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

NCT01025817 | Completed Phase 3 Results DMC

• 1 other identifier: CRAD001AUS92
• Study Type: interventional
• Target: 613
• Locations: 2 countries
• Sites: 50

Brief Summary

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.

Conditions

Kidney Transplant

Keywords

Kidney transplant; renal transplant; immunosuppression; mycophenolate mofetil; tacrolimus; everolimus

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Estimated Glomerular Filtration Rate (eGFR)

  12 Months

• Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease)

  12 Months

• Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy

  12 Months

• Number of Participants With Incidence of New Onset of Diabetes Mellitus

  12 Months

• Number of Participants With Incidence of Proteinuria Events

  Baseline and 12 Months

Study Arms (2)

Everolimus (EVR) & low dose of tacrolimus

EXPERIMENTAL

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

Mycophenolate mofetil & standard dose tacrolimus

ACTIVE COMPARATOR

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

Interventions

Everolimus and tacrolimus DRUG

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

Everolimus (EVR) & low dose of tacrolimus

mycophenolate mofetil and tacrolimus DRUG

Mycophenolate mofetil: - Dose form: 250 mg capsule - Dose: 2g per day - Frequency: 1g twice daily Tacrolimus: - Dose adjusted to maintain specific blood levels

Also known as: Active Comparator Control)

Mycophenolate mofetil & standard dose tacrolimus

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (50)

Novartis Investigative Site

Birmingham, Alabama, 35233, United States

Location

Novartis Investigative Site

Tucson, Arizona, 85742-5022, United States

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Novartis Investigative Site

Los Angeles, California, 90033, United States

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Novartis Investigative Site

Los Angeles, California, 90048, United States

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Novartis Investigative Site

Los Angeles, California, 90095, United States

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Novartis Investigative Site

Orange, California, 92868, United States

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Novartis Investigative Site

Sacramento, California, 95817, United States

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Novartis Investigative Site

San Diego, California, 92103, United States

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Novartis Investigative Site

San Diego, California, 92123, United States

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Novartis Investigative Site

San Francisco, California, 94115, United States

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Novartis Investigative Site

San Francisco, California, 94143-0780, United States

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Novartis Investigative Site

Aurora, Colorado, 80045, United States

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Novartis Investigative Site

Miami, Florida, 33136, United States

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Novartis Investigative Site

Orlando, Florida, 32804, United States

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Novartis Investigative Site

Tampa, Florida, 33606, United States

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Novartis Investigative Site

Chicago, Illinois, 60612, United States

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Novartis Investigative Site

Chicago, Illinois, 60637, United States

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Novartis Investigative Site

Baltimore, Maryland, 21201, United States

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Novartis Investigative Site

Boston, Massachusetts, 02111, United States

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Novartis Investigative Site

Worcester, Massachusetts, 01655, United States

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Novartis Investigative Site

Ann Arbor, Michigan, 48109-0331, United States

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Novartis Investigative Site

Detroit, Michigan, 48202-2689, United States

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Novartis Investigative Site

Detroit, Michigan, 48236, United States

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Novartis Investigative Site

Royal Oak, Michigan, 48073, United States

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Novartis Investigative Site

Minneapolis, Minnesota, 55455, United States

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Novartis Investigative Site

St Louis, Missouri, 63110, United States

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Novartis Investigative Site

Omaha, Nebraska, 68198-3285, United States

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Novartis Investigative Site

Livingston, New Jersey, 07039, United States

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Novartis Investigative Site

Buffalo, New York, 14215, United States

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Novartis Investigative Site

New York, New York, 10032, United States

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Novartis Investigative Site

Durham, North Carolina, 27710, United States

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Novartis Investigative Site

Greenville, North Carolina, 27834, United States

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Novartis Investigative Site

Portland, Oregon, 97239, United States

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Novartis Investigative Site

Harrisburg, Pennsylvania, 17105-8700, United States

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Novartis Investigative Site

Charleston, South Carolina, 29425, United States

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Novartis Investigative Site

Nashville, Tennessee, 37212-3139, United States

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Novartis Investigative Site

Dallas, Texas, 75246, United States

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Novartis Investigative Site

Fort Worth, Texas, 76104, United States

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Novartis Investigative Site

Galveston, Texas, 77555-0144, United States

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Novartis Investigative Site

Houston, Texas, 77030, United States

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Novartis Investigative Site

Lubbock, Texas, 79430, United States

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Novartis Investigative Site

Salt Lake City, Utah, 84132, United States

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Novartis Investigative Site

Burlington, Vermont, 05401, United States

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Novartis Investigative Site

Charlottesville, Virginia, 22908, United States

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Novartis Investigative Site

Norfolk, Virginia, 23507, United States

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Novartis Investigative Site

Richmond, Virginia, 23298, United States

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Novartis Investigative Site

Seattle, Washington, 98195, United States

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Novartis Investigative Site

Spokane, Washington, 99204, United States

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Novartis Investigative Site

Montreal, Quebec, H1T 2M4, Canada

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Novartis Investigative Site

Montreal, Quebec, H2L 4M1, Canada

Location

Related Publications (1)

• 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.

  PMID: 28141897 DERIVED

MeSH Terms

Interventions

Everolimus; Tacrolimus; Mycophenolic Acid

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Limitations and Caveats

HLA mismatches ≥3, everolimus group 261 vs MMF group 240

Results Point of Contact

• Title: Study Director
• Organization: Novartis

+1 (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 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2009
• First Posted: December 4, 2009
• Study Start: January 1, 2010
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: November 11, 2015
• Results First Posted: June 6, 2014

Record last verified: 2015-10

Locations

US (48); CA (2)