Hydroxychloroquine for Prevention of Recurrent Miscarriage.

NCT ID: NCT03165136

Last Updated: 2023-10-02

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-04
• Study Completion Date: 2026-02-01

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.

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.

Conditions

Recurrent Miscarriage; First Trimester Abortion

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Hydroxychloroquine

Intervention Type: DRUG

Hydroxychloroquine : 200 mg twice a day

Placebo

A similar placebo will be orally administrated every day.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

placebo of hydroxychloroquine

Interventions

Hydroxychloroquine

Hydroxychloroquine : 200 mg twice a day

Intervention Type: DRUG

Placebo

placebo of hydroxychloroquine

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• women aged from 18 to 38 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 38 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Brest

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elisabeth PASQUIER, MD

Role: PRINCIPAL_INVESTIGATOR

EA3878 - University Hospital of Brest

Locations

Centre Hospitalier Annecy Genevois

Annecy, , France

CH d'Auch

Auch, , France

CHU Besançon

Besançon, , France

CHRU de Brest

Brest, , France

CHU Estaing

Clermont-Ferrand, , France

CHRU de Lille

Lille, , France

Hôpital Nord - Unité mère-enfant

Marseille, , France

CH de Mont de Marsan

Mont-de-Marsan, , France

CHU de Nantes

Nantes, , France

Hopital Saint Antoine

Paris, , France

Hôpital Bichat

Paris, , France

Hopital Port Royal Cochin

Paris, , France

CHG François Mitterand

Pau, , France

Centre hospitalier de Cornouaille

Quimper, , France

Hôpital sud de Rennes

Rennes, , France

CHU de Saint Etienne - Hôpital Nord

Saint-Etienne, , France

Nouvel Hôpital Civil

Strasbourg, , France

CH de Bigorre

Tarbes, , France

Countries

France

References

Pasquier E, de Saint-Martin L, Marhic G, Chauleur C, Bohec C, Bretelle F, Lejeune-Saada V, Hannigsberg J, Plu-Bureau G, Cogulet V, Merviel P, Mottier D. Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study. BMJ Open. 2019 Mar 20;9(3):e025649. doi: 10.1136/bmjopen-2018-025649.

Reference Type: DERIVED

PMID: 30898821 (View on PubMed)

Other Identifiers

29BRC16.0045

Identifier Type: -

Identifier Source: org_study_id