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    Clinical Trial Results:
    Influenza vaccination After Myocardial Infarction (IAMI trial). A multicenter, prospective, randomized controlled clinical trial based on national angiography and angioplasty registries

    Summary
    EudraCT number
    		 2014-001354-42
    Trial protocol
    		 SE   DK   LV   CZ   NO   GB  
    Global end of trial date
    02 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Sep 2022
    First version publication date
    28 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IAMI-2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02831608
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Örebro University Hospital
    Sponsor organisation address
    Södra Grev Rosengatan, Örebro, Sweden, 70185
    Public contact
    Department of Cardiology, Örebro University Hospital, 46 19 602 10 00, ole.frobert@regionorebrolan.se
    Scientific contact
    Department of Cardiology, Örebro University Hospital, 46 19 602 10 00, ole.frobert@regionorebrolan.se
    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
    02 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    In a multicenter, prospective, randomized registry-based controlled clinical trial based on the SCAAR and SWEDEHEART platforms and other national registries in the participating countries to compare influenza vaccination and placebo in reducing future major adverse cardiac and cerebrovascular events in patients with myocardial infarction or stable coronary artery disease and an increased risk of future cardiovascular events.
    Protection of trial subjects
    The study was conducted in compliance with the protocol, regulatory requirements, good clinical practice (GCP) and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the World Medical Association.
    Background therapy
    		 All patients in the study received guideline-directed medical therapy without restrictions for myocardial infarction/chronic ischemic heart disease. Information of medical therapy at baseline was not recorded. Heart disease-relevant medications at discharge for the two treatment groups was recorded.
    Evidence for comparator
    		 Because influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention cardiovascular guidelines, it could be considered controversial to conduct a randomized clinical trial in which half of the patients received placebo. However, current guidelines are based mostly on evidence from observational studies, timing of influenza vaccination following an acute cardiovascular event is unknown, and influenza immunization rates remain low. In the IAMI study only patients not routinely receiving yearly influenza vaccination and not planning to be vaccinated during the current influenza season could be enrolled. Also, participants were allowed to obtain influenza vaccination after study enrollment on their own behalf.
    Actual start date of recruitment
    11 Oct 2016
    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
    Australia: 47
    Country: Number of subjects enrolled
    Bangladesh: 620
    Country: Number of subjects enrolled
    Norway: 21
    Country: Number of subjects enrolled
    Sweden: 999
    Country: Number of subjects enrolled
    United Kingdom: 162
    Country: Number of subjects enrolled
    Czechia: 110
    Country: Number of subjects enrolled
    Denmark: 574
    Country: Number of subjects enrolled
    Latvia: 38
    Worldwide total number of subjects
    2571
    EEA total number of subjects
    1742
    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)
    1694
    From 65 to 84 years
    833
    85 years and over
    44

    Subject disposition

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    Recruitment
    Recruitment details
    		 From October 11, 2016, to March 1, 2020, 6696 patients were screened, of whom 2571 provided written informed consent and underwent randomization; 2532 received influenza vaccination or placebo and were included in the modified intention-to-treat analysis.

    Pre-assignment
    Screening details
    		 6696 patients were screened, of whom 2571 provided written informed consent and underwent randomization. 4125 patients were not enrolled, due to the following reasons: already vaccinated or intending vaccination (N=1439), patient declined (N=1202), patient not eligible (N=580), other medical reason (N=430), logistical reasons (N=326), other (N=148)

    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, Carer, Assessor
    Blinding implementation details
    According to randomization, The IMP or placebo was prepared by an unblinded study nurse at each center, not otherwise involved or participating in the study. To ascertain blinding, the nurse could lay a piece of foil around the syringe to ensure that the patient could not see what was administered during the vaccination.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vaccine
    Arm description
    		 Subjects randomized to receive a single dose of influenza vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    VaxigripTetra
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Injection , Subcutaneous use
    Dosage and administration details
    0.5 mL suspension for injection administered as a subcutaneous injection in a single dose.

    Arm title
    		 Placebo
    Arm description
    		 Subjects randomized to receive a single dose of placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Subcutaneous use
    Dosage and administration details
    0.5 mL solution for injection administered as a subcutaneous injection in a single dose.

    Number of subjects in period 1
    		Vaccine Placebo
    Started
    1290
    1281
    Randomization
    1290
    1281
    Treatment
    1272
    1260
    Completed
    1272
    1260
    Not completed
    18
    21
         Consent withdrawn by subject
    11
    10
         Transferred
    4
    3
         Other
    -
    3
         Incorrectly randomized
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vaccine
    Reporting group description
    		 Subjects randomized to receive a single dose of influenza vaccine

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized to receive a single dose of placebo

    Reporting group values
    		 Vaccine Placebo Total
    Number of subjects
    		 1290 1281 2571
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age is reported for the subjects included in the m-ITT analysis, defined as all randomized patients according to their randomized treatment assignment and who received the study medication. Total number of subjects: 2532 Arm 1, Vaccine: 1272 Arm 2, Placebo: 1260
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ( 11.0 ) 59.6 ( 11.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 236 226 462
        Male
    		 1036 1034 2070
        Not reported
    		 18 21 39
    Diagnosis at inclusion
    Units: Subjects
        ST-segment elevation myocardial infarction
    		 665 683 1348
        Non-ST-segment elevation myocardial infarction
    		 568 551 1119
        Stable coronary artery disease
    		 6 2 8
        Not reported
    		 51 45 96
    Diabetes
    Units: Subjects
        Yes
    		 281 247 528
        No
    		 972 1007 1979
        Not reported
    		 37 27 64
    Smoking status
    Units: Subjects
        Never smoked
    		 463 461 924
        Former smoker
    		 332 328 660
        Current smoker
    		 437 433 870
        Not reported
    		 58 59 117
    Hyperlipidemia
    Units: Subjects
        Yes
    		 427 409 836
        No
    		 830 840 1670
        Not reported
    		 33 32 65
    Hypertension
    Units: Subjects
        Yes
    		 650 595 1245
        No
    		 601 656 1257
        Not reported
    		 39 30 69
    Previous myocardial infarction
    Units: Subjects
        Yes
    		 191 172 363
        No
    		 1062 1077 2139
        Not reported
    		 37 32 69
    Previous percutaneous coronary intervention
    Units: Subjects
        Yes
    		 138 129 267
        No
    		 1119 1128 2247
        Not reported
    		 33 24 57
    Previous coronary artery bypass grafting
    Units: Subjects
        Yes
    		 28 37 65
        No
    		 1230 1220 2450
        Not reported
    		 32 24 56
    Killip class ≥2
    Units: Subjects
        Yes
    		 50 45 95
        No
    		 1107 1110 2217
        Not reported
    		 133 126 259
    Number of diseased vessels
    Units: Subjects
        Normal
    		 33 27 60
        1-vessel disease
    		 546 590 1136
        2-vessel disease
    		 268 228 496
        3-vessel disease
    		 148 148 296
        Left main disease
    		 67 57 124
        Not reported
    		 228 231 459
    Body mass index
    Body-mass index is based on data reported for 1207 subjects in the vaccine group and 1201 subjects in the placebo group.
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 27.5 ( 5.0 ) 27.4 ( 5.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Vaccine
    Reporting group description
    		 Subjects randomized to receive a single dose of influenza vaccine

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized to receive a single dose of placebo

    Primary: All-cause death, myocardial infarction, stent thrombosis

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    End point title
    		 All-cause death, myocardial infarction, stent thrombosis
    End point description
    The primary end point was the composite of all-cause death, MI, or stent thrombosis at 12 months after randomization, assessed during a telephone interview with participants or next of kin. If the patient or relatives could not be contacted, information was collected through review of hospital records. Definitions: - Death: All reasons for death, i.e. cardiac, non-cardiac or unknown. - Myocardial infarction: ICD codes I21, I21.4 and I22, heart failure as I50 and stroke as I63.9. - New PCIs and stent thromboses are followed in SCAAR and the other national PCI registries.
    End point type
    Primary
    End point timeframe
    Primary endpoint was measured at 1 year after treatment.
    End point values
    		 Vaccine Placebo
    Number of subjects analysed
    1272
    1260
    Units: subjects
    67
    91
    Statistical analysis title
    		 Primary endpoint
    Comparison groups
    Vaccine v Placebo
    Number of subjects included in analysis
    2532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.99

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reporting of AE started after informed consent and when treatment with study medication had been given and continued until the patient left the hospital after the coronary angiography/PCI procedure up to a minimum of 7 days following influenza vaccination
    Adverse event reporting additional description
    Medical occurrences that were symptoms of existing disease, including exacerbations, or the PCI procedure were not defined as AE’s. Also elective hospitalisations for pre-treatment conditions were not AE’s nor expected reactions to vaccinations. AEs not to be reported were also those defined as study endpoints.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Vaccine
    Reporting group description
    		 Subjects randomized to receive a single dose of influenza vaccine

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized to receive a single dose of placebo

    Serious adverse events
    		 Vaccine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1272 (0.00%)
    0 / 1260 (0.00%)
         number of deaths (all causes)
    37
    61
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0.2%
    Non-serious adverse events
    		 Vaccine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 1272 (2.36%)
    16 / 1260 (1.27%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 1272 (0.31%)
    0 / 1260 (0.00%)
         occurrences all number
    4
    0
    Headache
         subjects affected / exposed
    2 / 1272 (0.16%)
    2 / 1260 (0.16%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1272 (0.00%)
    2 / 1260 (0.16%)
         occurrences all number
    0
    2
    Cholecystitis
         subjects affected / exposed
    0 / 1272 (0.00%)
    2 / 1260 (0.16%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 1272 (0.16%)
    0 / 1260 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    2 / 1272 (0.16%)
    0 / 1260 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Sore injection site
         subjects affected / exposed
    5 / 1272 (0.39%)
    1 / 1260 (0.08%)
         occurrences all number
    5
    1
    Urticaria
         subjects affected / exposed
    4 / 1272 (0.31%)
    1 / 1260 (0.08%)
         occurrences all number
    4
    1
    Pruritus
         subjects affected / exposed
    2 / 1272 (0.16%)
    2 / 1260 (0.16%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Chest pain
         subjects affected / exposed
    2 / 1272 (0.16%)
    2 / 1260 (0.16%)
         occurrences all number
    2
    2
    Myalgia
         subjects affected / exposed
    2 / 1272 (0.16%)
    1 / 1260 (0.08%)
         occurrences all number
    2
    1
    Infections and infestations
    Fever
         subjects affected / exposed
    3 / 1272 (0.24%)
    2 / 1260 (0.16%)
         occurrences all number
    3
    2
    Pneumonia
         subjects affected / exposed
    2 / 1272 (0.16%)
    1 / 1260 (0.08%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    Study protocol, Version 6.0: • Changed timeframes for vaccination from 42 hours following coronary angiography/PCI (NSTEMI and STEMI patients) to 72 hours to optimize compliance and facilitate the implementation of the study. • Clarification regarding unblinding
    11 Sep 2017
    Study protocol, Version 7.0: • Change of study title from Swedish national registries to national registries • Change of vaccine from Vaxigrip to VaxigripTetra and from Sanofi Pasteur MSD to Sanofi Pasteur Europe • Additional countries and sites • Clarification of exclusion criteria • Change in timeframe for enrolment and vaccination from 24 hours prior to coronary angiography/PCI (NSTEMI patients) up to 72 hours following coronary angiography/PCI for both NSTEMI and STEMI patients • Clarification that Informed consent shall be obtained by a medical doctor participating in the study. • Change in timeframe for vaccination (24 hours prior to coronary angiography/PCI (NSTEMI patients) since there is a risk that complications that arise after the procedure may be difficult to derive from the procedure itself or for study treatment, so no vaccination performed before coronary angiography/PCI procedure.
    10 Jul 2018
    Study protocol, Version 8.0: • Change in study period • Change in exclusion criteria
    11 Oct 2018
    Study protocol, Version 9.0: • Prolonged study period, inclusion to 2021 and follow up (exploratory endpoints) to 2026 • Additional study population, patients with stable coronary artery disease and an increased risk of future cardiovascular events. • Additional inclusion criteria; Patients with stable coronary artery disease ≥75 years of age undergoing angiography/PCI AND with at least one additional risk criterion • Addition that primay endpoints also can be obtained by telephone interviews and hospital records not only from national health registries, • Clarifications regarding secondary endpoints • Clarification regarding randomization in study-specific online Web-system for non-Swedish centers. • Addition that all endpoints will be adjudicated according to a separate Adjudication Charter. • Addition of text regarding additional study population

    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.
    Due to the COVID-19 pandemic, the DSMB decided on April 7 2020, to recommend a halt of the inclusion, since transmission of influenza was expected to decrease, and COVID-19 related deaths were deemed likely to make the results difficult to interpret.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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