Immunosuppressant Regimens for Living Fetuses Study
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Prednisone + hydroxychloroquine + anticoagulation Oral low-dose prednisone PLUS Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin |
Drug: Prednisone
10mg once daily orally
Drug: Hydroxychloroquine
100mg to 200mg twice daily orally
Drug: Aspirin
50mg once daily orally
Drug: low molecular weight heparin
Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous
Other Names:
|
| Experimental: Hydroxychloroquine + anticoagulation Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin |
Drug: Hydroxychloroquine
100mg to 200mg twice daily orally
Drug: Aspirin
50mg once daily orally
Drug: low molecular weight heparin
Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous
Other Names:
|
| Active Comparator: Anticoagulation Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin |
Drug: Aspirin
50mg once daily orally
Drug: low molecular weight heparin
Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Live birth rate [After 28 weeks of gestation]
Percentage of all cycles that lead to live birth
Secondary Outcome Measures
- Rate of miscarriage [Within 28 weeks of gestation]
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.
- Premature birth [between 28 and 37 weeks of gestations]
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)
- Intrauterine growth retardation [between 28 and 37 weeks of gestations]
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)
- Gestational age and weight at birth [post-partum 6 weeks]
the children's gestational age and weight at birth
- Survival at 28 days [post-partum 6 weeks]
still alive at 28 days
- Number of newborns with treatment-related adverse events assessed by 3 parameters [post-partum 6 weeks]
assess the number of the newborns with abnormal vision, hearing and length at 6 weeks
- Congenital abnormality [post-partum 6 weeks]
congenital heart conduction block, neonatal lupus or malformation
- Eclampsia [After 20 weeks of gestation]
New-onset hypertension after 20 weeks of gestation, with or without proteinuria > 300mg/24h, with or without any organ damage with seizures
- Number of participants with Infection [through study completion, an average of 1.5 years]
Infection of respiratory tract, digestive tract, urinary tract and skin
- Gestational diabetes mellitus [through study completion, an average of 1.5 years]
Clinical diagnosis of gestational diabetes mellitus
- Activity of UCTD [through study completion, an average of 1.5 years]
New onset or aggravation of symptoms like arthritis, rash, Reynolds phenomenon, proteinuria, etc.
- Number of participants who evolved to systemic lupus erythematosus(SLE) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of systemic lupus erythematosus
- Number of participants who evolved to Sjogren's syndrome(SS) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of Sjogren's syndrome
- Number of participants who evolved to systemic sclerosis(SSc) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of systemic sclerosis
- Number of participants who evolved to polymyositis(PM) or dermatomyositis(DM) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of polymyositis or dermatomyositis
- Number of participants who evolved to antiphospholipid syndrome (APS) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of antiphospholipid syndrome
- Number of participants who evolved to rheumatoid arthritis (RA) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of rheumatoid arthritis
- Number of participants who evolved to mixed connective tissue disease(MCTD) from undifferentiated connective tissue diseases(UCTD) [post-partum 6 weeks]
Clinical diagnosis of mixed connective tissue disease
Eligibility Criteria
Criteria
Inclusion criteria
Women who meet the following inclusion criteria will be eligible to participate in the study:
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At reproductive age (20-40 years old).
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Trying to conceive.
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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.
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Diagnosed with RSA[39]: two or more failed pregnancies of unknown origin.
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Providing written informed consent. Exclusion criteria
Women who meet any of the following criteria will be excluded from the study:
1.Any known etiology of previous pregnancy loss:
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Diagnosis of antiphospholipid antibody syndrome.
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Known paternal, maternal or embryo chromosome abnormality.
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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.
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Maternal anatomical abnormality: uterine malformation; Asherman syndrome; cervical incompetence; uterine fibrosis more than 5 cm.
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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*109/L, or Hemoglobine less than 85g/L, or Platelet less than 50~109/L.
3.Any active infection:
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Active viral hepatitis including hepatitis B virus (HBV), hepatitis C virus (HCV).
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Active infection including V aricella-zostervirus(VZV), human immunodeficiency virus (HIV), syphilis or tuberculosis.
4.Allergic to prednisone, hydroxychloroquine, low-molecular-weight heparin or aspirin.
5.Disease history as follows:
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Past history of digestive ulcers or upper gastrointestinal hemorrhage.
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Past history of malignancy.
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Past history of epilepsia or psychotic disorders. 6.Woman unable to consent or impossible to follow-up.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Renji Hospital | Shanghai | Shanghai | China | 200001 |
Sponsors and Collaborators
- RenJi Hospital
- The First Affiliated Hospital of Anhui Medical University
- China-Japan Union Hospital, Jilin University
- Wuxi No. 2 People's Hospital
- The First Affiliated Hospital with Nanjing Medical University
- Xiangya Hospital of Central South University
Investigators
- Study Chair: Liangjing Lu, RenJi Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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. Review.
- 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. Review.
- ILIFE Study