Platelet-Rich Plasma vs. Granulocyte Colony-Stimulating Factor vs. Placebo and Outcomes in Frozen Embryo Transfer

Wael Elbanna Clinic

Status and phase: Completed; Phase 4

Conditions: Infertility; Frozen Embryo Transfer (FET)

Treatments: Other: Saline; Drug: Granulocyte Colony Stimulating Factor; Other: Platelet Rich Plasma Arm

Study type: Interventional

Funder types: Other

Identifiers

NCT03945812

INDV-0909012

Details and patient eligibility

About

The goal of this clinical trial is to assess the impact of using Platelet-Rich Plasma (PRP) vs. Granulocyte Colony-Stimulating Factor (GCSF) vs. placebo on the outcomes of frozen embryo transfer (FET) in terms of clinical pregnancy rates. It will also assess their effect on chemical pregnancy rate, implantation rate, delivery outcomes, and endometrial parameters.

The main questions it aims to answer are:

Do the clinical pregnancy rates differ upon using PRP vs. GCSF vs. placebo during FET? What are the effects of PRP vs. GCSF vs. placebo during FET on chemical pregnancy rate, implantation rate, delivery outcomes, and endometrial parameters?

Researchers will compare the effect of administration of PRP vs. GCSF vs. placebo during FET on pregnancy outcomes.

Participants will be randomized to receive the study intervention seven days before embryo transfer: 1.0 ml of either PRP (prepared in-house), GCSF (Filgrastim, 300 mcg/1.0 mL), or 0.9% saline (placebo). The intervention will be administered by slow infusion into the uterine cavity with an intrauterine insemination catheter.

Full description

INTRODUCTION AND STUDY RATIONALE Despite the advancements in the treatment of infertility, repeated failure of implantation continues as a challenging difficulty.

Embryo implantation is affected by many factors. Many efforts were made to improve the implantation rate by different methods blastocyst transfer, assisted hatching, preimplantation genetic screening, hysteroscopy, removal of hydrosalpinges and endometrial scratch. Furthermore, infertility specialists suggested some empirical methods like the infusion in the uterine cavity of platelet-rich plasma (PRP) in patients with thin endometrium which has been shown to be effective in improving the pregnancy rate.

Another factor is granulocyte colony stimulating factor (GCSF) which has receptors in endometrial cells and may have a role in implantation. The use of GCSF in assisted reproductive technology (ART) has been tried by many research studies either via intrauterine or systemic administration.

There are limited studies that compared the impact of PRP and GCSF administration on the pregnancy rate and on the endometrial thickness with a small sample size.

The rationale behind this current study is to assess the impact of using PRP versus GCSF versus on the outcomes of FET in terms of pregnancy rates.

STUDY OBJECTIVES

Primary:

The primary objective of the study is to compare the clinical pregnancy rate determined by presence of fetal heart beat in transvaginal ultrasound after 6 weeks of embryo transfer in all groups.

Secondary:

To compare the following in the three study arms:

• Chemical pregnancy determined by positive serum β-HCG, 2 weeks after embryo transfer.
• Delivery outcomes: miscarriage and live bith rates.
• The implantation rate, calculated by dividing the number of gestational sacs observed via ultrasound by the number of embryos transferred.
• The change in endometrial parameters, assessed as endometrial thickness, Doppler indices, endometrial vascularization, blood volume histogram indices, and the histological dating of the endometrium.

SAMPLE SIZE CALCULATION The sample size was calculated using G*Power 3.1.9.7. Based on Jie Li et al. study, the clinical pregnancy rate in the GCSF group was 25.1% compared to 14.4% in the placebo or no-treatment group. Assuming a 10% improvement in the clinical pregnancy rate with GCSF, a two-sided alpha level of 5%, and achieving 80% power, the sample size was initially calculated to be 498 women. To account for a 25% anticipated dropout rate, the final sample size was adjusted to 624 women (208 in each group). Although no studies comparing PRP to placebo, specifically in our study population, were published before designing our study, a 22% improvement in the clinical pregnancy rate with PRP was observed in studies involving women with thin endometrium. To reach sufficient power to detect differences between the three study arms, our calculation was based on GCSF.

Li J, Mo S, Chen Y. The effect of G-CSF on infertile women undergoing IVF treatment: A meta-analysis. Systems Biology in Reproductive Medicine. 2017/07/04 2017;63(4):239-247. doi:10.1080/19396368.2017.1287225

STATISTICAL ANALYSIS We will compare participants' baseline demographics and clinical characteristics across the study's three arms: PRP, GCSF, and saline. Categorical variables will be presented as frequency and percentage and compared using the Chi-squared test (χ2). Normally distributed variables will be reported as mean (standard deviation; SD) and compared using one-way analysis of variance (ANOVA), while non-normally distributed will be reported as median (25th to 75th percentile) and compared using the Kruskal-Wallis test. A p-value of less than 0.05 will be considered statistically significant.

Clinical pregnancy rate will be adjusted by the endometrial thickness (thin versus normal (≥ 7 mm)) in all groups.

An interim analysis will be conducted by the Data Monitoring Committee (DMC) after 60% of participants have been enrolled in the study to assess the efficacy of the intervention arms.

SUB-GROUP ANALYSIS: to evaluate the clinical pregnancy rates among patients based on:

• Anti-Müllerian hormone (AMH) value <1 ng/ml (poor responders)
• Preimplantation genetic screening (PGS)
• Reepeated, two or more, failed implantations (RIF).
• Triple-layered endometrium, evaluated by TVUS in the mid-luteal phase.

Enrollment: 665 patients

Sex: Female

Ages: 20 to 40 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• All women aged 20-40 years
• Non-smoker
• BMI < 30
• Normal endometrial cavity confirmed by hysteroscopy and ultrasound
• Visiting the center for IVF by FET during the period of the study

Exclusion criteria

• History of anti-phospholipid syndrome confirmed by serological tests.
• History of any hematological and immunological disorders
• History of chromosomal or genetic abnormalities in the patient or in the family
• Any uterine abnormalities (congenital or acquired)
• Previous uterine surgeries except caesarean section
• Hypersensitivity to G-CSF
• Uncontrolled systemic disease

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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665 participants in 3 patient groups, including a placebo group

Granulocyte Colony Stimulating Factor Arm

Active Comparator group

Description:

Women in this group will receive GCSF with conventional hormonal therapy: Estradiol valerate 6mg/day from day 2 of menstrual cycle Vaginal sildenafil citrate 25mg / 6 hours Then frozen embryo transfer will be performed.

Treatment:

Drug: Granulocyte Colony Stimulating Factor

Platelet Rich Plasma Arm

Active Comparator group

Description:

Women in this group will receive PRP with conventional hormonal therapy: Estradiol valerate 6mg/day from day 2 of menstrual cycle Vaginal sildenafil citrate 25mg / 6 hours Then frozen embryo transfer will be performed.

Treatment:

Other: Platelet Rich Plasma Arm

Saline

Placebo Comparator group

Description:

Women in this group will receive saline with conventional hormonal therapy: Estradiol valerate 6mg/day from day 2 of menstrual cycle Vaginal sildenafil citrate 25mg / 6 hours Then frozen embryo transfer will be performed.

Treatment:

Other: Saline