Non-inferiority Study of Safety and Efficacy of Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in Kidney Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this phase 3b study is to compare the safety and efficacy of everolimus with low dose tacrolimus to mycophenolate mofetil with standard dose tacrolimus in kidney transplant recipients.

Official Title
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A 12 Month, Multi-center, Randomized, Open-label Non-inferiority Study Comparing Safety and Efficacy of Concentration-controlled Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in de Novo Renal Transplant Recipients

Conditions
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Kidney Transplant

Intervention / Treatment
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* Drug: Everolimus and tacrolimus
* Drug: mycophenolate mofetil and tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female renal recipients 18-70 years of age undergoing kidney transplantation, either primary or re-transplant; Recipient of a cadaveric, deceased donor (including expanded criteria donor organs and deceased donor organs after cardiac death), living unrelated or non-HLA identical living related donor kidney; Graft must be functional (producing greater than or equal to 100 ml of urine within 24 hours after transplantation) at time of randomization. Exclusion criteria: Donor organ with a cold ischemic time > 30 hours; Males or females who produce less than 100 ml of urine in the first 24 hours post-transplantation; Males or females who are recipients of ABO incompatible transplants, or T cell, or B cell crossmatch positive transplant; Males or females with severe total hypercholesterolemia or total hypertriglyceridemia (Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable); Males or females who have any surgical or any medical condition, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator, might alter the absorption, distribution, metabolism and/or excretion of study medication. Other protocol related inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: Everolimus (EVR) & low dose of tacrolimus<br>Everolimus (EVR) and tacrolimus treatment arm: Therapeutic drug monitoring of everolimus and tacrolimus was mandatory throughout the study. From Day 5 onwards, the everolimus 0.75 mg b.i.d. dose was increased if the trough level was < 3 ng/mL, or reduced if the trough level was > 8 ng/mL. Tacrolimus was initiated according to local practice. In this treatment arm, the tacrolimus dose was adjusted from Day 3 onwards, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From Month 2 until Month 6, the target tacrolimus trough level was 3 ng/mL to 6 ng/mL. After Month 6, the tacrolimus dose was adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. | Drug: Everolimus and tacrolimus<br>* Everolimus: Dosage form: 0.75 mg, 0.25 mg, and 0.5 mg tablets Dose: 1.5 mg per day Frequency: 0.75 mg twice daily Tacrolimus: Dose adjusted to maintain specific blood levels<br>|
| Active Comparator: Mycophenolate mofetil & standard dose tacrolimus<br>Mycophenolate mofetil and tacrolimus (MMF) treatment arm: MMF dose was initiated at 1 g b.i.d. (2 g/day). Adjustments were to be made for adverse events including, but not limited to, gastrointestinal intolerance and decrease in WBC. MMF trough or AUC was not used to adjust dosing. In this group, tacrolimus was initiated according to local practice. Tacrolimus dose was adjusted from Day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 12 ng/mL. From Month 2 until Month 6, target tacrolimus trough level was reduced to 7 - 10 ng/mL. After Month 6, target level of tacrolimus was reduced to 5 - 8 ng/mL. | Drug: mycophenolate mofetil and tacrolimus<br>* Mycophenolate mofetil: - Dose form: 250 mg capsule - Dose: 2g per day - Frequency: 1g twice daily Tacrolimus: - Dose adjusted to maintain specific blood levels<br>* Other names: Active Comparator Control);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Incidence of Composite Efficacy Failure | Efficacy failure rate used the composite endpoint of: (1) treated biopsy-proven acute rejection (BPAR)*, (2) graft loss**, (3) participant death or(4) loss to follow-up. *A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. **Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Glomerular Filtration Rate (eGFR) | Renal function was assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. MDRD formula: GFR [mL/min/1.73m˄2] = 186.3*(C˄-1.154)*(A˄-0.203)*G*R. DEFINITIONS: C = serum concentration of creatinine [mg/dL]; A = age [years]; G = 0.742 when gender is female, otherwise G = 1; R = 1.21 when race is black, otherwise R = 1 | 12 Months | 
| Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease) | Participants with incidence of CMV (viremia, syndrome and disease). CMV is cytomegalovirus. | 12 Months | 
| Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy | Participants with Incidence of BKV (viremia, viruria, or nephropathy). BKV is Polyomavirus type BK. | 12 Months | 
| Number of Participants With Incidence of New Onset of Diabetes Mellitus | Incidence of new onset diabetes mellitus defined as non-diabetic patients before transplantation, who are receiving glucose lowering treatment for more than 30 days post-transplant, or with a random plasma glucose ≥200 mg dL (11.1 mmol/L) with 2 fasting plasma glucose values ≥126 mg/dL (7 mmol/L) | 12 Months | 
| Number of Participants With Incidence of Proteinuria Events | Number of participants with Incidence of proteinuria events indicating chronic kidney disease | Baseline and 12 Months | 
| Number of Participants With Incidence of Adverse Events, Serious Adverse Events, and Tacrolimus-associated Adverse Events | Incidence of adverse events, serious adverse events, and tacrolimus-associated adverse events by System Organ Class | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplant, renal transplant, immunosuppression, mycophenolate mofetil, tacrolimus, everolimus