Comparison of Two Vaginal Progesterone Forms in Frozen Embryo Transfer (COPS)

Comparison of Patient Satisfaction, Convenience and Tolerability Between Two Vaginal Progesterone Formulations During Frozen Embryo Transfer

The goal of this observational study is to compare two commonly used vaginal progesterone formulations - soft capsules versus pessaries - in women undergoing frozen embryo transfer (FET). The main question it aims to answer is:

- Do soft vaginal progesterone capsules provide similar or better patient satisfaction, convenience, and tolerability compared with vaginal progesterone pessaries during preparation for frozen embryo transfer?

Participants undergoing FET who are prescribed vaginal progesterone as part of their endometrial preparation and luteal phase support will use one of the two formulations and complete patient-reported assessments regarding satisfaction, convenience, and tolerability. The study will also measure serum progesterone levels on the day of embryo transfer and evaluate pregnancy outcomes, including clinical pregnancy and live birth rates.

Study Overview

• Status: Recruiting
• Conditions: Infertility; Natural Cycle; Artificial Cycle; Frozen Embryo Transfer (FET)
• Intervention / Treatment: Other: Vaginal progesterone soft capsules; Other: Vaginal progesterone pessaries

Detailed Description

Over the past few decades, assisted reproductive technology (ART) treatments have seen their protocols updated by advances in cryopreservation methods, leading to the mainstream use of the frozen embryo transfer (FET) strategy (Nagy, Shapiro, & Chang, 2020). FET protocols are generally subdivided in either natural cycle (NC-FET) or artificial cycle (AC-FET), with several centers preferring the latter due to its flexibility in scheduling and ease of monitoring. Nonetheless, previous reports positing that AC-FET may be associated with an increased risk of miscarriage and hypertensive disorders during pregnancy have put this preference into question (Roelens, et al., 2022). Having said that, the natural proliferative phase frozen embryo transfer protocol (NPP-FET) has recently be proposed as a strategy which potentially allows for easier cycle scheduling while potentially maintaining the benefits of the natural cycle in terms of safer pregnancy outcomes (Godinho, Soares, & Ribeiro, 2021). Both AC-FET and NPP-FET protocols rely immensely on the use exogenous progesterone for luteal phase support (LPS), with the vaginal route being the most common in Europe due to its ease of use compared to intramuscular or subcutaneous alternatives.

Progesterone is a natural hormone produced mainly by the theca cells of the corpus luteum. When supplemented vaginally, endometrial progesterone concentrations reach a steady-state within 5 hours after administration, while serum progesterone levels remain elevated for about 48 hours with prolonged bioavailability (Bulletti, et al., 1997). In a systematic review of 18 randomized clinical trials comparing vaginal preparations for LPS, all tested preparations seemed to be equally effective and safe for assisted reproductive technology cycles (Child, Leonard, Evans, & Lass, 2018). However, studies assessing patient satisfaction are lacking (Beltsos, et al., 2014). Hence, the main objective of this study is to assess the level of satisfaction as well as understand the convenience and tolerability of two of the most common vaginal LPS formulations (soft capsules versus pessaries). The study will compare satisfaction levels, convenience and tolerability, serum progesterone levels on the FET day and pregnancy rates between the two therapeutic formulations.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Samuel Ribeiro; Phone Number: +351 218503210; Email: Samuel.Ribeiro@ivirma.com
• Study Contact Backup: Name: Belisa Silva; Phone Number: +351 218503210; Email: Belisa.Silva@ivirma.com

Study Locations

• Portugal
  • Lisbon, Portugal, 1800-282
    • Recruiting
    • Instituto Valenciano de Infertilidade (IVI Lisboa)
    • Contact: Samuel Ribeiro; Phone Number: +351 218 503 210; Email: Samuel.Ribeiro@ivirma.com

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of women aged 18 to 48 years undergoing frozen embryo transfer (FET) at IVI Lisboa. Eligible participants must have a BMI between 18.5 and <30 kg/m², be scheduled for a single blastocyst-stage transfer, and be prescribed vaginal progesterone for luteal phase support, either soft capsules (400 mg every 12 hours) or pessaries (400 mg every 12 hours). Both artificial cycle (AC-FET) and natural proliferative phase (NPP-FET) protocols are included. The study population reflects real-world patients receiving routine clinical care.

Description

Inclusion Criteria:

• Age: ≥18 and <49 years old;
• Body Mass Index (BMI) ≥18.5 Kg/m2 and <30 Kg/m2;
• Planned for single blastocyst stage transfer;
• Has been prescribed two vaginal 200mg soft capsules or one 400mg pessary of progesterone, each 12hours before and after FET;
• Either AC-FET or NPP-FET.

Exclusion Criteria:

• Women who have previously enrolled in this study;
• Those unable to comprehend the investigational nature of the proposed study;
• Rank of FET>3;
• Use of oral/injectable corticoids.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort 1 - vaginal progesterone soft capsules; Women undergoing FET who receive soft vaginal progesterone capsules (micronized progesterone 200 mg x 2 capsules every 12 h = 400 mg/12h) for endometrial preparation/luteal support as per routine care.	Other: Vaginal progesterone soft capsules; Whenever the endometrium is above 7 mm and serum progesterone is determined and if <1.5ng/ml, vaginal micronized progesterone soft capsules is initiated as part of routine clinical practice for luteal phase support during AC-FET or NPP-FET cycles. Typical dose: 400 mg every 12 hours (two 200 mg soft capsules). The choice of progesterone for luteal phase suport will be performed according to routine clinical practice at the discretion of both the physician and patient.
Cohort 2 - vaginal provesterone pessaries (ovules); Women undergoing FET who receive vaginal progesterone pessaries (400 mg x 1 pessary every 12 h) for endometrial preparation/luteal support as per routine care.	Other: Vaginal progesterone pessaries; Whenever the endometrium is above 7 mm and serum progesterone is determined and if <1.5ng/ml, vaginal progesterone pessaries is initiated as part of routine clinical practice for luteal phase support during AC-FET or NPP-FET cycles. Typical dose: 400 mg every 12 hours (one 400 mg pessary). The choice of progesterone for luteal phase suport will be performed according to routine clinical practice at the discretion of both the physician and patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare the patients' satisfaction, convenience and tolerability of two common vaginal progesterone formulations: soft capsules versus pessaries	Satisfaction levels, convenience and tolerability will be collected using a GDPR compliant online survey tool, filled by participants	5 days after starting progesterone supplementation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Progesterone(P4) level	Serum P4 levels collected via blood sample (as standard of care)	5 days after starting progesterone supplementation
Clinical pregnancy rates	Clinical pregnancy confirmation at 7 - 8 weeks gestational age, via transvaginal ultrasound	7 - 8 weeks of gestational age
Livebirth rates	Live birth rate, defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age	Livebirth after 22 completed weeks of gestational age

Collaborators and Investigators

• Sponsor: Instituto Valenciano de Infertilidade de Lisboa
• Collaborators: Gedeon Richter Ltd.
• Investigators: Principal Investigator: Samuel Ribeiro, Instituto Valenciano de Infertilidade de Lisboa (IVI Lisboa)

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: February 18, 2026
• First Submitted That Met QC Criteria: March 6, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Patient satisfaction; Frozen embryo transfer; Progesterone; Assisted reproduction; Endometrial preparation; Natural cycle; Natural proliferative phase (NPP-FET); Artificial cycle (AC-FET); Treatment tolerability
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Behavior; Treatment Adherence and Compliance; Health Behavior; Infertility; Patient Satisfaction
• Other Study ID Numbers: 2306-LIS-122-SS

Drug and device information, study documents

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