Zishen Yutai Pill for Patients With Recurrent Implantation Failure

Zishen Yutai Pill for Patients With Recurrent Implantation Failure: a Randomized, Double-blind, Parallel-group, Placebo-controlled Trial

The goal of this clinical trial is to evaluate the efficacy of Zishen Yutai Pill (ZYP) on pregnancy outcomes following embryo transfer and its safety in patients with recurrent implantation failure. The main question it aims to answer is whether ZYP can improve live birth rate in participant's frozen embryo transfer (FET) cycles.

Researchers will compare ZYP to a placebo (a look-alike substance with similar characteristics to ZYP) to see if it works to improve pregnancy outcomes.

Participants will:

1. Start to receive ZYP or placebo (5g per time, 3 times daily) within the first 5 days of their initial menstrual cycle, and will undergo FET in the following cycle. The medication will be taken without interruption till the day of pregnancy test (2 weeks after embryo transfer). Patients with positive results in β-HCG test will continue to take the drug until clinical pregnancy confirmation by ultrasound three weeks later. For those with a negative β-HCG result, the intervention will be stopped.
2. Baseline visit will be conducted on days 2-4 of the participant's first menstrual cycle. Subsequent clinic visits will follow the standard protocol for FET cycle, as outlined below:

Visit 1 (days 2-4 of the second menstrual cycle); Visit 2 (day of ovulation or day of endometrial transformation); Visit 3 (day of embryo transfer); Visit 4 (2 weeks after embryo transfer); Visit 5 (5 weeks after embryo transfer). Follow-up is scheduled at 10 weeks after embryo transfer (Visit 6) and after delivery (Visit 7), and these can be conducted remotely.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrent Implantation Failure
• Intervention / Treatment: Drug: Zishen Yutai Pill; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 878
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rong Li; Phone Number: +86 13701085402; Email: roseli001@sina.com
• Study Contact Backup: Name: Xiaoyu Long; Phone Number: +86-010-82264816; Email: doralonger@hotmail.com

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated Hospital of University of Science and Technology of China
      • Contact: Limin Wu; Phone Number: +86-0551-62283402; Email: wuliminmall@126.com
      • Principal Investigator: Limin Wu
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100191
      • Peking University Third Hospital
      • Principal Investigator: Rong Li
      • Contact: Rong Li; Phone Number: +86 13701085402; Email: roseli001@sina.com
    • Beijing, Beijing Municipality, China
      • Peking University People's Hospital
      • Contact: Li Tian; Phone Number: +86-010-88324436; Email: Tianli916916@126.com
      • Principal Investigator: Li Tian
  • Guangdong
    • Guangzhou, Guangdong, China
      • Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
      • Principal Investigator: Hui Chen
      • Contact: Hui Chen; Phone Number: +86-020-81332233; Email: zheling76@163.com
    • Guangzhou, Guangdong, China
      • Nanfang Hospital, Southern Medical University
      • Contact: Yuhua Shi; Phone Number: +86-020-62787614; Email: shiyuhua2003@126.com
      • Principal Investigator: Yuhua Shi
  • Hebei
    • Shijiazhuang, Hebei, China
      • The Second Hospital of Hebei Medical University
      • Contact: Guimin Hao; Phone Number: +86-0311-66002721; Email: Haoguimin@163.com
      • Principal Investigator: Guimin Hao
  • Henan
    • Zhengzhou, Henan, China
      • The Second Affiliated Hospital of Zhengzhou University
      • Contact: Yungai Xiang; Phone Number: +86-0371-63974718; Email: xiangyungai2063@126.com
      • Principal Investigator: Yungai Xiang
  • Hunan
    • Changsha, Hunan, China
      • Xiangya Hospital of Central South University
      • Contact: Yanping Li; Phone Number: +86-0731-89752849; Email: lisayanping@sina.com
      • Principal Investigator: Yanping Li
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Jiangsu Province Hospital
      • Contact: Feiyang Diao; Phone Number: +86-025-68302608; Email: phenix_y@163.com
      • Principal Investigator: Feiyang Diao
  • Shaanxi
    • Xi'an, Shaanxi, China
      • The First Affiliated Hospital of Xi'an Jiao Tong University
      • Contact: Haiyan Wang; Phone Number: +86-029-85323432; Email: bistory@mail.xjtu.edu.cn
      • Principal Investigator: Haiyan Wang
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Shanghai Ninth People's Hospital
      • Contact: Qifeng Lv; Phone Number: +86-021-63138341; Email: Lyuqifenf@126.com
      • Principal Investigator: Qifeng Lv
  • Sichuan
    • Chengdu, Sichuan, China
      • Sichuan Jinxin Xinan Women and Children's Hospital (Bisheng)
      • Contact: Xingyu Lv; Phone Number: +86-028-65118868; Email: lxyy323@163.com
      • Principal Investigator: Xingyu Lv
  • Zhejiang
    • Wenzhou, Zhejiang, China
      • The First Affiliated Hospital of Wenzhou Medical University
      • Principal Investigator: Haiyan Yang
      • Contact: Haiyan Yang; Phone Number: +86-0577-88069520; Email: 13957720491@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Meet the diagnostic criteria for recurrent implantation failure;
2. Aged between 20-40 years old (inclusive) when oocytes were retrieved, and <43 at enrollment;
3. Have at least 1 good-quality embryo for transfer;
4. Intend to undergo frozen-thawed embryo transfer;
5. Voluntary participation and signed informed consent.

Exclusion Criteria:

1. Concomitant unresolved intrauterine lesions (e.g., intrauterine adhesions grade III-IV, endometrial polyps ≥1 cm, acute endometritis), endometriosis (ASRM stage ≥III), or adenomyosis (uterine volume ≥8 weeks of gestation) that affect embryo implantation;
2. Intend to undergo FET after preimplantation genetic testing (PGT), including aneuploidy screening (PGT-A), monogenic disease testing (PGT-M), chromosomal structural rearrangement testing (PGT-SR);
3. Thin endometrium (<7 mm) before enrollment;
4. Concomitant severe genital malformations or genital neoplasms;
5. Contraindications to estrogen and progestogen (e.g., history of breast cancer);
6. Presence of medical contraindications to assisted reproductive technology, including that either partner has a severe psychiatric disorder, acute genitourinary tract infection, sexually transmitted disease, serious deleterious habit (e.g., drug abuse), or teratogenic exposure to radiation, toxic agent or medication that still under effect; or genetic diseases specified in the Law of the People's Republic of China on Maternal and Infant Health Care for which childbearing and PGT are contraindicated; or severe somatic diseases incompatible with pregnancy; or chromosomal abnormalities;
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × the upper limit of normal (ULN), or serum creatinine (Scr) > ULN;
8. Presence of poorly controlled severe systemic diseases, including cardiovascular, digestive, endocrine, and autoimmune diseases (e.g., antiphospholipid syndrome, Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis);
9. Use of traditional Chinese medicines with similar functions and indications to ZYP within 1 month before screening that may affect treatment efficacy. Chinese patent medicines such as Tiaojing Cuyun Pills, Kuntai Capsules, Peikun Pills, Qilin Pills, Jinfeng Pills, Gushen Antai Pills, and Chinese herbal decoctions containing Cuscutae Semen, Dipsaci Radix, Taxilli Herba, and Asini Corii Colla with kidney-tonifying and spleen-strengthening effects;
10. Allergy to any component of the study drugs;
11. Participated in another interventional trials within 1 month prior to enrollment;
12. Deemed unsuitable for this study by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZYP group; Zishen Yutai Pill, 5g per time, three times daily	Drug: Zishen Yutai Pill; Eligible participants start to receive ZYP within the first 5 days of their initial menstrual cycle, and will undergo frozen-thawed embryo transfer (FET) in the following cycle. The medication will be taken without interruption till the day of pregnancy test (two weeks after embryo transfer). Patients with positive results in β-HCG test will continue to take the drug until clinical pregnancy confirmation by ultrasound three weeks later. For those with negative β-HCG results, the intervention will be stopped.
Placebo Comparator: Placebo group; Placebo, 5g per time, three times daily	Drug: Placebo; Eligible participants start to receive placebo within the first 5 days of their initial menstrual cycle, and will undergo frozen-thawed embryo transfer (FET) in the following cycle. The medication will be taken without interruption till the day of pregnancy test (two weeks after embryo transfer). Patients with positive results in β-HCG test will continue to take the drug until clinical pregnancy confirmation by ultrasound three weeks later. For those with negative β-HCG results, the intervention will be stopped.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate	Live birth is defined as delivery of any viable infants after 28 weeks of gestation.	About 40 weeks after embryo transfer, up to a maximum duration of 52 weeks after enrollment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endometrial thickness (ovulation day/endometrial transformation day)	Natural cycle and hormone replacement therapy (HRT) cycle are two endometrial preparation methods before frozen embryo transfer.	On the day of ovulation (natural cycle) or on the day of endometrial transformation (HRT cycle), about 6 weeks after enrollment.
Endometrial pattern (ovulation day/endometrial transformation day)	Natural cycle and hormone replacement therapy (HRT) cycle are two endometrial preparation methods before frozen embryo transfer.	On the day of ovulation (natural cycle) or on the day of endometrial transformation (HRT cycle), about 6 weeks after enrollment.
Endometrial thickness (embryo transfer day)		On the day of embryo transfer, about 6-7 weeks after enrollment.
Endometrial pattern (embryo transfer day)		On the day of embryo transfer, about 6-7 weeks after enrollment.
β-HCG positive rate	Serum β-HCG level ≥ 20 IU/L at 2 weeks after embryo transfer is defined as positive.	At 2 weeks after embryo transfer, about 8 weeks after enrollment.
Implantation rate	Implantation rate is defined as the number of gestational sacs per the number of embryos transferred.	At 5 weeks after embryo transfer, about 11 weeks after enrollment.
Clinical pregnancy rate	Clinical pregnancy is defined as the presence of intrauterine gestation sac under transvaginal ultrasonography.	At 5 weeks after embryo transfer, about 11 weeks after enrollment.
Ongoing pregnancy rate	Ongoing pregnancy is defined as pregnancy with live fetus beyond 10 weeks after embryo transfer (approximately 12 weeks of gestation).	About 40 weeks after embryo transfer, up to a maximum duration of 52 weeks after enrollment.
Biochemical pregnancy loss rate	Biochemical pregnancy loss is defined as a positive serum β-HCG test with no evidence of a gestational sac on subsequent ultrasound.	At 5 weeks after embryo transfer, about 11 weeks after enrollment.
Clinical pregnancy loss rate	Clinical pregnancy loss is defined as the failure of a confirmed clinical pregnancy to progress to live birth.	About 40 weeks after embryo transfer, up to a maximum duration of 52 weeks after enrollment.
Gestational age at delivery		About 40 weeks after embryo transfer, up to a maximum duration of 52 weeks after enrollment.
Birthweight		About 40 weeks after embryo transfer, up to a maximum duration of 52 weeks after enrollment.
Rate of adverse events		About 40 weeks after embryo transfer, up to a maximum duration of 52 weeks after enrollment.

Collaborators and Investigators

• Sponsor: Peking University Third Hospital
• Investigators: Principal Investigator: Rong Li, MD, PhD, Peking University Third Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 10, 2026
• First Posted (Actual): June 11, 2026

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: randomized controlled trial; traditional Chinese medicine; recurrent implantation failure; frozen-thawed embryo transfer; Zishen Yutai pill
• Additional Relevant MeSH Terms: Zishen Yutai
• Other Study ID Numbers: BYSZYYY.ZSYTW-HBT-2026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data will be provided as supplementary materials upon publication in a peer-reviewed journal.
• IPD Sharing Time Frame: IPD will be shared within two years after publication in a peer-reviewed journal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No