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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00862979
Recruitment Status : Completed
First Posted : March 17, 2009
Results First Posted : June 25, 2018
Last Update Posted : August 7, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Heart Transplantation Drug: Everolimus (EVR) Drug: cyclosporine A (CyA) Drug: tacrolimus (TAC) Drug: Enteric coated mycophenolate sodium (EC-MPS) Drug: mycophenolate mofetil (MMF) Drug: Corticosteroids Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 24, 2009
Actual Primary Completion Date : March 6, 2017
Actual Study Completion Date : March 6, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: Prograf

Drug: Enteric coated mycophenolate sodium (EC-MPS)
180 mg or 360 mg tablet dosed 1440-2280 mg per day
Other Name: Myfortic

Drug: mycophenolate mofetil (MMF)
250 mg or 500 mg tablets with a dose of 1500-3000 mg per day
Other Name: CellCept

Drug: Corticosteroids
according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent




Primary Outcome Measures :
  1. Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 [ Time Frame: Month 6 to Month 9; Month 9 to Month 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.

  2. Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 [ Time Frame: Month 6 to Month 18 ]
    Major cardiac events (MACE) was defined as one of the following: any death, myocardial infarction, coronary artery bypass grafting

  3. Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 [ Time Frame: 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)

  4. Serum Creatinine at Month 6, 8, 9, 10 12 and 18 [ Time Frame: Month 6, 8, 9, 10 12 and 18 ]
    Serum Creatinine is an indicator of renal function measured in the blood

  5. Reciprocal Creatinine Slope Between Month 6 and Month 18 [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT00862979


Locations
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Germany
Novartis Investigative Site
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
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] January 19, 2016
Statistical Analysis Plan  [PDF] June 2, 2017

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00862979    
Other Study ID Numbers: CRAD001ADE14
2007-002671-14
First Posted: March 17, 2009    Key Record Dates
Results First Posted: June 25, 2018
Last Update Posted: August 7, 2018
Last Verified: July 2018
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Heart Transplantation
Cardiac Transplantation
CNI-sparing
renal function
CNI
Cyclosporine A
Everolimus
mycophenolic acid
Additional relevant MeSH terms:
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Cyclosporine
Mycophenolic Acid
Everolimus
Tacrolimus
Cyclosporins
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents