Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| The First Affiliated Hospital of Anhui Medical University | OTHER |
| China-Japan Union Hospital, Jilin University | OTHER |
| Wuxi No. 2 People's Hospital | OTHER |
Not provided
Not provided
Not provided
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.
Objective: To evaluate the effect of anticoagulation with or without immunomodulatory therapy on pregnancy outcomes of recurrent pregnancy loss with undifferentiated connective tissue diseases Design: a multi-center, randomised, open-label, paralleled study. Patients: Pregnant patients with recurrent pregnancy loss and undifferentiated connective tissue diseases without any known etiology for pregnancy loss (detailed in section 10).
Methods: 420 selected patients are divided into 3 parallel groups (detailed in section 8).
Randomization: Patients who present to relevant clinics for management of recurrent spontaneous abortion (RSA) will be evaluated for inclusion criteria and exclusion criteria by a formed physician. Once patient is eligible for the study, the co-investigator will obtain written patient's consent. Participants will be randomized into one of the 3 groups. Randomized numbers will be generated by pharmacology research personnel in Renji Hospital. Given the different administrated medications, neither the patient nor the provider will be blinded.
Follow-up: Consultation will be scheduled every 4 weeks from confirmed pregnancy until delivery. The co-investigator will complete a follow-up survey including clinical, biological data.
Missing data: Patients are willing to drop the study, unavailable, incompliant, with severe complications or with severe adverse effects. The missing data will be recorded in detail and be analysed with last pregnancy outcome.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prednisone + hydroxychloroquine + anticoagulation | Experimental | Oral low-dose prednisone PLUS Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin |
|
| Hydroxychloroquine + anticoagulation | Experimental | Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin |
|
| Anticoagulation | Active Comparator | Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prednisone | Drug | 10mg once daily orally |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Live birth rate | Percentage of all cycles that lead to live birth | After 28 weeks of gestation |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of miscarriage | Spontaneous pregnancy loss within 28 weeks of gestation, confirmed by pelvic ultrasound findings. This includes no yolk sac or embryo in a gestational sac and an embryo without cardiac activity. | Within 28 weeks of gestation |
| Premature birth |
Not provided
Inclusion criteria
Women who meet the following inclusion criteria will be eligible to participate in the study:
Women who meet any of the following criteria will be excluded from the study:
1.Any known etiology of previous pregnancy loss:
(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.
3.Any active infection:
4.Allergic to prednisone, hydroxychloroquine, low-molecular-weight heparin or aspirin.
5.Disease history as follows:
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Liangjing Lu | Contact | +86 13661472001 | lu_liangjing@163.com |
| Name | Affiliation | Role |
|---|---|---|
| Liangjing Lu | RenJi Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Renji Hospital | Recruiting | Shanghai | Shanghai Municipality | 200001 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10544849 | Background | Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999 Sep-Oct;17(5):615-20. | |
| 27457513 | 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. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D000074079 | Undifferentiated Connective Tissue Diseases |
| ID | Term |
|---|---|
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D011241 | Prednisone |
| D006886 | Hydroxychloroquine |
| D001241 | Aspirin |
| D006495 | Heparin, Low-Molecular-Weight |
| D017984 | Enoxaparin |
| D017985 | Dalteparin |
| D017762 | Nadroparin |
| ID | Term |
|---|---|
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
Not provided
Not provided
| The First Affiliated Hospital with Nanjing Medical University |
| OTHER |
| Xiangya Hospital of Central South University | OTHER |
Not provided
Not provided
Not provided
Not provided
Not provided
| Hydroxychloroquine |
| Drug |
100mg to 200mg twice daily orally |
|
| Aspirin | Drug | 50mg once daily orally |
|
| low molecular weight heparin | Drug | Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous |
|
|
live birth between 28 and 37 weeks of gestations Prematurity (live birth between 28 and 37 weeks of gestations); Eclampsia (new-onset hypertension after 20 weeks of gestation, +/- proteinuria > 300mg/24h, with or without any organ damage with seizures); Fetal abnormality (congenital heart conduction block, neonatal lupus or malformation) |
| between 28 and 37 weeks of gestations |
| Intrauterine growth retardation | weight below the 10th percentile for the gestational age Prematurity (live birth between 28 and 37 weeks of gestations); Eclampsia (new-onset hypertension after 20 weeks of gestation, +/- proteinuria > 300mg/24h, with or without any organ damage with seizures); Fetal abnormality (congenital heart conduction block, neonatal lupus or malformation) | between 28 and 37 weeks of gestations |
| Gestational age and weight at birth | the children's gestational age and weight at birth | post-partum 6 weeks |
| Survival at 28 days | still alive at 28 days | post-partum 6 weeks |
| Number of newborns with treatment-related adverse events assessed by 3 parameters | assess the number of the newborns with abnormal vision, hearing and length at 6 weeks | post-partum 6 weeks |
| Congenital abnormality | congenital heart conduction block, neonatal lupus or malformation | post-partum 6 weeks |
| Eclampsia | New-onset hypertension after 20 weeks of gestation, with or without proteinuria > 300mg/24h, with or without any organ damage with seizures | After 20 weeks of gestation |
| Number of participants with Infection | Infection of respiratory tract, digestive tract, urinary tract and skin | through study completion, an average of 1.5 years |
| Gestational diabetes mellitus | Clinical diagnosis of gestational diabetes mellitus | through study completion, an average of 1.5 years |
| Activity of UCTD | New onset or aggravation of symptoms like arthritis, rash, Reynolds phenomenon, proteinuria, etc. | through study completion, an average of 1.5 years |
| Number of participants who evolved to systemic lupus erythematosus(SLE) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of systemic lupus erythematosus | post-partum 6 weeks |
| Number of participants who evolved to Sjogren's syndrome(SS) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of Sjogren's syndrome | post-partum 6 weeks |
| Number of participants who evolved to systemic sclerosis(SSc) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of systemic sclerosis | post-partum 6 weeks |
| Number of participants who evolved to polymyositis(PM) or dermatomyositis(DM) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of polymyositis or dermatomyositis | post-partum 6 weeks |
| Number of participants who evolved to antiphospholipid syndrome (APS) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of antiphospholipid syndrome | post-partum 6 weeks |
| Number of participants who evolved to rheumatoid arthritis (RA) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of rheumatoid arthritis | post-partum 6 weeks |
| Number of participants who evolved to mixed connective tissue disease(MCTD) from undifferentiated connective tissue diseases(UCTD) | Clinical diagnosis of mixed connective tissue disease | post-partum 6 weeks |
| 28921728 | 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. |
| 1757934 | Result | 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. |
| 24917564 | Result | 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. |
| 27756248 | Result | Spinillo A, Beneventi F, Locatelli E, Ramoni V, Caporali R, Alpini C, Albonico G, Cavagnoli C, Montecucco C. The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study. BMC Pregnancy Childbirth. 2016 Oct 18;16(1):313. doi: 10.1186/s12884-016-1076-8. |
| 12090565 | 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. |
| 18667193 | 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. |
| 22635227 | 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. |
| 25280034 | 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. |
| 19390908 | 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. |
| 20528832 | 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. |
| 16716321 | 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. |
| 24818590 | 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. |
| 10648016 | Result | 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. |
| 17075810 | 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. |
| 25305214 | Result | Koh JH, Ko HS, Kwok SK, Ju JH, Park SH. Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. Lupus. 2015 Feb;24(2):210-7. doi: 10.1177/0961203314555352. Epub 2014 Oct 10. |
| 26384980 | 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. |
| 26429521 | Result | 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. |
| 20447951 | 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. |
| 32907619 | Derived | 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. |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |