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)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Simulect®
* Drug: Neoral®
* Drug: Certican®
* Drug: Myfortic®
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simulect 40mg + Neoral + Myfortic + steroids<br>A cumulative dose of 40 mg of Simulect® (20mg at Day 0 (D0) and 20mg at Day 4 (D4)+ Neoral® + Myfortic® + corticosteroids | Drug: Simulect®<br>* 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).<br>* Other names: Basiliximab;Drug: Neoral®<br>* Neoral® was provided to the study center in its commercial package as 10, 25, 50 or 100 mg soft capsules in thermoformed blister packs.<br>* Other names: Cyclosporine microemulsion;Drug: Myfortic®<br>* 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.<br>* Other names: mycophenolate sodium;Drug: Corticosteroids<br>* 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.<br>|
| Experimental: Simulect 80mg + Neoral + Myfortic + steroids<br>A cumulative dose of 80 mg of Simulect® (40mg at D0 and 40mg at D4) + Neoral® + Myfortic® + corticosteroids | Drug: Simulect®<br>* 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).<br>* Other names: Basiliximab;Drug: Neoral®<br>* Neoral® was provided to the study center in its commercial package as 10, 25, 50 or 100 mg soft capsules in thermoformed blister packs.<br>* Other names: Cyclosporine microemulsion;Drug: Myfortic®<br>* 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.<br>* Other names: mycophenolate sodium;Drug: Corticosteroids<br>* 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.<br>|
| Experimental: Simulect 80mg + Certican + Myfortic + steroids<br>A cumulative dose of 80 mg of Simulect® (40mg at D0 and 40mg at D4) + Certican® + Myfortic® + corticosteroids | Drug: Simulect®<br>* 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).<br>* Other names: Basiliximab;Drug: Certican®<br>* 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.<br>* Other names: Everolimus;Drug: Myfortic®<br>* 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.<br>* Other names: mycophenolate sodium;Drug: Corticosteroids<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNI-free, Basiliximab, renal transplantation, everolimus