Evaluation of a Long Versus Short Clomid Protocol for Controlled Ovarian Stimulation

Evaluation of a Long Versus Short Clomid Protocol for Controlled Ovarian Stimulation in Patients With Diminished Ovarian Reserve Undergoing In-vitro Fertilization: a Randomized Controlled Trial

The goal of this clinical trial is to evaluate a long Clomid protocol as compared to a 5-day Clomid protocol for ovarian stimulation in patients with diminished ovarian reserve undergoing ovarian stimulation for in-vitro fertilization. The aim of the long Clomid protocol is to intensify stimulation of the ovaries and reduce both cost and injection burden for patients. Participants will be randomized to receive the long Clomid protocol vs. the typical protocol involving Clomid only for 5 days followed by growth hormone-releasing hormone (GnRH) antagonist. The primary outcome the investigators will evaluate will be the number of mature eggs retrieved.

Study Overview

• Status: Recruiting
• Conditions: Infertility, Female
• Intervention / Treatment: Drug: Clomiphene Citrate

Detailed Description

Clomiphene citrate (Clomid) is often used for assisted reproductive technologies and may be used to augment ovarian stimulation with exogenous gonadotropins by stimulating pituitary follicle-stimulating hormone (FSH) release in addition. The mechanism of action of Clomid is antagonism at the estrogen receptor, and this stimulates FSH release from the pituitary. The typical Clomid-based protocol has involved clomid only given for the first five days of stimulation to allow for endometrial development later in the cycle for a fresh embryo transfer following the oocyte retrieval. This protocol involves the addition of a GnRH antagonist medication later in the cycle to prevent premature ovulation. Recent national trends in IVF, however, have moved towards frozen embryo transfers and use of preimplantation genetic testing, which obviates any concerns regarding the endometrium. Recent experience in our clinic has suggested that Clomid may also prevent premature ovulation by antagonizing the positive feedback that is responsible for the luteinizing hormone (LH) surge and ovulation. Given in this manner, Clomid can be given throughout the duration of an ovarian stimulation cycle, achieve higher FSH levels and degree of ovarian stimulation in patients with diminished ovarian reserve, and obviate the need for GnRH antagonist medication (another expensive subcutaneous injection). The objective of this study is to compare a "long Clomid protocol" (i.e. using Clomid throughout the entire duration of the IVF cycle) as compared to the typical 5-day clomid protocol. The investigators hypothesize that the long Clomid protocol will be non-inferior to the typical five-day course and obviate the need for GnRH antagonist by preventing premature ovulation. Patients with diminished ovarian reserve and anticipated poor response to ovarian stimulation will be randomized to the long Clomid protocol vs. a 5-day Clomid with GnRH antagonist protocol. The primary outcome will be oocyte yield. Secondary outcome will be premature ovulation, embryo development, and pregnancy outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Richard Paulson; Phone Number: 323-409-3026; Email: paulsonivf@havingbabies.com
• Study Contact Backup: Name: Rachel Mandelbaum; Phone Number: 323-409-3026; Email: mandelbaumivf@havingbabies.com

Study Locations

• United States
  • California
    • Pasadena, California, United States, 91101
      • Recruiting
      • HRC Fertility
      • Contact: Adriana Wong, MD MPH; Phone Number: 866-472-4483; Email: adriana.wong@havingbabies.com
      • Contact: Richard Paulson, MD; Phone Number: 866-472-4483; Email: paulsonivf@havingbabies.com
      • Sub-Investigator: Adriana Wong, MD MPH

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Undergoing IVF
• Must meet POSEIDON criteria based on clinic evaluation
• Female partner: Antral follicle count of 2 or more and age <45 at time of stimulation start
• Male partner/sperm source: Cannot be azoospermic
• Planning freeze-all cycle (regardless of blastocyst or cleavage stage culture) or fresh transfer if randomized to short Clomid group
• Planning 36-hour trigger window

Exclusion Criteria:

• Normal ovarian reserve or good response
• Allergy or adverse reaction to Clomid
• Minimal stimulation protocols
• History of prior premature ovulation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Long Clomid; Clomid with gonadotropins throughout the entire duration of ovarian stimulation without addition of GnRH antagonist	Drug: Clomiphene Citrate; Clomiphene citrate is an estrogen receptor antagonist that leads to pituitary FSH release and prevention of the LH surge.
Active Comparator: 5-day Clomid; Clomid only for 5 days at beginning of ovarian stimulation with gonadotropins, with GnRH antagonist added when the lead follicle reaches ~14mm.	Drug: Clomiphene Citrate; Clomiphene citrate is an estrogen receptor antagonist that leads to pituitary FSH release and prevention of the LH surge.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of mature oocytes	The number of mature oocytes retrieved at oocyte retrieval	Up to 1 month after study completion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that experience premature ovulation	Premature LH surge, progesterone rise and estradiol decrease, or evidence of premature ovulation (no oocytes on retrieval or free fluid and follicular collapse on ultrasound)	Up to 1 month after study completion
Number of oocytes that get fertilized and grow to the blastocyst stage	Fertilization rate and blastulation	Up to 1 month after study completion
Pregnancy outcomes	Clinical pregnancy rate, ongoing pregnancy rate, live birth rate	Up to 3 years after study completion

Collaborators and Investigators

• Sponsor: University of Southern California
• Investigators: Principal Investigator: Richard Paulson, paulsonivf@havingbabies.com

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 13, 2024
• First Submitted That Met QC Criteria: November 19, 2024
• First Posted (Actual): November 22, 2024

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Infertility; Infertility, Female; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Benzene Derivatives; Stilbenes; Benzylidene Compounds; Clomiphene
• Other Study ID Numbers: HS-23-00039

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes