Apixaban in End-stage Kidney Disease : A Pharmacokinetics Study

NCT03456648 | Completed Phase 2 FDA Drug

• 3 other identifiers: S571502015-003132-12CV562247
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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).

Conditions

ESRD; Anticoagulant Toxicity

Outcome Measures

Primary Outcomes (3)

• AUC0-T apixaban

  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.

  48 hours

• Cmax

  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

  48 hours

• Tmax

  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

  48 hours

Secondary Outcomes (1)

• Occurrence of SAE

  48 hours

Study Arms (4)

Part A : postdialysis low dose

EXPERIMENTAL

Interdialytic kinetics of low dose (2.5 mg apixaban) post-dialysis

Drug: apixaban

Part A: ipostdialysis high dose

EXPERIMENTAL

Interdialytic kinetics of high dose (5 mg apixaban) post-dialysis

Drug: apixaban

Part B : predialysis low dose

EXPERIMENTAL

Intra- and interrdialytic kinetics of low (2.5 mg) apixaban pre-dialysis

Drug: apixaban

Part B : predialysis high dose

EXPERIMENTAL

Intra- and interrdialytic kinetics of high (5 mg) apixaban pre-dialysis

Drug: apixaban

Interventions

apixaban DRUG

non-vitamin K oral anticoagulant (NOAC)

Also known as: Eliquis

Part A : postdialysis low dose; Part A: ipostdialysis high dose; Part B : predialysis high dose; Part B : predialysis low dose

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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 :
• week minimum for vaginal hormonal products (rings, creams, gels)
• week minimum for transdermal products
• week minimum for oral products Other parenteral products may require washout periods as long as 6 months.
• 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.
• Women must not be breastfeeding
• 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.
• 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.

Sponsors & Collaborators

• Universitaire Ziekenhuizen KU Leuven: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

University Hospitals Leuven

Leuven, Vlaams-brabant, 3000, Belgium

Location

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

apixaban

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single dose pharmacokinetics study

Study Record Dates

• First Submitted: February 20, 2017
• First Posted: March 7, 2018
• Study Start: September 25, 2016
• Primary Completion: August 24, 2018
• Study Completion: August 24, 2018
• Last Updated: October 17, 2018

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)