Immunosuppressant Regimens for Living Fetuses Study

NCT03671174 | Unknown

• 1 other identifier: ILIFE Study
• Study Type: interventional
• Target: 420
• Locations: 1 country
• Sites: 1

Brief Summary

Undifferentiated connective tissue diseases (UCTD) are known to increase the risk of pregnancy morbidities, including recurrent pregnancy loss. However, there is no consensus or guideline about the treatment for recurrent pregnancy loss in UCTD patients. Therefore, based on the tendency to thrombosis formation and placental inflammation in the pathogenesis of UCTD, this trial proposes to evaluate the effect of hydroxychloroquine with or without prednisone combined with anticoagulation on pregnancy outcomes in recurrent pregnancy loss patients with UCTD.

Conditions

Undifferentiated Connective Tissue Disease; Recurrent Pregnancy Loss

Outcome Measures

Primary Outcomes (1)

• Live birth rate

  Percentage of all cycles that lead to live birth

  After 28 weeks of gestation

Secondary Outcomes (18)

• Rate of miscarriage

  Within 28 weeks of gestation

• Premature birth

  between 28 and 37 weeks of gestations

• Intrauterine growth retardation

  between 28 and 37 weeks of gestations

• Gestational age and weight at birth

  post-partum 6 weeks

• Survival at 28 days

  post-partum 6 weeks

Study Arms (3)

Prednisone + hydroxychloroquine + anticoagulation

EXPERIMENTAL

Oral low-dose prednisone PLUS Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin

Drug: Prednisone; Drug: Hydroxychloroquine; Drug: Aspirin; Drug: low molecular weight heparin

Hydroxychloroquine + anticoagulation

EXPERIMENTAL

Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin

Drug: Hydroxychloroquine; Drug: Aspirin; Drug: low molecular weight heparin

Anticoagulation

ACTIVE COMPARATOR

Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin

Drug: Aspirin; Drug: low molecular weight heparin

Interventions

Prednisone DRUG

10mg once daily orally

Prednisone + hydroxychloroquine + anticoagulation

Hydroxychloroquine DRUG

100mg to 200mg twice daily orally

Hydroxychloroquine + anticoagulation; Prednisone + hydroxychloroquine + anticoagulation

Aspirin DRUG

50mg once daily orally

Anticoagulation; Hydroxychloroquine + anticoagulation; Prednisone + hydroxychloroquine + anticoagulation

low molecular weight heparin DRUG

Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous

Also known as: Enoxaparin, Dalteparin, Nadroparin

Anticoagulation; Hydroxychloroquine + anticoagulation; Prednisone + hydroxychloroquine + anticoagulation

Eligibility Criteria

• Age: 20 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• At reproductive age (20-40 years old).
• Trying to conceive.
• Diagnosed with UCTD\[2\]: at least one symptoms or signs suggesting connective tissue disease(CTD) and with at least one presence of auto-antibodies, including antinuclear antibody (ANA), anti-SSA antibody, while not fulfilling any classification criteria of a defined CTD.
• Diagnosed with RSA\[39\]: two or more failed pregnancies of unknown origin.

You may not qualify if:

• Women who meet any of the following criteria will be excluded from the study:
• Any known etiology of previous pregnancy loss:
• Diagnosis of antiphospholipid antibody syndrome.
• Known paternal, maternal or embryo chromosome abnormality.
• Maternal endocrine dysfunction: corpus luteal insufficiency; polycystic ovarian syndrome; premature ovarian failure (follicle stimulating hormone, FSH ≥20uU/L in follicular phase); hyperprolactinemia; thyroid disease; diabetes mellitus; other hypothalamic-pituitary-adrenal axis abnormality.
• Maternal anatomical abnormality: uterine malformation; Asherman syndrome; cervical incompetence; uterine fibrosis more than 5 cm.
• Vaginal infection. 2.Any known severe cardiac, hepatic, renal, hematological or endocrinal diseases:
• (1)Alanine transaminase (ALT) or aspartate transaminase(AST) more than twice the upper limit of normal.
• (2)Clearance of creatinine less than 30mL/min. (3)Leucocytes less than 2.5\*10\^9/L, or Hemoglobine less than 85g/L, or Platelet less than 50\~10\^9/L.
• Any active infection:
• Active viral hepatitis including hepatitis B virus (HBV), hepatitis C virus (HCV).
• Active infection including V aricella-zostervirus(VZV), human immunodeficiency virus (HIV), syphilis or tuberculosis.
• Allergic to prednisone, hydroxychloroquine, low-molecular-weight heparin or aspirin.
• Disease history as follows:
• Past history of digestive ulcers or upper gastrointestinal hemorrhage.

Sponsors & Collaborators

• RenJi Hospital: lead
• The First Affiliated Hospital of Anhui Medical University: collaborator
• China-Japan Union Hospital, Jilin University: collaborator
• Wuxi No. 2 People's Hospital: collaborator
• The First Affiliated Hospital with Nanjing Medical University: collaborator
• Xiangya Hospital of Central South University: collaborator

Study Sites (1)

Renji Hospital

Shanghai, Shanghai Municipality, 200001, China

RECRUITING

Related Publications (21)

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  PMID: 10544849 BACKGROUND

• Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R, Costedoat-Chalumeau N, Doria A, Fischer-Betz R, Forger F, Moraes-Fontes MF, Khamashta M, King J, Lojacono A, Marchiori F, Meroni PL, Mosca M, Motta M, Ostensen M, Pamfil C, Raio L, Schneider M, Svenungsson E, Tektonidou M, Yavuz S, Boumpas D, Tincani A. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis. 2017 Mar;76(3):476-485. doi: 10.1136/annrheumdis-2016-209770. Epub 2016 Jul 25.

  PMID: 27457513 BACKGROUND

• Spinillo A, Beneventi F, Caporali R, Ramoni V, Montecucco C. Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association? Am J Reprod Immunol. 2017 Dec;78(6). doi: 10.1111/aji.12762. Epub 2017 Sep 16.

  PMID: 28921728 BACKGROUND

• Alarcon GS, Williams GV, Singer JZ, Steen VD, Clegg DO, Paulus HE, Billingsley LM, Luggen ME, Polisson RP, Willkens RF, et al. Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease. J Rheumatol. 1991 Sep;18(9):1332-9.

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• Laczik R, Soltesz P, Szodoray P, Szekanecz Z, Kerekes G, Paragh G, Rajnavolgyi E, Abel G, Szegedi G, Bodolay E. Impaired endothelial function in patients with undifferentiated connective tissue disease: a follow-up study. Rheumatology (Oxford). 2014 Nov;53(11):2035-43. doi: 10.1093/rheumatology/keu236. Epub 2014 Jun 10.

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  PMID: 27756248 RESULT

• Mosca M, Neri R, Strigini F, Carmignani A, Totti D, Tavoni A, Bombardieri S. Pregnancy outcome in patients with undifferentiated connective tissue disease: a preliminary study on 25 pregnancies. Lupus. 2002;11(5):304-7. doi: 10.1191/0961203302lu187oa.

  PMID: 12090565 RESULT

• Spinillo A, Beneventi F, Epis OM, Montanari L, Mammoliti D, Ramoni V, Di Silverio E, Alpini C, Caporali R, Montecucco C. The effect of newly diagnosed undifferentiated connective tissue disease on pregnancy outcome. Am J Obstet Gynecol. 2008 Dec;199(6):632.e1-6. doi: 10.1016/j.ajog.2008.05.008. Epub 2008 Jul 29.

  PMID: 18667193 RESULT

• Alijotas-Reig J, Ferrer-Oliveras R; EUROAPS Study Group. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a preliminary first year report. Lupus. 2012 Jun;21(7):766-8. doi: 10.1177/0961203312440058.

  PMID: 22635227 RESULT

• Proietta M, Ferrero S, Ferri L, Cifani N, Bruno G, Del Porto F. Recurrent miscarriages in women not fulfilling classification criteria for antiphospholipid antibody syndrome. Int J Immunopathol Pharmacol. 2014 Jul-Sep;27(3):429-32. doi: 10.1177/039463201402700313.

  PMID: 25280034 RESULT

• Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, Barros R, Santos MJ, Sousa E, Barcelos A, Ines L. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009 Aug;28(8):915-21. doi: 10.1007/s10067-009-1175-2. Epub 2009 Apr 24.

  PMID: 19390908 RESULT

• Bansal AS. Joining the immunological dots in recurrent miscarriage. Am J Reprod Immunol. 2010 Nov;64(5):307-15. doi: 10.1111/j.1600-0897.2010.00864.x.

  PMID: 20528832 RESULT

• Tempfer CB, Kurz C, Bentz EK, Unfried G, Walch K, Czizek U, Huber JC. A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril. 2006 Jul;86(1):145-8. doi: 10.1016/j.fertnstert.2005.12.035. Epub 2006 May 23.

  PMID: 16716321 RESULT

• Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet. 2014 Oct;290(4):757-62. doi: 10.1007/s00404-014-3262-0. Epub 2014 May 13.

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• Gonzalez-Lopez L, Gamez-Nava JI, Jhangri G, Russell AS, Suarez-Almazor ME. Decreased progression to rheumatoid arthritis or other connective tissue diseases in patients with palindromic rheumatism treated with antimalarials. J Rheumatol. 2000 Jan;27(1):41-6.

  PMID: 10648016 RESULT

• Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 2006 Nov;54(11):3640-7. doi: 10.1002/art.22159.

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  PMID: 25305214 RESULT

• Luo Y, Zhang L, Fei Y, Li Y, Hao D, Liu Y, Zhao Y. Pregnancy outcome of 126 anti-SSA/Ro-positive patients during the past 24 years--a retrospective cohort study. Clin Rheumatol. 2015 Oct;34(10):1721-8. doi: 10.1007/s10067-015-3050-7. Epub 2015 Aug 26.

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• Sciascia S, Hunt BJ, Talavera-Garcia E, Lliso G, Khamashta MA, Cuadrado MJ. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol. 2016 Feb;214(2):273.e1-273.e8. doi: 10.1016/j.ajog.2015.09.078. Epub 2015 Sep 30.

  PMID: 26429521 RESULT

• Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, Salmon JE, Buyon JP. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis. 2010 Oct;69(10):1827-30. doi: 10.1136/ard.2009.119263. Epub 2010 May 6.

  PMID: 20447951 RESULT

• Yang S, Ni R, Lu Y, Wang S, Xie F, Zhang C, Lu L. A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the Immunosuppressant regimens for LIving FEtuses (ILIFE) trial. Trials. 2020 Sep 9;21(1):771. doi: 10.1186/s13063-020-04716-1.

  PMID: 32907619 DERIVED

MeSH Terms

Conditions

Undifferentiated Connective Tissue Diseases

Interventions

Prednisone; Hydroxychloroquine; Aspirin; Heparin, Low-Molecular-Weight; Enoxaparin; Dalteparin; Nadroparin

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Liangjing Lu

  RenJi Hospital

  STUDY CHAIR

Central Study Contacts

Liangjing Lu

CONTACT

+86 13661472001; lu_liangjing@163.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 30, 2018
• First Posted: September 14, 2018
• Study Start: August 2, 2019
• Primary Completion: September 1, 2021
• Study Completion: February 1, 2023
• Last Updated: August 12, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)