Clinical Trial Results:
The Effect of Spironolactone on Pain in Older People with Osteoarthris
Summary
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EudraCT number |
2013-002638-19 |
Trial protocol |
GB |
Global end of trial date |
28 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jul 2016
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First version publication date |
23 Jul 2016
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Other versions |
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 |
2012GR03
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Additional study identifiers
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ISRCTN number |
ISRCTN02046668 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Dundee / NHS Tayside
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Sponsor organisation address |
TASC, Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
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Public contact |
Dr Miles Witham, University of Dundee, 44 01382 383086, m.witham@dundee.ac.uk
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Scientific contact |
Dr Miles Witham, University of Dundee, 44 01382 383086, m.witham@dundee.ac.uk
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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 |
12 Mar 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Jan 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jan 2015
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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 |
This pilot study’s purpose it to provide preliminary evidence on which to base sample size calculations for a possible future trial which will answer the question: “Is spironolactone more effective than placebo in reducing knee pain in older people with symptomatic osteoarthritis (OA) of the knee, when given in addition to usual analgesia?”
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Protection of trial subjects |
Participants were recruited via a range of opt-in strategies to protect confidentiality and prevent unwanted contact. Informed consent was sought after ample time for participants to ask questions prior to engaging in trial procedures.
Participants were enrolled only if they met inclusion and exclusion criteria designed to minimize risk from the IMP - in particular screening checks on renal function, sodium and potassium were conducted, and concomitant use of medications likely to exacerbate side effects of spironolactone (ie ACEi, ARB, NSAID) were exclusion criteria
Frequent checks on blood pressure, renal function and electrolytes were conducted during the trial, and adverse events were sought at each study visit. A DMC was convened to review safety data during the trial.
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Background therapy |
Usual analgesic therapy was allowed during the trial as per normal clinical practice. Participants using NSAID medications were excluded from the trial due to the increased risk of interaction with spironolactone. | ||
Evidence for comparator |
Placebo was selected as comparator as the aim of the trial was to test the efficacy of spironolactone as add-on therapy to usual analgesics, rather than as a replacement for usual analgesia. Aldosterone is known to have pro-inflammatory effects, including stimulation of cytokine production, which might contribute to the low-level chronic inflammation seen in osteoarthritis. Spironolactone, as a blocker of aldosterone, might therefore be able to reverse this process. Data from a previous trial of spironolactone in older, functionally impaired people suggested an improvement in quality of life and a reduction in pain in the subgroup of participants with osteoarthritis (Am J Med 2013;126:590-7). This previous result provided the evidence that initiated this trial. | ||
Actual start date of recruitment |
01 Nov 2013
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Long term follow-up planned |
No
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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 |
United Kingdom: 86
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Worldwide total number of subjects |
86
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EEA total number of subjects |
86
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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) |
0
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From 65 to 84 years |
77
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85 years and over |
9
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Recruitment
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Recruitment details |
Recruited from primary care via Scottish Primary care research network; via advertising; via SHARE register | |||||||||
Pre-assignment
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Screening details |
Telephone prescreen, then screening visit to check eligibility criteria. Renal function and potassium checked at screening visit | |||||||||
Period 1
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Period 1 title |
Randomised treatment (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 |
Matching IMP and placebo (overencapsulated IMP) prepared by an independent provider (Tayside Pharmaceuticals), dispensed in identical bottles with no external indication of allocation group.
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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 |
Oral spironolactone 25mg once daily | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Spironolactone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
25mg once daily for 12 weeks
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Arm title
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Placebo | |||||||||
Arm description |
Matching placebo taken once a day for 12 weeks | |||||||||
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 |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo capsule taken orally once per day for 12 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Oral spironolactone 25mg once daily | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo taken once a day for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT analysis set
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomised participants (Intention to treat)
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End points reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Oral spironolactone 25mg once daily | ||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo taken once a day for 12 weeks | ||
Subject analysis set title |
ITT analysis set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomised participants (Intention to treat)
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End point title |
WOMAC pain subscale | ||||||||||||||||
End point description |
Unadjusted
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End point type |
Primary
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End point timeframe |
Change between baseline and 12 weeks
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Statistical analysis title |
Primary outcome analysis | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusting for baseline values and for site
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.19 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.53
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.27 | ||||||||||||||||
upper limit |
1.33 |
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End point title |
WOMAC stiffness subscale | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Change from baseline to 12 weeks
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Statistical analysis title |
Secondary outcome | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusting for baseline values and site
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.58 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||
Point estimate |
0.24
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.64 | ||||||||||||||||
upper limit |
1.13 |
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End point title |
WOMAC physical function subscale | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Change between baseline and 12 weeks
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Statistical analysis title |
Secondary outcome | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusted for baseline values and site
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.98 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.01
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.74 | ||||||||||||||||
upper limit |
0.76 |
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End point title |
EuroQol EQ5D | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Difference between baseline and 12 weeks
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Statistical analysis title |
Secondary outcome | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusted for baseline values, site and use of neuropathic drugs
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.34 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.04
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.04 | ||||||||||||||||
upper limit |
0.12 |
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End point title |
EuroQol EQ5D visual analog scale | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Change from baseline to 12 weeks
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Statistical analysis title |
Secondary analysis | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusted for baseline values, site and use of neuropathic drugs
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.78 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-0.86
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-6.9 | ||||||||||||||||
upper limit |
5.19 |
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End point title |
Urine CTX II | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Change between baseline and 12 weeks
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Statistical analysis title |
Secondary outcome | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusted for baseline values and site
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.69 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.21
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.83 | ||||||||||||||||
upper limit |
1.24 |
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End point title |
Serum matrix metalloproteinase 3 | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Difference between baseline and 12 weeks
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Statistical analysis title |
Secondary outcome | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusted for baseline values and site
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.46 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-1.98
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-7.32 | ||||||||||||||||
upper limit |
3.36 |
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End point title |
Morning cortisol | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Difference between baseline and 12 weeks
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Statistical analysis title |
Secondary outcome | ||||||||||||||||
Statistical analysis description |
Between-group mixed-model regression, adjusted for baseline values and site
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.47 | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
6.04
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-10.66 | ||||||||||||||||
upper limit |
22.73 |
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Adverse events information
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Timeframe for reporting adverse events |
screening visit to 12 week (final) visit
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
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Reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Oral spironolactone 25mg once daily | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo taken once a day for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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26 Sep 2013 |
Clarification of Safety assessment procedures. |
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27 Jan 2014 |
Addition of an exclusion criterion. |
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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/26413749 |