Non-inferiority Study of Safety and Efficacy of Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in Kidney Transplant Recipients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01025817
First received: November 19, 2009
Last updated: June 5, 2014
Last verified: April 2014
  Purpose

The purpose of this phase 3b study is to compare the safety and efficacy of everolimus with low dose tacrolimus to mycophenolate mofetil with standard dose tacrolimus in kidney transplant recipients.


Condition Intervention Phase
Kidney Transplant
Drug: Everolimus and tacrolimus
Drug: mycophenolate mofetil and tacrolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A 12 Month, Multi-center, Randomized, Open-label Non-inferiority Study Comparing Safety and Efficacy of Concentration-controlled Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in de Novo Renal Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Participants With Incidence of Composite Efficacy Failure [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Efficacy failure rate used the composite endpoint of: (1) treated biopsy-proven acute rejection (BPAR)*, (2) graft loss**, (3) participant death or(4) loss to follow-up. *A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. **Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis.


Secondary Outcome Measures:
  • Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Renal function was assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. MDRD formula: GFR [mL/min/1.73m˄2] = 186.3*(C˄-1.154)*(A˄-0.203)*G*R. DEFINITIONS: C = 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

  • Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease) [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Participants with incidence of CMV (viremia, syndrome and disease). CMV is cytomegalovirus.

  • Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Participants with Incidence of BKV (viremia, viruria, or nephropathy). BKV is Polyomavirus type BK.

  • Number of Participants With Incidence of New Onset of Diabetes Mellitus [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Incidence of new onset diabetes mellitus defined as non-diabetic patients before transplantation, who are receiving glucose lowering treatment for more than 30 days post-transplant, or with a random plasma glucose ≥200 mg dL (11.1 mmol/L) with 2 fasting plasma glucose values ≥126 mg/dL (7 mmol/L)

  • Number of Participants With Incidence of Proteinuria Events [ Time Frame: Baseline and 12 Months ] [ Designated as safety issue: No ]
    Number of participants with Incidence of proteinuria events indicating chronic kidney disease

  • Number of Participants With Incidence of Adverse Events, Serious Adverse Events, and Tacrolimus-associated Adverse Events [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Incidence of adverse events, serious adverse events, and tacrolimus-associated adverse events by System Organ Class


Enrollment: 613
Study Start Date: January 2010
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus (EVR) & low dose of tacrolimus
Everolimus (EVR) and tacrolimus treatment arm: Therapeutic drug monitoring of everolimus and tacrolimus was mandatory throughout the study. From Day 5 onwards, the everolimus 0.75 mg b.i.d. dose was increased if the trough level was < 3 ng/mL, or reduced if the trough level was > 8 ng/mL. Tacrolimus was initiated according to local practice. In this treatment arm, the tacrolimus dose was adjusted from Day 3 onwards, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From Month 2 until Month 6, the target tacrolimus trough level was 3 ng/mL to 6 ng/mL. After Month 6, the tacrolimus dose was adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL.
Drug: Everolimus and tacrolimus

Everolimus:

  • Dosage form: 0.75 mg, 0.25 mg, and 0.5 mg tablets
  • Dose: 1.5 mg per day
  • Frequency: 0.75 mg twice daily

Tacrolimus:

  • Dose adjusted to maintain specific blood levels
Active Comparator: Mycophenolate mofetil & standard dose tacrolimus
Mycophenolate mofetil and tacrolimus (MMF) treatment arm: MMF dose was initiated at 1 g b.i.d. (2 g/day). Adjustments were to be made for adverse events including, but not limited to, gastrointestinal intolerance and decrease in WBC. MMF trough or AUC was not used to adjust dosing. In this group, tacrolimus was initiated according to local practice. Tacrolimus dose was adjusted from Day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 12 ng/mL. From Month 2 until Month 6, target tacrolimus trough level was reduced to 7 - 10 ng/mL. After Month 6, target level of tacrolimus was reduced to 5 - 8 ng/mL.
Drug: mycophenolate mofetil and tacrolimus
Mycophenolate mofetil: - Dose form: 250 mg capsule - Dose: 2g per day - Frequency: 1g twice daily Tacrolimus: - Dose adjusted to maintain specific blood levels
Other Name: Active Comparator Control)

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Male or female renal recipients 18-70 years of age undergoing kidney transplantation, either primary or re-transplant;
  • Recipient of a cadaveric, deceased donor (including expanded criteria donor organs and deceased donor organs after cardiac death), living unrelated or non-HLA identical living related donor kidney;
  • Graft must be functional (producing greater than or equal to 100 ml of urine within 24 hours after transplantation) at time of randomization.

Exclusion criteria:

  • Donor organ with a cold ischemic time > 30 hours;
  • Males or females who produce less than 100 ml of urine in the first 24 hours post-transplantation;
  • Males or females who are recipients of ABO incompatible transplants, or T cell, or B cell crossmatch positive transplant;
  • Males or females with severe total hypercholesterolemia or total hypertriglyceridemia (Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable);
  • Males or females who have any surgical or any medical condition, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator, might alter the absorption, distribution, metabolism and/or excretion of study medication.

Other protocol related inclusion/exclusion criteria may apply.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01025817

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Locations
United States, Alabama
Novartis Investigative Site
Birmingham, Alabama, United States, 35233
United States, Arizona
Novartis Investigative Site
Tucson, Arizona, United States, 85742-5022
United States, California
Novartis Investigative Site
Los Angeles, California, United States, 90095
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Los Angeles, California, United States, 90033
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Los Angeles, California, United States, 90048
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Orange, California, United States, 92868
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Sacramento, California, United States, 95817
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San Diego, California, United States, 92103
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San Diego, California, United States, 92123
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San Francisco, California, United States, 94143-0780
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San Francisco, California, United States, 94115
United States, Colorado
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Aurora, Colorado, United States, 80045
United States, Florida
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Miami, Florida, United States, 33136
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Orlando, Florida, United States, 32804
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Tampa, Florida, United States, 33606
United States, Illinois
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Chicago, Illinois, United States, 60612
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Chicago, Illinois, United States, 60637
United States, Maryland
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Baltimore, Maryland, United States, 21201
United States, Massachusetts
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Boston, Massachusetts, United States, 02111
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Worcester, Massachusetts, United States, 01655
United States, Michigan
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Ann Arbor, Michigan, United States, 48109-0331
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Detroit, Michigan, United States, 48236
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Detroit, Michigan, United States, 48202-2689
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Royal Oak, Michigan, United States, 48073
United States, Minnesota
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Minneapolis, Minnesota, United States, 55455
United States, Missouri
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St. Louis, Missouri, United States, 63110
United States, Nebraska
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Omaha, Nebraska, United States, 68198-3285
United States, New Jersey
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Livingston, New Jersey, United States, 07039
United States, New York
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Buffalo, New York, United States, 14215
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New York, New York, United States, 10032
United States, North Carolina
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Durham, North Carolina, United States, 27710
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Greenville, North Carolina, United States, 27834
United States, Oregon
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Portland, Oregon, United States, 97239
United States, Pennsylvania
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Harrisburg, Pennsylvania, United States, 17105-8700
United States, South Carolina
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Charleston, South Carolina, United States, 29425
United States, Tennessee
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Nashville, Tennessee, United States, 37212-3139
United States, Texas
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Dallas, Texas, United States, 75246
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Fort Worth, Texas, United States, 76104
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Galveston, Texas, United States, 77555-0144
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Houston, Texas, United States, 77030
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Lubbock, Texas, United States, 79430
United States, Utah
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Salt Lake City, Utah, United States, 84132
United States, Vermont
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Burlington, Vermont, United States, 05401
United States, Virginia
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Charlottesville, Virginia, United States, 22908
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Norfolk, Virginia, United States, 23507
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Richmond, Virginia, United States, 23298
United States, Washington
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Seattle, Washington, United States, 98195
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Spokane, Washington, United States, 99204
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H1T 2M4
Novartis Investigative Site
Montreal, Quebec, Canada, H2L 4M1
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01025817     History of Changes
Other Study ID Numbers: CRAD001AUS92
Study First Received: November 19, 2009
Results First Received: March 3, 2014
Last Updated: June 5, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Novartis:
Kidney transplant
renal transplant
immunosuppression
mycophenolate mofetil
tacrolimus
everolimus

Additional relevant MeSH terms:
Everolimus
Mycophenolate mofetil
Mycophenolic Acid
Sirolimus
Tacrolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014