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Immunosuppressant Regimens for Living Fetuses Study

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ClinicalTrials.gov Identifier: NCT03671174
Recruitment Status : Recruiting
First Posted : September 14, 2018
Last Update Posted : August 12, 2019
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Liangjing Lu, RenJi Hospital

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
Undifferentiated Connective Tissue Disease Recurrent Pregnancy Loss Drug: Prednisone Drug: Hydroxychloroquine Drug: Aspirin Drug: low molecular weight heparin Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 420 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 2, 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine


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:
  • Enoxaparin
  • Dalteparin
  • Nadroparin

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:
  • Enoxaparin
  • Dalteparin
  • Nadroparin

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:
  • Enoxaparin
  • Dalteparin
  • Nadroparin




Primary Outcome Measures :
  1. Live birth rate [ Time Frame: After 28 weeks of gestation ]
    Percentage of all cycles that lead to live birth


Secondary Outcome Measures :
  1. Rate of miscarriage [ Time Frame: 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.

  2. Premature birth [ Time Frame: 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)

  3. Intrauterine growth retardation [ Time Frame: 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)

  4. Gestational age and weight at birth [ Time Frame: post-partum 6 weeks ]
    the children's gestational age and weight at birth

  5. Survival at 28 days [ Time Frame: post-partum 6 weeks ]
    still alive at 28 days

  6. Number of newborns with treatment-related adverse events assessed by 3 parameters [ Time Frame: post-partum 6 weeks ]
    assess the number of the newborns with abnormal vision, hearing and length at 6 weeks

  7. Congenital abnormality [ Time Frame: post-partum 6 weeks ]
    congenital heart conduction block, neonatal lupus or malformation

  8. Eclampsia [ Time Frame: 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

  9. Number of participants with Infection [ Time Frame: through study completion, an average of 1.5 years ]
    Infection of respiratory tract, digestive tract, urinary tract and skin

  10. Gestational diabetes mellitus [ Time Frame: through study completion, an average of 1.5 years ]
    Clinical diagnosis of gestational diabetes mellitus

  11. Activity of UCTD [ Time Frame: through study completion, an average of 1.5 years ]
    New onset or aggravation of symptoms like arthritis, rash, Reynolds phenomenon, proteinuria, etc.

  12. Number of participants who evolved to systemic lupus erythematosus(SLE) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of systemic lupus erythematosus

  13. Number of participants who evolved to Sjogren's syndrome(SS) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of Sjogren's syndrome

  14. Number of participants who evolved to systemic sclerosis(SSc) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of systemic sclerosis

  15. Number of participants who evolved to polymyositis(PM) or dermatomyositis(DM) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of polymyositis or dermatomyositis

  16. Number of participants who evolved to antiphospholipid syndrome (APS) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of antiphospholipid syndrome

  17. Number of participants who evolved to rheumatoid arthritis (RA) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of rheumatoid arthritis

  18. Number of participants who evolved to mixed connective tissue disease(MCTD) from undifferentiated connective tissue diseases(UCTD) [ Time Frame: post-partum 6 weeks ]
    Clinical diagnosis of mixed connective tissue disease



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03671174


Contacts
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Contact: Liangjing Lu +86 13661472001 lu_liangjing@163.com

Locations
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China, Shanghai
Renji Hospital Recruiting
Shanghai, Shanghai, China, 200001
Contact: Liangjing Lu    +8613661472001    lu_liangjing@163.com   
Contact: Shaoying Yang    +8613601984013    shaoying_yang@163.com   
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
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Study Chair: Liangjing Lu RenJi Hospital

Publications of Results:

Other Publications:
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Responsible Party: Liangjing Lu, Professor, RenJi Hospital
ClinicalTrials.gov Identifier: NCT03671174     History of Changes
Other Study ID Numbers: ILIFE Study
First Posted: September 14, 2018    Key Record Dates
Last Update Posted: August 12, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Connective Tissue Diseases
Undifferentiated Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Aspirin
Hydroxychloroquine
Prednisone
Heparin
Calcium heparin
Heparin, Low-Molecular-Weight
Dalteparin
Nadroparin
Immunosuppressive Agents
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors