A Study Investigating the Renal Tolerability, Efficacy, and Safety of a CNI-free Versus a Standard Regimen in de Novo Heart Transplant (HTx) Recipients (MANDELA)

A Multi-center, Randomized, Open-label, Parallel Group Study Investigating the Renal Tolerability, Efficacy and Safety of a CNI-free Regimen (Everolimus and MPA) Versus a CNI-regimen With Everolimus in Heart Transplant Recipients

This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.

Study Overview

• Status: Completed
• Conditions: Heart Transplantation
• Intervention / Treatment: Drug: Everolimus (EVR); Drug: cyclosporine A (CyA); Drug: tacrolimus (TAC); Drug: Corticosteroids; Drug: Enteric coated mycophenolate sodium (EC-MPS); Drug: mycophenolate mofetil (MMF)

Detailed Description

This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.

• Study Type: Interventional
• Enrollment (Actual): 162
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bad Oeynhausen, Germany, 32545
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Leipzig, Germany, 04289
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • München, Germany, 81377
    • Novartis Investigative Site
  • Regensburg, Germany, 93053
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Heart transplantation, 3 months prior to enrollment
• Patients have to receive an immunosuppressive regimen with Sandimmun® Optoral, Certican® and corticosteroids
• Sufficient graft function
• Sufficient renal function
• Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at baseline, and are required to practice an approved method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility

Exclusion criteria:

• Multi-organ recipients, re-transplantation, or previous transplant with any other organ.
• Patients who are recipients of A-B-O incompatible transplants
• Cold ischemia time >6 hours
• Historical or current peak PRA of > 25% at time of transplantation
• Already existing antibodies against the HLA-type of the receiving transplant 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
Active Comparator: CNI-regimen; CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids	Drug: Everolimus (EVR); Everolimus 0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL); Other Names: Certican, RAD001; Drug: cyclosporine A (CyA); 10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels for CNI-regimen group. For CNI-free-regimen dispense on month 6 to 9 only; Other Names: Sandimmun Optoral; Drug: tacrolimus (TAC); 0.5 mg, 1 mg, or 5 mg capsule given according to blood levels for CNI-regimen. For CNI-free-regimen give on month 6 to 9 only; Other Names: Prograf; Drug: Corticosteroids; according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent
Experimental: CNI-free-regimen; CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids	Drug: Everolimus (EVR); Everolimus 0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL); Other Names: Certican, RAD001; Drug: cyclosporine A (CyA); 10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels for CNI-regimen group. For CNI-free-regimen dispense on month 6 to 9 only; Other Names: Sandimmun Optoral; Drug: tacrolimus (TAC); 0.5 mg, 1 mg, or 5 mg capsule given according to blood levels for CNI-regimen. For CNI-free-regimen give on month 6 to 9 only; Other Names: Prograf; Drug: Corticosteroids; according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent; Drug: Enteric coated mycophenolate sodium (EC-MPS); 180 mg or 360 mg tablet dosed 1440-2280 mg per day; Other Names: Myfortic; Drug: mycophenolate mofetil (MMF); 250 mg or 500 mg tablets with a dose of 1500-3000 mg per day; Other Names: CellCept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18	Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 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 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18	Treatment failure was defined as composite endpoint of biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute rejection episodes associated with hemodynamic compromise, graft loss / re-transplant, death, loss to follow up (at least one condition must be present). If participant had an occurrence in each period it was counted for each period.	Month 6 to Month 9; Month 9 to Month 18
Occurrence of Major Cardiac Events (MACE) From Month 6 to 18	Major cardiac events (MACE) was defined as one of the following: any death, myocardial infarction, coronary artery bypass grafting	Month 6 to Month 18
Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18	Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18. 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 12 and 18
Serum Creatinine at Month 6, 8, 9, 10 12 and 18	Serum Creatinine is an indicator of renal function measured in the blood	Month 6, 8, 9, 10 12 and 18
Reciprocal Creatinine Slope Between Month 6 and Month 18	Reciprocal Creatinine Slope is an indication of renal function over time with a higher slope value indicating an improvement in renal function.	Between Month 6 and Month 18

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2009
• Primary Completion (Actual): March 6, 2017
• Study Completion (Actual): March 6, 2017

Study Registration Dates

• First Submitted: March 16, 2009
• First Submitted That Met QC Criteria: March 16, 2009
• First Posted (Estimate): March 17, 2009

Study Record Updates

• Last Update Posted (Actual): August 7, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Heart Transplantation; Everolimus; renal function; Cardiac Transplantation; CNI-sparing; CNI; Cyclosporine A; mycophenolic acid
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001ADE14; 2007-002671-14

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No