Clinical trial NCT03165136: Hydroxychloroquine for Prevention of Recurrent Miscarriage.
Official title: Prévention Des Fausses Couches Spontanées Répétées Par Hydroxychloroquine. Essai thérapeutique Multicentrique, randomisé, en Double Insu, Contre Placebo
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Recurrent Miscarriage
First Trimester Abortion
Keywords: Unexplained Recurrent Miscarriage
First trimester abortion
Hydroxychloroquine
Antiphospholipid antibody
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
First posted: 2017-05-24
Enrollment: 300
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 38
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double Blind Randomized clinical trial
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: A live and viable birth
timeFrame: At delivery
Secondary outcomes:
measure: a live and viable birth (for the subgroup analyses)
timeFrame: At delivery
measure: occurrence of pregnancy complications (Recurrent Miscarriage-any other premature termination of pregnancy-placental vascular disease)
timeFrame: Since the beginning of pregnancy up to delivery
measure: gestation time (in weeks of amenorrhea) at delivery,
timeFrame: At delivery up
measure: birth weight (in grams) at delivery
timeFrame: At delivery
measure: survival of the newborn
timeFrame: At 28 days of the newborn
measure: psychomotor development of the child (normal/abnormal)
timeFrame: at 6 months of age
measure: psychomotor development of the child (normal/abnormal)
timeFrame: at 12 months of age
measure: height (in centimeters)
timeFrame: at 6 months of age
measure: height (in centimeters)
timeFrame: at 12 months of age
measure: weight (in grams)
timeFrame: at 6 months of age
measure: weight (in grams)
timeFrame: at 12 months of age
measure: Cranial perimeter (in centimeters)
timeFrame: at 6 months of age
measure: Cranial perimeter (in centimeters)
timeFrame: at 12 months of age
Other outcomes:
Locations:
city: Annecy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Auch
country: France
facility: CH d'Auch
city: Besançon
country: France
facility: CHU Besançon
city: Brest
country: France
facility: CHRU de Brest
city: Clermont-Ferrand
country: France
facility: CHU Estaing
city: Lille
country: France
facility: CHRU de Lille
city: Marseille
country: France
facility: Hôpital Nord - Unité mère-enfant
city: Mont-de-Marsan
country: France
facility: CH de Mont de Marsan
city: Nantes
country: France
facility: CHU de Nantes
city: Paris 14
country: France
facility: Hopital Port Royal Cochin
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hôpital Bichat
city: Pau
country: France
facility: CHG François Mitterand
city: Quimper
country: France
facility: Centre hospitalier de Cornouaille
city: Rennes
country: France
facility: Hôpital sud de Rennes
city: Saint Etienne
country: France
facility: CHU de Saint Etienne - Hôpital Nord
city: Strasbourg
country: France
facility: Nouvel Hôpital Civil
city: Tarbes
country: France
facility: CH de Bigorre
Study officials:
affiliation: EA3878 - University Hospital of Brest
name: Elisabeth PASQUIER, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.