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Apixaban in End-stage Kidney Disease : A Pharmacokinetics Study

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ClinicalTrials.gov Identifier: NCT03456648
Recruitment Status : Completed
First Posted : March 7, 2018
Last Update Posted : October 17, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven

Brief Summary:

Apixaban is a novel oral direct factor Xa inhibitor; In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality (the ARISTOTLE trial). Given its favorable outcome profile compared to oral vitamin K antagonists in patients with normal kidney function and in patients with mild to moderate kidney disease and given the potential serious side-effects of oral vitamin K antagonists in end-stage kidney disease, apixaban may be an attractive alternative for systemic anticoagulation in dialysis patients. The pharmacokinetics of apixaban in end-stage renal disease is not well characterized.

The aim of the current study is to perform single dose pharmacokinetics / pharmacodynamics studies in patients treated with end-stage renal disease. The primary aim is to determine inter-dialytic pharmacokinetics of Apixaban, secondary aims are intra-dialytic pharmacokinetics and dose finding. Two doses of drugs will be studies (2.5 mg and 5 mg). Study drug will be administered at the end of a dialysis session (part A) and at the beginning of a dialysis session (Part B). Six (n=6) patients are scheduled to be included for each part and each dose.

Anti-Xa activity values (IIU/mL) will be converted to apixaban concentration data (ng/mL). Apixaban concentration-time profiles will be generated and observed values for the descriptive PK parameters Cmax (peak plasma concentration) and time to Cmax (Tmax) will be determined directly from these profiles. PK profiles will be further analyzed with non-compartmental analysis (NCA).


Condition or disease Intervention/treatment Phase
ESRD Anticoagulant Toxicity Drug: apixaban Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: Single dose pharmacokinetics study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Apixaban in End-stage Kidney Disease : A Pharmacokinetics Study
Actual Study Start Date : September 25, 2016
Actual Primary Completion Date : August 24, 2018
Actual Study Completion Date : August 24, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Apixaban

Arm Intervention/treatment
Experimental: Part A : postdialysis low dose
Interdialytic kinetics of low dose (2.5 mg apixaban) post-dialysis
Drug: apixaban
non-vitamin K oral anticoagulant (NOAC)
Other Name: Eliquis

Experimental: Part A: ipostdialysis high dose
Interdialytic kinetics of high dose (5 mg apixaban) post-dialysis
Drug: apixaban
non-vitamin K oral anticoagulant (NOAC)
Other Name: Eliquis

Experimental: Part B : predialysis low dose
Intra- and interrdialytic kinetics of low (2.5 mg) apixaban pre-dialysis
Drug: apixaban
non-vitamin K oral anticoagulant (NOAC)
Other Name: Eliquis

Experimental: Part B : predialysis high dose
Intra- and interrdialytic kinetics of high (5 mg) apixaban pre-dialysis
Drug: apixaban
non-vitamin K oral anticoagulant (NOAC)
Other Name: Eliquis




Primary Outcome Measures :
  1. AUC0-T apixaban [ Time Frame: 48 hours ]

    Anti-Xa activity values (IIU/mL) will be converted to apixaban concentration data (ng/mL) based on the previously demonstrated linear relationship (e.g. Frost et al., 2014 - PMID: 24697979).

    The area under the curve (AUC) between administration (time 0) and the last measurable data point (AUC0-T) will be calculated with the 'Lin up/Log down' trapezoidal method. The AUCT-∞ will be obtained from the last measureable concentration divided by λ, and will be summed with AUC0-T to obtain AUC0-∞ (total exposure).

    the slope (λ) of the terminal phase of the concentration-time profile will be determined by log-linear regression on the appropriate number (typically at least 3) of data points. The terminal (elimination) half-life (t1/2, λ) will be calculated from Ln(2)/λ.


  2. Cmax [ Time Frame: 48 hours ]
    Apixaban concentration-time profiles will be generated and observed values for the descriptive PK parameter Cmax (peak plasma concentration) will be determined directly from the time-concentration curve

  3. Tmax [ Time Frame: 48 hours ]
    Apixaban concentration-time profiles will be generated and observed values for the descriptive PK parameter time to Cmax (Tmax)) will be determined directly from the time-concentration curve


Secondary Outcome Measures :
  1. Occurrence of SAE [ Time Frame: 48 hours ]
    Occurrence of serious adverse events (SAE) will be analyzed as an important safety variable



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients aged 18 to 85 years
  • Treated with maintenance (dialysis vintage >3 months) thrice weekly hemodialysis
  • Written and signed informed consent

Exclusion Criteria:

  • Treated with oral vitamin K antagonists
  • Recent (< 4 weeks prior to informed consent) major surgery
  • Recent (< 4 weeks prior to informed consent) severe bleeding episode requiring blood transfusion and/ or hospitalization
  • Concurrent moderate to severe liver dysfunction
  • Participation in an interventional study with investigational medication

For women of childbearing potential the following criteria apply:

  • A women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40mIU/mL to confirm menopause.
  • Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH level. The duration of the washout period is a function of the type of HRT used. The duration of the washout period below are suggested guidelines and the investigators should use their judgement in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the washout period, the woman can be considered postmenopausal :

    • 1 week minimum for vaginal hormonal products (rings, creams, gels)
    • 4 week minimum for transdermal products
    • 8 week minimum for oral products Other parenteral products may require washout periods as long as 6 months.

      1. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug.
      2. Women must not be breastfeeding
      3. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Apixaban plus 5 half-lives of study drug (3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-treatment completion.
      4. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Apixaban plus 5 half-lives of the study drug (3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment completion.
      5. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to the use of one method of highly effective contraception as listed below:

  • Male condoms with spermicide
  • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
  • IUDs, such as ParaGard
  • Tubal ligation
  • Vasectomy.
  • Complete Abstinence Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03456648


Locations
Belgium
University Hospitals Leuven
Leuven, Vlaams-brabant, Belgium, 3000
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Bristol-Myers Squibb

Responsible Party: Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT03456648     History of Changes
Other Study ID Numbers: S57150
2015-003132-12 ( EudraCT Number )
CV562247 ( Other Grant/Funding Number: BMS )
First Posted: March 7, 2018    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Kidney Diseases
Kidney Failure, Chronic
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants