Use of Cyclosporin A for the Treatment of Recurrent Miscarriage

Miscarriage, Recurrent Clinical Trial

Official title:

A Randomized, Controlled Trial of Cyclosporin A for Women With Unexplained Recurrent Miscarriage

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02706470
• Other study ID #: 2013SY034
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• First received: February 2, 2016
• Last updated: March 12, 2016
• Start date: May 2016
• Est. completion date: December 2018

Study information

• Verified date: March 2016
• Source: Fudan University
• Contact: Jiangfeng Ye, MD
• Phone: 86-21-33189900
• Email: jiangfeng_ye[@]hotmail.com
• Is FDA regulated: No
• Health authority: China: Shanghai Municipal Commission of Health and Family Planning
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether Cyclosporin A (CsA) - an immunosuppressant drug - in early pregnancy will reduce the risk of miscarriage in women who had a history of unexplained recurrent miscarriages, as compared with that treated with Dydrogesterone-an active comparator. The hypothesis is based on the evidence found in vitro and in vivo experiments that CsA can induce maternal-fetal tolerance so that it may reduce the risk of miscarriage.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 384
• Est. completion date: December 2018
• Est. primary completion date: February 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

Inclusion Criteria:

• Both the woman and her husband agree to participate and sign the informed consent form.

• Have a history of two or more unexplained recurrent miscarriages.

• Spontaneous conception.

• Gestational age less than 5 weeks.

• Have a normal menstrual cycle (>=23 and <=35 days) and biphasic pattern of basal body temperature before pregnancy.

• No significant chromosomal aberrations in the couple.

• Semen quality tests show not apparent abnormalities in husband

Exclusion Criteria:

• Age below 18 or above 41 years at conception.

• Present pregnancy is a result of donor insemination or egg donation.

• Significant uterine anomalies detected by ultrasonography, hysterosalpingography, or hysteroscopy.

• Contraindications of CsA (e.g. severe infectious diseases, tumor or immunodeficiency) or Dydrogesterone.

• Smoking more than 20 daily.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Abortion, Habitual
• Abortion, Spontaneous
• Miscarriage, Recurrent

Intervention

Drug:
• Cyclosporin A
Patients will receive oral CsA in a dose of 50mg three times a day for 20-30 days since the occurrence of positive result in human chorionic gonadotropin (HCG) test in urine and 14 consecutive days of elevated basal body temperature. The dosage of CsA will be adjusted according to baseline and peak value of CsA blood concentration. If the baseline blood concentration of CsA is lower than 40ng/ml or the peak blood concentration of CsA is lower than 500ng/ml, the dosage of CsA will be increased to 75 mg three times a day.
• Dydrogesterone
Patients will receive oral dydrogesterone 10 mg three times a day for 30 days since the occurrence of positive result in HCG test in urine and 14 consecutive days of elevated basal body temperature.

Locations

Country	Name	City	State
China	Obstetrics and Gynecology Hospital of Fudan University	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Fudan University

Country where clinical trial is conducted

China, 

References & Publications (12)

Du MR, Dong L, Zhou WH, Yan FT, Li DJ. Cyclosporin a improves pregnancy outcome by promoting functions of trophoblasts and inducing maternal tolerance to the allogeneic fetus in abortion-prone matings in the mouse. Biol Reprod. 2007 May;76(5):906-14. Epub 2007 Jan 17. — View Citation

Du MR, Zhou WH, Dong L, Zhu XY, He YY, Yang JY, Li DJ. Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated AP1 and Ca2+/calcineurin/NFAT signaling pathways. Biol Reprod. 2008 Jun;78(6):1102-10. doi: 10.1095/biolreprod.107.063503. Epub 2008 Mar 5. — View Citation

Du MR, Zhou WH, Piao HL, Li MQ, Tang CL, Li DJ. Cyclosporin A promotes crosstalk between human cytotrophoblast and decidual stromal cell through up-regulating CXCL12/CXCR4 interaction. Hum Reprod. 2012 Jul;27(7):1955-65. doi: 10.1093/humrep/des111. Epub 2012 Apr 11. — View Citation

Du MR, Zhou WH, Yan FT, Zhu XY, He YY, Yang JY, Li DJ. Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells. Hum Reprod. 2007 Sep;22(9):2528-37. Epub 2007 Jul 18. — View Citation

Huang YH, Ma YL, Ma L, Mao JL, Zhang Y, Du MR, Li DJ. Cyclosporine A improves adhesion and invasion of mouse preimplantation embryos via upregulating integrin ß3 and matrix metalloproteinase-9. Int J Clin Exp Pathol. 2014 Mar 15;7(4):1379-88. eCollection 2014. — View Citation

Piao HL, Wang SC, Tao Y, Zhu R, Sun C, Fu Q, Du MR, Li DJ. Cyclosporine A enhances Th2 bias at the maternal-fetal interface in early human pregnancy with aid of the interaction between maternal and fetal cells. PLoS One. 2012;7(9):e45275. doi: 10.1371/journal.pone.0045275. Epub 2012 Sep 27. — View Citation

Tang CL, Zhao HB, Li MQ, Du MR, Meng YH, Li DJ. Focal adhesion kinase signaling is necessary for the Cyclosporin A-enhanced migration and invasion of human trophoblast cells. Placenta. 2012 Sep;33(9):704-11. doi: 10.1016/j.placenta.2012.06.007. Epub 2012 Jul 4. — View Citation

Wang SC, Tang ChL, Piao HL, Zhu R, Sun Ch, Tao Y, Fu Q, Li DJ, Du MR. Cyclosporine A promotes in vitro migration of human first-trimester trophoblasts via MAPK/ERK1/2-mediated NF-?B and Ca2+/calcineurin/NFAT signaling. Placenta. 2013 Apr;34(4):374-80. doi: 10.1016/j.placenta.2013.01.009. Epub 2013 Feb 11. — View Citation

Wang SC, Yu M, Li YH, Piao HL, Tang CL, Sun C, Zhu R, Li MQ, Jin LP, Li DJ, Du MR. Cyclosporin A promotes proliferating cell nuclear antigen expression and migration of human cytotrophoblast cells via the mitgen-activated protein kinase-3/1-mediated nuclear factor-?B signaling pathways. Int J Clin Exp Pathol. 2013 Sep 15;6(10):1999-2010. eCollection 2013. — View Citation

Zhao HB, Tang CL, Hou YL, Xue LR, Li MQ, Du MR, Li DJ. CXCL12/CXCR4 axis triggers the activation of EGF receptor and ERK signaling pathway in CsA-induced proliferation of human trophoblast cells. PLoS One. 2012;7(7):e38375. doi: 10.1371/journal.pone.0038375. Epub 2012 Jul 27. — View Citation

Zhou WH, Dong L, Du MR, Zhu XY, Li DJ. Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4. Reproduction. 2008 Mar;135(3):385-95. doi: 10.1530/REP-07-0063. — View Citation

Zhou WH, Du MR, Dong L, Zhu XY, Yang JY, He YY, Li DJ. Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway. Hum Reprod. 2007 Oct;22(10):2743-50. Epub 2007 Jun 12. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Live birth rate	The difference in the live birth rates between patients with recurrent miscarriage assigned oral CsA and Dydrogesterone.	Up to 36 months	No
Secondary	The difference in the rate of miscarriage between patients with recurrent miscarriage treated with CsA and Dydrogesterone.	The difference in the rates of miscarriage (pregnancy loss before 20 weeks gestation) between patients assigned oral CsA and Dydrogesterone.	Up to 36 months	No
Secondary	Fetal death	The difference in the rates of fetal death (fetal death after 20 weeks of gestational age) between patients assigned oral CsA and Dydrogesterone.	Up to 36 months	No
Secondary	The difference in the rate of premature delivery between patients treated with CsA and Dydrogesterone.	The difference in the rates of premature delivery (deliveries with gestational age less than 37 weeks) between patients assigned oral CsA and Dydrogesterone.	Up to 36 months	Yes
Secondary	Congenital malformations	The difference in the rates of congenital malformations between patients assigned oral CsA and Dydrogesterone.	Up to 36 months	Yes
Secondary	Maternal outcomes: morbidity of infectious disease	The difference of morbidity of infectious disease in pregnancy between two arms.	Up to 36 months	Yes