Clinical Trial Results:
The MIRAD study - Mineralocorticoid Receptor Antagonists in Type 2 Diabetes.
A randomised, double-blind, placebo-controlled study of the effect of Mineralocorticoid Receptor Antagonists in Type 2 Diabetes on glucose and fat metabolism, myocardial function and vascular function.
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Summary
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EudraCT number |
2015-002519-14 |
Trial protocol |
DK |
Global end of trial date |
10 Nov 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
02 May 2020
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First version publication date |
02 May 2020
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Other versions |
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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 |
2015-775
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02809963 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Herlev Hospital
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Sponsor organisation address |
Herlev ringvej 75, Herlev, Denmark, 2730
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Public contact |
Forskingsenheden, Herlev Hospital, caroline.michaela.kistorp@regionh.dk
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Scientific contact |
Forskingsenheden, Herlev Hospital, caroline.michaela.kistorp@regionh.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 |
02 Mar 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Nov 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Nov 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 |
Primary objective to investigate the effect of Eplerenone 200 mg once daily compared to placebo on:
• Liver fat content by proton MR spectroscopy
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Protection of trial subjects |
All participants were informed orally and in written form and gave their written consent prior to randomization.
The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice (GCP) and monitored by the GCP unit Bispebjerg, Copenhagen, Denmark, and in accordance with the Declaration of Helsinki and approved by the Danish Medicines Agency and the Regional Scientific Ethics Committee of the Capital region of Denmark.
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Background therapy |
Patients with type 2 diabetes and the presence of or high risk of cardiovascular disease were randomized to either eplerenone or placebo in addition to standard care therapy. Study medication (eplerenone/placebo) was administered as an add-on treatment to background therapy, and the protocol dictated that the investigators should adjust doses of the study medication in accordance with measurements of potassium and creatinine. Therefore, no downregulations in angiotensin-converting-enzyme (ACE)-inhibitor or angiotensin II receptor blocker (ARB) treatment were allowed prior to randomization or during the study. | ||
Evidence for comparator |
The design of the study was a randomized-double-blinded-placebo-controlled trial. Placebo vs active (eplerenone) treatment. | ||
Actual start date of recruitment |
19 Oct 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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: 140
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Worldwide total number of subjects |
140
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EEA total number of subjects |
140
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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) |
70
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From 65 to 84 years |
70
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with type 2 diabetes and the presence of or high risk of cardiovascular disease were randomized to either eplerenone or placebo in addition to standard care therapy between November 2015 and November 2017. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Key inclusion criteria were type 2 diabetes diagnosed at least 3 months prior to enrolment and known cardiovascular disease or NT-proBNP ≥ 70 ng/L or albuminuria . Key exclusion criteria were left ventricular ejection fraction < 40%, plasma potassium ≥ 5.0 mmol/L at screening, severe liver disease, or impaired kidney function eGFR < 40 ml/min/1.73m | ||||||||||||||||||
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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 | ||||||||||||||||||
Blinding implementation details |
Patients were randomized in blocks of ten 1:1 (eplerenone: placebo). Study treatment allocation was generated electronically and secured by the central pharmacy, Glostrup, Copenhagen, Denmark, which was not otherwise involved in patient randomization procedures. The central pharmacy packed and labeled the study medications.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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active | ||||||||||||||||||
Arm description |
Eplerenone treatment, a selective mineralocorticoid receptor antagonist, was the active arm. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
eplerenon
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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 |
Patients were randomized to either eplerenone 100–200 mg once daily or placebo for 26 weeks. Study medication treatment followed a fixed-dose titration protocol, with a starting dose of 50 mg increasing to a maximum dose of 200 mg for patients with a baseline eGFR ≥60 ml/min/1.73m2 and 100 mg for patients with a baseline eGFR 40–59 ml/min/1.73m2. The protocol dictated titration with 50 mg every second week in patients without adverse effects to the maximum dose at the 8-week visit. Plasma potassium and creatinine were measured according to the protocol at baseline and every second week before dose adjustment.
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Arm title
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placebo | ||||||||||||||||||
Arm description |
placebo was used to compare with eplerenone treatment (the active arm) | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
placebo
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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 |
Patients were randomized to either eplerenone 100–200 mg once daily or placebo for 26 weeks. Study medication treatment followed a fixed-dose titration protocol, with a starting dose of 50 mg increasing to a maximum dose of 200 mg for patients with a baseline eGFR ≥60 ml/min/1.73m2 and 100 mg for patients with a baseline eGFR 40–59 ml/min/1.73m2. The protocol dictated titration with 50 mg every second week in patients without adverse effects to the maximum dose at the 8-week visit. Plasma potassium and creatinine were measured according to the protocol at baseline and every second week before dose adjustment.
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Baseline characteristics reporting groups
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Reporting group title |
active
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Reporting group description |
Eplerenone treatment, a selective mineralocorticoid receptor antagonist, was the active arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
placebo
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Reporting group description |
placebo was used to compare with eplerenone treatment (the active arm) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
active
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Reporting group description |
Eplerenone treatment, a selective mineralocorticoid receptor antagonist, was the active arm. | ||
Reporting group title |
placebo
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Reporting group description |
placebo was used to compare with eplerenone treatment (the active arm) | ||
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End point title |
Liver fat content | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Change from baseline to end of study (week 26)
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Statistical analysis title |
mixed model with repeated visit statement | ||||||||||||
Statistical analysis description |
Analyses were performed using a mixed model with repeated visit statement, handling missing data using a maximum likelihood
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Comparison groups |
active v placebo
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Number of subjects included in analysis |
104
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
≤ 0.05 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.92
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.01 | ||||||||||||
upper limit |
3.81 | ||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - not applicable |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse event were recorded from the day of randomization to two weeks after end of study = time period of adverse events.
Patients were asked about adverse events at every visit including telephone visit (week 2, 4, 6, 8, 10, 14, 18, 22, 26).
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Adverse event reporting additional description |
See above
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
GCP-unit | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
F3-2013
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Reporting groups
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Reporting group title |
active
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Reporting group description |
Eplerenone treatment, a selective mineralocorticoid receptor antagonist, was the active arm. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
placebo
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Reporting group description |
placebo was used to compare with eplerenone treatment (the active arm) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 3% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/31183945 |
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