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    Clinical Trial Results:
    CLEAR SYNERGY (OASIS 9) A 2x2 factorial randomized controlled trial of CoLchicine and spironolactonE in patients with ST elevation myocARdial infarction/SYNERGY Stent Registry –Organization to Assess Strategies for Ischemic Syndromes 9

    Summary
    EudraCT number
    		 2017-000487-15
    Trial protocol
    		 ES   FI   CZ   NL   HU  
    Global end of trial date
    09 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2025
    First version publication date
    09 Apr 2025
    Other versions
    Summary report(s)
    		 OASIS_NEJM 2024
    OASIS_NEJM Spiro

    Trial information

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    Trial identification
    Sponsor protocol code
    CLSYN.1702
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03048825
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Population Health Research Institute (PHRI)
    Sponsor organisation address
    237 Barton Street East ON L8L 2x2 Hamilton (Canadá), Hamilton, Ontario, Canada,
    Public contact
    CLEAR SYNERGY Project Office, Population Health Research Institute, 1 9055274322 x41079, clear@phri.ca
    Scientific contact
    CLEAR SYNERGY Project Office, Population Health Research Institute, 1 9055274322 x41079, clear@phri.ca
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Nov 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Aug 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To determine the rate of major adverse cardiac events (MACE) in STEMI patients who have received a SYNERGY everolimus eluting stent compared to performance goal. 2. To determine if colchicine can reduce the incidence of cardiovascular (CV) death, myocardial infarction (MI), or stroke. 3. To determine if spironolactone can reduce the incidence of cardiovascular death or new or worsening heart failure.
    Protection of trial subjects
    After the first 90 days of treatment, all patients received the trial product once a day. However, after blinded interim analyses showed higher-than-expected rates of discontinuation and the Colchicine Cardiovascular Outcomes Trial (COLCOT) showed efficacy with once-daily colchicine, the steering committee adopted the regimen of once-daily colchicine at a dose of 0.5 mg or matching placebo throughout the remainder of the treatment period, beginning in September 2020
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Egypt: 143
    Country: Number of subjects enrolled
    Canada: 1860
    Country: Number of subjects enrolled
    Australia: 59
    Country: Number of subjects enrolled
    United States: 162
    Country: Number of subjects enrolled
    Switzerland: 93
    Country: Number of subjects enrolled
    Nepal: 123
    Country: Number of subjects enrolled
    Serbia: 507
    Country: Number of subjects enrolled
    North Macedonia: 2589
    Country: Number of subjects enrolled
    Netherlands: 487
    Country: Number of subjects enrolled
    Spain: 374
    Country: Number of subjects enrolled
    United Kingdom: 413
    Country: Number of subjects enrolled
    Czechia: 86
    Country: Number of subjects enrolled
    France: 126
    Country: Number of subjects enrolled
    Hungary: 40
    Worldwide total number of subjects
    7062
    EEA total number of subjects
    1113
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    4395
    From 65 to 84 years
    2589
    85 years and over
    78

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between February 1, 2018, and November 8, 2022, we enrolled 7062 patients from 104 centers in 14 countries; 3528 patients were assigned to receive colchicine and 3534 to receive placebo. 3537 were assigned to receive spironolactone and 3525 to receive placebo.

    Pre-assignment
    Screening details
    		 Patients were randomly assigned in a factorial 1:1:1:1 allocation to receive spironolactone and colchicine, colchicine and placebo, spironolactone and placebo, or placebo only as soon as possible after the index percutaneous coronary intervention. Randomization was stratified according the type of myocardial infarction: STEMI or NSTEMI.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Colchine
    Arm description
    		 Colchine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Colchine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Colchicine tablets of 0.5 mg

    Arm title
    		 Placebo
    Arm description
    		 Placebo vs Colchine
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets of 0.5 mg

    Arm title
    		 Spironolactone
    Arm description
    		 Spironolactone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Spironolactone tablets of 25 mg

    Arm title
    		 Placebo
    Arm description
    		 Placebo vs Spironolactone
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets of 25 mg

    Number of subjects in period 1
    		Colchine Placebo Spironolactone Placebo
    Started
    3528
    3534
    3537
    3525
    Completed
    3517
    3523
    3526
    3513
    Not completed
    11
    11
    11
    12
         Lost to follow-up
    11
    11
    11
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Colchine
    Reporting group description
    		 Colchine

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo vs Colchine

    Reporting group title
    Spironolactone
    Reporting group description
    		 Spironolactone

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo vs Spironolactone

    Reporting group values
    		 Colchine Placebo Spironolactone Placebo Total
    Number of subjects
    		 3528 3534 3537 3525 7062
    Age categorical
    Units: Subjects
        18-64 years
    		 2202 2193 2161 2234 4395
        From 65-84 year
    		 1296 1293 1333 1256 2589
        85 years and over
    		 30 48 43 35 78
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.6211305 ( 10.3297764 ) 60.6500288 ( 10.3235369 ) 60.8817807 ( 10.3477658 ) 60.3885651 ( 10.2995335 ) -
    Gender categorical
    Units: Subjects
        Female
    		 725 713 760 678 1438
        Male
    		 2803 2821 2777 2847 5624
    Subject analysis sets

    Subject analysis set title
    Colchicine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    At the beginning of the trial, colchicine dosage was based on weight for the first 90 days of treatment; patients weighing 70 kg or more received a dose of 0.5 mg of colchicine or matching placebo twice a day, and patients weighing less than 70 kg received a dose of 0.5 mg or matching placebo once a day. After the first 90 days of treatment, all patients received the trial product once a day

    Subject analysis set title
    Spironolactone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    We used a 2-by-2 factorial design in this international, investigator-initiated, prospective, randomized, placebo-controlled trial of spironolactone as compared with placebo and colchicine as compared with placebo in patients with acute myocardial infarction.

    Subject analysis set title
    Placebo (vs Colchine)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    At the beginning of the trial, colchicine dosage was based on weight for the first 90 days of treatment; patients weighing 70 kg or more received a dose of 0.5 mg of colchicine or matching placebo twice a day, and patients weighing less than 70 kg received a dose of 0.5 mg or matching placebo once a day. After the first 90 days of treatment, all patients received the trial product once a day

    Subject analysis set title
    Placebo (vs Spironolactone)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    We used a 2-by-2 factorial design in this international, investigator-initiated, prospective, randomized, placebo-controlled trial of spironolactone as compared with placebo and colchicine as compared with placebo in patients with acute myocardial infarction.

    Subject analysis sets values
    		 Colchicine Spironolactone Placebo (vs Colchine) Placebo (vs Spironolactone)
    Number of subjects
    3528
    3537
    3534
    3525
    Age categorical
    Units: Subjects
        18-64 years
    2202
    2161
    2193
    2234
        From 65-84 year
    1296
    1333
    1293
    1256
        85 years and over
    30
    43
    48
    35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.6211305 ( 10.3297764 )
    60.8817807 ( 10.3477658 )
    60.6500288 ( 10.3235369 )
    60.3885651 ( 10.2995335 )
    Gender categorical
    Units: Subjects
        Female
    725
    760
    713
    678
        Male
    2803
    2777
    2821
    2847

    End points

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    End points reporting groups
    Reporting group title
    Colchine
    Reporting group description
    		 Colchine

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo vs Colchine

    Reporting group title
    Spironolactone
    Reporting group description
    		 Spironolactone

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo vs Spironolactone

    Subject analysis set title
    Colchicine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    At the beginning of the trial, colchicine dosage was based on weight for the first 90 days of treatment; patients weighing 70 kg or more received a dose of 0.5 mg of colchicine or matching placebo twice a day, and patients weighing less than 70 kg received a dose of 0.5 mg or matching placebo once a day. After the first 90 days of treatment, all patients received the trial product once a day

    Subject analysis set title
    Spironolactone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    We used a 2-by-2 factorial design in this international, investigator-initiated, prospective, randomized, placebo-controlled trial of spironolactone as compared with placebo and colchicine as compared with placebo in patients with acute myocardial infarction.

    Subject analysis set title
    Placebo (vs Colchine)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    At the beginning of the trial, colchicine dosage was based on weight for the first 90 days of treatment; patients weighing 70 kg or more received a dose of 0.5 mg of colchicine or matching placebo twice a day, and patients weighing less than 70 kg received a dose of 0.5 mg or matching placebo once a day. After the first 90 days of treatment, all patients received the trial product once a day

    Subject analysis set title
    Placebo (vs Spironolactone)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    We used a 2-by-2 factorial design in this international, investigator-initiated, prospective, randomized, placebo-controlled trial of spironolactone as compared with placebo and colchicine as compared with placebo in patients with acute myocardial infarction.

    Primary: Death from cardiovascular causes or new or worsening heart failure

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    End point title
    		 Death from cardiovascular causes or new or worsening heart failure
    End point description
    End point type
    Primary
    End point timeframe
    The median time from symptom onset to randomization was 26.8 hours (interquartile range, 15.9 to 42.4), and the median time from randomization to the first dose of the trial product was 1.6 hours (interquartile range, 0.6 to 7.4)
    End point values
    		 Colchine Placebo Spironolactone Placebo Colchicine Spironolactone Placebo (vs Colchine) Placebo (vs Spironolactone)
    Number of subjects analysed
    3528
    3534
    3537
    3525
    3528
    3537
    3534
    3525
    Units: number
    322
    327
    183
    220
    322
    183
    327
    220
    Statistical analysis title
    		 Primary-outocome
    Comparison groups
    Colchine v Placebo
    Number of subjects included in analysis
    7062
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.93
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
    Statistical analysis title
    		 Primary-outocome
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    7062
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.51
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval

    Primary: Death from cardiovascular causes or new or worsening heart failure

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    End point title
    		 Death from cardiovascular causes or new or worsening heart failure
    End point description
    End point type
    Primary
    End point timeframe
    The median time from symptom onset to randomization was 26.8 hours (interquartile range, 15.9 to 42.4), and the median time from randomization to the first dose of the trial product was 1.6 hours (interquartile range, 0.6 to 7.4)
    End point values
    		 Colchine Placebo Spironolactone Placebo Colchicine Spironolactone Placebo (vs Colchine) Placebo (vs Spironolactone)
    Number of subjects analysed
    3528
    3534
    3537
    3525
    3528
    3537
    3534
    3525
    Units: number
    322
    327
    183
    220
    322
    183
    327
    220
    Statistical analysis title
    		 Primary outocme
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    7062
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.51
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
    Statistical analysis title
    		 Primary-outocome
    Comparison groups
    Colchine v Placebo
    Number of subjects included in analysis
    7062
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.93
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All SAEs were reported to the Sponsor by completing the SAE CRF within 24 hours of knowledge of the event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Colchinine vs Placebo
    Reporting group description
    		 -

    Reporting group title
    Spironolactone vs placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Colchinine vs Placebo Spironolactone vs placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 7062 (0.96%)
    59 / 7062 (0.84%)
         number of deaths (all causes)
    322
    183
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 7062 (0.00%)
    59 / 7062 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    59 / 59
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Serious adverse gastrointentinal event
         subjects affected / exposed
    68 / 7062 (0.96%)
    0 / 7062 (0.00%)
         occurrences causally related to treatment / all
    68 / 68
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Colchinine vs Placebo Spironolactone vs placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    594 / 7062 (8.41%)
    67 / 7062 (0.95%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 7062 (0.00%)
    67 / 7062 (0.95%)
         occurrences all number
    0
    67
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    594 / 7062 (8.41%)
    0 / 7062 (0.00%)
         occurrences all number
    594
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2019
    Approval Amendments Part I - Authorisation for new batches of Spinorolactone test batch 17C07O2A - 17C07P2A
    08 Jan 2021
    Protocol amendment v.5
    08 Nov 2023
    Protocol amendment v 6.0 Modification the study efficacy outcome definitions for colchicine and spironolactone arms and update outcome analysis accordingly. Updates to outcome event definitions for newly added outcome events of interest.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39555823
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