E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
High blood pressure with protein in the urine |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
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. |
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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. |
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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. |
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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. |
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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: a. acute kidney injury with creatinine >97 μmol/L (1.1 mg / dL) b. 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 |
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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. |
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E.5.2 | Secondary end point(s) |
To determine the effect of low-dose aspirin on the incidence of (stratified according to chorionicity) : o Delivery with PE at <32 weeks, <34 weeks, <37 weeks and at any gestation. o Features of severe PE including: o stroke o eclamspia o systolic blood pressure >160 mmHg on at least one occasion o diastolic blood pressure >110 mmHg on at least one occasion o respiratory failure requiring intubation or mechanical ventilation o myocardial ischemia or infarction o pulmonary edema o hepatic dysfuction (INR >1.2 in the absence of DIC) o hepatic hematoma or raprure o platelet count <100 x 109/litre o abnormal liver function enzymes (ALT or AST >67 iu/litre) o acute kidney injury o creatinine >150 μmol/L o cortical blindness o retinal detachment o tranfusion of any blood products o HELLP syndrome o placental abruption o postpartum hemorrhage (defined as blood loss ≥1 L within the first 24 hours after birth) o intensive therapy or high-dependency unit admission o confirmed sepsis (positive blood or urine cultures) up to post-natal discharge o total number of nights in hospital o Gestational hypertension (GH) o Birth at <32 weeks, <34 weeks and <37 weeks o Spontaneous o Iatrogenic for PE, GH or FGR o Iatrogenic for other reason o Death of one twin and / or both twins before discharge from hospital o Miscarriage of the whole pregnancy or death of one twin <24 weeks’ gestation. o Stillbirth or neonatal death of one or both twins at <32 weeks, <34 weeks, <37 weeks and at any gestation. o Birthweight <3rd, <5th and <10th percentile for gestational age. o Placental abruption (clinically or on placental examination) at <32 weeks, <34 weeks, <37 weeks and at any gestation. o Postpartum hemorrhage (defined as blood loss ≥1 L within the first 24 hours after birth). o 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 o Neonatal sepsis confirmed bacteremia in cultures o Encephalopathy grade (mild, moderate, severe) o Neonatal seizures o Anemia defined as low hemoglobin and / or hematocrit requiring blood transfusion o Respiratory distress syndrome defined as need of ventilation with or without surfactant o Necrotizing enterocolitis requiring surgical intervention o Composite of any of the above o Neonatal therapy o Neonatal intensive care unit admission o Ventilation defined as need of positive pressure (continuous positive airway pressure (CPAP) or nasal continuous positive airway pressure (NCPAP)) or intubation o Composite of any of the above o Length of stay in neonatal intensive care unit |
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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 |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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 |
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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
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The end of the study as a whole be defined as the last visit of the last participant with details of their complete pregnancy outcome |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 29 |
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 |