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Compare Apixaban and Vitamin-K Antagonists in Patients With Atrial Fibrillation (AF) and End-Stage Kidney Disease (ESKD) (AXADIA)

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ClinicalTrials.gov Identifier: NCT02933697
Recruitment Status : Recruiting
First Posted : October 14, 2016
Last Update Posted : October 23, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Pfizer
Information provided by (Responsible Party):
Atrial Fibrillation Network

Tracking Information
First Submitted Date  ICMJE October 7, 2016
First Posted Date  ICMJE October 14, 2016
Last Update Posted Date October 23, 2020
Actual Study Start Date  ICMJE June 20, 2017
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 21, 2020)		 Assess the safety of the factor Xa inhibitor apixaban versus a vitamin-K antagonist phenprocoumon in patients with NVAF and ESKD on hemodialysis. [ Time Frame: 6-60 months ]
The safety will be assessed by means of the incidence of major and clinically relevant, non-major bleeding as well as specific bleedings in dialysis patients (e.g., after shunt removal) on anticoagulation.
Original Primary Outcome Measures  ICMJE
 (submitted: October 12, 2016)		 Assess the safety of the factor Xa inhibitor apixaban versus a vitamin-K antagonist phenprocoumon in patients with NVAF and ESKD on hemodialysis. [ Time Frame: 6-24 months ]
The safety will be assessed by means of the incidence of major and clinically relevant, non-major bleeding as well as specific bleedings in dialysis patients (e.g., after shunt removal) on anticoagulation.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 21, 2020)		 Compare the efficacy of the factor Xa inhibitor apixaban with the VKA phenprocoumon regarding prevention of thromboembolic events in patients with ESKD on hemodialysis and AF [ Time Frame: 6-60 months ]
The efficacy of the factor Xa inhibitor apixaban with the VKA phenprocoumon regarding prevention of thromboembolic events in patients with ESKD on hemodialysis and AF
Original Secondary Outcome Measures  ICMJE
 (submitted: October 12, 2016)		 Compare the efficacy of the factor Xa inhibitor apixaban with the VKA phenprocoumon regarding prevention of thromboembolic events in patients with ESKD on hemodialysis and AF [ Time Frame: 6-24 months ]
Current Other Pre-specified Outcome Measures
 (submitted: October 21, 2020)		 Pharmacokinetic sub-study to determine plasma serum level [ Time Frame: 6-60 months ]
A pharmacokinetic sub-study will be conducted with a small number of patients in the apixaban treatment group (n= 28) in order to determine plasma serum level of apixaban prior and after hemodialysis.
Original Other Pre-specified Outcome Measures
 (submitted: October 12, 2016)		 Pharmacokinetic sub-study to determine plasma serum level [ Time Frame: 6-24 months ]
A pharmacokinetic sub-study will be conducted with a small number of patients in the apixaban treatment group (n= 28) in order to determine plasma serum level of apixaban prior and after hemodialysis.
 
Descriptive Information
Brief Title  ICMJE Compare Apixaban and Vitamin-K Antagonists in Patients With Atrial Fibrillation (AF) and End-Stage Kidney Disease (ESKD)
Official Title  ICMJE A Safety Study Assessing Oral Anticoagulation With Apixaban Versus Vitamin-K Antagonists in Patients With Atrial Fibrillation (AF) and End-Stage Kidney Disease (ESKD) on Chronic Hemodialysis Treatment
Brief Summary The Study is an open-labeled, randomized controlled trial, phase IIIb. Its objective is to assess the safety of the factor Xa inhibitor apixaban versus the vitamin-K antagonist (VKA) phenprocoumon in patients with NVAF and ESKD on hemodialysis. The safety will be assessed by means of the incidence of major and clinically relevant, non-major bleeding on anticoagulation.
Detailed Description

AXADIA is an investigator-driven, prospective, parallel-group, single country, multi-center phase IIIb trial to assess the safety of apixaban versus the vitamin-K antagonist phenprocoumon in patients with NVAF and ESKD on hemodialysis treatment. The trial will be conducted in about 25-30 sites in Germany.

The primary goal of this study is to assess the safety of two types of oral anticoagulants in patients with ESKD on hemodialysis with non-valvular atrial fibrillation (NVAF). The novel FXa inhibitor apixaban (at a reduced dose of 2x 2.5 mg/day) will be compared to the vitamin-K antagonist (VKA) phenprocoumon (target range: International Normalized Ratio (INR) 2.0-3.0) regarding bleeding rates during chronic administration for prevention of stroke or systemic embolism.

The primary hypothesis of the study is that oral anticoagulation with apixaban will improve the safety by significantly reducing bleeding rates in patients with ESKD on hemodialysis and NVAF compared to the VKA phenprocoumon.

A pharmacokinetic sub-study will be performed with 28 patients included in the apixaban treatment group to evaluate the systemic exposure of apixaban before and after hemodialysis session in this special population.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Atrial Fibrillation
  • End-stage Kidney Disease
Intervention  ICMJE
  • Drug: Apixaban
    Patients will be instructed to take one tablet of 2.5 mg twice daily: one tablet in the morning and one in the evening at approximately the same time every day (with about 12 hours gap) irrespective of the time of dialysis.
    Other Name: Eliquis
  • Drug: Phenprocoumon
    Subjects in phenprocoumon treatment group will receive phenprocoumon individually adjusted to an INR of 2.0-3.0 as recommended in the appropriate SmPC for AF patients.
    Other Name: Marcumar
Study Arms  ICMJE
  • Active Comparator: Apixaban
    2.5 mg apixaban twice daily for 6 to 60 months
    Intervention: Drug: Apixaban
  • Active Comparator: Vitamin-K antagonists (Phenprocoumon)
    Phenprocoumon by INR (Target: 2.0-3.0) treatment for 6 to 60 months
    Intervention: Drug: Phenprocoumon
Publications * Reinecke H, Jürgensmeyer S, Engelbertz C, Gerss J, Kirchhof P, Breithardt G, Bauersachs R, Wanner C. Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study. BMJ Open. 2018 Sep 10;8(9):e022690. doi: 10.1136/bmjopen-2018-022690.

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 21, 2020)		 79
Original Estimated Enrollment  ICMJE
 (submitted: October 12, 2016)		 222
Estimated Study Completion Date  ICMJE July 2023
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • End-stage kidney disease (ESKD) with chronic hemodialysis treatment 3 times per week (with about at least 3.5 hours per dialysis)
  • Chronic (i.e. repeated) paroxysmal, persistent or permanent atrial fibrillation (AF) or atrial flutter (AFL) documented by standard or Holter ECG on at least 2 separate days before (or apart from) hemodialysis procedures
  • Increased risk of stroke or systemic embolism identified by a CHA2DS2-VASc score of 2 or more as an indication for oral anticoagulation
  • Patients with ischemic stroke that meet the above criteria, can be included after more than 3 months if not severely handicapped (modified Rankin scale 0 or 1 of 6, i.e. no symptoms or no significant disability and able to carry out all usual activities, despite some symptoms (Farrell, Godwin, Richards, and Warlow (1991))
  • Males and females, aged 18 or older

Exclusion Criteria:

  • AF or AFL due to reversible causes (e.g., thyrotoxicosis, pericarditis)
  • Patients with a new onset of hemodialysis within the last 3 months
  • Clinically significant (moderate or severe) aortic and mitral stenosis
  • Conditions other than AF or AFL that require chronic anticoagulation (e.g., a prosthetic mechanical heart valve).
  • Active infective endocarditis
  • Any planned interventional or surgical AF or AFL ablation procedure
  • Any active bleeding
  • A serious bleeding event in the previous 6 months before screening
  • Inadequately controlled (HbA1c levels >8.5%) or untreated diabetes
  • History of malignant neoplasms at high risk of current bleeding (see summary of product characteristics (SmPC) of study drugs)
  • Known indication for treatment with NSAIDs (see SmPC of study drugs) - acetylsalicylic acid (ASA) up to 100 mg per day is allowed
  • Known Antiphospholipid Syndrome requiring anticoagulation
  • Impaired liver function e.g., caused by active infection with HIV, HBV or HCV, hepatitis or other liver damage (No limits for ALT and AST values are defined in this study protocol, although mentioned in the SmPC because they are frequently elevated in dialysis patients. In case of clinically relevant increase of ALT or AST level, patient's eligibility is to be decided by the responsible investigator)
  • Any type of stroke within 3 months prior to baseline
  • Other indication for anticoagulation than AF or AFL
  • Valvular heart disease requiring surgery
  • A high risk of bleeding (e.g., active peptic ulcer disease, a platelet count of <100,000 per cubic millimeter or hemoglobin level of <8 g per deciliter)
  • Documented hemorrhagic tendencies or blood dyscrasias
  • Current alcohol or drug abuse
  • Life expectancy of less than 1 year
  • Indication for dual platelet inhibition at baseline (ASA ≤ 100 mg/day is allowed, clopidrogel is excluded at any dose).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sabine Jürgensmeyer, Dr. 0049 (0) 251 980 ext 1346 info-axadia@af-net.eu
Contact: Simone Mähner 0049 (0) 251 980 ext 1330 info-axadia@af-net.eu
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02933697
Other Study ID Numbers  ICMJE AXADIA - AFNET 8
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Atrial Fibrillation Network
Study Sponsor  ICMJE Atrial Fibrillation Network
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Pfizer
Investigators  ICMJE
Principal Investigator: Holger Reinecke, Prof. Dr. Universitätsklinikum Münster
PRS Account Atrial Fibrillation Network
Verification Date October 2020

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