Clinical Trials Register

Summary
EudraCT Number:	2018-004160-58
Sponsor's Protocol Code Number:	CHASAP
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-07-10
Trial 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

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2018-004160-58

A.3

Full title of the trial

Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy, a multicenter prospective randomized double-blind placebo-controlled trial

Hypertension chronique et acide acétyl salicylique pendant la grossesse, essai multicentrique prospectif randomisé en double aveugle contrôlé par placebo

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy, a multicenter prospective randomized double-blind placebo-controlled trial

A.4.1

Sponsor's protocol code number

CHASAP

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Centre hospitalier intercommunal de Créteil
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DGOS
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre hospitalier intercommunal de Créteil
B.5.2	Functional name of contact point	coordinating investigator
B.5.3	Address:
B.5.3.1	Street Address	40 avenue de Verdun
B.5.3.2	Town/ city	Créteil
B.5.3.3	Post code	94000
B.5.3.4	Country	France
B.5.4	Telephone number	+33145175543
B.5.5	Fax number	+33145175542
B.5.6	E-mail	bassam.haddad@chicreteil.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ACARD 150mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Polfa S.A.Pharmaceutical Works
D.2.1.2	Country which granted the Marketing Authorisation	Poland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ACARD 150 mg
D.3.2	Product code	BLOZ 5527611
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.2	Current sponsor code	ACARD
D.3.9.4	EV Substance Code	SUB12730MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Buccal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pregnant women with chronic hypertension

Femmes enceintes souffrant d'hypertension chronique

E.1.1.1

Medical condition in easily understood language

Pregnant women with chronic hypertension

Femmes enceintes souffrant d'hypertension chronique

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	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10036557
E.1.2	Term	Pregnancy associated hypertension
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10010164
E.1.2	Term	Hypertension complications
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to compare, in pregnant women with CHTN, the efficacy of Aspirin (acetylsalicylic acid) 150 mg/day with a placebo in the prevention of maternal-fetal morbidity and mortality (preeclampsia, placental abruption, IUGR, perinatal death, maternal death, and preterm delivery).

Comparer, chez les femmes enceintes souffrant d'hypertension chronique, l'efficacité de l'Aspirine (acide acétylsalicylique) à une dose de 150 mg / jour avec un placebo, dans la prévention de la morbidité et de la mortalité materno-fœtales (pré-éclampsie, décollement placentaire, RCIU, décès périnatal, décès maternel et accouchement prématuré)

E.2.2

Secondary objectives of the trial

Secondary objectives are:
- To estimate the preventive effect of low-dose aspirin on each of the main objective events individually,
- To estimate this preventive effect on: the severity of PE, IUGR, and preterm birth; the risk of miscarriage, fetal death, neonatal death; neonatal morbidity (stay in neonatal intensive care unit, assisted ventilation > 24 hours, hyaline membrane disease, stage III or IV intraventricular hemorrhage),
- To evaluate the potential toxicity of the treatment: major maternal hemorrhagic event (externalized active bleeding, intracranial, intraocular, retroperitoneal, articular bleeding), or minor
- To analyze the patients' compliance with the treatment (follow-up diary) and its relation to the effectiveness of the treatment in its preventive action on the main endpoint,
- The constitution of a biological collection

- Estimer l'effet préventif de l'aspirine à faible dose sur chacun des principaux événements objectifs pris individuellement,
- Estimer cet effet préventif sur : la gravité de l'EP, du RCIU et des naissances prématurées ; le risque de fausse couche, de mort fœtale, de mort néonatale ; la morbidité néonatale (séjour en unité de soins intensifs néonatals, ventilation assistée > 24 heures, maladie de la membrane hyaline, hémorragie intraventriculaire de stade III ou IV),
- Pour évaluer la toxicité potentielle du traitement : événement hémorragique maternel majeur (saignement actif externalisé, saignement intracrânien, intraoculaire, rétro péritonéal, articulaire), ou mineur
- Analyser l'observance du traitement par les patients (journal de suivi) et sa relation avec l'efficacité du traitement dans son action préventive sur le paramètre principal,
- La constitution d'une collection biologique

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Pregnant patient between 10 and 14 weeks of gestation + 6 days
- Chronic hypertension, whether treated or not, know before pregnancy or diagnosed before randomization
- Singleton pregnancy
- Signed the written informed consent
- Affiliation to social security

- Femmes enceintes entre 10 semaines et 14 semaines + 6 jours
- Hypertension chronique, qu'elle soit traitée ou non
- Grossesse singleton
- Consentement éclairé écrit signé
- Affiliation à la sécurité sociale

E.4

Principal exclusion criteria

- Medical history requiring anticoagulation (antiphospholipid syndrome, deep vein thromboembolic disease, pulmonary embolism, atherothrombosis, patient with mechanical heart valves),
- Patient receiving aspirin for another indication outside pregnancy,
- Patient with significant proteinuria (> 300mg/24 hours or a proteinuria/creatininuria ratio ≥ 30mg/mmol),
- Active bleeding,
- History of severe PE with delivery < 34 weeks of gestation,
- Hypersensitivity to salicylates such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs),
- Platelet count lower than 100,000 cells/microliter,
- Any constitutional or acquired hemorrhagic disease,
- Human immunodeficiency virus, or hepatitis B virus, or hepatitis C virus positive serum,
- Patient included in an another interventional study,
- Age <18 years old,
- Women under the protection of justice,
- Patients with psychiatric follow-up, poor understanding of French or cognitive problems,
- Duodenal ulcer,
- Severe renal impairment,
- Severe hepatic insufficiency,
- Severe cardiac impairment,
- Gout,
- Patients with known glucose-6-phosphate dehydrogenase deficiency

- Antécédents médicaux nécessitant une anticoagulation (syndrome des antiphospholipides, maladie thromboembolique veineuse profonde, embolie pulmonaire, athérothrombose, patient avec des valves cardiaques mécaniques),
- Patient recevant de l'aspirine pour une autre indication en dehors de la grossesse,
- Patient présentant une protéinurie importante (> 300mg/24 heures ou un rapport protéinurie/créatinurie ≥ 30mg/mmol),
- Saignement actif,
- Antécédents de pré-éclampsie sévère avec accouchement < 34 semaines d’aménorrhée,
- Antécédents d'hypersensibilité aux salicylés et aux substances d'activité proche, notamment anti-inflammatoires non-stéroidiens
- Nombre de plaquettes < à 100 000 /µL ,
- Toute maladie hémorragique constitutionnelle ou acquise, Virus de l'immunodéficience humaine, ou virus de l'hépatite B, ou sérum positif pour le virus de l'hépatite C,
- Patient inclus dans une autre étude interventionnelle
- Âge <18 ans,
- Femmes sous la protection de la justice,
- Patients ayant un suivi psychiatrique, une mauvaise compréhension du français ou des problèmes cognitifs.
- Ulcère gastro-duodénal en évolution
- Insuffisance rénale sévère
- Insuffisance hépatique sévère
- Insuffisance cardiaque sévère
- Patiente souffrant de goutte
- Déficit connu en gluocose-6-phosphate-déshydrogénase

E.5 End points

E.5.1

Primary end point(s)

It is a composite morbidity-mortality criterion that includes the occurrence during pregnancy or postpartum of at least one of the following events:
- Preeclampsia
- IUGR <10th percentile
- Placental abruption
- Preterm birth < 37 weeks of gestation
- Perinatal death (death from 22 weeks of gestation until 28 days after birth)
- Maternal death

Il s'agit d'un critère composite de morbidité-mortalité comprenant au moins un des éléments suivants :
- Pré-éclampsie (précoce ou tardive)
- Poids à la naissance <10 percentile
- Décollement placentaire
- La mort périnatale
- Décès maternel
- Accouchement prématuré < 37 semaines de gestation

E.5.1.1

Timepoint(s) of evaluation of this end point

occurrence during pregnancy or postpartum

Survenue pendant la grossesse ou le post-partum

E.5.2

Secondary end point(s)

- Each of the events of primary end-point taken individually,
- Rate of severe PE
- Rate of severe IUGR (< 5th percentile of birth weight),
- Rate of severe preterm delivery (< 34 weeks of gestation),
- Rate of fetal loss (fetal loss between 10 and 21 weeks of gestation),
- Rate of fetal death (fetal death from 22 weeks of gestation until delivery),
- Rate of neonatal death (death from birth until 28 days),
- Neonatal morbidity
- stay in a neonatal intensive care unit,
- assisted ventilation > 24 hours,
- hyaline membrane disease,
- intraventricular hemorrhages stage III or IV,
- Potential toxicity of the treatment: major maternal bleeding event (active externalized, intracranial, intra-ocular, retroperitoneal, articular), or minor,
- Compliance of treatment (diary) and its relationship with the efficacy of the preventive effect on primary outcome,
- Circulating and urinary angiogenic profile associated with maternal and fetal clinical data: sFLT1 (serum and urine), PlGF (serum and urine)

- Chacun des événements du point final primaire pris individuellement,
- Taux d'EP sévère.
- Hypertension sévère (pression artérielle systolique > 160 mm Hg et/ou pression artérielle diastolique > 110 mm Hg)
- Maux de tête, troubles visuels, douleurs épigastriques
- Oligurie < 500 ml/24h ou créatinine sérique > 120 μmol/L
- Eclampsie
- Œdème pulmonaire
- Décollement placentaire
- Numération plaquettaire < 100000/ L ou LDH > 600 U/L ou AST > 70 ou deux fois la normale
- Taux de RCIU grave (< 5e percentile du poids à la naissance),
- Taux d'accouchement prématuré sévère (< 34 semaines de gestation),
- Taux de perte fœtale (perte fœtale entre 10 et 21 semaines de gestation),
- Taux de mortalité fœtale (mort fœtale à partir de 22 semaines de gestation jusqu'à l'accouchement),
- Taux de mortalité néonatale (décès depuis la naissance jusqu'à 28 jours),
- Morbidité néonatale
- Séjourner dans une unité de soins intensifs néonatals,
- Ventilation assistée > 24 heures,
- Maladie de la membrane hyaline,
- Les hémorragies intraventriculaires de stade III ou IV,
- Toxicité potentielle du traitement : hémorragie maternelle majeure (active externalisée, intracrânienne, intra-oculaire, rétropéritonéale, articulaire) ou mineure,
- L'observance du traitement (journal) et sa relation avec l'efficacité de l'effet préventif sur le résultat primaire,
- Profil angiogénique circulatoire et urinaire associé aux données cliniques maternelles et fœtales : sFLT1 (sérum et urine), PlGF (sérum et urine)

E.5.2.1

Timepoint(s) of evaluation of this end point

occurrence during pregnancy or postpartum

Survenue pendant la grossesse ou le post-partum

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

last visit of the last subject

Dernière visite de la dernière patiente incluse

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

500

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

500

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)

None

aucun

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-08-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-06-11

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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