Inhibition of Aldosterone to Reduce Myocardial Diffuse Fibrosis in Patients With Paroxysmal and Persistent Atrial Fibrillation in Preventing Recurrent Episodes of Atrial Fibrillation

NCT02764619 | Unknown Phase 3 DMC

• 1 other identifier: SPI-IIT-001
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 1

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.

Conditions

Atrial Fibrillation

Keywords

Upstream therapy, spironolactone; Atrial remodelling; Modified look-locker inversion recover (MOLLI) sequences; T1 mapping; Diffuse myocardial fibrosis

Outcome Measures

Primary Outcomes (3)

• Determine change (∆) in diffuse myocardial fibrosis between groups, assessed by cardiovascular magnetic resonance (CMR) T1 mapping.

  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.

  Change from baseline at 12 months

• Determine difference (α) in myocardial stiffness between groups, assessed by strain analysis.

  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.

  At time of randomization, 6 and 12 months

• Determine difference (β) in left atrial phasic function between groups, assessed by transthoracic echocardiography.

  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.

  At time of randomization and 12 months

Secondary Outcomes (4)

• Arrhythmic composite endpoint.

  12 months from randomization

• Life quality, assessed by SF-12.

  At time of randomization and 12 months

• Determine level of collagen turnover between groups, measured in blood.

  At time of randomization, 6 and 12 months

• Adverse events

  15 months from randomization

Study Arms (2)

Aldo group

ACTIVE COMPARATOR

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

Control group

PLACEBO COMPARATOR

Matched placebo, 1 pill once daily, added to optimal medical treatment (usual care) for atrial fibrillation.

Drug: Placebo

Interventions

Spironolactone DRUG

Also known as: Spirix, Spiron, Hexalacton

Aldo group

Placebo DRUG

Control group

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Svendborg Hospital: lead
• Region of Southern Denmark: collaborator
• Takeda: collaborator

Study Sites (1)

Department of Cardiovascular Research, Medical Department, Odense University Hospital, Svendborg

Svendborg, Region Syddanmark, 5700, Denmark

Location

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Spironolactone

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Kenneth Egstrup, Professor

  Department of Cardiovascular Research, Medical Department, Odense University Hospital, Svendborg

  STUDY DIRECTOR

• Dragana Rujic, MD, Ph.D.sc.

  Department of Cardiovascular Research, Medical Department, Odense University Hospital, Svendborg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, ph.d.-student

Study Record Dates

• First Submitted: March 27, 2016
• First Posted: May 6, 2016
• Study Start: December 1, 2013
• Primary Completion: February 1, 2017
• Study Completion: April 1, 2017
• Last Updated: May 17, 2016

Record last verified: 2016-05

Locations

DK (1)