Prévention Des Fausses Couches Spontanées Répétées Par Hydroxychloroquine. Essai thérapeutique Multicentrique, randomisé, en Double Insu, Contre Placebo
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 300
- 试验地点
- 18
- 主要终点
- A live and viable birth
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Active drug and placebo will be exactly the same
入排标准
- 年龄范围
- 18 Years 至 38 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Hydroxychloroquine (Drug)
Placebo
A similar placebo will be orally administrated every day.
干预措施: Placebo (Drug)
结局指标
主要结局
A live and viable birth
时间窗: 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
次要结局
- gestation time (in weeks of amenorrhea) at delivery,(At delivery up)
- birth weight (in grams) at delivery(At delivery)
- survival of the newborn(At 28 days of the newborn)
- psychomotor development of the child (normal/abnormal)(at 12 months of age)
- height (in centimeters)(at 12 months of age)
- weight (in grams)(at 12 months of age)
- Cranial perimeter (in centimeters)(at 12 months of age)
- a live and viable birth (for the subgroup analyses)(At delivery)
- occurrence of pregnancy complications (Recurrent Miscarriage-any other premature termination of pregnancy-placental vascular disease)(Since the beginning of pregnancy up to delivery)