Clinical Trial Results:
Inhibition of aldosterone to diminish diffuse myocardial fibrosis in atrial fibrillation
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Summary
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EudraCT number |
2013-000797-30 |
Trial protocol |
DK |
Global end of trial date |
26 Mar 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Mar 2021
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First version publication date |
14 Mar 2021
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Other versions |
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Summary report(s) |
Methods and results summary |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SPI-IIT-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02764619 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Amendment 3, protocol 3.0: SPI-IIT-002 | ||
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Sponsors
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Sponsor organisation name |
Odense University Hospital, Svendborg
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Sponsor organisation address |
Baageoes Alle 15, Svendborg, Denmark, 5700
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Public contact |
Dragana Rujic , Department of Medical Research, Odense University Hospital, Svendborg Hospital, +45 63202402, kenneth.egstrup@rsyd.dk
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Scientific contact |
Dragana Rujic , Department of Medical Research, Odense University Hospital, Svendborg Hospital, 42533158 63202402, dragana.rujic@rsyd.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Feb 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Mar 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Mar 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate whether or not therapy with a mineralocorticoid receptor antagonist (MRA), in this case spironolactone, added to optimal medical treatment in normotensive or hypertensive patients with paroxysmal or persistent atrial fibrillation diminishes diffuse myocardial fibrosis in left atria and ventricle, atrial remodeling and thus improve left atrial function as compared with conventional treatment.
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Protection of trial subjects |
Reports of adverse events (AE) were collected throughout the study period, classified and graded according to seriousness, intensity, outcome, and causality with study medication. Adverse events of special interest were gynecomastia, hyperkalemia, and worsening of renal function compared to baseline. Breast tissue pain or discomfort ≥ 1 month, or visually apparent gynecomastia were regarded as a serious AE, and the subject was withdrawn from the study. The severity of hyperkalemia was defined according to the European Resuscitation Council guidelines into mild (5.5–5.9 mmol/L), moderate (6.0–6.4 mmol/L), and severe (>6.5 mmol/L). The worsening of renal function was defined according to the Kidney Disease Improving Global Outcomes Guidelines. A relative increase in serum creatinine or estimated glomerular filtration rate (calculated by MDRD) <25% from baseline and serum potassium <6.0 mmol/L was considered acceptable. In case of a moderate increase of serum creatinine 25–29% from baseline or moderate hyperkalemia 6.0-6.4 mmol/L, potassium supplements, concomitant treatment with ACEI/ARB, or temporarily study medication was removed. The subject was withdrawn from the study if the serum creatinine or eGFR increased by ≥30% compared to baseline, or the serum creatinine increased ≥200 micromoles/L, or in case of serious hyperkalemia (≥6.5 mmol/L).
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Background therapy |
Optimal medical therapy for concomitant medical conditions such as hypertension, diabetes mellitus, thyroid diseases, and atrial fibrillation was encouraged. Optimal therapy for atrial fibrillation included beta-blockers, verapamil, diltiazem, digoxin, and anticoagulant therapy, where appropriate. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Oct 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 125
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Worldwide total number of subjects |
125
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EEA total number of subjects |
125
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
50
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From 65 to 84 years |
75
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85 years and over |
0
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Recruitment
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Recruitment details |
This was a single center study conducted at Odense University Hospital, Svendborg Hospital, Denmark from November 2013 through February 2017. All eligible inpatients and outpatients with paroxysmal or persistent atrial fibrillation were recruited from the Department of Cardiology, Odense University Hospital, Svendborg. | |||||||||
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Pre-assignment
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Screening details |
Demographic, clinical and laboratory data were collected at baseline (pre-treatment). Clinical data included measurements of blood pressure, height, weight, and 12-lead ECG. Office blood pressure was recorded three times after 10 minutes of supine rest. Lab parameters: potassium, sodium, creatinine, BUN, eGR, hemoglobin, hematocrite. | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
Study subjects were randomly assigned (1:1 ratio) to receive either spironolactone 25 mg (Spirix® 25 mg) or placebo once daily, using a permuted block design with variable block size (between 1 and 4) stratified by type of AF (paroxysmal and persistent AF). Blinding was done by Odense University Hospital, Pharmacy.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Spironolactone | |||||||||
Arm description |
Intervention arm | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Spironolactone oo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
A tablet containing 25 mg, administered once daily
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Arm title
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Placebo | |||||||||
Arm description |
Control arm, placebo | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Intervention arm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Control arm, placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Intervention arm | ||
Reporting group title |
Placebo
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Reporting group description |
Control arm, placebo | ||
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End point title |
Laft atrial post-contrast T1 time | ||||||||||||
End point description |
Post-contrast T1 times were measured on left atrial wall and the myocardium of left ventricle
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End point type |
Primary
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End point timeframe |
12 months
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| Notes [1] - Data from CMR study are presented [2] - Data from CMR study are presented |
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Statistical analysis title |
Mixed linear model with maximized likelihood | ||||||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Confidence interval |
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End point title |
Peak strain values from left atrium [3] | ||||||||||||
End point description |
Co-primary endpoints
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End point type |
Primary
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End point timeframe |
12 months
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Same method as aforementioned, mixed linear method |
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| Notes [4] - Data are presented from CMR study [5] - Data are presented from CMR study |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Peak strain value from left ventricle [6] | ||||||||||||
End point description |
Co-primary endpoint
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End point type |
Primary
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End point timeframe |
12 months
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Same method as before, linear mixed model |
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| Notes [7] - cmr data , gls [8] - cmr data, gls |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Left ventricular post-contrast T1 time [9] | ||||||||||||
End point description |
Co-primary end-point
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End point type |
Primary
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End point timeframe |
12 months
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Same method as aforementioned, mixed linear method |
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| Notes [10] - cmr data, post-contrast T1 time [11] - cmr data, post- contrast T1 time on LV |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
LAVI | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 months
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| Notes [12] - cmr data, LAVI [13] - cmr data, lavi |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Recurrences of atrial fibrillation | |||||||||
End point description |
1. Free from recurrence of atrial fibrillation
2. Total number recurrences of atrial fibrillation
3. Total number recurrences of atrial fibrillation after 90 days blanking period
4. Total number DC cardioversions
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End point type |
Secondary
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End point timeframe |
12 months
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| No statistical analyses for this end point | ||||||||||
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End point title |
Gynecomastia | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 months
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| No statistical analyses for this end point | ||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
12 months
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Adverse event reporting additional description |
All subjects in the trial were followed for 12 months
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Assessment type |
Non-systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
3
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| Frequency threshold for reporting non-serious adverse events: 1% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Same method as aforementioned, mixed linear method |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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01 Nov 2015 |
1.The primary targeted sample size is decreased from 150 to 130 eligible participants.
2. Primary end-points are altered based on statistical calculations and assumptions following newest literature. The primary end-points regarding burden of atrial fibrillation (AF burden) and biomarkers measured in blood are replaced as secondary endpoints. With a sample size of 130 participants the trial will have reasonable statistical power (>80 %, p<0.05) to detect an effect on primary end-points regarding measurements on cardiovascular magnetic resonance (CMR) and transthoracic echocardiography.
3.Endpoints regarding cardiovascular magnetic resonance (CMR) and transthoracic echocardiography (TTE) are left unchanged.
4.Eligibility of study participants:
• Detection of one AF-episode of either paroxysmal or persistent AF on 12-lead ECG or Holter monitoring with AF-episode lasting ≥ 30 seconds within the last 12 months prior to the screening visit.
• Eligible subjects are recruited regardless of symptoms of AF estimated by EHRA classification I-IV.
• Patients with CHA2DS2-VASc score ≥ 1 will be encouraged to start anticoagulant treatment, but will not be excluded if there are reasonable reasons not to, i.e. risk of bleeding. Patients can choose between standard anticoagulation therapies, i.e. warfarin or non vitamin-K oral anticoagulants (NOAC) such as dabigatran, apixaban and rivaroxaban.
5.Secondary end-point regarding patient diaries is removed and will not be used in statistical analysis or interpretation of data in this trial. Previously collected patient diaries will be properly destructed.
6. By 01.12.2015 the screening area will be extended to the whole Funen. This will comprise inpatients from the Departments of Cardiology at Odense University Hospital and Svendborg Hospital and outpatients from the Outpatients Clinic of Cardiology at Odense University Hospital, Nyborg Hospital and Svendborg Hospital.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
