Clinical Trials Register

Summary
EudraCT Number:	2015-002182-38
Sponsor's Protocol Code Number:	2015/074/HP
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-08-05
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

2015-002182-38

A.3

Full title of the trial

Study of the Plaquenil® efficacy on the endothelial dysfunction and its vascular consequences during the antiphospholipid syndrom

Etude de l'efficacité du Plaquenil® sur la dysfonction endothéliale et ses conséquences vasculaires au cours du syndrome des antiphopholipides.

A.3.1

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

Study of the Plaquenil® efficacy on the endothelial dysfunction and its vascular consequences during the antiphospholipid syndrom

Etude de l'efficacité du Plaquenil® sur la dysfonction endothéliale et ses conséquences vasculaires au cours du syndrome des antiphopholipides.

A.3.2

Name or abbreviated title of the trial where available

APLAQUINE

A.4.1

Sponsor's protocol code number

2015/074/HP

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	CHU - Hôpitaux de Rouen
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	CHU - Hôpitaux de Rouen
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	CHU - Hôpitaux de Rouen
B.5.2	Functional name of contact point	Florence GRELLET
B.5.3	Address:
B.5.3.1	Street Address	1 rue de germont
B.5.3.2	Town/ city	ROUEN Cedex
B.5.3.3	Post code	76031
B.5.3.4	Country	France
B.5.4	Telephone number	00330232888265
B.5.5	Fax number	00330232888287
B.5.6	E-mail	Secretariat.DRC@chu-rouen.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	Plaquenil
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Aventis
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.4	Pharmaceutical form	Film-coated 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	HYDROXYCHLOROQUINE SULFATE
D.3.9.1	CAS number	747-36-4
D.3.9.4	EV Substance Code	SUB02587MIG
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	200
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	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients must meet the classification criteria for arterial antiphospholipids syndrom. They must have had a confirmed episode of arterial thrombosis and the presence of 2 tests performed at 12 weeks apart of anti-cardiolipin (IgG or IgM ),and anti-B2GP1 (IgG or IgM ), or circulating anticoagulants.

Les patients devront répondre aux critères de classification pour le SAPL artériel primaire. Ils devront avoir eu un épisode de thrombose artérielle confirmée ainsi que la présence sur 2 tests effectués à 12 semaines d’intervalle d’anticorps anticardiolipine IgG ou IgM, anti B2GP1 IgG ou IgM à titres significatifs ou un anticoagulant circulant.

E.1.1.1

Medical condition in easily understood language

Antiphospholipid syndrome

Syndrome des antiphospholipides

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10002817
E.1.2	Term	Antiphospholipid syndrome
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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 main objective is to assess the effect of Plaquenil® on endothelial function, comparatively to a control group, in a population of patient suffering of primary arterial antiphospholipid syndrome

Evaluer l'effet du Plaquenil® sur la fonction endothéliale vasomotrice chez des patients atteints de SAPL primaire artériel comparativement à un groupe contrôle

E.2.2

Secondary objectives of the trial

1. Evaluating the effect of Plaquenil® on endothelial glycocalyx
2. Evaluating the effect of Plaquenil® on the inflammatory profile
3. Evaluating the effect of Plaquenil® on the oxydative stress level
4. Evaluating the effect of Plaquenil® on the via tissue factor
5. HCQ assay

1. Evaluer l’effet du Plaquenil® sur le glycocalyx endothélial
2. Evaluer l’effet du Plaquenil® sur le profil inflammatoire
3. Evaluer l’effet du Plaquenil® sur le niveau de stress oxydant
4. Evaluer l’effet du Plaquenil® sur un paramètre d’hémostase : le facteur tissulaire
5. Doser l’hydroxychloroquinémie

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Patients > 18 years old
-Patients must meet the classification criteria for arterial antiphospholipid syndrom. They must have had a confirmed episode of arterial thrombosis and the presence of 2 tests performed at 12 weeks apart of anti-cardiolipin (IgG or IgM ),and anti-B2GP1 (IgG or IgM ), or circulating anticoagulants.
-Patients must be clinically stable (NB : all of stages severity disease will be accepted)
-Patients with medical insurance
-Having read and understood the information letter and signed the consent form
-For women of childbearing age, they needs to take a effective contraception since 1 month (progestin or intrauterin device or tubal ligation) with a negative pregnancy test. (NB: Will be considered postmenopausal women with amenorrhea for more than 2 years)

• Patient > 18 ans
• SAPL artériel primaire (les patients devront répondre aux critères de classification pour le SAPL artériel : antécédent d’un épisode de thrombose artérielle confirmée ainsi que la présence sur 2 tests effectués à 12 semaines d’intervalle d’anticorps anticardiolipine IgG ou IgM, anti B2GP1 IgG ou IgM à titres significatifs ou un anticoagulant circulant).
• Patient devant être stable cliniquement (NB : tous les stades de gravité de la maladie seront acceptés)
• Patient affilié à un régime de Sécurité Sociale
• Patient ayant lu et compris la lettre d’information et signé le formulaire de consentement
• Pour les femmes en âge de procréer, prise d’une contraception efficace depuis 1 mois (progestative ou dispositif intra-utérin ou ligature des trompes) avec un test de grossesse négatif. (NB : seront considérées comme ménopausées les femmes présentant une aménorrhée depuis plus de 2 ans)

E.4

Principal exclusion criteria

- Treatment with hydroxychloroquine (Plaquenil®) already established or stopped for less than 3 months
-Contraindications to Plaquenil® (retinopathy) and sensitivity to chloroquine or hydroxychloroquine or any of the other constituents of Plaquenil®
-Patients presenting a non-arterial or secondary antiphospholipid syndrome
-Symptomatic atherosclerotic disease: Myocardial infarction, angina, coronary revascularization, stroke or transient constituted, arteritis obliterans of lower limbs.
-Heart failure and / or significant valvulopathy.
-Secondary arterial hypertension.
-Severe hypertension (DBP ≥ 110 mm Hg and / or SBP ≥ 180 mm Hg)
-Atrial fibrillation.
-BMI > 35 kg / m2.
-Diabetes diagnosed since more than 3 months.
-Severe chronic renal impairment (creatinine clearance <30 ml / min according to the Cockroft formula).
-Patients with ophthalmic conditions defined by ophthalmologists which oppose the treatment by hydroxychloroquine
-Introduction of any treatment with platelet aggregation inhibitor or anti-inflammatory non-steroid within 7 days preceding the study
-Allergy to lactose
- Contraindications to trinitrine
-Pregnant or breastfeeding women or absence of contraception used
-Person deprived of liberty by an administrative or judicial decision or person placed under judicial protection (guardianship, trusteeship)
- Patients participating in another trial or participated in another trial during the last month

• Traitement par hydroxychloroquine (Plaquenil®) déjà instauré ou arrêté depuis moins de 3 mois
• Contre-indications au Plaquenil® (rétinopathies) et hypersensibilité à la chloroquine ou à l'hydroxychloroquine ou à l'un des autres constituants du Plaquenil®
• Patients porteurs d'un SAPL non artériel, ou secondaire.
• Maladie athéromateuse symptomatique: Infarctus du myocarde, angor, revascularisation coronarienne, accident vasculaire cérébral constitué ou transitoire, artérite oblitérante des membres inférieurs.
• Insuffisance cardiaque et/ou valvulopathie significative.
• Hypertension artérielle secondaire.
• Hypertension artérielle sévère (PAD ≥ 110 mm Hg et/ou PAS ≥ 180 mm hg
• Diabète diagnostiqué depuis plus de 3 mois.
• Insuffisance rénale chronique sévère (clairance de la créatinine < 30 ml/min selon la formule de Cockroft).
• Fibrillation auriculaire.
• IMC >35 kg/m2.
• Femmes enceintes ou allaitantes ou absence de contraception avérée
• Contre-indication ophtalmologique à la mise sous Plaquenil définie par les ophtalmologistes.
• Contre-indication à la trinitrine
• Allergie au lactose
• Personne privée de liberté par une décision administrative ou judiciaire ou personne placée sous sauvegarde de justice (tutelle ou curatelle)
• Patient participant à un autre essai ou ayant participé à un autre essai médicamenteux dans le mois précédent

E.5 End points

E.5.1

Primary end point(s)

Measuring the variation of the endothelium-dependent dilatation of the brachial artery between baseline and after 6 months of treatment

Mesure de la variation de la dilatation endothélium-dépendante de l'artère humérale (FMD) entre l'inclusion et après 6 mois de traitement.

E.5.1.1

Timepoint(s) of evaluation of this end point

- inclusion day , 3 and 6 months

- Inclusion, 3 mois et 6 mois

E.5.2

Secondary end point(s)

Measuring the thickness of the endothelial glycocalyx
Assays soluble compounds of the glycocalyx
Evaluation of oxidative stress
Evaluation of the inflammatory component
Determination of plasma tissue factor
Assay of hydroxychloroquine

Mesure de l’épaisseur du glycocalyx endothélial et dosages des composés solubles du glycocalyx;
Evaluation du stress oxydant (dosage des nitrites plasmatiques et des TBARS (acides thio-barbituriques)) ; Evaluation de la composante inflammatoire (dosage du TNFα) ; mesure du facteur tissulaire plasmatique ; dosage de l’hydroxychloroquine.

E.5.2.1

Timepoint(s) of evaluation of this end point

- inclusion day 3 and 6 months

- Inclusion, 3 mois et 6 mois

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

LVLS

Dernière visite du dernier patient

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

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

Yes

F.3.3.3

Pregnant women

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

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 : expected normal treatment of that condition

Aucun : traitement habituel à la pathologie

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

2015-08-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-28

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-08-05

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