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    Summary
    EudraCT Number:2018-000770-29
    Sponsor's Protocol Code Number:Ireland-RctV8
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-06-11
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2018-000770-29
    A.3Full title of the trial
    Investigating the role of early low-dose aspirin in diabetes: A phase III multicentre double-blinded placebo-controlled randomised trial of low-dose aspirin initiated in the first trimester of diabetes pregnancy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Investigating the Role of Early Low-dose Aspirin in Diabetes
    A.3.2Name or abbreviated title of the trial where available
    IRELAnD
    A.4.1Sponsor's protocol code numberIreland-RctV8
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorThe Rotunda Hospital
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHealth Research Board
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoyal College of Surgeons in Ireland
    B.5.2Functional name of contact pointMuiris Dowling
    B.5.3 Address:
    B.5.3.1Street AddressRCSI 111 St Stephen’s Green
    B.5.3.2Town/ cityDublin
    B.5.3.3Post codeDublin 2
    B.5.3.4CountryIreland
    B.5.4Telephone number+353876245669
    B.5.6E-mailmauricedowling@rcsi.ie
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tromalyt
    D.2.1.1.2Name of the Marketing Authorisation holderMEDA PHARMA SL
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTromalyt
    D.3.2Product code 59,210
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNACETYLSALICYLIC ACID
    D.3.9.3Other descriptive nameAspirin
    D.3.9.4EV Substance CodeSUB12730MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number66 to 98
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pregestational type I or type II diabetes
    E.1.1.1Medical condition in easily understood language
    Pregnant women with type I or type II diabetes
    E.1.1.2Therapeutic area Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10045228
    E.1.2Term Type I diabetes mellitus
    E.1.2System Organ Class 100000004861
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10045242
    E.1.2Term Type II diabetes mellitus
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the effect of aspirin therapy initiated in the first trimester of pregnancy in women with pregestational type I or type II diabetes on a composite clinical measure of placental dysfunction (preeclampsia, preterm birth less than 34 weeks, birth weight below the 10th centile or perinatal mortality).
    E.2.2Secondary objectives of the trial
    a. Differences between the intervention and control groups will be measured for the following parameters of neonatal morbidity
    • Gestational age at delivery
    • Birth weight
    • NICU admission
    • Respiratory morbidity
    • Apgar score <7 at 5 minutes
    • Umbilical artery acidosis at birth (cord pH <7.2)
    • Interventricular haemorrhage
    • Culture-proven sepsis
    • Necrotising enterocolitis
    • Hypoxic ischaemic encephalopathy

    b. Differences between the aspirin and control groups will be measured for maternal outcomes not directly related to primary outcome, including:
    • Mode of delivery
    • Haemorrhage
    • Sepsis

    c. The effect of low-dose aspirin initiated in the first trimester of diabetes pregnancy on microalbuminuria will be evaluated
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Ability to comprehend the Patient Information Leaflet and to provide signed and dated informed consent.
    • Willing to comply with all study procedures and be available for the duration of the study
    • Female, age >18 years
    • Singleton pregnancy, ongoing at 11 – 13+6 weeks’ gestation
    • Pre-pregnancy diagnosis of type I or type II diabetes of at least 6 months’ duration
    • Fulfillment of each criterion must be clearly evidenced (in lab reports or correspondence) and/or documented in the medical records.
    E.4Principal exclusion criteria
    • Aspirin hypersensitivity (prior bronchospasm/ urticarial/ angioedema with aspirin)
    • Active or recurrent peptic ulceration (2 or more distinct episodes of proven ulceration or bleeding), repetitive gastric symptoms or history of intolerance of NSAIDs
    • Known bleeding diathesis (hypothrombinaemia, haemophilia, von Willebrands’ disease)
    • Multifetal gestation
    • Breastfeeding
    • Severe early-onset preeclampsia in a previous pregnancy
    • Patient already on aspirin at the time of screening
    • Established chronic renal disease (progressive loss of renal function of at least 3 months’ duration), clinically significant liver disorder, hyperuricemia (Gout), glucose-6-phosphate dehydrogenase (G6PD) deficiency or heart failure (This exclusion criterion will be assessed from patient’s medical history not from screening laboratory tests).
    • Blood clotting disorder or treatment with anticoagulants at the time of recruitment or with anti-platelet therapy (Anticoagulants commenced after recruitment will not constitute exclusion from the trial).
    • Macroalbuminuria (24-hour urinary protein 300g or greater, or spot urinary protein/creatinine ratio >0.3 in the first trimester or dipstick proteinuria >/= +2
    • Chronic hypertension (antihypertensive therapy in first trimester)
    • Inability to speak or read English
    • Use of any other medication that would constitute a risk to a patient taking aspirin in the opinion of the investigator ((including Interferon-α and Methotrexate)
    • Inflammatory bowel disease (Crohn’s disease or Ulcerative colitis)
    • Use of any other investigational medicinal product within the previous 30 days
    • The presence of any illness or condition that might interfere with the patient’s ability to comply with the study procedures
    • The presence of any illness or condition (including recent surgery) that renders the patient unsuitable for treatment with aspirin in the opinion of the investigator
    • Hyperemesis gravidarum
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is a composite clinical measure of placental dysfunction (preeclampsia, preterm birth less than 34 weeks, birth weight below the 10th centile or perinatal mortality), with individual components measured as follows:
    -Preeclampsia:
    Hypertension (i) greater than or equal to 140mmHg systolic or greater than or equal to 90mmHg diastolic on two occasions at least 4 hours apart after 20 weeks’ gestation in a woman with a previously normal blood pressure.
    Or (ii) greater than or equal to 160mmHg systolic or greater than or equal to 110mmHg diastolic (such hypertension can be confirmed within a short interval (minutes) to facilitate timely antihypertensive therapy.
    And
    Proteinuria: Greater than or equal to 300mg per 24-hour urine collection, or a urinary protein: creatinine ratio greater than or equal to 0.3 or +3 proteinuria on dipstick urinalysis.
    Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following:
    • Thrombocytopenia (platelet count less than 100,000/microliter)
    • Renal insufficiency (serum creatinine concentrations greater than 97umol/L or a doubling of the serum creatinine concentration in the absence of other renal disease)
    • Impaired liver function (elevated blood concentrations of liver transaminases to twice normal concentration)
    • Pulmonary oedema
    • Cerebral or visual symptoms
    Blood pressure will be measured at all study visits. Urine will be examined by dipstick analysis at all prenatal study visits. Urinary protein-creatinine ratio or 24-hour quantitation will be evaluated at the first study visit (visit 1, and thereafter at visits 3,5,7, and 9-16, or at any intervening study visit or patient encounter where +1 proteinuria or more is identified on dipstick urinalysis.
    Full blood count (platelet count), liver profile and serum renal profile (urea and creatinine) will be measured at the first study visit (visit 2) and thereafter at any study visit or patient encounter where the patient is found to be hypertensive (as per above definition).
    -Birth weight less than the 10th percentile for gestational age:
    Birth weight will be measured on the day of birth and plotted on standard WHO UK RCPCH growth charts (per gender).
    -Preterm birth less than 34+0 weeks:
    Gestational age at birth will be verified with respect to the Estimated Date of Delivery calculated at the first study visit. The accuracy of gestational age will take into account menstrual dates, IVF dates where applicable, and sonographic estimation of gestational age determined at the first study visit (prior to 12 weeks’ gestational age). In accordance with conventional principles for pregnancy dating, where a discrepancy of greater than 5 days exists between the menstrual-dates-derived EDD and the sonographic measurement of crown-rump length prior to 12 weeks’ gestational age, the ultrasound-derived EDD will apply.
    -Perinatal mortality:
    Stillbirth or neonatal death after 24 completed weeks of gestation and within 28 days of birth.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Blood pressure will be measured at all study visits. Urine will be examined by dipstick analysis at all prenatal study visits. Urinary protein-creatinine ratio or 24-hour quantitation will be evaluated at the first study visit (visit 1, and thereafter at visits 3,5,7, and 9-16, or at any intervening study visit or patient encounter where +1 proteinuria or more is identified on dipstick urinalysis.
    Full blood count (platelet count), liver profile and serum renal profile (urea and creatinine) will be measured at the first study visit (visit 2) and thereafter at any study visit or patient encounter where the patient is found to be hypertensive (as per above definition).
    Birth weight will be measured on the day of birth
    Gestational age at birth
    E.5.2Secondary end point(s)
    Parameters of neonatal morbidity:
    • Gestational age at delivery (recorded at the time of birth, in weeks and days post Last Menstrual Period, or in accordance with ultrasound-derived gestational age, as above)
    • Birth weight (recorded (in grams) on the day of birth)
    • NICU admission (requirement to be admitted to the Neonatal Intensive Care Unit for any purpose other than routine antibiotic administration)
    • Respiratory morbidity: A diagnosis of respiratory morbidity will be considered for any infant requiring invasive or non-invasive respiratory support, supported by radiographic criteria where available and length of oxygen-dependence will be recorded. For infants requiring respiratory support, the following variables will be recorded:
    o Duration of invasive ventilation
    o Duration of CPAP/ High-flow O2
    o Duration of O2
    o Duration of hospital stay
    o Use of nitric oxide
    o Number and type of inotropes
    o Duration of inotrope use
    • Apgar score <7 at 5 minutes: Apgar score will be recorded within 5 minutes of birth, as per standard clinical care.
    • Umbilical artery acidosis at birth (cord pH <7.2): Umbilical arterial pH and acid-base status will be measured where clinically indicated at birth (namely in an infant born in the setting of suspected perinatal compromise). In addition to cord pH, the first infant pH will also be recorded, if obtained.
    • Intracranial haemorrhage: Evidence of bleeding within the intraventricular or periventricular areas of the neonatal brain, identified with cranial ultrasound or alternate imaging.
    • Culture-proven sepsis: A diagnosis of neonatal sepsis will be made when appropriate clinical features are confirmed by positive microbiological cultures.
    • Necrotising enterocolitis: Defined as presence of radiologic signs (Bell Stage II or greater).
    • Hypoxic ischaemic encephalopathy: A diagnosis of hypoxic ischemic encephalopathy will be recorded where the following criteria are met:
    o Apgar score ≤5 at 10 minutes after birth
    o Continued need for endotracheal or mask ventilation at 10 minutes after birth
    o Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord arterial or capillary pH <7.0 or a base deficit ≥16mmol/L)
    o And/ or clinical seizures or moderate to severe encephalopathy using the Sarnat grading system
    • Shoulder dystocia: Shoulder dystocia is defined as a vaginal cephalic delivery that requires additional obstetric manoeuvres to deliver the fetus after the head has delivered and gentle traction has failed.

    Maternal outcomes not directly related to primary outcome:
    • Mode of delivery: Recorded on day of delivery, as follows:
    Spontaneous vaginal birth (with spontaneous onset of labour)
    Spontaneous vaginal birth (with induction of labour)
    Assisted vaginal birth (forceps) with spontaneous onset of labour
    Assisted vaginal birth (forceps) with induction of labour
    Assisted vaginal birth (ventouse) with spontaneous onset of labour
    Assisted vaginal birth (ventouse) with induction of labour
    Emergency intrapartum Caesarean section with induction of labour
    Emergency intrapartum Caesarean section with spontaneous onset of labour
    Emergency pre-labour Caesarean section (i.e. unscheduled)
    Elective Caesarean section (scheduled)
    Elective Caesarean section with spontaneous onset of labour

    • Haemorrhage: Loss of 500ml of blood or more from the genital tract within 24 hours of delivery. Peripartum blood loss will be recorded as average or excessive (500ml or more) for all deliveries. In addition, requirement for the following measures to reduce peripartum blood loss will be recorded:
    Oxytocin 10IU, oxytocin infusion, ergometrine, syntometrine, hemabate, misoprostol, intrauterine balloon tamponade, B-Lynch suture, interventional radiologic manoeuvres, hysterectomy, blood transfusion (including number and nature of blood products)
    • Sepsis: Culture-proven infection in addition to systemic manifestations of infection
    E.5.2.1Timepoint(s) of evaluation of this end point
    Parameters of neonatal morbidity: Recorded at birth

    Maternal outcomes not directly related to primary outcome:
    Recorded on day of delivery
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The trial will end when the last recruited woman is discharged from hospital, and has attended the 6-week postnatal visit, her infant is discharged from the Neonatal Unit (NNU) and all delivery/baby data is collected.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 360
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state360
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After treatment participation, patients will be followed as per clinical practice. There will be no arrangements for the IMP to be provided to trial subjects post trial participation. Individual participants may withdraw consent at any time. The reporting of serious adverse events will follow the HPRA guidance and a case will be made for withdrawal of a participant from the trial, or indeed, early termination of the trial as a whole by the DSMB
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation HRB Mother and Baby Clinical Trials Network
    G.4.3.4Network Country Ireland
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-03-21
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