Nordic Everolimus (Certican) Trial in Heart and Lung Transplantation (NOCTET)

Nordic Everolimus (Certican) Trial in Heart and Lung Transplantation: Results at 24 Months

This study investigated whether initiation of everolimus together with reduction of calcineurin inhibitors (CNI) in maintenance heart or lung transplant patients with renal impairment would improve renal function.

Study Overview

• Status: Completed
• Conditions: Disorder Related to Cardiac Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Calcineurin inhibitors (CNI); Drug: Steroids; Drug: Mycophenolic acid (MPA)/azathioprine (AZA)

• Study Type: Interventional
• Enrollment (Actual): 282
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Arhus, Denmark, DK-8200
    • Novartis Investigative Site
  • Copenhagen, Denmark, 2100
    • Novartis Investigative Site
• Norway
  • Oslo, Norway
    • Novartis Investigative Site
• Sweden
  • Goteborg, Sweden, 413 45
    • Novartis Investigative Site
  • Linkoping, Sweden, 581 85
    • Novartis Investigative Site
  • Lund, Sweden, 22185
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Patients who have undergone a heart or lung transplantation more than 12 months ago.
• Patients receiving Neoral® or Prograf®.
• Patients with a measured or calculated glomerular filtration rate (GFR) > 20 and < 70 mL/min/1.73m^2. For patients with a GFR > 60 and < 70 mL/min/1.73m^2, a deteriorated renal function since the time of transplantation must be documented by at least one post-transplant GFR level that is > 10% above the GFR level at the time of inclusion.
• Patients willing and capable of giving written informed consent for study participation and able to participate in the study for 12 months.
• Females of potential childbearing age must have a negative serum pregnancy test within 7 days prior to enrollment. Effective contraception must be used during the trial and for 6 weeks following discontinuation of the study medication, even where there has been a history of infertility.

Exclusion criteria:

• Patients who are recipients of multiple organ transplants.
• Patients with measured GFR < 20 mL/min/1.73m^2 or > 70 mL/min/1.73m^2.
• Patients with a treated acute rejection episode within the last 3 months.
• Patients with a platelet count of < 50,000/mm^3 or with a white blood cell count of ≤ 2,500/mm^3 or with a hemoglobin value < 8 g/dL.
• Presence of severe hypercholesterolemia (≥ 8.0 mmol/L) or hypertriglyceridemia (≥ 6.0 mmol/L) despite conventional lipid lowering treatment.
• Patients currently treated or who have been treated with a mammalian target of rapamycin (mTOR) inhibitor.
• Patients who have received an investigational drug within 4 weeks.
• Patients who are human immunodeficiency virus positive or who have a current severe systemic infection requiring continued therapy according to investigator judgment.
• Present use of any immunosuppressive drugs other than Neoral®/Prograf®, mycophenolic acid/azathioprine (MPA/AZA), and/or steroids.
• Patients with a known hypersensitivity to drugs similar to everolimus.
• Symptoms of significant mental illness which, in the opinion of the investigator, may interfere with the patient's ability to comply with the protocol. History of drug or alcohol abuse within 1 year of baseline.
• Inability to cooperate or communicate with the investigator.
• Patients with any past (within the last 5 years) or present malignancy other than excised squamous or basal cell carcinoma.
• Females of childbearing potential that are planning to become pregnant, who are pregnant and/or lactating, or who are unwilling to use effective means of contraception.
• Patients with a planned coronary revascularization or patients who have experienced a major adverse cardiovascular event (MACE) within the last 3 months.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus + CNI reduction; Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice.	Drug: Everolimus; 0.75-1.5 mg twice daily. At the week 1 visit and thereafter, the dose was adjusted to target blood concentration in the range 3-8 ng/mL.; Other Names: Certican; Drug: Calcineurin inhibitors (CNI); Calcineurin inhibitors include cyclosporine, pimecrolimus, and tacrolimus.; Drug: Steroids; Steroid treatment was according to local practice. If steroids were given, the baseline dose of prednisone or equivalent was to be kept unchanged for all treatment groups for the total study duration, unless a medical condition dictated a change.
Active Comparator: Control; CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.	Drug: Calcineurin inhibitors (CNI); Calcineurin inhibitors include cyclosporine, pimecrolimus, and tacrolimus.; Drug: Steroids; Steroid treatment was according to local practice. If steroids were given, the baseline dose of prednisone or equivalent was to be kept unchanged for all treatment groups for the total study duration, unless a medical condition dictated a change.; Drug: Mycophenolic acid (MPA)/azathioprine (AZA); In the standard CNI arm, all immunosuppressants including (MPA) and azathioprine (AZA) continued unchanged as per local practice.; Other Names: Neoral®/Prograf®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to Month 12	Renal function was assessed by determining the measured glomerular filtration rate (mGFR) using creatinine ethylenediamine tetraacetic acid (Cr-EDTA) clearance or an equivalent method. A positive change score indicates improved renal function.	Baseline to Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to End of Study (Month 24)	Renal function was assessed by determining the measured glomerular filtration rate (mGFR) using creatinine ethylenediamine tetraacetic acid (Cr-EDTA) clearance or an equivalent method. A positive change score indicates improved renal function.	Baseline to end of study (Month 24)
Change in Serum Creatinine From Baseline to End of Study (Month 24)	Renal function was assessed by determining serum creatinine using standard laboratory methods. A positive change score indicates improved renal function.	Baseline to end of study (Month 24)
Number of Patients With Biopsy-proven Acute Rejection From Month 12 to End of Study (Month 24)	Biopsy-proved acute rejection was defined as a treated acute rejection confirmed by biopsy, graded locally according to the International Society for Heart & Lung Transplantation (ISHLT) criteria. A treated acute rejection was defined as an acute rejection clinically suspected, whether biopsy-proven or not, which had been treated and confirmed by the investigator according to the response to therapy.	Month 12 to end of study (Month 24)
Number of Patients Who Died and Number of Patients With Graft Loss From Month 12 to End of Study (Month 24)	Number of patients not alive and number of patients with loss of their graft.	Month 12 to end of study (Month 24)
Number of Patients in Need of Dialysis From Month 12 to End of Study (Month 24)		Month 12 to end of study (Month 24)
Change in Forced Expiratory Volume in 1 Second (FEV1) From Baseline to End of Study (Month 24) in the Lung Transplant Subgroup	Forced expiratory volume in 1 second (FEV1) was measured by spirometry conducted according to internationally accepted standards. FEV1 is the volume delivered in the first second of a forced vital capacity (FVC) maneuver. A positive change score indicates improved lung function.	Baseline to end of study (Month 24)
Change in Forced Vital Capacity (FVC) From Baseline to End of Study (Month 24) in the Lung Transplant Subgroup	Forced vital capacity (FVC) was measured by spirometry conducted according to internationally accepted standards. FVC is the volume delivered during an expiration made as forcefully and completely as possible starting from full inspiration. A positive change score indicates improved lung function.	Baseline to end of study (Month 24)
Change in Left Ventricular Function (Diameter and Thickness Parameters) From Baseline to End of Study (Month 24) in the Heart Transplant Subgroup	Left ventricular function was assessed by echocardiography which was performed according to local routine practice. Echocardiography parameters were left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal wall thickness (IVSTd), and posterior wall thickness (PWTd). A positive change score indicates improved left ventricular function.	Baseline to end of study (Month 24)
Change in Left Ventricular Function (Filling and Ejection Fraction Parameters) From Baseline to End of Study (Month 24) in the Heart Transplant Subgroup	Left ventricular function was assessed by echocardiography which was performed according to local routine practice. Echocardiography parameters were filling fraction (FF) and ejection fraction (EF). A positive change score indicates improved left ventricular function.	Baseline to end of study (Month 24)
Mean Days of Hospitalization From Baseline to End of Study (Month 24)		Baseline to end of study (Month 24)
Number of Patients Discontinued From the Study Due to Adverse Events From Month 12 to End of Study (Month 24)		Month 12 to end of study (Month 24)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Norum HM, Michelsen AE, Lekva T, Arora S, Otterdal K, Olsen MB, Kong XY, Gude E, Andreassen AK, Solbu D, Karason K, Dellgren G, Gullestad L, Aukrust P, Ueland T. Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression. Am J Transplant. 2019 Apr;19(4):1050-1060. doi: 10.1111/ajt.15141. Epub 2018 Nov 5.
• Arora S, Erikstad I, Ueland T, Sigurdardottir V, Ekmehag B, Jansson K, Eiskjaer H, Botker HE, Mortensen SA, Saunamaki K, Gude E, Ragnarsson A, Solbu D, Aukrust P, Gullestad L. Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus--results of a multicenter trial. Am J Transplant. 2012 Oct;12(10):2700-9. doi: 10.1111/j.1600-6143.2012.04234.x. Epub 2012 Sep 7.
• Arora S, Gude E, Sigurdardottir V, Mortensen SA, Eiskjaer H, Riise G, Mared L, Bjortuft O, Ekmehag B, Jansson K, Simonsen S, Aukrust P, Solbu D, Iversen M, Gullestad L. Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: the significance of baseline glomerular filtration rate. J Heart Lung Transplant. 2012 Mar;31(3):259-65. doi: 10.1016/j.healun.2011.12.010.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: September 15, 2006
• First Submitted That Met QC Criteria: September 15, 2006
• First Posted (Estimate): September 19, 2006

Study Record Updates

• Last Update Posted (Actual): July 30, 2020
• Last Update Submitted That Met QC Criteria: July 27, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: everolimus; immunosuppressants; thoracic transplant recipients
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Azathioprine; Mycophenolic Acid; Everolimus; Calcineurin Inhibitors
• Other Study ID Numbers: CRAD001AIC01

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