytic uremic syndrome
• EBV-negative patients receiving a graft from an EBV-positive donor (EBV D+R-)

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Simulect 40mg + Neoral + Myfortic + steroids; A cumulative dose of 40 mg of Simulect® (20mg at Day 0 (D0) and 20mg at Day 4 (D4)+ Neoral® + Myfortic® + corticosteroids	Drug: Simulect®; Simulect® was provided to the study center in its commercial package containing a powder vial with 20 mg of active product and sterile water for injection. The solution should be used immediately after reconstitution. The infusion was prepared by adding at least 50 mL of physiologic or 5% glucose solution to the reconstituted solution (at least 100 mL for 40 mg of Simulect®). Simulect® was transported and kept in a cold environment (2-8°C) as recommended in the summary of product characteristics (SPC).; Other Names: Basiliximab; Drug: Neoral®; Neoral® was provided to the study center in its commercial package as 10, 25, 50 or 100 mg soft capsules in thermoformed blister packs.; Other Names: Cyclosporine microemulsion; Drug: Myfortic®; Myfortic® was administered orally b.i.d. with a 12-hour interval. Tablets could be taken either with or outside meals but consistently throughout the study. To maintain the integrity of the enteric coating, tablets were not to be crushed. Myfortic® treatment was initiated either preoperatively or within 24 hours post transplantation according to local practice in each center. Starting dose was to be 2160 mg/day (1080 mg b.i.d.) for at least 2 weeks and for at most 4 weeks. Patients were then to receive 1440 mg/day (720 mg b.i.d.) until the end of the study. Myfortic® was administered as concomitant treatment to all patients, using the same regimen for all 3 study groups. It was provided to the study center in its commercial package as 180 and 360 mg gastro-resistant tablets.; Other Names: mycophenolate sodium; Drug: Corticosteroids; Corticosteroid i.v. therapy could be administered peri or per operatively according to local practice in each center with the same scheme for each patient in the center. Oral corticotherapy was to be initiated rapidly, within one week following transplantation, with a minimal dose of 20 mg/day. Thereafter, the dose was to be decreased according to local practice but oral corticosteroids were to be continued throughout the study with a minimal dose of 5 mg/day.
EXPERIMENTAL: Simulect 80mg + Neoral + Myfortic + steroids; A cumulative dose of 80 mg of Simulect® (40mg at D0 and 40mg at D4) + Neoral® + Myfortic® + corticosteroids	Drug: Simulect®; Simulect® was provided to the study center in its commercial package containing a powder vial with 20 mg of active product and sterile water for injection. The solution should be used immediately after reconstitution. The infusion was prepared by adding at least 50 mL of physiologic or 5% glucose solution to the reconstituted solution (at least 100 mL for 40 mg of Simulect®). Simulect® was transported and kept in a cold environment (2-8°C) as recommended in the summary of product characteristics (SPC).; Other Names: Basiliximab; Drug: Neoral®; Neoral® was provided to the study center in its commercial package as 10, 25, 50 or 100 mg soft capsules in thermoformed blister packs.; Other Names: Cyclosporine microemulsion; Drug: Myfortic®; Myfortic® was administered orally b.i.d. with a 12-hour interval. Tablets could be taken either with or outside meals but consistently throughout the study. To maintain the integrity of the enteric coating, tablets were not to be crushed. Myfortic® treatment was initiated either preoperatively or within 24 hours post transplantation according to local practice in each center. Starting dose was to be 2160 mg/day (1080 mg b.i.d.) for at least 2 weeks and for at most 4 weeks. Patients were then to receive 1440 mg/day (720 mg b.i.d.) until the end of the study. Myfortic® was administered as concomitant treatment to all patients, using the same regimen for all 3 study groups. It was provided to the study center in its commercial package as 180 and 360 mg gastro-resistant tablets.; Other Names: mycophenolate sodium; Drug: Corticosteroids; Corticosteroid i.v. therapy could be administered peri or per operatively according to local practice in each center with the same scheme for each patient in the center. Oral corticotherapy was to be initiated rapidly, within one week following transplantation, with a minimal dose of 20 mg/day. Thereafter, the dose was to be decreased according to local practice but oral corticosteroids were to be continued throughout the study with a minimal dose of 5 mg/day.
EXPERIMENTAL: Simulect 80mg + Certican + Myfortic + steroids; A cumulative dose of 80 mg of Simulect® (40mg at D0 and 40mg at D4) + Certican® + Myfortic® + corticosteroids	Drug: Simulect®; Simulect® was provided to the study center in its commercial package containing a powder vial with 20 mg of active product and sterile water for injection. The solution should be used immediately after reconstitution. The infusion was prepared by adding at least 50 mL of physiologic or 5% glucose solution to the reconstituted solution (at least 100 mL for 40 mg of Simulect®). Simulect® was transported and kept in a cold environment (2-8°C) as recommended in the summary of product characteristics (SPC).; Other Names: Basiliximab; Drug: Myfortic®; Myfortic® was administered orally b.i.d. with a 12-hour interval. Tablets could be taken either with or outside meals but consistently throughout the study. To maintain the integrity of the enteric coating, tablets were not to be crushed. Myfortic® treatment was initiated either preoperatively or within 24 hours post transplantation according to local practice in each center. Starting dose was to be 2160 mg/day (1080 mg b.i.d.) for at least 2 weeks and for at most 4 weeks. Patients were then to receive 1440 mg/day (720 mg b.i.d.) until the end of the study. Myfortic® was administered as concomitant treatment to all patients, using the same regimen for all 3 study groups. It was provided to the study center in its commercial package as 180 and 360 mg gastro-resistant tablets.; Other Names: mycophenolate sodium; Drug: Corticosteroids; Corticosteroid i.v. therapy could be administered peri or per operatively according to local practice in each center with the same scheme for each patient in the center. Oral corticotherapy was to be initiated rapidly, within one week following transplantation, with a minimal dose of 20 mg/day. Thereafter, the dose was to be decreased according to local practice but oral corticosteroids were to be continued throughout the study with a minimal dose of 5 mg/day.; Drug: Certican®; Certican® was provided to the study center in its commercial package as 0.75, 0.5 and 0.25 mg tablets in thermoformed blister packs.; Other Names: Everolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) of CD25 Saturation by Basiliximab From Day 0 to Day 84	CD25 saturation is the percentage of T cells expressing CD25. Mean AUC of CD25 was calculated only for patients who received two Simulect® injections.	Day 84 (Week 12) after transplantation
Saturation Rate of CD25 Antigen Saturation by Basiliximab	CD25 saturation is the percentage of T cells expressing CD25	Day 0, Day 1, Day 4, Day 6, Day 14, Day 21, Day 28, Day 42, Day 56 and Day 84 (Week 12) post-transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of Basiliximab Binding to CD25 Receptors From Day 0 to Day 84	Mean AUC was calculated only for patients who received two Simulect injections.	Day 84 (Week 12) post-transplantation
Percentage of T-cells That Bind Basiliximab to CD25 Receptors	This is the percentage of T cells binding basiliximab at all timepoints.	Day 0, Day 1, Day 4, Day 6, Day 14, Day 21, Day 28, Day 42, Day 56 and Day 84 (Week 12) post-transplantation
Proportion of CD3+, CD4+, CD8+, CD19+ and CD56+ T Cells	Cell counts of various subpopulations of T, B and NK lymphocytes (CD3, CD4, CD8, CD19 and CD56) (flow cytometry).	Day 0, Day 6, Day 42, Day 84 (Week 12)
Percentage of Participants With of Biopsy Proven Acute Rejection (BPAR)	BPAR is one of the components of treatment failure. One assessment of efficacy was BPAR. Renal graft biopsies were performed and the renal tissue was examined to determine if there was acute rejection of the renal transplant.	Day 84 (Week 12), Week 24 post-transplantation
Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) According to Type and Severity	Antibody mediated acute rejection: C4d deposition, presence of circulating antidonor antibody, morphologic evidence of acute tissue injury such as acute tubular necrosis-like minimal inflammation or capillary and/or glomerular inflammation and/or thromboses or arterial inflammation. Cellular acute rejection: acute T-cell mediated rejection Type IA: Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells) Type IB: Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells) Type IIA: Mild to moderate intimal arteritis. Type IIB: Severe intimal arteritis comprising > 25% of the lumenal area. Type III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation).	Day 84 (Week 12), Week 24 post-transplantation
Percentage of Participants With of Treatment Failures	Treatment failure was defined either as a BPAR, a graft loss, a death or a loss to follow-up. An extended treatment failure was also defined including treated borderline lesions, BPAR, graft loss, death or loss to follow-up. Treated borderline lesions were considered as acute rejection by investigators and DMC experts.	Day 84 (Week 12), Week 24
Estimated Glomerular Filtration Rate (eGFR) at Day 8 and Week 24	(MDRDa formula) with imputation by last observation carried forward (LOCF)	Day 8, Week 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Thibault G, Paintaud G, Legendre C, Merville P, Coulon M, Chasseuil E, Ternant D, Rostaing L, Durrbach A, Di Giambattista F, Buchler M, Lebranchu Y. CD25 blockade in kidney transplant patients randomized to standard-dose or high-dose basiliximab with cyclosporine, or high-dose basiliximab in a calcineurin inhibitor-free regimen. Transpl Int. 2016 Feb;29(2):184-95. doi: 10.1111/tri.12688. Epub 2015 Oct 8.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: September 29, 2011
• First Submitted That Met QC Criteria: May 8, 2012
• First Posted (ESTIMATE): May 10, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): July 25, 2014
• Last Update Submitted That Met QC Criteria: June 26, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: everolimus; renal transplantation; CNI-free; Basiliximab
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Everolimus; Basiliximab; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CCHI621AFR05; 2010-024231-16 (EUDRACT_NUMBER)