Efficacy Regarding Renal Function of Everolimus in Combination With Specific Standard Immunosuppressive Regimen Lung Transplant Recipients

Study Overview
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Brief Summary
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This trial evaluated the efficacy of an everolimus-based quadruple low immunosuppressive regimen versus a standard immunosuppressive regimen concerning kidney function in lung transplant recipients.

Official Title
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A 2-arm, Prospective, Randomized, Controlled, Open-label, 12 Month Phase III Trial to Evaluate the Efficacy Regarding Renal Function of Everolimus in Combination With a Centre Specific Standard Immunosuppressive Regimen Consisting of CNI, Purinantagonists and Steroids Versus a Standard Triple Immunosuppressive Regimen in Lung Transplant Recipients.

Conditions
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Lung Transplantation

Intervention / Treatment
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* Drug: standard therapy
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Adult recipients of de novo cadaveric lung transplants 3-18 months prior to enrollment Exclusion criteria: Patients with thrombocytopenia (platelets <100,000/mm³), with an absolute neutrophil count of <1,500/mm³ or leucopenia (leucocytes <3000/mm³), with anemia with Hb < 8g/dl at time of screening Patients with uncontrolled hypercholesterolemia (> 350 mg/dL; > 9.1 mmol/L) or hypertriglyceridemia (> 750 mg/dL; > 8.5 mmol/L) at time of screening Patients with a history of malignancy of any organ system, treated or untreated, during the last five years, whether or not there is evidence of local recurrence or metastases, except squamous or basal cell carcinoma of the skin Other protocol-defined inclusion/exclusion criteria may apply

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quadruple low level IS regimen<br>quadruple immunosuppressive (IS) regimen consisting of everolimus, CNI, MPA and steroids | Drug: Everolimus<br>* quadruple immunosuppressive regimen consisting of everolimus, CNI, MPA and steroids<br>* Other names: RAD001;|
| Experimental: Centre specific triple IS regimen<br>centre specific CNI-based triple drug immunosuppression (IS) | Drug: standard therapy<br>* centre specific CNI-based triple drug immunosuppression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculated Glomerular Filtration Rate (cGFR) According to Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) at 12 Months | Calculated Glomerular Filtration Rate (cGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) at 12 months The CKD-EPI equation, expressed as a single equation, is GFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)^-1.209 × 0.993Age × 1.018 (if female) × 1.159 (if black), where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/ĸ or 1, and max indicates the maximum of Scr/κ or 1 | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculated Glomerular Filtration Rate (cGFR) According to Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) at Month 1, 3, 6, 9, 12 | Calculated Glomerular Filtration Rate (cGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) at Month 1, 3, 6, 9 and 12. The CKD-EPI equation, expressed as a single equation, is GFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)^-1.209 × 0.993Age × 1.018 (if female) × 1.159 (if black), where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/ĸ or 1, and max indicates the maximum of Scr/κ or 1 | Month 1, 3, 6, 9, 12 | 
| Calculated Glomerular Filtration Rate (cGFR) According to Cystatin C-based Hoek's Formula at Month 1, 3, 6, 9, 12 | Calculated Glomerular Filtration Rate (cGFR) according to Cystatin C-based Hoek's formula at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 1, 3, 6, 9, 12 | Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 1, 3, 6, 9, 12 cGFR (in mL/min/1.73 m2) = 186.3*(C-1.154)*(A-0.203)*G*R where C = the 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. | Month 1, 3, 6, 9, 12 | 
| Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 1, 3, 6, 9, 12 | Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 1, 3, 6, 9, 12 For men: GFR=(140-Age) x Body weight (kg) / 72 x Serum Creatinine (mg/dl) For women: GFR=0.85 (140 -Age) x Body weight(kg)/ 72 x Serum Creatinine (mg/dl) | Month 1, 3, 6, 9, 12 | 
| Incidence of Patients Experiencing a Decline in GFR of < 10, 10-15, 15-20, 20-25 and > 25 mL/Min From Baseline to Month 6 and 12. | Incidence of patients experiencing a decline in GFR of < 10, 10-15, 15-20, 20-25 and > 25 mL/min from Baseline to Month 6 and 12calculated by the CKD-EPI method. Participants are counted in each decline level observed for that participant; this means participants may be counted in more than 1 decline level. | Baseline, Month 6, Month 12 | 
| Incidence of Renal Replacement Therapy at Month 6 and Month 12 | Incidence of renal replacement therapy at Month 6 and Month 12: There were no incidences in either group where renal replacement therapy was required | Month 6, Month 12 | 
| Time to Renal Replacement Therapy at Month 6 and Month 12 | Time to renal replacement therapy at Month 6 and Month 12: There were no incidences in either group where renal replacement therapy was required | Month 6, Month 12 | 
| Incidence of Acute Rejection Episodes at Month 6 and Month 12 | Incidence of acute rejection episodes at Month 6 and Month 12. This table counts multiple occurrences of rejection in the same patient as different incidents. Every incident is associated with both an A and a B classification. Classification A: Acute Rejection Grade 0 - none, Grade 1-minimal, Grade 2- mild, Grade 3-moderate, Grade 4-Severe; Classification B: Airway Inflammation-Grade 0-none, Grade 1R-low grade, Grade 2R-high grade, Grade X-ungradeable | Month 6, Month 12 | 
| Incidence of Graft Loss/Re-transplantation at Month 6 and Month 12 | Incidence of graft loss/re-transplantation at Month 6 and Month 12 | Month 6, Month 12 | 
| Incidence of Bronchiolitis Obliterans Syndrome (BOS) at Month 6 and Month 12 | Incidence of Bronchiolitis obliterans syndrome (BOS) at Month 6 and Month 12 BOS 0 is FEV1 > 90% of baseline and FEF25-75% > 75% of baseline; BOS 0-p is FEV1 81-90% of baseline and/or FEF25-75% ≤ 75% of baseline; BOS 1 is FEV1 66-80% of baseline; BOS 2 is FEV1 51-65% of baseline; BOS 3 is FEV1 ≤ 50% of baseline | Month 6, Month 12 | 
| Incidence of Death at Month 6 and Month 12 | Incidence of death at Month 6 and Month 12 | Month 6, Month 12 | 
| Quality of Life (QoL, SF36) at Month 6 and Month 12 | Quality of Life (QoL, SF36) at Month 6 and Month 12 Scores can range from a minimum of 0 (maximum disability) to a maximum of 100 (no disability). | Month 6, Month 12 | 
| Exercise Capacity 6-Minute Walk Test(6MWT) at Month 6 and Month 12 | Exercise capacity (6MWT) at Month 6 and Month 12 Measured by the Borg Scale. THE BORG SCALE 0 is Nothing at all, 0.5 is Very, very slight (just noticeable); 1 is Very slight, 2 is Slight (light); 3 is Moderate; 4 is Somewhat severe; 5 is Severe (heavy), 7 is Very severe, 10 is Very, very severe (maximal)The higher the Borg score implies increased shortness of breath and/or increased fatigue. | Month 6, Month 12 | 
| Incidence of Treated Arterial Hypertension up to Month 12 | Incidence of treated of arterial hypertension up to Month 12 | up to Month 12 | 
| Incidence of Diabetes Mellitus up to Month 12 | Incidence of Diabetes Mellitus up to Month 12 | up to Month 12 | 
| Trough Levels of Everolimus at Month 1, 3, 6, 9, 12 | Trough levels of everolimus at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Adherence to Target Ranges of Everolimus at Month 1, 3, 6, 9, 12 | Adherence to target ranges of everolimus at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Trough Levels of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12 | Trough levels of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Adherence to Target Ranges of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12 | Adherence to target ranges of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Trough Levels of Tacrolimus at Month 1, 3, 6, 9, 12 | Trough levels of Tacrolimus at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Adherence to Target Ranges of Tacrolimus at Month 1, 3, 6, 9, 12 | Adherence to target ranges of Tacrolimus at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Incidence of Bacterial, Viral, and Fungal Infections at Month 12 | Incidence of bacterial, viral, and fungal infections at Month 12 | Month 12 | 
| Triglyceride Levels at Month 1, 3, 6, 9, 12 | Triglyceride levels at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Total Cholesterol Levels at Month 1, 3, 6, 9, 12 | Total Cholesterol levels at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| Low-Density Lipoprotein (LDL)Cholesterol Levels at Month 1, 3, 6, 9, 12 | LDL Cholesterol levels at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 
| High-Density Lipoprotein (HDL)Cholesterol Levels at Month 1, 3, 6, 9, 12 | HDL Cholesterol levels at Month 1, 3, 6, 9, 12 | Month 1, 3, 6, 9, 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung transplantation, everolimus, kidney function, renal function