| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Preeclampsia |
| Preeclampsia |
|
| E.1.1.1 | Medical condition in easily understood language |
| High blood pressure with protein in the urine |
| Pressione alta e proteine nelle urine |
|
| E.1.1.2 | Therapeutic 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.1.2 | Version | 23.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10084825 |
| E.1.2 | Term | Superimposed pre-eclampsia |
| E.1.2 | System Organ Class | 10036585 - Pregnancy, puerperium and perinatal conditions |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate whether aspirin therapy will reduce the incidence of preeclampsia in women who are carrying a twin pregnancy. |
| Valutare se la terapia con Aspirina riduce l’incidenza di preeclampsia nelle donne portatrici di gravidanza gemellare |
|
| E.2.2 | Secondary objectives of the trial |
| To determine the effect of low-dose aspirin on the incidence of preeclampsia with delivery at <32 weeks, <34 weeks, <37 weeks and at any gestation, preterm birth, death of one twin or both twins before discharge from hospital, miscarriage or stillbirth, delivery of small for gestational age neonate, placental abruption, postpartum hemorrhage, neonatal morbidity including intraventricular hemorrhage grade II or above, neonatal sepsis, anemia, respiratory distress syndrome, necrotizing enterocolitis, neonatal therapy including admission to neonatal intensive care unit, ventilation and length of stay in neonatal intensive care unit. |
| Determinare gli effetti di basse dosi di aspirina sull’incidenza di preeclampsia, di parto prima delle 32 settimane, prima delle 34 settimane, prima delle 37 settimane, di parto a qualsiasi epoca gestazionale, incidenza di parto pretermine, di morte di un gemello o di entrambi I gemelli prima della dimissione dall’ospedale, di aborto o di nati morti, di parto con neonate piccolo per epoca gestazionale, di distacco di placenta, di emorragia postpartum, di morbilità neonatale inclusa emorragia intraventricolare di II grado o superiore, di sepsi neonatale, anemia, di sindrome da distress respiratorio, di enterocolite necrotizzante, di terapia neonatale incluso il ricovero in terapia intensiva neonatale, di ventilazione e durata dell’ospedalizzazione in TIN. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age > 18 years;
• DCDA or MCDA twin pregnancies;
• Both live fetuses at 11+2-13+6 weeks of gestation;
• Informed and written consent. |
• Età >18 anni
• Gravidanze gemellari BCBA o MCBA
• Entrambi i feti vivi a 11+2-13+6 settimane
• Firma del Consenso informato |
|
| E.4 | Principal exclusion criteria |
• Monoamniotic twins
• Triplet pregnancies that had undergone embryo reduction to twins or with one vanishing twin
• Pregnancies complicated by major fetal abnormality or nuchal translucency thickness >3.5 mm identified at the 11+2-13+6 weeks scan;¿
• MCDA twin pregnancies in which there are early signs of TTTS or sFGR defined by a 20% discordance in CRL at the 11+2-13+6 weeks' scan;
• Those who lack capacity and who are unable to provide informed consent to take part;¿
• Women taking low-dose aspirin regularly (administration must have ceased >7 days prior to randomization);
• Participation in another drug trial within the previous 7 days;¿
• Haemorrhagic diathesis; coagulation disorders such as haemophilia and thrombocytopenia or concurrent anticoagulant therapy;¿
• Active or history of recurrent peptic ulceration and/or gastric/intestinal haemorrhage, or other kinds of bleeding such as cerebrovascular haemorrhages;¿
• Patients who are suffering from known gout, severe hepatic impairment or severe renal impairment;
• Hypersensitivity to salicylic acid compounds or prostaglandin synthetase inhibitors (e.g. certain asthma patients who may suffer an attack or faint and certain patients who may suffer from bronchospasm, rhinitis and urticaria) or to any excipients (see section 6.1 of the SmPC for details);¿• Patients on long term non-steroidal anti-inflammatory medication;¿
• Not fluent in local language and absence of interpreter
• Any other reason the clinical investigators think will prevent the potential participant from complying with the trial protocol. |
• Gravidanza gemellare monoamniotica
• Gravidanza trigemina sottoposta a embrioriduzione di un gemello o con vanishing twin
• Gravidanza complicata da malformazione maggione o da translucenza nucale > 3.5 mm identificata nell’ecografia a 11+2-13+6 settimane
• Gravidanze MCBA nelle quali sono presenti segni precoci di TTTs o sFGR definita da una discordanza di CRL del 20% nell’ecografia a 11+2-13+6 settimane
• Coloro che non hanno capacità di intendere e volere e che non sono in grado di fornire il consenso per partecipare allo studio
• Donne già in terapia con basse dosi di Aspirina (la somministrazione deve essere interrotta >7 giorni prima della randomizzazione)
• Partecipazione ad altro studio farmacologico nei precedenti 7 giorni
• Diatesi emorragica , disordini della coagulazione come emofilia o trombocitopenia o in terapia anticoagulante
• Storia anamnestica di ulcera peptica e/o emorragia gastrica/intestinale, o altre tipi di sanguinamenti cerebrovascolari
• Pazienti che soffrono di gotta, patologia epatica o renale grave
• Ipersensibilità ai composti dell’acido acetilsalicilico o agli inibitori delle prostaglandine sintetasi (ad es. pazienti asmatiche con attacchi o svenimenti o pazienti con broncospasmi, riniti o orticaria) o ad altri eccipienti (vedi sezione 6.1 del SmPC per dettagli)
• Pazienti in terapia con farmaci anti-infiammatori non steroidei
• Dificoltà nella comprensione linguistica in assenza di interprete
• Qualsiasi altro motivo che, secondo i ricercatori, possa impedire la corretta applicazione del protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine if the prophylactic use of low-dose aspirin from the first- trimester of pregnancy in women with twin pregnancy can reduce the incidence of PE with delivery <37 weeks' gestation.
PE will be defined as per the American College of Obstetricians and Gynecologists (ACOG 2013). The systolic blood pressure should be =140 mm Hg and / or the diastolic should be =90 mm Hg on at least two occasions four hours apart developing =20 weeks' gestation in previously normotensive women (blood pressure <140/90 mm Hg) accompanied by one or more of the following new onset conditions at = 20 weeks' gestation:
1. Proteinuria defined as =300mg in 24 hours or urinary creatinine ratio =30mg/mmol (0.3mg/mg) or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-hour collection is available.
2. Maternal organ dysfunction defined as any one of the following:
. acute kidney injury with creatinine >97 µmol/L (1.1 mg / dL) ¿
. liver involvement with elevated transaminases (ALT or AST >90 IU/L ¿
or twice the normal concentration)¿c. hematological complications (thrombocytopenia with platelet count <100,000/µL), disseminated intravascular coagulation or hemolysis.¿d. neurological complications such as eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, persistent visual scotomata |
Valutare se l’uso profilattico di aspirina a basse dosi dal primo trimestre di gravidanza nelle donne portatrici di gravidanza gemellare può ridurre l’incidenza di PE con parto <37 settimane di epoca gestazionale.
PE viene definita secondo I criteri dell’American College of obstetrician and Gynecologist (ACOG 2013). Pressione sistolica deve essere =140 mm Hg e /o la pressione diastolica =90 mm Hg almeno in due occasioni a distanza di 4 ore, sviluppandosi ad epoca gestazionale =20 settimane in donne precedentemente normotese (pressione sanguigna <140/90 mmHg) accompagnata da una delle seguenti condizioni di nuova insorgenza =20 settimane:
1. Proteinuria definite come = 300 mg nelle 24 ore oppure la frazione della creatinina =30mg/mmol (0.3mg/mg) oppure 2 letture di almeno 2+ di proteine nello stick urine se la diuresi delle 24 ore non è disponibile
2. Disfunzione d’organo definita come uno dei seguenti:
a. Insufficienza renale acuta con creatinina >97 µmol/L (1.1 mg / dL)
b. Compromissione epatica con transaminasi elevate (ALT or AST >90 IU/L ¿oppure il doppio della concentrazione normale)
c. Complicanze ematologiche (trombocitopenia con conta piastrinica < 100,000/mcmol) coagulazione intravascolare disseminata
d. Complicanze neurologiche come eclampsia, stato confusionale, cecità, ictus, cloni, mal di testa grave, scotomi persistenti |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The pregnancy outcomes will be collated prospectively and where there is documentation of hypertensive disease, the outcomes will be further investigated to confirm or refute pre-eclamptic criteria as defined within our protocol. |
| Gli esiti della gravidanza saranno raccolti in modo prospettico e, laddove vi sia documentazione di malattia ipertensiva, gli esiti saranno ulteriormente studiati per confermare o confutare i criteri pre-eclamptici come definiti nel nostro protocollo. |
|
| E.5.2 | Secondary end point(s) |
To determine the effect of low-dose aspirin on the incidence of (stratified according to chorionicity):
- Delivery with PE at <32 weeks, <34 weeks, <37 weeks and at any gestation.
- Features of severe PE including:
- stroke
- eclamspia
- systolic blood pressure >160 mmHg on at least one occasion
- diastolic blood pressure >110 mmHg on at least one occasion
- respiratory failure requiring intubation or mechanical ventilation¿o myocardial ischemia or -infarction
- pulmonary edema
- hepatic dysfuction (INR >1.2 in the absence of DIC)¿,
- hepatic hematoma or raprure
- platelet count <100 x 109/litre
- abnormal liver function enzymes (ALT or AST >67 iu/litre)
- acute kidney injury
- creatinine >150 µmol/L
- cortical blindness
- retinal detachment
- tranfusion of any blood products
- HELLP syndrome
- placental abruption
- postpartum hemorrhage (defined as blood loss =1 L within the first 24 hours after birth)
- intensive therapy or high-dependency unit admission
- confirmed sepsis (positive blood or urine cultures) up to post-natal discharge
- total number of nights in hospital
- Gestational hypertension (GH)
- Birth at <32 weeks, <34 weeks and <37 weeks
- Spontaneous¿, Iatrogenic for PE, GH or FGR
- Iatrogenic for other reason
- Death of one twin and / or both twins before discharge from hospital,
- Miscarriage of the whole pregnancy or death of one twin <24 weeks' gestation,
- Stillbirth or neonatal death of one or both twins at <32 weeks, <34 weeks, <37 weeks and at any gestation,
- Birthweight <3rd, <5th and <10th percentile for gestational age
- Placental abruption (clinically or on placental examination) at <32 weeks, <34 weeks, <37 weeks and at any gestation
- Postpartum hemorrhage (defined as blood loss =1 L within the first 24 hours after birth).
- Neonatal morbidity¿o Intraventricular hemorrhage (IVH) grade II or above – Defined as bleeding into the ventricles: Grade II (moderate) – IVH occupies <50% of the lateral ventricle volume¿; Grade III (severe) – IVH occupies =50% of the lateral ventricle volume; Grade IV (severe) – Hemorrhagic infarction in periventricular white matter ipsilateral to a large IVH¿
- Neonatal sepsis confirmed bacteremia in cultures
- Encephalopathy grade (mild, moderate, severe)
- Neonatal seizures
- Anemia defined as low hemoglobin and / or hematocrit requiring blood transfusion
- Respiratory distress syndrome defined as need of ventilation with or without surfactant
- Necrotizing enterocolitis requiring surgical intervention
- Composite of any of the above
- Neonatal therapy
- Neonatal intensive care unit admission
- Ventilation defined as need of positive pressure (continuous positive airway pressure (CPAP) or nasal continuous positive airway pressure (NCPAP)) or intubation
- Composite of any of the above
- Length of stay in neonatal intensive care unit |
Determinare gli effetti di aspirina a basse dosi sull’incidenza (stratificata in base alla corionicità) di:
- Parto con PE <32 settimane , <34 settimane, <37 settimane e a qualsiasi epoca gestazionale
- Caratteristiche della PE severa inclusi
- Infarto
- Eclamspia
- Pressione sistolica >160 mmHg almeno in un’occasione¿,
- Pressione diastolica >110 mmHg ¿almeno in un’occasione,
- Insufficienza respiratoria che richiede intubazione o ventilazione
- Ischemia o infarto miocardico,
- Edema polmonare
- Disfunzione epatica (INR >1.2 in assenza di DIC
- Ematoma epatico o rottura epatica
- Conta piastrinica <100 x 109/litri
- Enzimi della funzionalità epatica anormali (ALT or AST >67 iu/litre)
- Insufficienza renale acuta
- Creatinina>150 µmol/L
- Cecità corticale
- Distacco di retina
- Trasfusione di qualsiasi emocomponente
- HELLP syndrome
- Distacco di placenta
- Emorragia del postpartum (definita come perdita di sangue =1 entro le prime 24 ore dopo il parto)
- Ricovero in terapia intensiva ,
- Sepsi confermata (colture ematiche o urinarie positive) fino alla dimissione postnatale
- Numero totale di notti in ospedale
- Ipertensione gestazionale (GH)
- Parto <32 settimane, <34 settimane e <37 settimane :
o Spontaneo
o Iatrogeno per PE, GH o FGR
o Iatrogeno per altri motivi,
- Morte di uno e/o entrambi I gemelli prima della dimissione dall’ospedale
- Aborto di tutta la gravidanza o morte di un gemello < 24 settimane di gestazione
- Nato morto o morte neonatale di un o entrambi I gemelli <32 settimane, <34 settimane, <37 settimane e a qualsiasi epoca gestazionale,
- Peso alla nascita <3°, <5° e <10 °percentile per epoca gestazionale
- Distacco di placenta (clinico o all’esame placentare) <32 settimane, <34 settimane, <37 settimane e a qualsiasi epoca gestazionale
- Emorragia del post partum (definita come perdita di sangue =1 entro le prime 24 ore dopo il parto)¿
- Morbidità neonatale
- Emorragia intraventricolare (IVH) di II grado o superiore – Definita come sanguinamento intraventricolare:
o Grado II (moderato) – IVH occupa <50% del volume del ventricolo laterale
o Grado III (severa) – IVH occupa =50% del volume del ventricolo laterale;
o Grado IV (severa) – Infarcimento emorragico nella sostanza Bianca periventricolare omolaterale alla IVH
- Sepsi neonatale confermata da batteriemia nelle colture
- Encefalopatia (lieve, moderata, severa)
- Convulsioni neonatali
- Anemia definita come bassa emoglobina e/o ematocrito che richiede trasfusioni di sangue
- Sindrome da distress respiratorio definita come necessità di ventilazione con o senza surfactante
- Enterocolite necrotizzante che richiede intervento chirurgico
- Esito composito di qualsiasi dei precedenti
- Terapia neonatale
- Ricovero in terapia intensive neonatale
- ventilazione definita come necessità di pressione positiva (pressione positive continua sulle vie aeree (CPAP) o pressione positive continua sulle vie aeree nasali (NCPAP) o intubazione
- Esito composito di qualsiasi dei precedenti
- Durata del ricovero in terapia intensive neonatale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Similarly within the cohort documented to have hypertensive disease, the parameters set out in the protocol in terms of details for severity of disease will be noted. The fetal outcomes will be derived from the pregnancy databases and merged within the database; Così come all’interno della coorte saranno documentati i parametri per la malattia ipertensiva, così saranno annotati i dettagli per la severità della malattia stessa. Gli esiti fetali saranno derivati dai database della gravidanza e uniti all'interno del database |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Israel |
| Austria |
| Poland |
| Bulgaria |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| Portugal |
| United Kingdom |
|
| E.8.7 | Trial 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 end of the study as a whole will be defined as the last visit of the last participant with details of their complete pregnancy outcome. |
| La fine dello studio nel suo insieme sarà definita come l'ultima visita dell'ultima partecipante con i dettagli dell'esito completo della gravidanza. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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