Nordic Everolimus (Certican) Trial in Heart and Lung Transplantation

NCT00377962 | Completed Phase 4 Results

• 1 other identifier: CRAD001AIC01
• Study Type: interventional
• Target: 282
• Locations: 3 countries
• Sites: 6

Brief Summary

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.

Conditions

Disorder Related to Cardiac Transplantation

Keywords

thoracic transplant recipients; everolimus; immunosuppressants

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to End of Study (Month 24)

  Baseline to end of study (Month 24)

• Change in Serum Creatinine From Baseline to End of Study (Month 24)

  Baseline to end of study (Month 24)

• Number of Patients With Biopsy-proven Acute Rejection From Month 12 to End of Study (Month 24)

  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)

  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)

Study Arms (2)

Everolimus + CNI reduction

EXPERIMENTAL

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; Drug: Calcineurin inhibitors (CNI); Drug: Steroids

Control

ACTIVE COMPARATOR

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: Mycophenolic acid (MPA)/azathioprine (AZA); Drug: Calcineurin inhibitors (CNI); Drug: Steroids

Interventions

Everolimus DRUG

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.

Also known as: Certican

Everolimus + CNI reduction

Mycophenolic acid (MPA)/azathioprine (AZA) DRUG

In the standard CNI arm, all immunosuppressants including (MPA) and azathioprine (AZA) continued unchanged as per local practice.

Also known as: Neoral®/Prograf®

Control

Calcineurin inhibitors (CNI) DRUG

Calcineurin inhibitors include cyclosporine, pimecrolimus, and tacrolimus.

Control; Everolimus + CNI reduction

Steroids DRUG

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.

Control; Everolimus + CNI reduction

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who have undergone a heart or lung transplantation more than 12 months ago.
• Patients receiving Neoral® or Prograf®.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (6)

Novartis Investigative Site

Aarhus, DK-8200, Denmark

Location

Novartis Investigative Site

Copenhagen, 2100, Denmark

Location

Novartis Investigative Site

Oslo, Norway

Location

Novartis Investigative Site

Gothenburg, 413 45, Sweden

Location

Novartis Investigative Site

Linköping, 581 85, Sweden

Location

Novartis Investigative Site

Lund, 22185, Sweden

Location

Related Publications (3)

• 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.

  PMID: 30312541 DERIVED

• 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.

  PMID: 22958738 DERIVED

• 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.

  PMID: 22333403 DERIVED

MeSH Terms

Interventions

Everolimus; Mycophenolic Acid; Calcineurin Inhibitors; Steroids

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862 778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2006
• First Posted: September 19, 2006
• Study Start: December 1, 2005
• Primary Completion: February 1, 2010
• Study Completion: February 1, 2010
• Last Updated: July 30, 2020
• Results First Posted: April 18, 2011

Record last verified: 2020-07

Locations

SE (3); DK (2); NO (1)