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Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss

Primary Purpose

Recurrent Pregnancy Loss

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Hydroxychloroquine
Sponsored by
Ain Shams University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Recurrent Pregnancy Loss

Eligibility Criteria

18 Years - 35 Years (Adult)FemaleDoes not accept 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 .

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Placebo Comparator

    Experimental

    No Intervention

    Arm Label

    Group A (control group)

    Group B ( Hydroxychloroquine group )

    Study Director

    Arm Description

    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

    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 )

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

    Outcomes

    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
    Describing 200 mg of HCQ daily in unexplained recurrent pregnancy loss start once she makes sure of pregnancy till 20 weeks of pregnancy

    Secondary Outcome Measures

    Full Information

    First Posted
    November 23, 2021
    Last Updated
    February 9, 2022
    Sponsor
    Ain Shams University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05237843
    Brief Title
    Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss
    Official Title
    Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss ,Double Blinded Randomized Controlled Trial .
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2021
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    March 1, 2022 (Anticipated)
    Primary Completion Date
    November 2022 (Anticipated)
    Study Completion Date
    January 2023 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Ain Shams University

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No

    5. Study Description

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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Recurrent Pregnancy Loss

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    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 therapy
    Masking
    ParticipantCare ProviderInvestigator
    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 ).
    Allocation
    Randomized
    Enrollment
    70 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Group A (control group)
    Arm Type
    Placebo Comparator
    Arm Description
    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
    Arm Title
    Group B ( Hydroxychloroquine group )
    Arm Type
    Experimental
    Arm Description
    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 )
    Arm Title
    Study Director
    Arm Type
    No Intervention
    Arm Description
    Only those directing the study know the treatment that each participant receives Placebo OR Hydroxychloroquin
    Intervention Type
    Drug
    Intervention Name(s)
    Hydroxychloroquine
    Other Intervention Name(s)
    placebo - Aspirin (LDA) - Clexan (LMWH)
    Intervention Description
    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 )
    Primary Outcome Measure Information:
    Title
    To investigate HCQ as a new edition in URPL protocol in change rate of pregnancy loss side by side with anticoagulant traditional treatment
    Description
    Describing 200 mg of HCQ daily in unexplained recurrent pregnancy loss start once she makes sure of pregnancy till 20 weeks of pregnancy
    Time Frame
    one year to be completed

    10. Eligibility

    Sex
    Female
    Gender Based
    Yes
    Gender Eligibility Description
    study will go on pregnant females
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    35 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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 .

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    Data obtained through this study may be provided to new guide for recurrent pregnancy lss. Data or samples shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party
    IPD Sharing Time Frame
    Basline
    IPD Sharing Access Criteria
    Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact: yasmineabdoud@gmail.com
    Citations:
    PubMed Identifier
    23942472
    Citation
    Alijotas-Reig J, Garrido-Gimenez C. Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv. 2013 Jun;68(6):445-66. doi: 10.1097/OGX.0b013e31828aca19.
    Results Reference
    result
    PubMed Identifier
    24995856
    Citation
    de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014 Jul 4;2014(7):CD004734. doi: 10.1002/14651858.CD004734.pub4.
    Results Reference
    result
    PubMed Identifier
    19439078
    Citation
    Sperber K, Hom C, Chao CP, Shapiro D, Ash J. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr Rheumatol Online J. 2009 May 13;7:9. doi: 10.1186/1546-0096-7-9.
    Results Reference
    result
    PubMed Identifier
    25681385
    Citation
    Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J. 2015 Mar;91(1073):151-62. doi: 10.1136/postgradmedj-2014-132672. Epub 2015 Feb 13.
    Results Reference
    result
    PubMed Identifier
    21718553
    Citation
    Duckitt K, Qureshi A. Recurrent miscarriage. BMJ Clin Evid. 2011 Feb 1;2011:1409.
    Results Reference
    result
    PubMed Identifier
    24581729
    Citation
    Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta. 2014 Apr;35(4):241-8. doi: 10.1016/j.placenta.2014.02.004. Epub 2014 Feb 14.
    Results Reference
    result
    PubMed Identifier
    26371706
    Citation
    Liang PY, Diao LH, Huang CY, Lian RC, Chen X, Li GG, Zhao J, Li YY, He XB, Zeng Y. The pro-inflammatory and anti-inflammatory cytokine profile in peripheral blood of women with recurrent implantation failure. Reprod Biomed Online. 2015 Dec;31(6):823-6. doi: 10.1016/j.rbmo.2015.08.009. Epub 2015 Aug 21.
    Results Reference
    result
    PubMed Identifier
    10632428
    Citation
    Lim KJ, Odukoya OA, Ajjan RA, Li TC, Weetman AP, Cooke ID. The role of T-helper cytokines in human reproduction. Fertil Steril. 2000 Jan;73(1):136-42. doi: 10.1016/s0015-0282(99)00457-4.
    Results Reference
    result
    PubMed Identifier
    21112094
    Citation
    Otun HA, Lash GE, Innes BA, Bulmer JN, Naruse K, Hannon T, Searle RF, Robson SC. Effect of tumour necrosis factor-alpha in combination with interferon-gamma on first trimester extravillous trophoblast invasion. J Reprod Immunol. 2011 Jan;88(1):1-11. doi: 10.1016/j.jri.2010.10.003. Epub 2010 Nov 26.
    Results Reference
    result
    PubMed Identifier
    9344498
    Citation
    Haddad EK, Duclos AJ, Antecka E, Lapp WS, Baines MG. Role of interferon-gamma in the priming of decidual macrophages for nitric oxide production and early pregnancy loss. Cell Immunol. 1997 Oct 10;181(1):68-75. doi: 10.1006/cimm.1997.1199.
    Results Reference
    result
    PubMed Identifier
    27100512
    Citation
    Onishi A, St Ange K, Dordick JS, Linhardt RJ. Heparin and anticoagulation. Front Biosci (Landmark Ed). 2016 Jun 1;21(7):1372-92. doi: 10.2741/4462.
    Results Reference
    result
    PubMed Identifier
    25653897
    Citation
    Quaranta M, Erez O, Mastrolia SA, Koifman A, Leron E, Eshkoli T, Mazor M, Holcberg G. The physiologic and therapeutic role of heparin in implantation and placentation. PeerJ. 2015 Jan 6;3:e691. doi: 10.7717/peerj.691. eCollection 2015.
    Results Reference
    result
    PubMed Identifier
    21871597
    Citation
    Wu XX, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol. 2011 Dec;205(6):576.e7-14. doi: 10.1016/j.ajog.2011.06.064. Epub 2011 Jun 24.
    Results Reference
    result
    PubMed Identifier
    22002012
    Citation
    Osadchy A, Ratnapalan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol. 2011 Dec;38(12):2504-8. doi: 10.3899/jrheum.110686. Epub 2011 Oct 15.
    Results Reference
    result
    Links:
    URL
    http://worldwidescience.org/topicpages/i/improving+pregnancy+outcome.html
    Description
    Obstetrical APS : Is there a place for hydroxychloroquine to improve the pregnancy outcome?

    Learn more about this trial

    Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss

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