Efficacy and Safety of Gushen Antai Pill on Ongoing Pregnancy Rate in Women With Normal Ovarian Reserve Undergoing IVF-ET

Overview

The purpose of this study is to investigate whether oral Gushen Antai pills supplementation for luteal support from the day of human chorionic gonadotropin trigger will improve clinical and ongoing pregnancy rates in women with normal ovarian reserve in fresh embryo transfer cycles.

Full Title of Study: “Efficacy and Safety of Gushen Antai Pill on Ongoing Pregnancy Rate in Women With Normal Ovarian Reserve Undergoing in Vitro Fertilization Embryo Transfer: A Prospective, Multicentre, Randomised, Double-blind, Placebo-controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 2021

Detailed Description

Infertility is a growing reproductive health problem, and it is estimated that approximately 15% of couples of reproductive ages are affected. The invention and popularity of IVF-ET technology, although improving sperm egg encounter and fertilization barriers and implanting early embryos from the uterine cavity in vitro, still do not solve the problem of the uterine implantation environment or endometrial receptivity, and the pregnancy rate needs to be further improved. However, traditional Chinese medicine (TCM) has an original theoretical understanding and exact efficacy for gynecological diseases, therefore, it is necessary to supplement TCM interventions with endometrial receptivity as described above. TCM is a kind of traditional treatment method with thousands of years history in China, and some previous studies have shown its unique experience in assisting pregnancy and reduce vaginal bleeding in early pregnancy . Similar to the notion of "hypothalamus- pituitary-ovary axis" that is established by Western medicine, TCM also has deeply studied the reproductive regulation of kidney and proposed the concept of "kidney-Tian Gui-Chong Ren-uterine axis." According to TCM, "Kidney Governs Reproduction," and female infertility is closely related to kidney deficiency, and the main therapeutic principle of it involves tonification of the kidney. GSATP is widely used as an adjunctive therapy in women with threatened abortion in China and the clinical effects reflected by the patients remained satisfactory. The function of GSATP is nourishing yin and tonifying the kidney, strengthening Chong and prevent miscarriage. GSATP is used in the early threatened abortion, which belongs to the kidney yin deficiency syndrome of traditional Chinese medicine. GSATP is made up of Dodder, uncaria, Scutellaria, Atractylodes macrocephala, white peony, rehmannia, Polygonum multiflorum, Dipsacus, Cistanche deserticola, mulberry parasitism. The main components of GSATP include baicalin, Atractylodes macrocephala polysaccharide, flavonoids from Cuscuta chinensis, rhynchophylline, polysaccharides, Cistanche polysaccharides, stilbene glycosides and anthraquinone glycosides and triterpenoid saponins, etc. Modern pharmacological studies have found that these ingredients can improve vascular function, regulate immune activity, inhibit uterine contraction and improve ovarian endocrine function, so GSATP may play a role in promoting embryo implantation and preventing pregnancy. However, to improve the success rate of embryo implantation is a complex process and has not been fully studied. Therefore, in treating complex diseases, multi-targeted therapy such as TCM might have unique advantages over western medicine treatment alone. Although GSATP is associated with very good response in patients, lack of high-quality evidence-based medicine has restricted its promotion. The combination of evidence-based medicine, modern medicine and traditional Chinese medicine is a huge field that involves continuous attention and efforts. GSATP dramatically increased the ongoing pregnancy rate and decreased the prevalence of vaginal bleeding in patients undergoing frozen thawed embryo transfer in our previous study. Recently, it was demonstrated that luteal support combined with GSATP could dramatically increase embryo implantation and clinical pregnancy rates, as well as early pregnancy loss rates, in IVF-ET fresh embryo transfer cycles. However, the study's methodological deficiencies prevented it from reaching a definitive conclusion about GSATP's treatment effect. This was mostly attributed to the unspecified randomization process, the absence of distribution concealment and blinding, no placebo control, and vague inclusion and exclusion criteria. As a result, a well-designed randomized clinical trial is essential to estimate the efficiency and safety of GSATP in optimizing reproductive outcomes in women with normal ovarian reserve during fresh embryo transfer cycles.

Interventions

  • Drug: Gushen Antai Pill
    • The Gushen Antai Pill (GSATP, Z20030144) is composed of 10 herbs including radix-polygoni multiflori, radix rehmanniae praeparata, cistanche salsa, radix dipsaci, uncaria, semen cuscutae, rhizoma atractylodis macrocephalae, radix scutellariae, radix paeoniae lactiflorae. Its production follows GMP standards and takes the form of water honey pills, each bag of 6g.
  • Drug: Placebo pill
    • The placebo pill is produced by Beijing boran Pharmaceutical Co., Ltd. It can simulate the appearance, color and smell of GSATP formula, but it has no clinical effect because it has no active ingredients.

Arms, Groups and Cohorts

  • Experimental: GSATP group
    • Gushen Antai Pill (GSATP, 6g* 9 bags, Beijing bran Pharmaceutical Inc.) was required to be taken orally, 6g three times daily combined with 20 mg intramuscular injection of progesterone (1 ml / 20 mg, Tianjin Jinyao Pharmaceutical Co., Ltd.) from the oocyte retrival day until 6 weeks after embryo transfer.
  • Placebo Comparator: Placebo group
    • Placebo pill is made up of a certain amount of starch and glucose, and is shaped like GSATP according to the national drug standards of the State Food and Drug Administration of China. Placebo pill was required to be taken orally, 6g three times daily combined with 40 mg intramuscular injection of progesterone (1 ml / 20 mg, Tianjin Jinyao Pharmaceutical Co., Ltd.) from the oocyte retrival day until 6 weeks after embryo transfer.

Clinical Trial Outcome Measures

Primary Measures

  • Ongoing pregnancy rate
    • Time Frame: 10 weeks after the day of embryo transfer
    • A fetal heartbeat detected by transvaginal ultrasonography [Detected via ultrasound]

Secondary Measures

  • Positive pregnancy rate
    • Time Frame: 2 weeks after the day of embryo transfer
    • Serum β-hCG level ≥ 10mIU/mL, 14 days after embryo transfer. [Detected via ELISA]
  • Embryo implantation rate
    • Time Frame: 3 weeks after the day of embryo transfer
    • The number of intrauterine gestational sacs observed divided by the number of embryos transferred. [Detected via ultrasound]
  • Clinical pregnancy rate
    • Time Frame: 4 weeks after the day of embryo transfer
    • An intrauterine gestational sac with fetal heartbeat detected by transvaginal ultrasonography. [Detected via ultrasound]
  • Ectopic pregnancy rate
    • Time Frame: 4 weeks after the day of embryo transfer
    • A pregnancy in which implantation takes place outside the uterine cavity. [Detected via ultrasound]
  • Pregnancy loss rate
    • Time Frame: 10 weeks after the day of embryo transfer
    • Clinically recognized spontaneous loss of pregnancy before the completion of twelve gestational weeks. [Detected via ultrasound]
  • Multiple pregnancy rate
    • Time Frame: 10 weeks after the day of embryo transfer
    • There were two or more simultaneous fetuses in the uterine cavity. [Detected via ultrasound]
  • The prevalence of pregnancy constipation
    • Time Frame: 10 weeks after the day of embryo transfer
    • Functional constipation as the presence of at least two out of six symptoms: straining, lumpy or hard stools, a sensation of incomplete evacuation, a sensation of anorectal obstruction/blockage, manual manoeuvres to facilitate defecation and fewer than three spontaneous bowel movements per week. Symptoms must be present at 25% of the defecations and last at least one months. [Evaluated via questionnaire]
  • The prevalence of threatened abortion
    • Time Frame: 10 weeks after the day of embryo transfer
    • Abdominal pain and vaginal bleeding happened in the first trimester, but the intrauterine fetus still survived. [Detected via ultrasound]

Participating in This Clinical Trial

Inclusion Criteria

  • Patients with normal ovarian function reserve (AFC ≥ 5, AMH ≥ 1.2ng/ml). – Patients with regular menstrual cycle (21-35 days) and normal ovulation. Exclusion Criteria:

  • Age ≥ 43 years old. – Body mass index (BMI) ≥ 35 Kg/m2. – "Freeze-all" strategy. – History of two or more previous spontaneous abortions. – Karyotype abnormalities. – Polycystic ovary syndrome. – Severe endometriosis. – Untreated hydrosalpinx. – Congenital or acquired abnormalities of uterine anatomy. – Combined contraindications to assisted reproductive technology or pregnancy, such as uncontrolled abnormalities of liver and kidney function, diabetes mellitus (glycosylated haemoglobin ≤7%, fasting blood glucose <10 mmol/L ), hypertension, thyroid disease, symptomatic heart disease, moderate to severe anaemia, history of malignancy or thromboembolism or propensity to thrombosis, severe psychiatric disorder, acute infections of the genitourinary system, sexually transmitted diseases, serious adverse habits such as drug abuse, exposure to teratogenic amounts of radiation, toxins, or drugs (such as prednisone or other hormones, adrenaline, antibiotics, or hypertension, cardiovascular, or antiviral medications) during the active procedure period , and uterine factor infertility or physical illness which prevents the ability to bear a pregnancy.

Gender Eligibility: Female

Minimum Age: 21 Years

Maximum Age: 42 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Shandong University of Traditional Chinese Medicine
  • Provider of Information About this Clinical Study
    • Principal Investigator: Jing-Yan Song, Principal Investigator – Shandong University of Traditional Chinese Medicine
  • Overall Contact(s)
    • Zhen-Gao Sun, M.D., +86-13708938621, sunzhengao77@126.com

References

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Ried K. Chinese herbal medicine for female infertility: an updated meta-analysis. Complement Ther Med. 2015 Feb;23(1):116-28. doi: 10.1016/j.ctim.2014.12.004. Epub 2015 Jan 3. Review.

Smith CA, Armour M, Ee C. Complementary Therapies and Medicines and Reproductive Medicine. Semin Reprod Med. 2016 Mar;34(2):67-73. doi: 10.1055/s-0035-1571194. Epub 2016 Feb 11. Review.

Shen L-H. Observation on the effect of Gushen Antai pill combined withprogesterone on Early Threatened Abortion [in Chinese]. Chin J Maternal Child HealthCare. 2012; 27:4628-9

Qin D-N, She B-R, She Y-C. Effects of Flavonoids from Cuscuta chinensis on reproductivefunction of experimental animals and human villi [in Chinese]. Chin J New Drugs Clin Pharmacol. 2000; 11(6):349-51.

Chen W-X, Chen S-H, Li W-J, Shu Q, Jiang D-Q. Modern pharmacological study on the sedative effect of baicalein andAtractylodes macrocephala [in Chinese]. J Clin Rational Drug Use. 2012; 5(12B):177-8.

Ma B. Research progress on hypotensive effect and mechanism of Uncariarhynchophylla [in Chinese]. China Med Guide. 2011; 8(7):12-4.

Wang P. Modern pharmacological research and clinical application of Rehmannia glutinosa [in Chinese]. Modern Distance Educ Trad Chin Med China. 2008; 6(8):986

Cao XL, Song JY, Zhang XX, Chen YH, Teng YL, Liu HP, Deng TY, Sun ZG. Effects of a Chinese Patent Medicine Gushen'antai Pills on Ongoing Pregnancy Rate of Hormone Therapy FET Cycles: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Front Endocrinol (Lausanne). 2020 Sep 23;11:581719. doi: 10.3389/fendo.2020.581719. eCollection 2020.

Lu Y, Long XL. Clinical efficacy of Gushen Antai pill combined with progesterone after in vitro fertilization and embryo transfer [in Chinese]. Maternal and Child Health Care of China. 2017;32(9):1980-2.

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