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Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (NOAH)

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ClinicalTrials.gov Identifier: NCT02618577
Recruitment Status : Terminated (following a recommendation from the data safety and monitoring board due to safety concerns and a tendency towards futility.)
First Posted : December 1, 2015
Last Update Posted : July 28, 2023
Sponsor:
Collaborators:
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Information provided by (Responsible Party):
Atrial Fibrillation Network

Tracking Information
First Submitted Date  ICMJE November 27, 2015
First Posted Date  ICMJE December 1, 2015
Last Update Posted Date July 28, 2023
Actual Study Start Date  ICMJE February 2016
Actual Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 27, 2023)
stroke, systemic embolism, or cardiovascular death [ Time Frame: 28 months ]
Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death
Original Primary Outcome Measures  ICMJE
 (submitted: November 27, 2015)
Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death [ Time Frame: 28 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 27, 2023)
  • Components of the primary outcome [ Time Frame: 28 months ]
    All-cause death Major bleeding events according to the ISTH definitions Quality of life changes at 12 and 24 months compared to baseline Patient satisfaction at 12 and 24 months compared to baseline Cost effectiveness and health resource utilisation Patient autonomy changes at 12 and 24 months compared to baseline including chronic consequences of stroke (aphasia, hemianopia ("mild stroke")) Cognitive function at 12 and 24 months compared to baseline
  • Major Adverse Cardiac Events (MACEs: cardiac death, myocardial infarction, acute coronary syndrome (ACS) [ Time Frame: 28 months ]
    PCI, CABG
  • All-cause death [ Time Frame: 28 months ]
    All-cause death
  • Major bleeding events [ Time Frame: 28 months ]
    according to the International Society on Thrombosis and Haemostasis (ISTH) definitions
  • Quality of life changes at 12 and 24 months compared to baseline [ Time Frame: 28 months ]
    assessed by EQ-5D including its visual-analogue scale and by the Karnofsky scale
  • Patient satisfaction at 12 and 24 months compared to baseline [ Time Frame: 28 months ]
    assessed by PACT-Q
  • Cost effectiveness and health resource utilisation [ Time Frame: 28 months ]
    estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies
  • Changes of autonomy status in patients with stroke during study participation [ Time Frame: 28 Months ]
    potentially assessed at each FU visit by modified Rankin scale; a maximum of 2 subsequent assessments in FU per patient with stroke should be performed
  • Cognitive function [ Time Frame: 28 months ]
    MoCA test at 12 and 24 months compared to baseline
Original Secondary Outcome Measures  ICMJE
 (submitted: November 27, 2015)
  • Components of the primary outcome [ Time Frame: 28 months ]
    All-cause death Major bleeding events according to the ISTH definitions Quality of life changes at 12 and 24 months compared to baseline Patient satisfaction at 12 and 24 months compared to baseline Cost effectiveness and health resource utilisation Patient autonomy changes at 12 and 24 months compared to baseline including chronic consequences of stroke (aphasia, hemianopia ("mild stroke")) Cognitive function at 12 and 24 months compared to baseline
  • All-cause death, [ Time Frame: 28 months ]
  • Major bleeding events according to the International Society on Thrombosis and Haemostasis (ISTH) definitions [ Time Frame: 28 months ]
  • Quality of life changes at 12 and 24 months compared to baseline (assessed by EQ-5D including its visual-analogue scale and by the Karnofsky scale) [ Time Frame: 28 months ]
  • Patient satisfaction at 12 and 24 months compared to baseline (assessed by modified EHRA score (36) and PACT-Q ) [ Time Frame: 28 months ]
  • Cost effectiveness and health resource utilisation estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies, [ Time Frame: 28 months ]
  • Patient autonomy changes at 12 and 24 months compared to baseline including chronic consequences of stroke (aphasia, hemianopia ("mild stroke")) as assessed by modified Rankin score and NIHSS in conjunction with Karnofsky and EQ-5D [ Time Frame: 28 Months ]
  • Cognitive function (MoCA) at 12 and 24 months compared to baseline [ Time Frame: 28 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes
Official Title  ICMJE Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes - An Investigator-driven, Prospective, Randomised, Double-blind, Multi-centre Trial Initiated by the European Society of Cardiology and AFNET
Brief Summary NOAH is an investigator-initiated, prospective, parallel-group, double-blind, randomised, multi-centre trial. The objective of the trial is to demonstrate that oral anticoagulation using the NOAC edoxaban is superior to current therapy to pre-vent stroke, systemic embolism, or cardiovascular death in patients with AHRE and at least two stroke risk factors but without AF. The trial will be conducted in several European countries.
Detailed Description

Atrial fibrillation (AF) is a common cause of stroke, especially ischemic stroke. So far, all available data that demonstrate a beneficial effect of oral anticoagulation for stroke prevention have been collected in populations with AF documented by conventional ECG recordings. It is well established that a large proportion of AF episodes remain undiagnosed ("silent AF"), and many of these patients present with a stroke as the first clinical sign of AF. Earlier initiation of anticoagulation could prevent such events. Continuous monitoring of atrial rhythm by implanted devices could close this diagnostic gap. Pacemakers, defibrillators, and cardiac resynchronisation devices already provide automated algorithms alerting to the occurrence of highly organised atrial tachyarrhythmia episodes, also called "subclinical atrial fibrillation" or, more commonly, "atrial high rate episodes" (AHRE). Data from large prospectively followed patient cohorts demonstrated that stroke rate is increased in patients with AHRE. A sizeable portion of these patients develops clinically detected AF over time. In these patients, AHRE can be considered as an early manifestation of paroxysmal AF. A few AHRE patients do not develop clinically overt AF, and the absolute stroke rates are lower in patients with AHRE when compared to stroke rates in patients with clinically diagnosed AF. In light of the bleeding complications associated with oral anticoagulant therapy, there is thus uncertainty about the optimal antithrombotic therapy in patients with AHREs.

The Non-vitamin K antagonist Oral anticoagulants (NOACs) provide similar or slightly better stroke prevention, and appear slightly safer compared to vitamin K antagonists (VKAs). In addition, no individual therapy adjustment of NOACs has to be performed. Edoxaban, a newly introduced NOAC, at a dose regime of 60 mg once daily (OD) has a favourable profile compared to dose-adjusted VKA therapy: In the ENGAGE-TIMI 48 trial, edoxaban prevented strokes at least as effectively as VKA therapy but caused less major bleeding events than VKA therapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase 3b
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Atrial High Rate Episodes
Intervention  ICMJE
  • Drug: Edoxaban

    Edoxaban will be applied at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics:

    Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein-P inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole.

    Other Names:
    • Lixiana
    • Savaysa
  • Drug: ASA
    ASA 100 mg tablets or Placebo, based on accepted indication for the latter, including peripherial or coronary artery disease, a prior myocardial infarction, or a prior stroke.
    Other Name: ASS
Study Arms  ICMJE
  • Experimental: Edoxaban

    Edoxaban will be applied in NOAH at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics:

    Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein-P inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole.

    Intervention: Drug: Edoxaban
  • Active Comparator: ASA or Placebo
    Either one tablet of ASA 100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg or one placebo tablet matching in colour, weight, form and size to ASA 100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg will be administered per day depending on the indication for use of antiplatelet therapy as assessed by the responsible investigator
    Intervention: Drug: ASA
Publications *

*   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 Terminated
Actual Enrollment  ICMJE
 (submitted: July 27, 2023)
2608
Original Estimated Enrollment  ICMJE
 (submitted: November 27, 2015)
3400
Actual Study Completion Date  ICMJE December 31, 2022
Actual Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pacemaker, defibrillator or insertable cardiac monitor implanted for any reason with feature of detection of AHRE, implanted at least 2 months prior to randomisation
  • AHRE detection feature activated for adequate detection of AHRE (refer to Appendix XIII)
  • AHRE (≥ 170 bpm atrial rate and ≥ 6 min duration) documented by the implanted device via its atrial lead and stored digitally. Any AHRE episode recorded is potentially eligible, but AHRE episodes detected in the first 2 months after implantation of a new device involving placement or repositioning of atrial electrodes are not eligible. AHRE episodes recorded in the first two months after a simple "box change" operation, i.e. exchange of a pacemaker or defibrillator device without exchange or repositioning of atrial electrodes, are eligible
  • Provision of signed informed consent
  • Age ≥ 65 years

In addition, at least one of the following cardiovascular conditions leading to a modified CHA2DS2VASc score of 2 or more:

  • Age ≥ 75 years
  • Heart failure (clinically overt or LVEF < 45%)
  • Arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihyper-tensive therapy or resting blood pressure > 145/90 mmHg)
  • Diabetes mellitus
  • Prior stroke or transient ischemic attack (TIA)
  • Vascular disease (previous myocardial infarction, peripheral, carotid/cerebral, or aortic plaques on transesophageal echocardiogram [TEE])
  • Provision of signed informed consent

Exclusion Criteria:

  • Any disease that limits life expectancy to less than 1 year
  • Participation in another controlled clinical trial, either within the past two months or still ongoing
  • Previous participation in the present trial NOAH - AFNET 6
  • Drug abuse or clinically manifest alcohol abuse
  • Any history of overt AF or atrial flutter
  • Indication for oral anticoagulation (e.g. deep venous thrombosis)
  • Contraindication for oral anticoagulation in general
  • Contraindication for edoxaban as stated in the current SmPC
  • Indication for long-term antiplatelet therapy other than acetylsalicylic acid or a need for treatment with any antiplatelet agent in addition to edoxaban, especially dual antiplatelet therapy (DAPT). Patients with a transient requirement for DAPT (e.g. after receiving a stent) will be eligible when the need for DAPT is no longer present
  • Acute coronary syndrome, coronary revascularisation (PCI or bypass surgery), or overt stroke within 30 days prior to randomisation
  • End stage renal disease (creatinine clearance (CrCl) < 15 ml/min as calculated by the Cockcroft-Gault method)
  • All persons exempt from participation in a clinical trial by law
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Bulgaria,   Czechia,   Denmark,   France,   Germany,   Greece,   Hungary,   Italy,   Netherlands,   Poland,   Portugal,   Romania,   Spain,   Sweden,   Ukraine,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02618577
Other Study ID Numbers  ICMJE NOAH - AFNET 6
2015-003997-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Atrial Fibrillation Network
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Atrial Fibrillation Network
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
  • Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Investigators  ICMJE
Principal Investigator: Paulus Kirchhof, Prof. Dr. University Clinic of Hamburg-Eppendorf, Hamburg, Germany
PRS Account Atrial Fibrillation Network
Verification Date July 2023

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