HYDROxychloroquine in Syndrome Primary AntiPhospholipid (HYDROSAPL)

Evaluation of the Benefit of Adjuvant Treatment With Hydroxychloroquine to the Usual Medical Management for Obtaining an Uncomplicated Term Pregnancy in Primary Obstetric Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is defined by thrombosis or obstetric complication (≥ 3 spontaneous miscarriages or fetal death or prematurity <34 weeks gestation-related amenorrhea (SA)) associated with antiphospholipid antibodies. The rate of term pregnancies has been improved by conventional treatment (aspirin 100 mg / day with low molecular weight heparin (LMWH) in an isocoagulant dose) to almost 75%. In the PROMISSE study, when considering progressive pregnancies after 20 weeks, 19% of pregnancies presented at least one complication despite the treatment (maternal, fetal or neonatal complications) related to APS. In the European APS register, maternal complications and IUGR were observed in 13% of cases, and prematurity in approximately 14% of cases despite treatment. In a previous study of 72 pregnancies during a LAS, we observed, under aspirin and LMWH, 25% of fetal losses, and 10% of at least one maternal and / or fetal complication or prematurity. The presence of lupus, a history of thrombosis, a circulating anticoagulant (ACC) and a triple positivity of antiphospholipids are considered to be factors associated with a poor obstetrical prognosis. Hydroxychloroquine (HCQ) has anti-inflammatory and anti-thrombotic properties. In vitro studies have shown that HCQ is able to restore the expression of placental annexin V, which has an anticoagulant effect and prevent the attachment of antiphospholipid antibodies to the placenta.

HCQ during lupus decreases the thrombotic risk and its usefulness during thrombotic APS has been shown in a French series. In a European study, the addition of the HCQ to conventional treatment improved term pregnancies by 70% in the event of refractory APS. Its use during pregnancies of patients with lupus, the numerous data on tolerance during pregnancy and the follow-up of children born to mothers exposed to the HCQ demonstrates a reassuring tolerance profile for the mother and the fetus.

The objective of this clinical trial is to evaluate the benefit of addition or no of hydroxychloroquine to conventional treatment in obstetric APS.

Study Overview

• Status: Recruiting
• Conditions: Anticoagulants; Antiphospholipid Syndrome in Pregnancy
• Intervention / Treatment: Drug: Plaquenil 200Mg Tablet; Drug: Placebo oral tablet

Detailed Description

The consecutive patientes with APS will be recruited in different ways based on daily practice; Patients fulfilling all criteria may be randomized following receipt of written informed consent.

The randomization will be stratified by center and by, the presence of anticoagulant antibody.

Te included patients will be randomized to receive conventional APS treatment (aspirin with low-molecular-weight heparin) combined with hydroxychloroquine or placebo.

In the two groups, the hydroxychloroquine or placebo will be initiated in the patients with ongoing pregnancy (≤14 week of gestation).

After the inclusion visit, the patients will be followed by the investigator every months until the end of the pregnancy and at 6 weeks postpartum.

At each visit, a clinical examination, routine biological analysis, APL antibody and complement determination will be performed. Hydroxychloroquine blood levels, PFA, Xa inhibition,and treatment adherence will be assessed during pregnancy.

At Inclusion :

- Maternal blood samples 20 ml of blood will be collected at the same time as the sample routinely collected just before delivery when the women are perfused.

At delivery

- Cord fluid : will be collected at the same as cord fluid pH is routinely measured just after delivery. The aliquots previously labelled and stowed in the specific boxes for the study will be stored locally and will be transported to the "Centre de Ressources Biologiques"(CRB) of the Saint Antoine Hospital. Last visit for children : At 12 months The patient will be contacted by phone by the local medical team to collect the following data: Children's anthropometric data; safety data ; possible hospitalization..

• Study Type: Interventional
• Enrollment (Anticipated): 110
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Olivier FAIN, MD-PhD; Phone Number: 00 33 01 49 28 21 04; Email: olivier.fain@aphp.fr
• Study Contact Backup: Name: Arsène MEKINIAN, MD; Phone Number: 00 33 01 49 28 21 04; Email: arsene.mekinian@aphp.fr

Study Locations

• France
  • Paris, France, 75012
    • Recruiting
    • Hôpital Saint Antoine
    • Contact: Makinian Pr Arsène; Phone Number: +33149282104; Email: arsene.mekinian@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Age >18 years

• Spontaneous consecutive pregnancy ongoing before the 14th week of gestation

  -- SAPL obstetrics (modified Sapporo criteria = Sydney criteria) with fetal death ≥10 weeks of gestation without further explanation; and / or preeclampsia (or HELLP syndrome) and / or prematurity <34SA with placental insufficiency (with or without thrombotic SAPL)

• Signed informed consent

Exclusion Criteria:

• Other SAPL subgroups: early isolated miscarriages <10 weeks

• Contraindication to hydroxychloroquine:

  • retinopathy,
  • hypersensitivity to chloroquine or hydroxychloroquine or to any of the other ingredients especially lactose
• Associated systemic lupus, associated Sjogren syndrome
• Treatment with hydroxychloroquine in progress
• Patient under guardianship or curatorship
• Patient deprived of liberty
• Lack of Social Insurance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydroxychloroquine; Hydroxychloroquine will be prescribed upon confirmation of pregancy at a dosage of 400 mg / day. Either in 2 doses (1 tablet of 200 mg in the morning and 1 tablet of 200 mg in the evening). Or in a single take: 2 tablets of 200 mg. Treatment will be continueted during the pregnancy and will be stopped at delivery.	Drug: Plaquenil 200Mg Tablet; Hydroxychloroquine will be taken at a dosage of 400 mg / day until delivery
Placebo Comparator: Placebo group; Placebo will be prescribed upon confirmation of pregancy at a dosage of 400 mg / day. Either in 2 doses (1 tablet of 200 mg in the morning and 1 tablet of 200 mg in the evening). Or in a single take: 2 tablets of 200 mg. Treatment will be continueted during the pregnancy and will be stopped at delivery.	Drug: Placebo oral tablet; placebo will be taken at a dosage of 400 mg / day until delivery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of term pregnancies with a eutrophic child	eutrophic child = a full term birth without maternal, fetal or neonatal complications	at delivery

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Arsène MEKINIAN, MD, Internal Medecine_Hospital Saint Antoine

Publications and helpful links

General Publications

• Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet. 2010 Oct 30;376(9751):1498-509. doi: 10.1016/S0140-6736(10)60709-X. Epub 2010 Sep 6.
• Fain O, Mekinian A. [Antiphospholipid syndrome]. Rev Prat. 2011 Nov;61(9):1261-2. No abstract available. French.
• Mekinian A, Lachassinne E, Nicaise-Roland P, Carbillon L, Motta M, Vicaut E, Boinot C, Avcin T, Letoumelin P, De Carolis S, Rovere-Querini P, Lambert M, Derenne S, Pourrat O, Stirnemann J, Chollet-Martin S, Biasini-Rebaioli C, Rovelli R, Lojacono A, Ambrozic A, Botta A, Benbara A, Pierre F, Allegri F, Nuzzo M, Hatron PY, Tincani A, Fain O, Aurousseau MH, Boffa MC. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2013 Feb;72(2):217-22. doi: 10.1136/annrheumdis-2011-201167. Epub 2012 May 15.
• Mekinian A, Loire-Berson P, Nicaise-Roland P, Lachassinne E, Stirnemann J, Boffa MC, Chollet-Martin S, Carbillon L, Fain O. Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. J Reprod Immunol. 2012 Jun;94(2):222-6. doi: 10.1016/j.jri.2012.02.004. Epub 2012 Mar 3.
• Mekinian A, Lazzaroni MG, Kuzenko A, Alijotas-Reig J, Ruffatti A, Levy P, Canti V, Bremme K, Bezanahary H, Bertero T, Dhote R, Maurier F, Andreoli L, Benbara A, Tigazin A, Carbillon L, Nicaise-Roland P, Tincani A, Fain O; SNFMI and the European Forum on Antiphospholipid Antibodies. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study. Autoimmun Rev. 2015 Jun;14(6):498-502. doi: 10.1016/j.autrev.2015.01.012. Epub 2015 Jan 21.

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2021
• Primary Completion (Anticipated): October 2, 2024
• Study Completion (Anticipated): October 2, 2025

Study Registration Dates

• First Submitted: February 17, 2020
• First Submitted That Met QC Criteria: February 17, 2020
• First Posted (Actual): February 19, 2020

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: February 28, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Aspirin; APS; Anticoagulants; Pregancy; Heparin Low-Molecular-Weight
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Syndrome; Antiphospholipid Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: P160944J

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No