Clinical trial NCT06896747: Evaluating Mechanically Engineered Stem Cell Exosomes for Treating Endometrial Injury: A Clinical Study
Official title: Evaluation of the Therapeutic Effects of Mechanically Engineered Umbilical Cord-Derived Stem Cell Exosomes on Endometrial Injury: A Prospective, Non-Randomized, Parallel-Controlled Clinical Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Thin Endometrial Lining
Female Infertility
Intrauterine Adhesions
Lead sponsor: Tang-Du Hospital
Sponsor class: OTHER
Collaborators: name: Xi'an Jiaotong University
First posted: 2025-03-26
Enrollment: 90
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to evaluate if engineered mechanically umbilical cord-derived stem cell exosomes, or conventional umbilical cord -derived stem cell exosomes, can improve endometrial thickness in women with thin endometrium.

The main questions it aims to answer are:

Can exosomes delivered via subendometrial injection improve endometrial thickness or clinical pregnancy rates compared to PRP (platelet-rich plasma)? Are there significant differences in endometrial thickness between the two treatment groups? Researchers will compare the intervention groups, which one group receives mechanical exosomes and the other receives conventional esosomes via subendometrial injection, to the control group, which receives PRP via the same methods, to see if exosomes provide superior therapeutic effects.

Participants will:

Receive either mechanical exosomesor or conventional esosomes or PRP through subendometrial injection.

Be monitored for changes in endometrial parameters.

Detailed description: This study is a prospective, non-randomized controlled clinical trial designed to evaluate the efficacy and safety of mechanically engineered umbilical cord mesenchymal stem cell-derived exosomes (ME-UCMSC-Exo) and conventional umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exo) in the treatment of thin endometrium secondary to severe intrauterine adhesions (IUA) following hysteroscopic adhesiolysis. Thin endometrium is a significant challenge in reproductive medicine, associated with poor embryo implantation rates, recurrent implantation failure (RIF), and increased risk of pregnancy complications. Despite conventional hormonal therapies, effective endometrial regeneration remains a clinical challenge.

Emerging regenerative therapies, including exosome-based interventions, offer promising avenues for enhancing endometrial repair and pregnancy outcomes. Exosomes, extracellular vesicles secreted by stem cells, play a crucial role in tissue regeneration by delivering bioactive molecules such as proteins, microRNAs (miRNAs), and growth factors to target cells. The study aims to determine whether mechanically engineered exosomes, which leverage biophysical modulation during the culture process, demonstrate superior efficacy compared to conventional exosomes and platelet-rich plasma (PRP), a widely used biological intervention for thin endometrium.

Study Design This is a prospective, non-randomized, parallel-controlled study.

Patients will be divided into three groups:

Control Group (PRP Group): Endometrial injection of autologous platelet-rich plasma (PRP).

Conventional Exosome Group: Endometrial injection of UCMSC-derived exosomes. Mechanically Engineered Exosome Group: Endometrial injection of ME-UCMSC-derived exosomes.

Primary endpoint: Change in endometrial thickness. Secondary endpoints: Clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate, and safety assessments (including hypersensitivity reactions, infection, and long-term complications).

Intervention Details Each participant will receive a single intra-endometrial injection using a hysteroscopic-guided 17G needle during the proliferative phase (D3-D7 of the menstrual cycle).

PRP Group: 1-1.5mL PRP per injection site (autologous). UCMSC-Exo Group: 1-1.5mL conventional exosome solution per site. ME-UCMSC-Exo Group: 1-1.5mL mechanically engineered exosome solution per site. Rationale for PRP as a Positive Control PRP is used as a positive control due to its established efficacy in improving endometrial thickness and pregnancy outcomes. Meta-analyses of RCTs have demonstrated that PRP significantly enhances endometrial thickness (MD: 1.23mm, 95% CI: 0.87-1.59, p=0.000) and improves clinical pregnancy rates (RR: 2.04, 95% CI: 1.52-2.76, p=0.000). Additionally, PRP is autologous, safe, and widely used in reproductive medicine, making it a suitable comparative intervention for evaluating the therapeutic efficacy of exosomes.

Eligibility Criteria

Inclusion Criteria:

1. Females aged 20-40 years (inclusive of boundary values);
2. Normal ovarian reserve function (criteria: AFC ≥ 7, AMH \> 1.1 ng/mL);
3. History of transcervical resection of adhesions (TCRA);
4. Received PRP treatment after TCRA;
5. At least one embryo transfer (ET) cycle in which they underwent standard ovarian stimulation (fresh cycle) or standard hormone replacement therapy (FET cycle), with an endometrial thickness of \<7 mm;
6. Planned to continue IVF/ICSI/FET-assisted conception;
7. Able to accept and adhere to treatment and follow-up and willing to sign an informed consent form.

Exclusion Criteria:

1. Patients with severe systemic diseases, surgical contraindications, or cycle contraindications;
2. Patients with reproductive tract infections, genital tuberculosis, pelvic inflammatory disease, or malignant tumors of reproductive organs;
3. Patients with systemic diseases that cause uterine bleeding;
4. Patients allergic to any drugs, materials, or components used in this study;
5. Patients at high risk for hormone-dependent tumors such as breast cancer or ovarian tumors;
6. Patients with untreated submucosal fibroids of any size (FIGO 0/I/II), uterine fibroids ≥5 cm (FIGO III, IV, V, VI, VII), adenomyosis, unicornuate uterus, bicornuate uterus, or endometrial polyps;
7. Patients with hydrosalpinx ≥3 cm or hydrosalpinx of any size with significant vaginal discharge;
8. Patients with ovarian endometriotic cysts (chocolate cysts) ≥4 cm;
9. Patients who participated in other clinical trials within 3 months before surgery or during the study period;
10. Patients unable to tolerate anesthesia;
11. Patients with genetic abnormalities;
12. Other patients deemed unsuitable for participation in this study by the investigator.

Statistical Considerations \& Sample Size Estimated sample size: 90 patients (30 per group). Primary outcome variable: Endometrial thickness increase post-treatment. Sample size calculation based on ANOVA analysis and post-hoc Tukey HSD test to compare all intergroup differences while controlling the familywise error rate at α=0.05.

Considering a 10% dropout rate, a total of 90 patients will be recruited.

Follow-up and Outcome Assessment

Patients will be monitored at multiple time points:

1. Baseline (Pre-intervention assessment).
2. Short-term efficacy evaluations:

   Day of progesterone (P) transformation P+7 days Next embryo transfer cycle (HCG trigger day / FET cycle day of progesterone start).
3. Pregnancy outcomes:

   Biochemical pregnancy (Day 15 post-ET). Clinical pregnancy confirmation (Week 5-6). Live birth rate and perinatal complications (up to 1 year post-intervention).

   Safety evaluations:
4. Immediate adverse reactions (allergic responses, infections).
5. Long-term safety (90-day, 1-year follow-up including tumor markers, liver/kidney function tests, and ultrasound assessments).

Scientific \& Clinical Significance This is the first clinical study evaluating mechanically engineered and conventional umbilical cord-derived stem cell exosome therapy for thin endometrium.

If successful, the study will establish a novel, cell-free regenerative therapy for patients with refractory thin endometrium.

Findings could pave the way for future exosome-based treatments in reproductive medicine, expanding therapeutic options for women with uterine factor infertility.

Eligibility criteria: Inclusion Criteria:

1. Females aged 20-40 years (inclusive of boundary values);
2. Normal ovarian reserve function (criteria: AFC ≥ 7, AMH \> 1.1 ng/mL);
3. History of transcervical resection of adhesions (TCRA);
4. Received PRP treatment after TCRA;
5. At least one embryo transfer (ET) cycle in which they underwent standard ovarian stimulation (fresh cycle) or standard hormone replacement therapy (FET cycle), with an endometrial thickness of \<7 mm;
6. Planned to continue IVF/ICSI/FET-assisted conception;
7. Able to accept and adhere to treatment and follow-up and willing to sign an informed consent form.

Exclusion Criteria:

1. Patients with severe systemic diseases, surgical contraindications, or cycle contraindications;
2. Patients with reproductive tract infections, genital tuberculosis, pelvic inflammatory disease, or malignant tumors of reproductive organs;
3. Patients with systemic diseases that cause uterine bleeding;
4. Patients allergic to any drugs, materials, or components used in this study;
5. Patients at high risk for hormone-dependent tumors such as breast cancer or ovarian tumors;
6. Patients with untreated submucosal fibroids of any size (FIGO 0/I/II), uterine fibroids ≥5 cm (FIGO III, IV, V, VI, VII), adenomyosis, unicornuate uterus, bicornuate uterus, or endometrial polyps;
7. Patients with hydrosalpinx ≥3 cm or hydrosalpinx of any size with significant vaginal discharge;
8. Patients with ovarian endometriotic cysts (chocolate cysts) ≥4 cm;
9. Patients who participated in other clinical trials within 3 months before surgery or during the study period;
10. Patients unable to tolerate anesthesia;
11. Patients with genetic abnormalities;
12. Other patients deemed unsuitable for participation in this study by the investigator.

Primary outcomes:
measure: Endometrial thickness
timeFrame: 30-90days
Secondary outcomes:
measure: clinical pregnancy
timeFrame: 1-6 months
Other outcomes:
Locations:
city: Xi'an
country: China
facility: Tang-Du Hospital
state: Shaanxi
city: Xi'an
country: China
facility: Tang-Du Hospital
state: Shaanxi
Study officials:
affiliation: Air Force Military Medical University, China
name: The Fourth Military Medical University
role: PRINCIPAL_INVESTIGATOR
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