Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss

Sponsor

Ain Shams University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05237843

Collaborator

(none)

Enrollment

Arms

10.1

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

To investigate efficacy and safety of Hydroxychloroquin in improving pregnancy outcome in women with unexplained recurrent pregnancy loss .

Condition or Disease	Intervention/Treatment	Phase
Recurrent Pregnancy Loss	Drug: Hydroxychloroquine	Phase 1

Detailed Description

Recurrent pregnancy loss (RPL) remains a significant challenge in obstetrical practice. It is not only emotionally devastating for expectant women but is also medically challenging. Approximately 1-3% of women have recurrent spontaneous abortion, defined as ≥3 pregnancy losses before the age of viability .The European Society of Human Reproduction and Embryology (ESHRE 2021) defined RPL as three or more consecutive losses. The American College of Obstetrics and Gynecology (ACOG 2020) defined RPL as two or more consecutive losses and the American Society for Reproductive Medicine (ASRM 2021) defined RPL as two or more failed pregnancies.

RPL maybe due to uterine anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation/platelet defects . Many of these causes are treatable . However, in about 40%-50% of pregnancy-loss cases, there is no identifiable cause. As such, the term "unexplained recurrent pregnancy loss" (URPL) is the spontaneous loss of three or more consecutive pregnancies without an identifiable risk factor .

Endometrial environment plays a crucial place in embryo implantation and early placental development. In normal pregnancy, the survival of the semi-allogeneic fetus is dependent on the induction of maternal immune tolerance, with decrease regulatory T cells and Th-2 anti-inflammatory profile in peripheral blood and endometrium .

Several reports show a misbalance of immune cells and cytokines expression such as increased Th1 to Th2 cytokine ratio in women with recurrent miscarriage and implantation failure .The excess activation of the proinflammatory pathways may inhibit the proliferation and invasion of the extravillous trophoblast and induce the activation of the immune cells with a direct damage to the trophoblast . So several studies have highlighted the immune deregulation to explain URM , Consequently, it has been hypothesized that immunomodulatory drugs could be a relevant therapy in URM .Among them, various treatments have been recently used, as HCQ . .

Heparin-based drugs are essential in treating thrombosis and embolisms and preventing thromboembolic phenomena. Heparin works primarily by inhibiting thrombin (factor IIa) and factor Xa. Heparin use is associated with the risk of bleeding, osteoporosis and heparin-induced thrombocytopenia so requiring close monitoring .Apart from its antithrombotic effects, heparin has anti-inflammatory effect which consist to prevent the endothelial cells adhesion to the endothelium; heparin can bind selectins and integrins and interfere with complement activation. But these anti-thrombotic treatments have been used for several years to enhance live birth rates in URM, but failed to reach significant efficacy .

Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines , Few in vitro studies showed a potential benefit of hydroxychloroquine in early trophoblastic migration and implantation. Hydroxychloroquine restored trophoblastic fusion and differentiation and restored the annexin A5 expression .

Hydroxychloroquine is widely used during the pregnancy, in particular in patients with systemic lupus erythematous. The main severe adverse effects in mothers include the allergic reactions, potential heart toxicity, and retinopathy. The retinal toxicity mainly concerns treatment duration of more than 5 years and the risk remain low in patients with regular follow-up . Audio-vestibular and ophthalmological studies of children at 12 months of life born from mothers under hydroxychloroquine during pregnancy showed no apparent abnormality and were similar to non-exposed children.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Group A (control group) : 35 women in this group will receive only the standard treatment in the form of low- dose aspirin (LDA) 81 mg/day (Jusprin® 81mg which manufactured by Future Pharmaceutical Company), and LMWH (Enoxaparin, Clexane® which manufactured by SANOFI company) with a dose ( .5 mg/kg) subcutaneously injected/24 hr . LDA ought to be begun before origination, while LMWH ought to be begun after confirmation of pregnancy by detecting fetal viability by ultrasound plus Placebo specially manufactured tablets in our Ain shams faculty of pharmacy . Group B ( Hydroxychloroquine group ) : This group included 35 women who will administered Hydroxychloroquine 200 mg (Hydroquine® 200mg which fabricated by MinaPharm Company) one tablets / day in addition to the standard therapyGroup A (control group) : 35 women in this group will receive only the standard treatment in the form of low- dose aspirin (LDA) 81 mg/day (Jusprin® 81mg which manufactured by Future Pharmaceutical Company), and LMWH (Enoxaparin, Clexane® which manufactured by SANOFI company) with a dose ( .5 mg/kg) subcutaneously injected/24 hr . LDA ought to be begun before origination, while LMWH ought to be begun after confirmation of pregnancy by detecting fetal viability by ultrasound plus Placebo specially manufactured tablets in our Ain shams faculty of pharmacy . Group B ( Hydroxychloroquine group ) : This group included 35 women who will administered Hydroxychloroquine 200 mg (Hydroquine® 200mg which fabricated by MinaPharm Company) one tablets / day in addition to the standard therapy

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Each 70 sequential patient numbers were composed murky envelope while task code composed different paper that then fixed inside. At hour predisposition visit individual control opened envelope to uncover task, continued like manner (bunch A or B ).

Primary Purpose:

Prevention

Official Title:

Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss ,Double Blinded Randomized Controlled Trial .

Anticipated Study Start Date :

Mar 1, 2022

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Group A (control group) 35 women in this group will receive only the standard treatment in the form of : low- dose aspirin (LDA) 81 mg/day orally (Jusprin® 81mg which manufactured by Future Pharmaceutical Company), LMWH (Enoxaparin, Clexane® which manufactured by SANOFI company) with a dose ( .5 mg/kg) subcutaneously injected/24 hr . LDA ought to be begun before origination, while LMWH ought to be begun after confirmation of pregnancy by detecting fetal viability by ultrasound till age of viability (20wks) -PLUS Placebo specially manufactured tablets in Ain shams faculty of pharmacy will start once known she is pregnan	Drug: Hydroxychloroquine Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines ( Mekinian A et al ,2015 ) , Few in vitro studies showed a potential benefit of hydroxychloroquine in early trophoblastic migration and implantation. Hydroxychloroquine restored trophoblastic fusion and differentiation and restored the annexin A5 expression.( Guller S et al ,2011 ) Other Names: placebo - Aspirin (LDA) - Clexan (LMWH)
Experimental: Group B ( Hydroxychloroquine group ) This group included 35 women who will administered Hydroxychloroquine 200 mg (Hydroquine® 200mg which fabricated by MinaPharm Company) one tablets / day once known she is pregnant in addition to the standard therapy (LMWH + LDA )	Drug: Hydroxychloroquine Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines ( Mekinian A et al ,2015 ) , Few in vitro studies showed a potential benefit of hydroxychloroquine in early trophoblastic migration and implantation. Hydroxychloroquine restored trophoblastic fusion and differentiation and restored the annexin A5 expression.( Guller S et al ,2011 ) Other Names: placebo - Aspirin (LDA) - Clexan (LMWH)
No Intervention: Study Director Only those directing the study know the treatment that each participant receives Placebo OR Hydroxychloroquin

Arm

Intervention/Treatment

Placebo Comparator: Group A (control group)

35 women in this group will receive only the standard treatment in the form of : low- dose aspirin (LDA) 81 mg/day orally (Jusprin® 81mg which manufactured by Future Pharmaceutical Company), LMWH (Enoxaparin, Clexane® which manufactured by SANOFI company) with a dose ( .5 mg/kg) subcutaneously injected/24 hr . LDA ought to be begun before origination, while LMWH ought to be begun after confirmation of pregnancy by detecting fetal viability by ultrasound till age of viability (20wks) -PLUS Placebo specially manufactured tablets in Ain shams faculty of pharmacy will start once known she is pregnan

Drug: Hydroxychloroquine

Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines ( Mekinian A et al ,2015 ) , Few in vitro studies showed a potential benefit of hydroxychloroquine in early trophoblastic migration and implantation. Hydroxychloroquine restored trophoblastic fusion and differentiation and restored the annexin A5 expression.( Guller S et al ,2011 )

Other Names:

placebo - Aspirin (LDA) - Clexan (LMWH)

Experimental: Group B ( Hydroxychloroquine group )

This group included 35 women who will administered Hydroxychloroquine 200 mg (Hydroquine® 200mg which fabricated by MinaPharm Company) one tablets / day once known she is pregnant in addition to the standard therapy (LMWH + LDA )

Drug: Hydroxychloroquine

Other Names:

placebo - Aspirin (LDA) - Clexan (LMWH)

No Intervention: Study Director

Only those directing the study know the treatment that each participant receives Placebo OR Hydroxychloroquin

Outcome Measures

Primary Outcome Measures

To investigate HCQ as a new edition in URPL protocol in change rate of pregnancy loss side by side with anticoagulant traditional treatment [one year to be completed]
Describing 200 mg of HCQ daily in unexplained recurrent pregnancy loss start once she makes sure of pregnancy till 20 weeks of pregnancy

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Women aged between 18 and 35 years inclusive.
Women with at least three previous consecutive miscarriages in the first trimester of pregnancy of unknown origin with no uterine cavity abnormality that might explain recurrent miscarriage at 3D ultrasonography
Women who have given their informed consent.
Patient who did received standard treatment and failed in an ongoing pregnancy

Exclusion Criteria:

Previous history VTE (venous thromboembolization)
Persistent positive APL antibodies: lupus anticoagulant and/or APL (anticardiolipin or anticardiolipin IgG or IgM) titers >99th percentile or >40 with at least 12 weeks interval between two positive determinations (persistent antibodies) or a specific clinical setting of APS (thrombotic or obstetrical, apart from RM in the first trimester of pregnancy) .
Known contraindication to a treatment by HCQ (retinopathy, hypersensitivity to chloroquine or HCQ, G6PD deficiency, acute intermittent porphyria, chronic liver or kidney insufficiency, extensive cutaneous psoriasis not controlled by local treatment, significant chronic digestive or haematologic disease) .
Indication to a treatment by HCQ (rheumatoid arthritis, Lupus, solar eczema) or previous exposure for >5years to HCQ.
BMI > 35
Condition may have an effect on immune reaction e.g. history of HCV or HBV .
Endocrinopathies such as ( DM ,thyroid disorders , hyperprolactinemia ) .
History of hormonal contraception or intrauterine device usage in last 3 months preceeding .