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Drug Interaction Study of Apixaban With Cyclosporine or Tacrolimus in Transplant Recipients (ACT-KLR)

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: NCT04023760
Recruitment Status : Completed
First Posted : July 18, 2019
Last Update Posted : May 3, 2021
Sponsor:
Collaborators:
Saskatchewan Health Research Foundation
Lung Association of Saskatchewan
Information provided by (Responsible Party):
Holly Mansell, University of Saskatchewan

Tracking Information
First Submitted Date  ICMJE June 28, 2019
First Posted Date  ICMJE July 18, 2019
Last Update Posted Date May 3, 2021
Actual Study Start Date  ICMJE June 26, 2019
Actual Primary Completion Date March 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
  • Apixaban area under the plasma concentration curve between 0 and 72 hours (AUC(0-72)). [ Time Frame: Days 1-3 ]
    Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm
  • Apixaban peak plasma concentration (Cmax) [ Time Frame: Days 1-3 ]
    Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
  • Safety and tolerability of Apixaban when co-administered with cyclosporine assessed by capturing incidence of adverse events [ Time Frame: Days 1-4 ]
    Number of participants who experience an adverse events based on the results of laboratory safety tests and the results of vital sign measurements, physical examinations, and clinical laboratory tests
  • Safety and tolerability of Apixaban when co-administered with tacrolimus assessed by capturing incidence of adverse events [ Time Frame: Days 1-4 ]
    Number of participants who experience an adverse events based on the results of laboratory safety tests and the results of vital sign measurements, physical examinations, and clinical laboratory tests
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 16, 2019)
  • Differences in area under the plasma concentration curve between 0 and 72 hours AUC (0-72)) in kidney and lung transplant recipients [ Time Frame: Days 1-3 ]
    Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm
  • Differences in peak plasma concentration (Cmax) hours between kidney and lung transplant recipients [ Time Frame: Days 1-3 ]
    Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm
  • Differences in area under the plasma concentration curve between 0 and 72 hours AUC(0-72)) between transplant recipients and healthy subjects [ Time Frame: Days 1-3 ]
    Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm
  • Differences in peak plasma concentration (Cmax) hours between transplant recipients and healthy subjects [ Time Frame: Days 1-3 ]
    Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Drug Interaction Study of Apixaban With Cyclosporine or Tacrolimus in Transplant Recipients
Official Title  ICMJE Pharmacokinetics of Apixaban and Tacrolimus or Cyclosporine in Kidney and Lung Transplant Recipients
Brief Summary This study aims to evaluate the pharmacokinetics (PK) of apixaban in kidney and lung transplant recipients stabilized on either cyclosporine or tacrolimus as part of their immunosuppressive therapy.
Detailed Description

Solid organ transplantation is a lifesaving option for many patients with end-stage organ disease. After transplant surgery, patients must take immunosuppressive therapy, which carries significant risk for drug-drug interactions and adverse medication-related events.

Transplant recipients are at an increased risk for co-morbidities traditionally managed with warfarin, such as venous thromboembolism and atrial fibrillation. Apixaban has the potential to provide safer and more effective treatment, without additional monitoring of the INR, but it has not been studied in conjunction with anti-rejection agents in this population. Apixaban is metabolized by CYP3A4 and P-gp and BCRP transporters. As part of their immunosuppressive therapy, solid organ transplant recipients are maintained on calcineurin inhibitors, which are weak CYP3A4 as well as potent P-gp and BCRP inhibitors. A study was recently undertaken to evaluate the potential drug-drug interaction between cyclosporine or tacrolimus and apixaban in healthy subjects (ClinicalTrials.gov Identifier: NCT03083782) . The results indicated that the change in apixaban exposure was not clinically relevant.

PK studies in healthy volunteers are a first step for determining the nature and extent of potential drug-drug interactions. However, follow-up studies in the actual patient populations are essential for ensuring safety and tolerability, and providing clinicians the confidence to use these combinations. The purpose of this study is to confirm the pharmacokinetic characteristics and safety of apixaban in combination with tacrolimus and cyclosporine in stable kidney and lung transplant recipients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Pharmacokinetics
  • Kidney Transplant
  • Lung Transplant
Intervention  ICMJE Drug: Apixaban
Study subjects given a single-dose of apixaban 10 mg.
Other Name: Eliquis
Study Arms  ICMJE
  • Experimental: Treatment group A: Cyclosporine in transplant recipients
    A single oral dose of 10 mg apixaban will be administered to kidney or lung transplant recipients stabilized on cyclosporine as part of their immunosuppressive regimen
    Intervention: Drug: Apixaban
  • Active Comparator: Cyclosporine in healthy subjects

    Results from Treatment group A will be compared to previously obtained data in healthy participants receiving a single dose of apixaban with a daily dose of 100 mg of cyclosporine at steady state concentration (Bashir et al. Clin Transl Sci. 2018 Jul 3. doi: 10.1111/cts.12580)

    Transplant recipients require continuous immunosuppression so it will not be possible to stop the cyclosporine or tacrolimus to serve as a control. As such PK plasma time curves will be compared to data in healthy volunteers.

    Intervention: Drug: Apixaban
  • Experimental: Treatment group B: Tacrolimus in transplant recipients
    A single oral dose of 10 mg apixaban will be administered to kidney or lung transplant recipients stabilized on tacrolimus as part of their immunosuppressive regimen
    Intervention: Drug: Apixaban
  • Active Comparator: Tacrolimus in healthy subjects

    Results from Treatment group B will be compared to previously obtained data in healthy participants receiving a single dose of apixaban with a daily dose of 100 mg of tacrolimus at steady state concentration (Bashir et al. Clin Transl Sci. 2018 Jul 3. doi: 10.1111/cts.12580)

    Transplant recipients require continuous immunosuppression so it will not be possible to stop the cyclosporine or tacrolimus to serve as a control. As such PK plasma time curves will be compared to data in healthy volunteers.

    Intervention: Drug: Apixaban
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 24, 2020)
14
Original Estimated Enrollment  ICMJE
 (submitted: July 16, 2019)
32
Actual Study Completion Date  ICMJE March 30, 2020
Actual Primary Completion Date March 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Kidney or lung transplant patients followed as outpatients who are currently stabilized on immunosuppressive therapy with tacrolimus or cyclosporine
  • Age 18 or older
  • At least six months after transplantation
  • Lack of transplant rejection within the last 12 weeks
  • Creatinine clearance at least above 15ml/min as calculated by Cockroft-Gault formula
  • Negative urine pregnancy test for female patients of childbearing potential
  • Consent to the study
  • Be a nonsmoker for at least approximately 6 months prior to the study
  • Have a prothrombin time (PT) and activated partial thromboplastin time (PTT) level below the upper limit of normal
  • Have a hemoglobin level of above at least 80g/L
  • Be willing to refrain from the use of anticoagulants and antiplatelet medications including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) for two weeks prior and during the entire period of study participation
  • Be willing to avoid drinking grapefruit juice or consuming natural health products for two weeks prior and during the study period
  • Be willing to avoid alcohol and cannabis for 48 hours before the study and for the entire duration of the study
  • Be willing to comply with trial restrictions
  • Be deemed safe to participate by the study physician

Exclusion Criteria:

  • Patients on antiplatelet therapy for any cardiovascular treatment (such as clopidogrel, prasugrel, ticagrelor). Patients on prophylactic aspirin will be eligible otherwise.
  • Patients not receiving tacrolimus or cyclosporine
  • A history of an anaphylactic or severe systemic reactions to apixaban
  • Any form of substance abuse or major untreated psychiatric disorder
  • Pregnancy or lactation
  • Tacrolimus or cyclosporine changes within the last two weeks
  • Receiving concurrent therapy with warfarin, or are taking medications known to be strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) such as azole-antimycotics antifungals (e.g., ketoconazole, voriconazole.)
  • Has congenitial or acquired coagulation disorders
  • Has moderate or severe hepatic disease or other clinically relevant bleeding risk
  • Use of any drugs or products which at the discretion of the investigator would increase bleeding risk
  • Has any unstable medical condition that could interfere with the study
  • Is considered inappropriate for participation by the investigator for any reason
  • Clinically significant active bleeding, including gastrointestinal bleeding
  • Lesions or conditions at increased risk of clinically significant bleeding, e.g., recent cerebral infarction (ischemic or hemorrhagic), active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis
  • Patients who donate blood within 56 days of participating in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04023760
Other Study ID Numbers  ICMJE 99861
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Current Responsible Party Holly Mansell, University of Saskatchewan
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Saskatchewan
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Saskatchewan Health Research Foundation
  • Lung Association of Saskatchewan
Investigators  ICMJE Not Provided
PRS Account University of Saskatchewan
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP