Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study

Abstract

IntroductionRecurrent miscarriage (RM), defined by three or more consecutive losses during the first trimester of pregnancy, affects 1%–2% of fertile couples. Standard investigations fail to reveal any apparent cause in ~50% of couples. However, on the basis of animal models and clinical studies, several hypotheses have been put forward concerning underlying mechanisms of RM: altered ovarian reserve, progesterone defect, thrombotic and/or endothelial dysfunction and immunological disturbances. Nonetheless, no study has yet reached conclusive beneficial clinical evidence for a potential treatment in unexplained RM. Hydroxychloroquine (HCQ) is a molecule with extensive safety data during pregnancy. The pharmacological properties of HCQ (eg, antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious) could be effective against some mechanisms of unexplained RM. Furthermore, eventhough clinical benefit of HCQ is suggested in prevention of thrombotic and late obstetric events in antiphospholipid (APL) syndrome, there are no data suggesting the benefit of HCQ in RM in the presence of APL antibodies.Methods and analysisTaken all together and given the low cost of HCQ, the aim of this multicentre, randomised, placebo-controlled, double-blind study is to investigate whether HCQ would improve the live birth rate in women with RM, irrespective of maternal thrombophilic status: (1) no known thrombophilia, (2) inherited thrombophilia or (3) APL antibodies. The primary end point is a live and viable birth. After confirming eligibility and obtaining consent, 300 non-pregnant women will be randomised into two parallel groups for a daily oral treatment (HCQ 400 mg or placebo), initiated before conception and stopped at 10 weeks’ gestation. If pregnancy does not occur after 1 year, the treatment will be stopped.Ethics and disseminationAgreement from the French National Public Health and Drug Security Agency (160765A-22) and ethical approval from the Committee for the Protection of Persons of NORD-OUEST I (2016-001330-97) have been obtained.Trial registration numbersNCT0316513; Pre-results.

Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates

“…Apart from APS, HCQ is also being explored for its potential utility in patients with recurrent pregnancy loss. In this French RCT (the BBQ trial), patients with recurrent pregnancy loss shall be treated with HCQ 400 mg daily or placebo starting pre-conception until the 10 th week of pregnancy, with the objective of assessing whether treatment improves pregnancy outcomes in such patients [ 18 ].…”

16th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric Antiphospholipid Syndrome

“…The HCQ for Prevention of RM or BBQ study is a French trial investigating if HCQ might improve pregnancy outcomes as measured by live and viable birth when given at a daily dose of 400 mg and stopped at the end of 10 WG in women with ≥3 losses in the first trimester of pregnancy (ClinicalTrials.gov: NCT03165136, estimated study completion date: February 2023. 106 Similarly, a Danish study, HCQ for Recurrent Pregnancy Loss, is currently recruiting women without aPL antibody positivity with recurrent miscarriages (ClinicalTrials.gov: NCT03305263, estimated study completion date: January 2023).…”

Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage

“…Two phase‐3 multicentre double‐blind randomised clinical trials are ongoing and are investigating the preventive effect of HCQ on fetal loss in women with a history of RM. One trial is a French study, namely, “HCQ for Prevention of RM or BBQ” (ClinicalTrials.gov: NCT03165136; estimated study completion date: February 2023), which compares HCQ to a placebo in women with RM (three or more losses in the first trimester of pregnancy) regardless of their thrombophilia status. HCQ is orally administered before conception onset at a daily dose of 400 mg and is stopped at the end of 10 WG.…”