Immunosuppressant Regimens for Living Fetuses Study

Recurrent Pregnancy Loss Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03671174
• Other study ID #: ILIFE Study
• Status: Recruiting
• Phase: N/A
• Start date: August 2, 2019
• Est. completion date: February 2023

Study information

• Verified date: August 2019
• Source: RenJi Hospital
• Contact: Liangjing Lu
• Phone: +86 13661472001
• Email: lu_liangjing[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 420
• Est. completion date: February 2023
• Est. primary completion date: September 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Abortion, Habitual
• Connective Tissue Diseases
• Recurrent Pregnancy Loss
• Undifferentiated Connective Tissue Disease
• Undifferentiated Connective Tissue Diseases

Intervention

Drug:
• Prednisone
10mg once daily orally
• Hydroxychloroquine
100mg to 200mg twice daily orally
• Aspirin
50mg once daily orally
• low molecular weight heparin
Enoxaparin 40mg once daily subcutaneous or dalteparin 5000IU once daily subcutaneous or nadroparin calcium 4100U once daily subcutaneous

Locations

Country	Name	City	State
China	Renji Hospital	Shanghai	Shanghai

Sponsors (6)

Lead Sponsor	Collaborator
RenJi Hospital	China-Japan Union Hospital, Jilin University, The First Affiliated Hospital of Anhui Medical University, The First Affiliated Hospital with Nanjing Medical University, Wuxi No. 2 People's Hospital, Xiangya Hospital of Central South University

Country where clinical trial is conducted

China, 

References & Publications (20)

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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. — View Citation

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. Review. — View Citation

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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 controlle — View Citation

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 — View Citation

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 — View Citation

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. — View Citation

Laczik R, Soltesz P, Szodoray P, Szekanecz Z, Kerekes G, Paragh G, Rajnavölgyi 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;5 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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):63 — View Citation

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 stud — View Citation

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Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, Barros R, Santos MJ, Sousa E, Barcelos A, Inês L. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009 Aug;28(8):915-21. doi: 10.100 — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Live birth rate	Percentage of all cycles that lead to live birth	After 28 weeks of gestation
Secondary	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
Secondary	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
Secondary	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
Secondary	Gestational age and weight at birth	the children's gestational age and weight at birth	post-partum 6 weeks
Secondary	Survival at 28 days	still alive at 28 days	post-partum 6 weeks
Secondary	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
Secondary	Congenital abnormality	congenital heart conduction block, neonatal lupus or malformation	post-partum 6 weeks
Secondary	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
Secondary	Number of participants with Infection	Infection of respiratory tract, digestive tract, urinary tract and skin	through study completion, an average of 1.5 years
Secondary	Gestational diabetes mellitus	Clinical diagnosis of gestational diabetes mellitus	through study completion, an average of 1.5 years
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of participants who evolved to systemic sclerosis(SSc) from undifferentiated connective tissue diseases(UCTD)	Clinical diagnosis of systemic sclerosis	post-partum 6 weeks
Secondary	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
Secondary	Number of participants who evolved to antiphospholipid syndrome (APS) from undifferentiated connective tissue diseases(UCTD)	Clinical diagnosis of antiphospholipid syndrome	post-partum 6 weeks
Secondary	Number of participants who evolved to rheumatoid arthritis (RA) from undifferentiated connective tissue diseases(UCTD)	Clinical diagnosis of rheumatoid arthritis	post-partum 6 weeks
Secondary	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