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Inhibition of Aldosterone to Reduce Myocardial Diffuse Fibrosis in Patients With Paroxysmal and Persistent Atrial Fibrillation in Preventing Recurrent Episodes of Atrial Fibrillation (INSPIRE-AF)

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ClinicalTrials.gov Identifier: NCT02764619
Recruitment Status : Unknown
Verified May 2016 by Dragana Rujic, Svendborg Hospital.
Recruitment status was:  Active, not recruiting
First Posted : May 6, 2016
Last Update Posted : May 17, 2016
Sponsor:
Collaborators:
Region of Southern Denmark
Takeda
Information provided by (Responsible Party):
Dragana Rujic, Svendborg Hospital

Brief Summary:
A randomized, double-blinded, placebo-controlled study to evaluate the effect of spironolactone in addition to conventional treatment compared with placebo in patients with paroxysmal and persistent atrial fibrillation with preserved left ventricular ejection fraction by T1 mapping, structure and function of left atrium and ventricle assessed by transthoracic echocardiography and cardiac magnetic resonance (CMR), the number of recurrent episodes of atrial fibrillation and biomarkers measured in blood.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Drug: Spironolactone Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 125 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 3, Prospective, Randomized, Double-blinded, Placebo-controlled Study to Evaluate Efficacy of add-on Therapy With Spironolactone to Reduce Diffuse Myocardial Fibrosis Thus Preventing Recurrent Episodes of Atrial Fibrillation in Patients With Paroxysmal or Persistent Atrial Fibrillation and Preserved Ejection Fraction Compared to Usual Care.
Study Start Date : December 2013
Estimated Primary Completion Date : February 2017
Estimated Study Completion Date : April 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Aldo group
Fixed dose of spironolactone, Spirix (Takeda Pharma A/S), 25 mg once daily, added to optimal medical treatment (usual care) for atrial fibrillation.
Drug: Spironolactone
Other Names:
  • Spirix
  • Spiron
  • Hexalacton

Placebo Comparator: Control group
Matched placebo, 1 pill once daily, added to optimal medical treatment (usual care) for atrial fibrillation.
Drug: Placebo



Primary Outcome Measures :
  1. Determine change (∆) in diffuse myocardial fibrosis between groups, assessed by cardiovascular magnetic resonance (CMR) T1 mapping. [ Time Frame: Change from baseline at 12 months ]
    The study aims to non-invasively quantify extracellular volume fraction (ECV) in left atrium and ventricle as surrogate marker of diffuse myocardial fibrosis. T1 relaxation times (T1 values) will be obtained from T1 mapping. T1 values are given in [ms]. Extracellular volume fraction (ECV) will be calculated using pre-contrast and post-contrast T1 values for myocardium and blood pool (using hematocrit) using following formula: ECV = (√T1 "myocardium post-contrast" - 1 / T1 "myocardium pre-contrast") (1 / T1 "blood post-contrast" - 1 / T1 "blood pre-contrast") x (1- hematocrit). ECV is given in percentage.

  2. Determine difference (α) in myocardial stiffness between groups, assessed by strain analysis. [ Time Frame: At time of randomization, 6 and 12 months ]
    The study aims to characterize longitudinal changes in imaging characteristics.Strain is a dimensionless quantity and is produced by application of stress. It represents the fractional or percentage change from the original or unstressed dimension and includes both lengthening, or expansion (positive strains) and shortening, or compression (negative strains). Strain rate is the temporal derivative of strain and is a measure of the rate of deformation, with units of [1/s]. The strain rate is also equivalent to the shortening velocity per fiber length.

  3. Determine difference (β) in left atrial phasic function between groups, assessed by transthoracic echocardiography. [ Time Frame: At time of randomization and 12 months ]
    Left atrial phasic function is measured by the volumetric method, where LA volumes are measured at different time points of the cardiac cycle. Left atrial volumes on time curves are indexed to body surface area and are given in [mL/m2]. Speckle tracking is a technique that is complementing phasic function measures with myocardial deformation. Quantitative curves are representing all segments showing wall deformation during the cardiac cycle.


Secondary Outcome Measures :
  1. Arrhythmic composite endpoint. [ Time Frame: 12 months from randomization ]
    Burden of atrial fibrillation, where recurrent episodes of atrial fibrillation are documented with 12-lead ECG recordings and serial Holter monitoring. AF burden assessed as cumulative AF burden, registered on 12-lead ECG recordings and serial 48-hour Holter monitoring, where a recurrent episode of AF is defined as AF ≥ 30 seconds of duration. AF burden will also include the total duration of AF, recorded on Holter monitoring.

  2. Life quality, assessed by SF-12. [ Time Frame: At time of randomization and 12 months ]
  3. Determine level of collagen turnover between groups, measured in blood. [ Time Frame: At time of randomization, 6 and 12 months ]

    The aims of the study are:

    • To investigate whether or not the burden of diffuse myocardial fibrosis (T1 mapping) is associated with biomarkers measured in blood.
    • To investigate whether or not left atrial volume and function is associated with biomarkers measured in blood.

    Additional biomarkers may be included as the research in those fields progresses during the conduct of this clinical trial.


  4. Adverse events [ Time Frame: 15 months from randomization ]
    Adverse events (AE's) and serious adverse events (SAE's) of special interest that is hyperkalemia (serum potassium ≥ 5,5 mmol/l and serum potassium ≥ 6 mmol/l), worsening renal function (WRF) defined as a 30 % reduction in estimated glomerular filtration rate (eGFR) from baseline and gynecomastia ( Common Terminology Criteria for Adverse Events version 5.0, grade ≥ 1).



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Patients ≥ 18 years of age, male or female.
  • Paroxysmal or persistent atrial fibrillation on one occasion, detected on 12-lead ECG or Holter monitoring with atrial fibrillation episode lasting ≥ 30 seconds within last 12 months prior to the screening visit.
  • Women with childbearing potency must use effective contraception (e.g. implants, hormonal depot injections, combined oral contraceptives, intra-uterine devices or vasectomized partner). Men enrolled in this study must agree to use adequate barrier birth control measures during the treatment period of the study. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation.
  • Written informed consent signed before any study-specific procedure.

Exclusion Criteria:

  • Permanent AF.
  • Previous radiofrequency ablation and / or previous surgical therapy of AF.
  • Heart failure (New York Heart Association [NYHA] ≥ II or/and left ventricular ejection fraction [LVEF] less than 40%).
  • Severe coronary artery disease (acute coronary syndrome (ACS) within 6 months prior to the screening visit, previous coronary artery bypass graft [CABG] or stabile angina pectoris classified with Canadian Cardiovascular Society [CCS] ≥II). The definition of ACS is from the current European Society of Cardiology (ESC) and American College of Cardiology (ACC) / American Heart Association (AHA) guidelines.
  • Stroke or transient ischemic cerebral attack within 6 months prior to the screening visit.
  • Pregnant women, breastfeeding women or women of childbearing potential not on adequate birth control.
  • Presence of severe and hemodynamically significant valvular heart disease.
  • Hepatic insufficiency classified as Child-Pugh B or C .
  • Any disease that limits life expectancy to less than 1 year.
  • Participation in another clinical trial, either within the last 30 days or ongoing.
  • Morbus Addison.
  • Ongoing therapy with class IC agents (flecainide, propafenone) or amiodarone, dronedarone sotalol.
  • Chronic kidney disease (estimated glomerular filtration rate [eGFR] ≤ 45 ml/min/1,73 m2 [MDRD]).
  • Intolerance or contradictions to spironolactone, i.e. latest product resume on Spirix®.
  • Patients who are noncompliant with treatment.
  • Mental disorders suspected to interact with study outcome or any other patient characteristics that may interfere with adherence to the study protocol, such as dementia, substance abuse.
  • Any surgical or medical condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety.
  • Baseline serum potassium ≥ 5,0 mmol/l or serum sodium < 135 mmol/l. Note: one re-assessment of electrolytes is allowed.

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): NCT02764619


Locations
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Denmark
Department of Cardiovascular Research, Medical Department, Odense University Hospital, Svendborg
Svendborg, Region of Southern Denmark, Denmark, 5700
Sponsors and Collaborators
Svendborg Hospital
Region of Southern Denmark
Takeda
Investigators
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Study Director: Kenneth Egstrup, Professor Department of Cardiovascular Research, Medical Department, Odense University Hospital, Svendborg
Principal Investigator: Dragana Rujic, MD, Ph.D.sc. Department of Cardiovascular Research, Medical Department, Odense University Hospital, Svendborg

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Responsible Party: Dragana Rujic, MD, ph.d.-student, Svendborg Hospital
ClinicalTrials.gov Identifier: NCT02764619    
Other Study ID Numbers: SPI-IIT-001
First Posted: May 6, 2016    Key Record Dates
Last Update Posted: May 17, 2016
Last Verified: May 2016
Keywords provided by Dragana Rujic, Svendborg Hospital:
Upstream therapy, spironolactone
Atrial remodelling
Modified look-locker inversion recover (MOLLI) sequences
T1 mapping
Diffuse myocardial fibrosis
Additional relevant MeSH terms:
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Atrial Fibrillation
Fibrosis
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents