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

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

Tracking Information

• First Submitted Date: June 28, 2019
• First Posted Date: July 18, 2019
• Last Update Posted Date: May 3, 2021
• Actual Study Start Date: June 26, 2019
• Actual Primary Completion Date: March 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: 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: Drug Interaction Study of Apixaban With Cyclosporine or Tacrolimus in Transplant Recipients
• Official Title: 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: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Other

Condition

• Pharmacokinetics
• Kidney Transplant
• Lung Transplant

Intervention

Drug: Apixaban

Study subjects given a single-dose of apixaban 10 mg.

Other Name: Eliquis

Study Arms

• 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 *

• Bashir B, Stickle DF, Chervoneva I, Kraft WK. Drug-Drug Interaction Study of Apixaban with Cyclosporine and Tacrolimus in Healthy Volunteers. Clin Transl Sci. 2018 Nov;11(6):590-596. doi: 10.1111/cts.12580. Epub 2018 Jul 27.
• Mansell H, Shoker A, Alcorn J, Fenton ME, Tam JS, Semchuk W, Bashir B, Kraft WK, Yao S, Douketis JD. Pharmacokinetics of apixaban and tacrolimus or cyclosporine in kidney and lung transplant recipients. Clin Transl Sci. 2022 Jul;15(7):1687-1697. doi: 10.1111/cts.13284. Epub 2022 May 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 24, 2020): 14
• Original Estimated Enrollment (submitted: July 16, 2019): 32
• Actual Study Completion Date: March 30, 2020
• Actual Primary Completion Date: March 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT04023760
• Other Study ID Numbers: 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

• Plan to Share IPD: Yes

• Current Responsible Party: Holly Mansell, University of Saskatchewan
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Saskatchewan
• Original Study Sponsor: Same as current

Collaborators

• Saskatchewan Health Research Foundation
• Lung Association of Saskatchewan

• Investigators: Not Provided
• PRS Account: University of Saskatchewan
• Verification Date: April 2021