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

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

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.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant
• Intervention / Treatment: Drug: Everolimus and tacrolimus; Drug: mycophenolate mofetil and tacrolimus

• Study Type: Interventional
• Enrollment (Actual): 613
• Phase: Phase 3

Contacts and Locations

Study Locations

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

• 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.

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
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 Names: Active Comparator Control)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Incidence of Composite Efficacy Failure	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.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Glomerular Filtration Rate (eGFR)	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	12 Months
Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease)	Participants with incidence of CMV (viremia, syndrome and disease). CMV is cytomegalovirus.	12 Months
Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy	Participants with Incidence of BKV (viremia, viruria, or nephropathy). BKV is Polyomavirus type BK.	12 Months
Number of Participants With Incidence of New Onset of Diabetes Mellitus	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)	12 Months
Number of Participants With Incidence of Proteinuria Events	Number of participants with Incidence of proteinuria events indicating chronic kidney disease	Baseline and 12 Months
Number of Participants With Incidence of Adverse Events, Serious Adverse Events, and Tacrolimus-associated Adverse Events	Incidence of adverse events, serious adverse events, and tacrolimus-associated adverse events by System Organ Class	12 Months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Shihab F, Qazi Y, Mulgaonkar S, McCague K, Patel D, Peddi VR, Shaffer D. Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus. Am J Transplant. 2017 Sep;17(9):2363-2371. doi: 10.1111/ajt.14215. Epub 2017 Mar 4.

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: November 19, 2009
• First Submitted That Met QC Criteria: December 3, 2009
• First Posted (Estimate): December 4, 2009

Study Record Updates

• Last Update Posted (Estimate): November 11, 2015
• Last Update Submitted That Met QC Criteria: October 13, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: immunosuppression; everolimus; Kidney transplant; mycophenolate mofetil; renal transplant; tacrolimus
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus
• Other Study ID Numbers: CRAD001AUS92