A Phase 2 interventional study of apixaban in ESRD and Anticoagulant Toxicity, sponsored by Universitaire Ziekenhuizen KU Leuven. Completed at 1 site in Belgium. Open to participants aged 18 Years to 85 Years. Per ClinicalTrials.gov, last updated 2018-10-17.
Sponsored by Universitaire Ziekenhuizen KU Leuven · Phase 2, Interventional, and Treatment
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).
RATIONALE
Chronic Kidney Disease (CKD) is one of the epidemics of modern times. In the recent National Health and Nutrition Examination Survey (NHANES), the overall prevalence of CKD (stages 1 to 4) increased from 10.0% in 1988-1994 to 13.1% in 1999-2004 (1). Mounting data point to the lethal synergy between chronic kidney disease (CKD) and cardiovascular disease (CVD) (2,3,4) Atrial fibrillation (AF) is an important co-morbid condition in patients with CKD. While prevalence differs from region to region, it is estimated that between 5 and 10% of dialysis patients have AF (5). Analyses of the US renal data system (USRDS) demonstrate that the prevalence of AF in patients with hemodialysis continues to rise (6). Prevalent AF is positively associated with all-cause mortality and stroke, similar to that of the general population (5).
The choice of the optimal anticoagulation regimen for hemodialysis patients with AF is hampered by lack of randomized controlled trials. Observational data support the use of the CHADS2-score for risk stratification of AF in HD (5). Cost-utility analyses suggest that warfarin appears to be the optimal therapy to prevent thromboembolic stroke in hemodialysis patients with AF (7). These analyses however extrapolate the decrease in risk of stroke observed in randomized trials of oral vitamin K antagonist therapy in the general population (7). Both retrospective and prospective observational data however observe an increased risk for stroke in HD patients receiving oral vitamin K antagonist therapy for AF (8,5).
Recent findings shed a worrisome light on the pleiotropic effects of oral vitamin K antagonist therapy in patients with advanced chronic kidney disease. Besides promoting undercarboxylation of the pro- and anticoagulant factors (II, VII, IX, X, protein S, protein C) several other glutamine-domain containing proteins remain undercarboxylated. Matrix-Gla protein is a powerful calcification inhibitor. Nonphosphorylated matrix-Gla protein has been associated with overall mortality and cardiovascular mortality in HD patients (9). Observational data suggest that patients treated with oral vitamin K antagonists demonstrate higher valvular and coronary calcium (10). Prospective trials currently investigate the effects of vitamin K supplementation on the evolution of vascular calcification in patients with end-stage kidney disease and on aortic valve calcifications.
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) (11). An important benefit of apixaban as compared to other recent NOACs, e.g. dabigatran and rivaroxaban, is that the elimination is less dependent on kidney function as only 25% is excreted renally and 75% is excreted through the hepatobiliary system, with a mean elimination half-life of 8-15 hours in healthy adults.
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.
HYPOTHESIS The pharmacokinetics profile of apixaban allows safe use in patients with end-stage renal disease
STUDY DESIGN Open label non-randomized phase II pharmacokinetics study.
STUDY AIMS
Primary:
To determine inter-dialytic pharmacokinetics of Apixaban
Secondary:
DOSING AND TIMING Part A - interdialytic kinetics Dose titration
Part B - intra- plus interdialytic pharmacokinetics Dose titration
NUMBER OF STUDY PARTICIPANTS
We aim to include 6 patients for each part and dosage:
Part A - Interdialytic kinetics 2.5 mg N = 6 5 mg N = 6
Part B - Intra- plus interdialytic kinetics 2.5 mg N = 6 5 mg N = 6
Based on previous publications on single dose pharmacokinetics of apixaban in healthy volunteers (12), we expect that 6 patients per part will provide sufficient data to generate PK profiles.
SCHEDULED BLOOD SAMPLING
Part A - Interdialytic kinetics (post-dialysis dosing)
Part B - Intradialytic kinetics (pre-dialysis dosing)
ANALYTICAL TECHNIQUES
Apixaban concentrations (ng/mL) will be determined based on a calibration curve with Apixaban (Apixaban Calibrator and controls, Hyphen).
Conventional anticoagulation used for hemodialysis is by heparin or low molecular weight heparins (LMWH). This will lead to significant interference with the proposed chromogenic anti-Xa activity assays. To exclude interference of anticoagulation for hemodialysis during the study period, the routine anticoagulation will be switched to regional citrate anticoagulation according to local protocol during the study period. The following will be applied.
PHARMACOKINETICS ANALYSES
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). 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). Briefly, 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. 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). Similarly, after plotting plasma concentration-time products as a function of time, Area under the first Moment Curve (AUMC) values will be calculated. The mean residence time (MRT, h) will be obtained from AUMC/AUC. Mean half-life (t1/2) will be calculated as Ln(2)×MRT. Oral ('apparent') clearance (Cl/F) values will be obtained by dividing dose by AUC. The volume of distribution at steady (Vdss/F) will be obtained as MRT x Cl/F. As alternative to NCA, the feasibility of analyzing the data with a 1-compartmental model with first order absorption will be explored as well. Summary statistics will be tabulated for all relevant PK parameters: (i) the descriptive parameters Cmax, Tmax and AUC0-∞ (total exposure), (ii) MRT and mean t1/2, (iii) the primary (fundamental) PK parameters Cl/F and Vd/F. Reported parameters will enable appropriate comparison with previously published data on apixaban PK in various populations. For the purpose of dose finding, AUC0-∞ (total exposure) represents the key parameter.
2,108 studies on the registry are indexed under Kidney Failure, Chronic; 273 are open to participants now.
This study's enrollment of 24 is below the median of 57 across 1,569 interventional studies indexed under Kidney Failure, Chronic.
Browse Kidney Failure, Chronic studies →Universitaire Ziekenhuizen KU Leuven is the lead sponsor of 963 studies on the registry; 267 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
For women of the following criteria apply:
Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed FSH levels and may require a 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 :
8 week minimum for oral products Other parenteral products may require washout periods as long as 6 months.
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:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Washout period
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Interdialytic kinetics of low dose (2.5 mg apixaban) post-dialysis
Drug: apixaban
Interdialytic kinetics of high dose (5 mg apixaban) post-dialysis
Drug: apixaban
Intra- and interrdialytic kinetics of low (2.5 mg) apixaban pre-dialysis
Drug: apixaban
Intra- and interrdialytic kinetics of high (5 mg) apixaban pre-dialysis
Drug: apixaban
non-vitamin K oral anticoagulant (NOAC)
Also known as: Eliquis
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.
Time frame: 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
Time frame: 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
Time frame: 48 hours
Occurrence of SAE
Occurrence of serious adverse events (SAE) will be analyzed as an important safety variable
Time frame: 48 hours
Plan to share: No
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Ran from Sep 2016 to primary completion in Aug 2018, 22 months.
Of 41 non-industry phase 2 interventional studies under Kidney Failure, Chronic, half reached primary completion within 35 months of starting (the median), counting those still running; a quarter within 25 and three quarters within 52. This study's 22 months is below that.
Counting every sponsor, half of 67 studies reached it within 32 months; a quarter within 17 and three quarters within 55.
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This study is completed, as verified in Mar 2018. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Apixaban
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