Effectiveness Of Bushen Tongzhi Formula Pretreatment On Pregnancy Outcomes In Infertile Women With Diminished Ovarian Reserve Undergoing In Vitro Fertilization And Embryo Transfer: Study Protocol For A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (PRIME Study)

This is a multicenter, randomized, double-blind, placebo-controlled, superiority clinical trial. The study aims to evaluate the efficacy and safety of a standardized traditional Chinese medicine (TCM) formula, the "Bushen Tongzhi Formula" (also referred to as the "Xiehe DOR Bushen Tongzhi Formula"), as a pretreatment and adjuvant therapy in infertile women with Diminished Ovarian Reserve (DOR) undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

Background DOR, characterized by a reduced quantity and/or quality of oocytes, presents a significant challenge in assisted reproductive technology (ART), often leading to poor ovarian response, fewer retrievable oocytes, and lower pregnancy rates. While controlled ovarian stimulation protocols continue to evolve, there remains a critical need for interventions that can improve ovarian function and oocyte quality prior to ART cycles. TCM, guided by the theory of "the kidney governing reproduction," offers a potential approach by addressing the root pattern of "kidney essence deficiency," which is central to DOR in TCM diagnostics. Preliminary observations of the Bushen Tongzhi Formula have suggested potential benefits, but robust evidence from large-scale, rigorously designed trials is lacking.

Study Population The study will enroll 348 infertile female participants, aged 22 to 39 years, diagnosed with DOR according to standardized criteria (requiring at least two of the following: baseline FSH 10-25 IU/L, AMH <1.1 ng/mL, or antral follicle count <7). All participants must also meet TCM diagnostic criteria for Kidney Deficiency pattern and be planning to undergo a fresh IVF/ICSI cycle. Key exclusions include significant uterine abnormalities, known chromosomal disorders, severe medical or psychiatric conditions, active genital infections, advanced endometriosis, plans for donor egg or PGT cycles, and a history of multiple prior IVF failures.

Interventions Eligible participants will be randomly assigned in a 1:1 ratio via a centralized interactive web response system (IWRS), stratified by study site and age.

Experimental Group: Participants will take the Bushen Tongzhi Formula granules (20g, three times daily) for a 3-month pretreatment phase. Upon starting their standardized IVF/ICSI protocol, they will continue the herbal medication concurrently for up to an additional 3 months, stopping upon confirmation of clinical pregnancy. The maximum total treatment duration is 6 months.

Control Group: Participants will follow an identical regimen but will take a matched placebo granules that are indistinguishable from the active drug in appearance, taste, and packaging.

Both groups will receive standard lifestyle counseling and undergo the same clinic-directed IVF/ICSI protocols, including gonadotropin stimulation, trigger, egg retrieval, fertilization, and embryo transfer.

Outcomes The primary outcome is the cumulative clinical pregnancy rate resulting from a single egg retrieval cycle (including fresh and subsequent frozen embryo transfers from that cycle).

Secondary outcomes encompass multiple dimensions:

Ovarian Response: Gonadotropin dose/duration, number of oocytes retrieved, MII oocyte rate, cycle cancellation rate.

Embryological Outcomes: Fertilization rate, cleavage rate, high-quality embryo rate, blastocyst formation rate.

Endometrial Receptivity: Endometrial thickness and pattern on day of trigger/transfer.

Pregnancy & Neonatal Outcomes: Biochemical pregnancy, ongoing pregnancy, miscarriage, ectopic pregnancy, and live birth rates; neonatal birth weight and major malformations.

TCM Efficacy: Change in Kidney Deficiency symptom score.

Safety: Incidence and severity of adverse events (AEs) and serious AEs (SAEs); changes in vital signs, body mass index, and laboratory parameters (hematology, liver and kidney function).

Study Procedures & Data Collection The study employs a pragmatic, integrated data collection strategy to minimize participant burden. Key efficacy and safety data are captured at predefined visits (V0-V9) spanning screening, treatment, and pregnancy follow-up. Crucially, data from routine ART procedures (egg retrieval, embryology, pregnancy tests, ultrasound scans) are extracted by trained staff from hospital electronic medical records and laboratory systems, eliminating the need for extra visits solely for research purposes. Post-intervention pregnancy and neonatal outcomes are collected via medical record review and structured telephone interviews at 42 days and 6 months postpartum.

Statistical Analysis The sample size of 348 participants (174 per group) was calculated to detect an absolute 15% improvement in the cumulative clinical pregnancy rate (from 25% in the control group to 40% in the experimental group) with 80% power and a one-sided alpha of 0.025, accounting for a 15% dropout rate. The primary analysis will be performed on the Full Analysis Set (intent-to-treat principle) using the Cochran-Mantel-Haenszel test, controlling for study site. A superiority conclusion will be reached if the lower bound of the 95% confidence interval for the difference in rates is greater than zero and the p-value is <0.025. Secondary continuous and categorical outcomes will be analyzed using ANCOVA (adjusted for baseline) and appropriate chi-square tests, respectively. Safety will be analyzed in the Safety Set.