Immunosuppressant Regimens for Living Fetuses Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Three-arm, Multicenter, Open-label Randomized Controlled Trial of Hydroxychloroquine and Low-dose Prednisone on Recurrent Spontaneous Abortion With Undifferentiated Connective Tissue Diseases: Protocol for the Immunosuppressant Regimens for Living FEtuses (ILIFE) Trial

Conditions
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Undifferentiated Connective Tissue Disease, Recurrent Pregnancy Loss

Intervention / Treatment
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* Drug: Prednisone
* Drug: Hydroxychloroquine
* Drug: Aspirin
* Drug: low molecular weight heparin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Women who meet the following inclusion criteria will be eligible to participate in the study: 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. 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: 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. 3.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. 4.Allergic to prednisone, hydroxychloroquine, low-molecular-weight heparin or aspirin. 5.Disease history as follows: Past history of digestive ulcers or upper gastrointestinal hemorrhage. Past history of malignancy. Past history of epilepsia or psychotic disorders. 6.Woman unable to consent or impossible to follow-up.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisone + hydroxychloroquine + anticoagulation<br>Oral low-dose prednisone PLUS Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin | Drug: Prednisone<br>* 10mg once daily orally<br>Drug: Hydroxychloroquine<br>* 100mg to 200mg twice daily orally<br>Drug: Aspirin<br>* 50mg once daily orally<br>Drug: low molecular weight heparin<br>* Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous<br>* Other names: Nadroparin;|
| Experimental: Hydroxychloroquine + anticoagulation<br>Oral hydroxychloroquine PLUS Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin | Drug: Hydroxychloroquine<br>* 100mg to 200mg twice daily orally<br>Drug: Aspirin<br>* 50mg once daily orally<br>Drug: low molecular weight heparin<br>* Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous<br>* Other names: Nadroparin;|
| Active Comparator: Anticoagulation<br>Oral low-dose aspirin PLUS subcutaneous low-molecular-weight heparin | Drug: Aspirin<br>* 50mg once daily orally<br>Drug: low molecular weight heparin<br>* Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous<br>* Other names: Nadroparin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rate | Percentage of all cycles that lead to live birth | After 28 weeks of gestation | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 |