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Hydroxychloroquine for Prevention of Recurrent Miscarriage. (BBQ)

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ClinicalTrials.gov Identifier: NCT03165136
Recruitment Status : Recruiting
First Posted : May 24, 2017
Last Update Posted : June 17, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Brest

Brief Summary:

Recurrent miscarriage (RM) defined by >=3 consecutive losses affects 1% of fertile couples. Most women have recurrent early loss with a failure of development before 10 weeks' gestation. Standard investigations fail to reveal any apparent cause in >50% of couples.

No study has demonstrated any benefit of any medication in women with Unexplained RM, in the presence or absence of an inherited thrombophilia.

Moreover, the benefit of aspirin and/or heparin has not been proved in women with Antiphospholipid (APL) antibody without other clinical manifestations of Antiphospholipid Syndrome.

Hydroxychloroquine (HQ) is a molecule whose properties (anti-thrombotic, vascular-protective, immunomodulatory, improved glucose tolerance, lipid-lowering, anti-infectious) could be useful against mechanisms of Unexplained RM.

There is no data concerning the benefit of HQ in RM in the presence or absence of antiphospholipid antibodies or any inherited thrombophilia.

Administration in (Systemic Lupus erythematosus (SLE) women and for Malaria prevention provides extensive safety data during pregnancy.

Oral administration makes possible treatment since the preconception period. For all of that and its low cost, hydroxychloroquine should be evaluated in RM whatever the woman thrombophilic status.


Condition or disease Intervention/treatment Phase
Recurrent Miscarriage First Trimester Abortion Drug: Hydroxychloroquine Drug: Placebo Phase 3

Detailed Description:

Regarding the mechanisms of unexplained RM, on the basis of animal models and clinical studies, many hypotheses were raised:

  • Reduced ovarian reserve,
  • Progesterone defect: a double-blind trial did not show any benefit of progesterone therapy.
  • Thrombotic mechanisms and/or endothelial dysfunction: An association with some inherited thrombophilias was suggested. A prothrombotic state outside of pregnancy was measured in women with previous RM and without known thrombophilia.
  • Immunological disturbances (high titers of anti-thyroid or APL antibodies, maternal carriage of specific HLA alleles and immunological reactions against male-specific minor antigens, increased numbers of peripheral blood natural killer, overexpression of TOLL receptors, increase of TH1 and TH17 processes). Consequently, immunomodulatory treatments were proposed and assessed (no impact of intravenous immunoglobulins and no conclusive benefit of corticosteroids).
  • Miscellaneous: BMI> 30 and chronic endometritis. Besides, the experience gained from previous clinical trials in RM leads us to emphasize, that subcutaneous administration of heparin limits its assessment among fertile women. Indeed, the treatment could not be administrated before conception and consequently the exposure was often too short (injections cannot be routinely initiated before 5 weeks).

Except psychological support, there is no treatment whose benefit has been proved in unexplained RM, in the presence or in the absence of an inherited thrombophilia. Moreover the absence of benefit of some treatments has been clearly demonstrated. Although the prognostic is not so poor (live-birth rates around 70%), proposed therapeutic interventions are sometimes excessive (regarding possible side effects and cost): as intravenous immunoglobulins, assisted procreation ...anti-TNF.

Consequently, for the management of these distressed patients, investigating other therapeutic options is highly needed.

Regarding recurrent miscarriage in women with high titers of antiphospholipid but without any other previous clinical event listed in the antiphospholipid syndrome, the benefit of antithrombotic treatment remains controversial (negative results of the HepASA trial) and hydroxychloroquine has never been assessed, although retrospective studies are encouraging.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double Blind Randomized clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Active drug and placebo will be exactly the same
Primary Purpose: Treatment
Official Title: Prévention Des Fausses Couches Spontanées Répétées Par Hydroxychloroquine. Essai thérapeutique Multicentrique, randomisé, en Double Insu, Contre Placebo
Actual Study Start Date : December 4, 2017
Estimated Primary Completion Date : November 1, 2023
Estimated Study Completion Date : February 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Miscarriage

Arm Intervention/treatment
Experimental: Hydroxychloroquine
The treatment will be orally administrated, at a daily dose of 400 mg of hydroxychloroquine . The treatment will be started before conception and will be stopped at the end of the tenth week of gestation or before in case of pregnancy loss.
Drug: Hydroxychloroquine
Hydroxychloroquine : 200 mg twice a day

Placebo Comparator: Placebo
A similar placebo will be orally administrated every day.
Drug: Placebo
placebo of hydroxychloroquine




Primary Outcome Measures :
  1. A live and viable birth [ Time Frame: At delivery ]
    In case of preterm and/or low birth weight, we define the viability by the decision to transfer the newborn to a neonatal intensive care unit


Secondary Outcome Measures :
  1. a live and viable birth (for the subgroup analyses) [ Time Frame: At delivery ]
  2. occurrence of pregnancy complications (Recurrent Miscarriage-any other premature termination of pregnancy-placental vascular disease) [ Time Frame: Since the beginning of pregnancy up to delivery ]
  3. gestation time (in weeks of amenorrhea) at delivery, [ Time Frame: At delivery up ]
  4. birth weight (in grams) at delivery [ Time Frame: At delivery ]
  5. survival of the newborn [ Time Frame: At 28 days of the newborn ]
  6. psychomotor development of the child (normal/abnormal) [ Time Frame: at 6 months of age ]
  7. psychomotor development of the child (normal/abnormal) [ Time Frame: at 12 months of age ]
  8. height (in centimeters) [ Time Frame: at 6 months of age ]
  9. height (in centimeters) [ Time Frame: at 12 months of age ]
  10. weight (in grams) [ Time Frame: at 6 months of age ]
  11. weight (in grams) [ Time Frame: at 12 months of age ]
  12. Cranial perimeter (in centimeters) [ Time Frame: at 6 months of age ]
  13. Cranial perimeter (in centimeters) [ Time Frame: at 12 months of age ]


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Ages Eligible for Study:   18 Years to 37 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • women aged from 18 to 37 years,
  • women trying to conceive,
  • women with at least 3 previous consecutive miscarriage in the first pregnancy trimester, of unknown origin (normal parental karyotypes, no uterine cavity abnormality, no antiphospholipid syndrome with other clinical events than RM in the first trimester of pregnancy.)
  • women who have given their informed consent

Exclusion Criteria:

  • ongoing pregnancy,
  • Normal pregnancy since the last miscarriage,
  • Uterine cavity abnormality,
  • Abnormal parental karyotype,
  • Antiphospholipid syndrome defined as both persistent positive antiphospholipid antibodies (40 IU or more of anticardiolipin or anti beta2 GPI IgG or IgM, and/or lupus anticoagulant) and a specific clinical setting (thrombotic or obstetrical, apart from RM)
  • women with a contraindication or an indication to a treatment by hydroxychloroquine
  • Previous exposure > 4 years to chloroquine or hydroxychloroquine
  • impossible follow up

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03165136


Contacts
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Contact: Elisabeth PASQUIER, MD 33298145018 elisabeth.pasquier@chu-brest.fr
Contact: Gisèle MARHIC, Ing 336979937954 gisele.marhic@chu-brest.fr

Locations
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France
CH d'Auch Recruiting
Auch, France, 32008
Contact: Véronique Lejeune-Saada       v.lejeune@ch-auch.fr   
CHU Besançon Recruiting
Besançon, France, 25030
Contact: Aude Bourtembourg-Matras       a1bourtembourg@chu-besancon.fr   
CHRU de Brest Recruiting
Brest, France, 29609
Contact: Elisabeth PASQUIER       elisabeth.pasquier@chu-brest.fr   
Contact: Gisèle MARHIC       gisele.marhic@chu-brest.fr   
CHU Estaing Recruiting
Clermont-Ferrand, France
Contact: Denis Gallot       dgallot@chu-clermontferrand.fr   
CHRU de Lille Not yet recruiting
Lille, France, 59037
Contact: Véronique Debarge       veronique.debarge@chru-lille.fr   
Hôpital Nord - Unité mère-enfant Recruiting
Marseille, France, 13015
Contact: Florence Bretelle       florence.bretelle@ap-hm.fr   
CH de Mont de Marsan Recruiting
Mont-de-Marsan, France, 40000
Contact: Sophie Defer       sophie.defert@ch-mdm.fr   
CHU de Nantes Recruiting
Nantes, France, 44093
Contact: Norbet Winer       norbert.winer@chu-nantes.fr   
Hopital Port Royal Cochin Recruiting
Paris 14, France, 75679
Contact: Geneviève Plu-Bureau       genevieve.plu-bureau@aphp.fr   
Hopital Saint Antoine Recruiting
Paris, France, 75012
Contact: Arsène Mekinian       arsene.mekinian@aphp.fr   
Hôpital Bichat Not yet recruiting
Paris, France, 75018
Contact: Dominique Luton       dluton@free.fr   
CHG François Mitterand Recruiting
Pau, France, 64 000
Contact: Caroline Bohec       caroline.bohec@ch-pau.fr   
Centre hospitalier de Cornouaille Recruiting
Quimper, France, 29000
Contact: Charles Bellot       c.bellot@ch-cornouaille.fr   
Hôpital sud de Rennes Recruiting
Rennes, France, 35200
Contact: Céline Pimentel       celine.pimentel@chu.rennes.fr   
CHU de Saint Etienne - Hôpital Nord Recruiting
Saint Etienne, France, 42 270
Contact: Céline Chauleur       celine.chauleur@chu-st-etienne.fr   
Nouvel Hôpital Civil Not yet recruiting
Strasbourg, France, 67091
Contact: Vincent Poindron       vincent.poindron@chru-strasbourg.fr   
CH de Bigorre Recruiting
Tarbes, France, 65013
Contact: Giulia Mencattini       g.mencattini@ch-tarbes-vic.fr   
Sponsors and Collaborators
University Hospital, Brest
Investigators
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Principal Investigator: Elisabeth PASQUIER, MD EA3878 - University Hospital of Brest

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Responsible Party: University Hospital, Brest
ClinicalTrials.gov Identifier: NCT03165136     History of Changes
Other Study ID Numbers: 29BRC16.0045
First Posted: May 24, 2017    Key Record Dates
Last Update Posted: June 17, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Brest:
Unexplained Recurrent Miscarriage
First trimester abortion
Hydroxychloroquine
Antiphospholipid antibody

Additional relevant MeSH terms:
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Abortion, Spontaneous
Abortion, Habitual
Pregnancy Complications
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents