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Efficacy Regarding Renal Function of Everolimus in Combination With Specific Standard Immunosuppressive Regimen Lung Transplant Recipients (4EVERLUNG)

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ClinicalTrials.gov Identifier: NCT01404325
Recruitment Status : Completed
First Posted : July 28, 2011
Results First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Lung Transplantation Drug: standard therapy Drug: Everolimus Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : February 1, 2012
Actual Primary Completion Date : January 5, 2017
Actual Study Completion Date : January 5, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Quadruple low level IS regimen
quadruple immunosuppressive (IS) regimen consisting of everolimus, CNI, MPA and steroids
Drug: Everolimus
quadruple immunosuppressive regimen consisting of everolimus, CNI, MPA and steroids
Other Name: RAD001

Experimental: Centre specific triple IS regimen
centre specific CNI-based triple drug immunosuppression (IS)
Drug: standard therapy
centre specific CNI-based triple drug immunosuppression




Primary Outcome Measures :
  1. Calculated Glomerular Filtration Rate (cGFR) According to Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) at 12 Months [ Time Frame: Month 12 ]
    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


Secondary Outcome Measures :
  1. Calculated Glomerular Filtration Rate (cGFR) According to Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) at Month 1, 3, 6, 9, 12 [ Time Frame: 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

  2. Calculated Glomerular Filtration Rate (cGFR) According to Cystatin C-based Hoek's Formula at Month 1, 3, 6, 9, 12 [ Time Frame: 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

  3. Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 1, 3, 6, 9, 12 [ Time Frame: 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.

  4. Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 1, 3, 6, 9, 12 [ Time Frame: 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)

  5. 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. [ Time Frame: Baseline, Month 6, Month 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.

  6. Incidence of Renal Replacement Therapy at Month 6 and Month 12 [ Time Frame: Month 6, 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

  7. Time to Renal Replacement Therapy at Month 6 and Month 12 [ Time Frame: Month 6, 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

  8. Incidence of Acute Rejection Episodes at Month 6 and Month 12 [ Time Frame: Month 6, 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


  9. Incidence of Graft Loss/Re-transplantation at Month 6 and Month 12 [ Time Frame: Month 6, Month 12 ]
    Incidence of graft loss/re-transplantation at Month 6 and Month 12

  10. Incidence of Bronchiolitis Obliterans Syndrome (BOS) at Month 6 and Month 12 [ Time Frame: Month 6, 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

  11. Incidence of Death at Month 6 and Month 12 [ Time Frame: Month 6, Month 12 ]
    Incidence of death at Month 6 and Month 12

  12. Quality of Life (QoL, SF36) at Month 6 and Month 12 [ Time Frame: Month 6, 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).

  13. Exercise Capacity 6-Minute Walk Test(6MWT) at Month 6 and Month 12 [ Time Frame: Month 6, 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.

  14. Incidence of Treated Arterial Hypertension up to Month 12 [ Time Frame: up to Month 12 ]
    Incidence of treated of arterial hypertension up to Month 12

  15. Incidence of Diabetes Mellitus up to Month 12 [ Time Frame: up to Month 12 ]
    Incidence of Diabetes Mellitus up to Month 12

  16. Trough Levels of Everolimus at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Trough levels of everolimus at Month 1, 3, 6, 9, 12

  17. Adherence to Target Ranges of Everolimus at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Adherence to target ranges of everolimus at Month 1, 3, 6, 9, 12

  18. Trough Levels of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Trough levels of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12

  19. Adherence to Target Ranges of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Adherence to target ranges of Cyclosporine A (CsA) at Month 1, 3, 6, 9, 12

  20. Trough Levels of Tacrolimus at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Trough levels of Tacrolimus at Month 1, 3, 6, 9, 12

  21. Adherence to Target Ranges of Tacrolimus at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Adherence to target ranges of Tacrolimus at Month 1, 3, 6, 9, 12

  22. Incidence of Bacterial, Viral, and Fungal Infections at Month 12 [ Time Frame: Month 12 ]
    Incidence of bacterial, viral, and fungal infections at Month 12

  23. Triglyceride Levels at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Triglyceride levels at Month 1, 3, 6, 9, 12

  24. Total Cholesterol Levels at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    Total Cholesterol levels at Month 1, 3, 6, 9, 12

  25. Low-Density Lipoprotein (LDL)Cholesterol Levels at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    LDL Cholesterol levels at Month 1, 3, 6, 9, 12

  26. High-Density Lipoprotein (HDL)Cholesterol Levels at Month 1, 3, 6, 9, 12 [ Time Frame: Month 1, 3, 6, 9, 12 ]
    HDL Cholesterol levels at Month 1, 3, 6, 9, 12



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01404325


Locations
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Germany
Novartis Investigative Site
Berlin, Germany, 10117
Novartis Investigative Site
Berlin, Germany, 13353
Novartis Investigative Site
Essen, Germany, 45147
Novartis Investigative Site
Freiburg, Germany, 79106
Novartis Investigative Site
Hamburg, Germany, 20246
Novartis Investigative Site
Hannover, Germany, 30625
Novartis Investigative Site
Homburg, Germany, 66421
Novartis Investigative Site
Leipzig, Germany, 04103
Novartis Investigative Site
Muenchen, Germany, 81377
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01404325     History of Changes
Other Study ID Numbers: CRAD001ADE36
2011-001539-21 ( EudraCT Number )
First Posted: July 28, 2011    Key Record Dates
Results First Posted: March 14, 2019
Last Update Posted: March 14, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Lung transplantation
everolimus
kidney function
renal function
Additional relevant MeSH terms:
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Sirolimus
Everolimus
Immunosuppressive Agents
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents