Clinical trial NCT03671174: Immunosuppressant Regimens for Living Fetuses Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Undifferentiated Connective Tissue Disease
Recurrent Pregnancy Loss
Lead sponsor: RenJi Hospital
Sponsor class: OTHER
Collaborators: name: The First Affiliated Hospital of Anhui Medical University
name: China-Japan Union Hospital, Jilin University
name: Wuxi No. 2 People's Hospital
name: The First Affiliated Hospital with Nanjing Medical University
name: Xiangya Hospital of Central South University
First posted: 2018-09-14
Enrollment: 420
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion criteria

Women who meet the following inclusion criteria will be eligible to participate in the study:

1. At reproductive age (20-40 years old).
2. Trying to conceive.
3. 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.
4. Diagnosed with RSA\[39\]: two or more failed pregnancies of unknown origin.
5. 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:

1. Diagnosis of antiphospholipid antibody syndrome.
2. Known paternal, maternal or embryo chromosome abnormality.
3. 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.
4. Maternal anatomical abnormality: uterine malformation; Asherman syndrome; cervical incompetence; uterine fibrosis more than 5 cm.
5. 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:

1. Active viral hepatitis including hepatitis B virus (HBV), hepatitis C virus (HCV).
2. 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:

1. Past history of digestive ulcers or upper gastrointestinal hemorrhage.
2. Past history of malignancy.
3. Past history of epilepsia or psychotic disorders. 6.Woman unable to consent or impossible to follow-up.

Primary outcomes:
measure: Live birth rate
timeFrame: After 28 weeks of gestation
Secondary outcomes:
measure: Rate of miscarriage
timeFrame: Within 28 weeks of gestation
measure: Premature birth
timeFrame: between 28 and 37 weeks of gestations
measure: Intrauterine growth retardation
timeFrame: between 28 and 37 weeks of gestations
measure: Gestational age and weight at birth
timeFrame: post-partum 6 weeks
measure: Survival at 28 days
timeFrame: post-partum 6 weeks
measure: Number of newborns with treatment-related adverse events assessed by 3 parameters
timeFrame: post-partum 6 weeks
measure: Congenital abnormality
timeFrame: post-partum 6 weeks
measure: Eclampsia
timeFrame: After 20 weeks of gestation
measure: Number of participants with Infection
timeFrame: through study completion, an average of 1.5 years
measure: Gestational diabetes mellitus
timeFrame: through study completion, an average of 1.5 years
measure: Activity of UCTD
timeFrame: through study completion, an average of 1.5 years
measure: Number of participants who evolved to systemic lupus erythematosus(SLE) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
measure: Number of participants who evolved to Sjogren's syndrome(SS) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
measure: Number of participants who evolved to systemic sclerosis(SSc) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
measure: Number of participants who evolved to polymyositis(PM) or dermatomyositis(DM) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
measure: Number of participants who evolved to antiphospholipid syndrome (APS) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
measure: Number of participants who evolved to rheumatoid arthritis (RA) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
measure: Number of participants who evolved to mixed connective tissue disease(MCTD) from undifferentiated connective tissue diseases(UCTD)
timeFrame: post-partum 6 weeks
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Renji Hospital
state: Shanghai
Study officials:
affiliation: RenJi Hospital
name: Liangjing Lu
role: STUDY_CHAIR
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