Everolimus in de Novo Kidney Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study was to evaluate whether delayed (i.e. 28 ± 4 days post-transplant) administration of everolimus after transplantation reduces the risk of wound healing complications in comparison with immediate administration in de novo renal transplant patients (proportion of patients without wound/surgical complications related to initial transplant surgery) between randomization and 3 months after transplantation.

Official Title
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A 3-month, Multicenter, Randomized, Open Label Study to Evaluate the Impact of Early Versus Delayed Introduction of Everolimus on Wound Healing in de Novo Kidney Transplant Recipients With a Follow-up Evaluation at 12 Month After Transplant (NEVERWOUND Study)

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Mycophenolate sodium
* Drug: Cyclosporine
* Drug: Steroids


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Patients who are willing and able to participate in the study and who provide written informed consent before performing any study related procedure; Men or women ≥18 years at transplant; Recipients of 1st or 2nd single kidney transplant from deceased donor or living unrelated/related donor > 14 years; Key Exclusion criteria: Patients who are recipients of multiple organs transplant, including two kidneys; Historical or current peak PRA > 50%. Patients with already existing antibodies against the donor; Thrombocytopenia (platelets < 75,000/mm³), absolute neutrophil count <1,500/mm³, leucopenia (leucocytes < 2,500/mm³) or hemoglobin < 7 g/dL; Body mass index (BMI) > 30 Kg/m2;

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate Everolimus (IE)<br>Everolimus was started within 48 hours after graft reperfusion at a starting dose of 0.75 mg twice daily in combination with low-dose cyclosporine and steroids for 3 months. | Drug: Everolimus<br>* Everolimus was provided in blisters containing 0.25 and 0.75 mg tablets and was taken orally.<br>* Other names: Certican®;Drug: Cyclosporine<br>* Cyclosporine was supplied as blisters containing 100 mg, 50 mg, 25 mg and 10 mg soft-gelatin capsules and was administered orally.<br>* Other names: Neoral®;Drug: Steroids<br>* Steroids were administered according to local clinical practice.<br>|
| Experimental: Delayed Everolimus<br>The standard dose of mycophenolate sodium was administered within 48 hours after graft reperfusion in combination with a full dose of cyclosporine and steroids. After28 +/- 4 days of treatment, mycophenolate sodium was discontinued and everolimus was introduced at a starting dose of 0.75 mg twice daily for 3 months. | Drug: Everolimus<br>* Everolimus was provided in blisters containing 0.25 and 0.75 mg tablets and was taken orally.<br>* Other names: Certican®;Drug: Mycophenolate sodium<br>* Two 360 mg tablets were administered twice daily at 12-hour intervals. The tablets were swallowed whole in order to maintain the integrity of the enteric coating.<br>* Other names: Myfortic®;Drug: Cyclosporine<br>* Cyclosporine was supplied as blisters containing 100 mg, 50 mg, 25 mg and 10 mg soft-gelatin capsules and was administered orally.<br>* Other names: Neoral®;Drug: Steroids<br>* Steroids were administered according to local clinical practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Without Wound Healing Complications - Worst-case Scenario | The percentage of participants without wound healing complications was assessed. Wound healing complications consisted of lymphorrhea, fluid collections, wound dehiscence, wound infections and incisional hernia. In the worst-case scenario, failure, i.e. at least one healing complication occurrence, was identified in one of the following cases: wound complication occurrence, missing information about wound complication occurrence, or study discontinuation due to any reason. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Without Wound Healing Complications - Worst-case Scenario | The percentage of participants without wound healing complications was assessed. Wound healing complications consisted of lymphorrhea, fluid collections, wound dehiscence, wound infections and incisional hernia. In the worst-case scenario, failure, i.e. at least one healing complication occurrence, was identified in one of the following cases: wound complication occurrence, missing information about wound complication occurrence or study discontinuation due to any reason for participants who did not complete the 12 month follow-up visit. | 12 months | 
| Percentage of Participants Who Experienced Treatment Failure - Worst-case Scenario | The percentage of participants who experienced treatment failure was assessed. Treatment failure was defined as the occurrence of at least one failure event among death, graft loss or biopsy-proven acute rejection (BPAR). In the worst-case scenario, treatment failure was identified in one of the following cases: occurrence of at least one treatment failure event or study discontinuation due to any reason. | 3 months | 
| Patient Survival Rate: Percentage of Deaths - Worst-case Scenario | The percentage of deaths was assessed. In the worst-case scenario, failure, i.e. death, was identified in one of the following cases: participant's death or study discontinuation due to any reason. | 3 Months, 12 months | 
| Participant/Graft Survival Rate: Percentage of Participants With Failure Events of Death or Graft Loss - Worst-case Scenario | The percentage of participants who experienced death or graft loss was assessed. In the worst-case scenario, failure, i.e. participants death or graft loss, was identified in one of the following cases: occurrence of at least one failure event or study discontinuation due to any reason. | 3 months | 
| Graft Survival Rate: Percentage of Participants With Graft Loss - Worst-case Scenario | The percentage of participants who experienced graft loss was assessed. In the worst-case scenario, failure, i.e. graft loss, was identified in one of the following cases: occurrence of graft loss or discontinuation due to any reason. | 3 months, 12 months | 
| Percentage of Participants With BPAR - Worst-case Scenario | A biopsy-proven acute rejection was defined as a biopsy graded IA, IB, IIA, IIB or III. In the worst-case scenario, failure, i.e. BPAR, was identified in one of the following cases: occurrence of BPAR or study discontinuation due to any reason. | 3 Months, 12 months | 
| Percentage of Participants With Delayed Graft Function (DGF) - | DGF was defined as the need for dialysis in the first week after transplant, excluding Renal Replacement Therapy within the first 24 hours after transplantation. | 3 Months | 
| Duration of DGF | The duration of DGF was defined as the elapsed time from first to last day of post-transplant dialysis. | 3 months | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) (Calculated With Modified Diet in Renal Disease (MDRD)-4 Formula - ITT | Renal function was assessed by measuring serum creatinine and serum urea and by calculating creatinine clearance using the MDRD-4 formula. eGFR = 186.3*(serum creatinine [mg/dL])^-1.154 * (age at screening) -0.203 * (0.742 if female) * (1.21 if African American). A positive change from baseline indicates improvement. | baseline, 3 Months | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) (Calculated With Modified Diet in Renal Disease (MDRD)-4 Formula - Modified ITT | Renal function was assessed by measuring serum creatinine and serum urea and by calculating creatinine clearance using the MDRD-4 formula. eGFR = 186.3*(serum creatinine [mg/dL])^-1.154 * (age at screening) -0.203 * (0.742 if female) * (1.21 if African American). A positive change from baseline indicates improvement. | baseline, 12 months | 
| Change From Baseline in Serum Creatinine - ITT | Blood samples were collected to assess serum creatinine measurements. A negative change from baseline indicates improvement. | baseline, 3 months | 
| Change From Baseline in Serum Creatinine - Modified ITT | Blood samples were collected to assess serum creatinine measurements. A negative change from baseline indicates improvement. | baseline, 12 months | 
| Percentage of Participants With Proteinuria | Incidence of proteinuria (>1,000 mg/day in urine collected in 24 hours or > 1.0 if measured on the urine protein/creatinine concentration ratio in a spot urine sample) was assessed. | 3 months | 
| Percentage of Participants With Acute Rejection (AR) | AR was defined as an episode of increased serum creatinine >30% that was clinically diagnosed as an acute rejection but was not biopsy proven. | 12 months | 
| Percentage of Participants With a New Onset of Malignancy | The percentage of participants with a new onset of malignancy was assessed. | 12 months | 
| Percentage of Participants With a New Onset of Diabetes | The percentage of participants with a new onset of diabetes was assessed. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppression, Kidney transplantation, everolimus, safety