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    Clinical Trial Results:
    Aspirin for Optimising Pregnancy Outcome in Pregestational Diabetes: Pilot for The IRELAND Study (Investigating the Role of Early Low-dose Aspirin iN preexisting Diabetes)

    Summary
    EudraCT number
    2014-001332-11
    Trial protocol
    IE  
    Global end of trial date
    06 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Apr 2020
    First version publication date
    04 Apr 2020
    Other versions
    Summary report(s)
    EudraCT 2014-001332-11 Clinical Trial Report Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    IRELANDPILOTV1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Royal College of Surgeons Ireland
    Sponsor organisation address
    111 St Stephens Green, Dublin, Ireland, Dublin 2
    Public contact
    Mandy Jackson, Royal College of Surgeons, 00353 18093863, mandyjackson@rcsi.ie
    Scientific contact
    Mandy Jackson, Royal College of Surgeons, 00353 18093863, mandyjackson@rcsi.ie
    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
    06 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The definitive IRELAND Study aims to investigate whether low-dose aspirin prescribed routinely to woman with pre-existing diabetes, initiated at 8+0 – 12 weeks’ gestation and continued until 36 weeks gestation may modify the risk of adverse perinatal outcomes related to placental dysfunction. The purpose of the pilot phase of this study is to determine rates of patient participation and compliance with aspirin therapy throughout pregnancy in this high-risk population. Primary objectives: 1. Proportion of eligible women who agree to participate in the pilot study. 2. Compliance with the study protocol, as judged by platelet function monitoring 3. Proportion of study participants who complete the study, with complete ascertainment of laboratory markers of glycaemic control, renal function and platelet function at all scheduled timepoints
    Protection of trial subjects
    Not applicable
    Background therapy
    Not applicable
    Evidence for comparator
    The comparator group was a non treated (no aspirin) control group. The rationale for this control group is based on the lack of evidenced based recommendations (see NICE, RCOG, ACOG, HSE) for the use of aspirin in pregnant women with diabetes.
    Actual start date of recruitment
    26 May 2015
    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
    Ireland: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    24 subjects signed consent with one subject withdrawing consent prior to randomisation so 23 subjects were enrolled. Subjects were recruited from two maternity hospitals in Ireland. The first subject was recruited on 26-May-2015.

    Pre-assignment
    Screening details
    40 subjects were screened. 16 of these patients screen failed due to reasons including; miscarriage before 12 weeks gestation, difficultly communicating in English, taking Aspirin in the first trimester before the recruitment phase, twin pregnancies, screening after 12 weeks gestation and diagnoses of diabetes < 6 months prior to recruitment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The trial was open label. No blinding of either the research participant or of the investigator occurred. Both the research participant and the investigator were aware of the investigational medicinal product that the research participant was allocated to receive.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Aspirin arm
    Arm description
    Aspirin therapy 75mg daily commencing after a satisfactory 1st trimester assessment, to include sonographic confirmation of fetal cardiac activity followed by 4-weekly blood draws for platelet function (dynamic platelet assay), serum fructosamine and renal profile, with quantification of microalbuminuria in each trimester(aspirin arm). Prenatal care will be delivered through the Combined Obstetric Endocrine service. Aspirin was provided free of charge to the patient.
    Arm type
    Experimental

    Investigational medicinal product name
    Aspirin (Acetylsalicylic acid) 75mg
    Investigational medicinal product code
    ATC code: B01A C06
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Arm 1: Aspirin Therapy: Aspirin 75mg daily commenced after satisfactory routine first trimester assessments, to include sonographic confirmation of foetal cardiac activity. Monthly blood was drawn during pregnancy up to week 36 for platelet function, serum fructosamine, and renal profile, with quantification of microalbuminuria in first and third trimester. Prenatal care was delivered as standard through the Combined Obstetric Endocrine service. Aspirin was provided free of charge to the participants through the local pharmacy in the hospital

    Arm title
    Control arm
    Arm description
    Arm 2: Control Group: No aspirin therapy. Monthly blood was drawn during pregnancy up to week 36 for platelet function, serum fructosamine, and renal profile, with quantification of microalbuminuria in first and third trimester. Prenatal care was delivered as standard through the Combined Obstetric Endocrine service.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Aspirin arm Control arm
    Started
    13
    10
    Data Safety Monitoring Board Meeting
    13
    10
    Completed
    13
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aspirin arm
    Reporting group description
    Aspirin therapy 75mg daily commencing after a satisfactory 1st trimester assessment, to include sonographic confirmation of fetal cardiac activity followed by 4-weekly blood draws for platelet function (dynamic platelet assay), serum fructosamine and renal profile, with quantification of microalbuminuria in each trimester(aspirin arm). Prenatal care will be delivered through the Combined Obstetric Endocrine service. Aspirin was provided free of charge to the patient.

    Reporting group title
    Control arm
    Reporting group description
    Arm 2: Control Group: No aspirin therapy. Monthly blood was drawn during pregnancy up to week 36 for platelet function, serum fructosamine, and renal profile, with quantification of microalbuminuria in first and third trimester. Prenatal care was delivered as standard through the Combined Obstetric Endocrine service.

    Reporting group values
    Aspirin arm Control arm Total
    Number of subjects
    13 10 23
    Age categorical
    Units: Subjects
    Age continuous
    Age was equally distributed between both groups. Mean age was 32 years with minimum of 18 and maximum of 42 years.
    Units: years
        arithmetic mean (full range (min-max))
    32 (18 to 42) 32 (18 to 42) -
    Gender categorical
    Units: Subjects
        Female
    13 10 23
        Male
    0 0 0
    Ethnicity
    The total enrolled subjects (n=23) can be divided into 3 ethnicities; Asian, African and Caucasian
    Units: Subjects
        Asian
    3 2 5
        African
    2 0 2
        Caucasian
    8 8 16
    Diabetes Type
    Units: Subjects
        Type 1
    6 5 11
        Type 2
    7 5 12

    End points

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    End points reporting groups
    Reporting group title
    Aspirin arm
    Reporting group description
    Aspirin therapy 75mg daily commencing after a satisfactory 1st trimester assessment, to include sonographic confirmation of fetal cardiac activity followed by 4-weekly blood draws for platelet function (dynamic platelet assay), serum fructosamine and renal profile, with quantification of microalbuminuria in each trimester(aspirin arm). Prenatal care will be delivered through the Combined Obstetric Endocrine service. Aspirin was provided free of charge to the patient.

    Reporting group title
    Control arm
    Reporting group description
    Arm 2: Control Group: No aspirin therapy. Monthly blood was drawn during pregnancy up to week 36 for platelet function, serum fructosamine, and renal profile, with quantification of microalbuminuria in first and third trimester. Prenatal care was delivered as standard through the Combined Obstetric Endocrine service.

    Subject analysis set title
    Overall
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Overall number of women who agreed to participate in the trial.

    Primary: proportion of women who agree to participate in the study

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    End point title
    proportion of women who agree to participate in the study [1]
    End point description
    This endpoint was assessed by counting the number of women who were approached to take part in the study, the number who agreed to take part and the number who dropped out or were subsequently included on an intention to treat basis only.
    End point type
    Primary
    End point timeframe
    4 month period
    Notes
    [1] - 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: This is a pilot study and so no statistical analysis (e.g. hypothesis tests) were performed.
    End point values
    Overall
    Number of subjects analysed
    23
    Units: number of women
        No. of women approached for participation
    47
        No. of women who agreed to participate
    23
        No. of women who dropped out or included in ITT
    2
    Attachments
    Endpoint 1 supporting extract from final report
    No statistical analyses for this end point

    Primary: compliance with study protocol

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    End point title
    compliance with study protocol [2]
    End point description
    Compliance with the study protocol – assessing the number of patients who underwent all designated assessments as outlined within the designated time period for set assessments as specified in the study protocol
    End point type
    Primary
    End point timeframe
    6-8 months
    Notes
    [2] - 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: This is a pilot study and so no statistical analysis (e.g. hypothesis tests) were performed.
    End point values
    Overall
    Number of subjects analysed
    Units: Subjects
    23
    Attachments
    Endpoint 2 supporting extract from final report
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All Adverse Events occurring during the study observed by the investigator or reported by the subject were captured from Visit 1 until the post delivery visit.
    Adverse event reporting additional description
    All Adverse Events occurring during the study observed by the investigator or reported by the subject, whether or not attributed to the study medication were recorded on the Case Report Form and all Serious Adverse Events were reported to the Sponsor within 24 hours of the site's knowledge of the event except for the non-reportable events
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Aspirin Group
    Reporting group description
    Subjects exposed to Aspirin

    Reporting group title
    Non-aspirin group
    Reporting group description
    Control group who were not exposed to aspirin

    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: Non-serious adverse events were not reported by the investigator in the final study report. A summary of the Serious Adverse Events that occurred during the trial have been provided.
    Serious adverse events
    Aspirin Group Non-aspirin group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 13 (92.31%)
    6 / 10 (60.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Intentional Product Misuse
    Additional description: Patient attended for visit 7 at 37+4 and was still taking aspirin. Patient discontinued at week 37+4 and delivered at week 38+2
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
    Additional description: Admitted for 24 urine collection and BP monitoring and PET bloods. PET bloods normal 24 hour urine collection normal.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal Death
    Additional description: Intrauterine death/late miscarriage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal hypokinesia
    Additional description: Patient previously lost 11stone and has gastric band in place. Reports reduced fetal movement Admitted for CTG which showed normal fetal activity
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum haemorrhage
    Additional description: 1000cc blood loss secondary to atonic uterus. No blood transfusion needed
         subjects affected / exposed
    4 / 13 (30.77%)
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
    Additional description: But 24 hours urinary protein collection was within normal range. Final diagnosis was Pregnancy Induced Hypertension
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal growth restriction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
    Additional description: Allergic reaction to Novorapid
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vulvovaginal pain
    Additional description: Admitted with vaginal pain candidias diagnosed. Pt prescribed antifungal and discharged.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
    Additional description: Admitted for observation following history of PV bleed
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
    Additional description: Admitted with 24hr history of nausea, no diarrhoea. Subject was given IV stemetil and ranitidine FBC and U&E normal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: Admitted with 24hr history of vomiting no diarrhoea. Subject was given IV stemetil and ranitidine FBC and U&E normal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
    Additional description: Admitted from emergency room with sore throat and started on antibiotics
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis of pregnancy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    Additional description: Left leg pain from calf radiating to the groin for 1 day. Subject described pain as sharp pain rated 8/10. Subject was given Innohep as a precaution and sent for scan at a nearby hospital. No DVT was observed.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Aspirin Group Non-aspirin group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2016
    The protocol Version 3, dated 29-Jan-2015 was substantially amended to Version 4, dated 18-Jul-2016 to include a list of non-reportable adverse events. The protocol safety reporting section 12.1 was amended to list events anticipated in pregnancy as non-reportable events unless deemed by clinicians and/or investigators to occur to a disproportionate degree. These events are considered to be ‘normal and expected’ occurrences for the patient population and in particular were not influenced by the administration of aspirin. Treatment of these symptoms was as per clinical guidelines. The following events were listed in the protocol as not requiring reporting:  Nausea/ vomiting prior to 14 weeks’ gestational age  Hospitalisation for labour and delivery  Poor glycaemic control  Hospitalisation for poor glycaemic control  Pelvic girdle dysfunction  Indigestion  Fatigue  Constipation  Shortness of breath  Urinary frequency/ nocturia  Migraine and tension headache  Nosebleeds and bleeding gums  Varicose veins  Haemorrhoids  Back pain  Palpitations  Carpal tunnel syndrome  Fetal normal variants on ultrasound: Pyelectasis, choroid plexus cysts, echogenic intracardiac focus

    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
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