E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pregnant women with Antiphospholipid Syndrom (APS) and Lupus Antocoagulant (LAC) |
Patientes enceintes atteintes d’un Syndrome des Antiphospholipides (SAPL) et/ou d’un Lupus Erythémateux Systémique et porteuse de l’anticorps Anticoagulant circulant (ACC) de type lupique |
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E.1.1.1 | Medical condition in easily understood language |
Pregnant women with Antiphospholipid Syndrom (APS) and Lupus Antocoagulant (LAC) |
Patientes enceintes atteintes d’un Syndrome des Antiphospholipides (SAPL) et/ou d’un Lupus Erythémateux Systémique et porteuse de l’anticorps Anticoagulant circulant (ACC) de type lupique |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058347 |
E.1.2 | Term | Lupus anticoagulant positive |
E.1.2 | System Organ Class | 100000004848 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058355 |
E.1.2 | Term | Lupus anticoagulant |
E.1.2 | System Organ Class | 100000004848 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether TNF-α blockade added to a regimen of heparin and low dose aspirin during pregnancy reduces the rate of APOs in women with APS1 (prior vascular thrombosis and/or pregnancy morbidity) and LAC |
Déterminer si un traitement anti-TNF ajouté à un traitement standard d’héparine et d’aspirine à faible dose pendant la grossesse réduit le taux de morbi-mortalité périnatale chez les femmes atteintes de SAPL associé ou non à un Lupus systémique et porteuses d’un ACC. |
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E.2.2 | Secondary objectives of the trial |
To determine whether TNF-α blockade during pregnancy favorably alters angiogenic markers of poor placental vascularization in women with APS and LAC |
Déterminer si le traitement par anti-TNFα pendant la grossesse modifie favorablement les marqueurs angiogéniques d’une mauvaise vascularisation placentaire chez les femmes atteintes de SAPL associé ou non à un Lupus systémique et porteuses d’un ACC. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Pregnant as defined by positive test for elevated ß-HCG and having a live, appropriate-size embryo by ultrasound, but < 8 weeks gestation;
2. Antiphospholipid syndrome (APS)
3. Positive LAC, on two or more occasions greater than 12 weeks apart, one of which must be within the previous 18 months. If a candidate for the study is newly diagnosed (<12 weeks) with APS, meets clinical criteria for APS and has one positive LAC confirmed by review of the medical record, she may be consented and screened. At baseline, LAC will be measured at the study core lab and she will be enrolled if it is found to be positive. The LAC measurement will be repeated 12 weeks after the initial determination and, if positive, she will remain in the study.
4. Age 18-40 (+364 days) years of age and able to give informed consent;
5. Laboratory hematocrit > 26% at time of screening. |
1. Grossesse confirmée par un test positif avec une concentration de ß-HCG élevée ou par échographie, mais <8 semaines d’aménorrhées (SA);
2. Syndrome des antiphospholipides (SAPL) (et/ou Lupus)
3. Anticorps anticoagulant circulant de type lupique (ACC) positif, confirmé à deux reprises et à plus de 12 semaines d'intervalle, dont l'une doit se situer dans les 18 mois précédant l’inclusion. Si une patiente est nouvellement diagnostiquée pour un SAPL (moins de 12 semaines), et l’ACC positif, elle peut être incluse. La mesure de l’ACC sera répétée 12 semaines après la première évaluation. Si la détermination est à nouveau positive, elle restera dans l'étude.
4. Etre âgée de 18 à 40 ans (+364 jours) et pouvoir donner son consentement éclairé;
5. Hématocrite > 26% au moment du dépistage.
Le diagnostic de SAPL avec ACC sera confirmé par l'investigateur principal du centre par un examen des dossiers médicaux. |
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E.4 | Principal exclusion criteria |
1. Hypertension (BP >140/90) present at screening;
2. Multifetal gestation;
3. Type 1 or type 2 diabetes antedating pregnancy;
4. SLE patients requiring prednisone >10 mg/day;
5. Platelet count <100,000 per microliter;
6. Women currently taking prednisone greater than 10 mg daily for an autoimmune disorder, other than immune thrombocytopenia; More than 60 mg once daily in a tapering regimen or 20 mg once daily in a maintenance regimen for immune thrombocytopenia
7. Women with urinary excretion with greater than 500 mg (0.5 g) per day (spot urine protein/creatinine ratio 0.5);
8. Serum creatinine >1.2 mg/dL;
9. History of tuberculosis or untreated positive PPD;
10. Women with a tuberculin skin test induration of 5 mm or greater; or positive quantiFERON-gold test
11. Women with HIV, Hepatitis B or Hepatitis C positive status;
12. Concomitant participation in another interventional research study;
13. Known contraindications or relative contraindications to certolizumab :
a. Active infection, e.g., chronic hepatitis B.
b. History of recurrent infection, e.g., recurrent cellulitis, or opportunistic infection.
c. History of prior active/treated endemic mycoses in the last two years (including coccidioidomycosis, blastomycosis, or histoplasmosis).
d. History of heart failure.
e. History of peripheral demyelinating disease or Guillian-Barré syndrome.
f. History of hematologic malignancy.
g. Prior adverse reaction to certolizumab or other anti-TNF-α agent.
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1. Hypertension (PA> 140/90)
2. Grossesse multiple
3. Diabète de type 1 ou de type 2 précédant la grossesse
4. Femmes avec un Lupus Erythémateux Systémique nécessitant plus de 10mg/jour de prednisone
5. Taux de plaquettes <100 000 par microlitre à l’inclusion
6. Femmes prenant actuellement :
a. Plus de 10 mg par jour de prednisone pour une maladie auto-immune autre que le Purpura Thrombopénique Immunologique (PTI);
b. Plus de 60 mg/jour dans le cadre d'un traitement d’attaque ou 20 mg/jour dans un régime d'entretien en cas de PTI;
7. Protéinurie > 500 mg (0,5 g) par jour (ratio urinaire protéinurie/créatinurie : 0,5 g/g);
8. Créatinine sérique> 1,2 mg / dL;
9. Antécédents de tuberculose ou d’IdR anormalement positive non traitée
10. Femmes présentant une induration au test cutané de à la tuberculine de 5 mm ou plus; ou test quantiFERON-gold positif
11. Femmes ayant le statut positif au VIH, à l'hépatite B ou à l'hépatite C;
12. Contre-indications connues ou relatives au certolizumab
a) Infection active, par exemple l'hépatite B chronique.
b) Antécédents d'infection récurrente, par exemple, cellulite récurrente ou infection opportuniste.
c) Antécédents de mycoses endémiques actives / traitées antérieurement au cours des deux dernières années (dont coccidioïdomycose, blastomycose ou histoplasmose).
d) Antécédents médicaux d'insuffisance cardiaque.
e) Antécédents de démyélinisation périphérique ou de syndrome de Guillian-Barré.
f) Antécédents de malignité hématologique.
g) Réaction indésirable au certolizumab ou à un autre agent anti-TNFα.
13. Participation dans une autre recherche clinique
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome will be a composite of two APOs associated with poor placentation in women with APS and LAC:
(1) fetal death (>10 wks gestation)
(2) severe PE or PI requiring delivery prior to 34 wks gestation. PE and severe PE will be diagnosed according to U.S. criteria. PI as an antenatal diagnosis requiring delivery will be defined as (1) abnormal or non-reassuring fetal surveillance test(s), e.g. a non-reactive non-stress test or biophysical profile score <6, suggestive of fetal hypoxemia, (2) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent or reverse end-diastolic flow in the umbilical artery, (3) oligohydramnios, e.g. an amniotic fluid index of <5 cm or single deepest vertical pocket less than 2 cm, or (4) ultrasound estimated fetal weight ≤5th percentile |
Critère composite (mort fœtale, pré-éclampsie sévère <34 SA, oligohydramnios, retard de croissance intra-uterin (RCIU) <5ème percentile) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
10 weeks gestation
34 weeks gestation |
10 SA
34SA |
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E.5.2 | Secondary end point(s) |
Secondary clinical outcomes will include :
(1) neonatal death due to complications of prematurity because of preterm delivery for PE or PI,
(2) preterm labor or preterm rupture of membranes resulting in delivery prior to 36 weeks gestation,
(3) PE or PI not requiring delivery prior to 34 weeks gestation,
(4) gestational age at delivery,
(5) maternal thrombosis,
(6) small-for-gestational age birthweight (<10th percentile)
(7) known adverse reactions to certolizumab.
(8) biomarkers of APOs : impact of TNF- α blockade on angiogenic factors and their relationship to PE and PI. |
Mort néonatale, prématurité avant 36SA,
Pré-éclampsie >= 34 SA,
Terme de naissance,
Retard de croissance <10ème percentile,
Effets secondaires du Certolizumab,
Thrombose maternelle |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
36 weeks gestation
Delivery Time |
36SA
Date accouchement |
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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 | No |
E.6.3 | Therapy | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
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 | No |
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 |
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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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LVLS |
Dernière visite du dernier patient inclus |
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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 | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 67 |