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

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.

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.

Study Overview

• Status: Completed
• Conditions: Lung Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: standard therapy

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • 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
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Kneidinger N, Valtin C, Hettich I, Frye BC, Wald A, Wilkens H, Bessa V, Gottlieb J. Five-year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-up of the 4EVERLUNG Study. Transplantation. 2022 Sep 1;106(9):1867-1874. doi: 10.1097/TP.0000000000004095. Epub 2022 Mar 8.
• Gottlieb J, Neurohr C, Muller-Quernheim J, Wirtz H, Sill B, Wilkens H, Bessa V, Knosalla C, Porstner M, Capusan C, Struber M. A randomized trial of everolimus-based quadruple therapy vs standard triple therapy early after lung transplantation. Am J Transplant. 2019 Jun;19(6):1759-1769. doi: 10.1111/ajt.15251. Epub 2019 Feb 5.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2012
• Primary Completion (Actual): January 5, 2017
• Study Completion (Actual): January 5, 2017

Study Registration Dates

• First Submitted: July 13, 2011
• First Submitted That Met QC Criteria: July 27, 2011
• First Posted (Estimate): July 28, 2011

Study Record Updates

• Last Update Posted (Actual): March 14, 2019
• Last Update Submitted That Met QC Criteria: November 21, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: everolimus; Lung transplantation; renal function; kidney function
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001ADE36; 2011-001539-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No