Oral Microdose Lupron Versus Luteal Estradiol Trial in Poor Responder In Vitro Fertilization (IVF) Patients (OMLET)

A Randomized Controlled Trial of Treatment Protocols to Optimize Outcomes in Poor Responder In Vitro Fertilization (IVF) Patients: E2 Patch/Antagonist Protocol Versus OCP/Microdose Lupron Protocol

Hundreds of thousands of couples in the United States experience infertility each year. When initial measures do not help, some couples require a process called ovarian stimulation and in vitro fertilization (IVF). Usually, a woman produces at most one egg each month. Ovarian stimulation helps these women make more than one egg per month. However, this involves taking hormones that stimulate the ovary to produce many eggs at one time. The stimulatory hormones injected with a small needle. The eggs are removed from the ovary through a surgical procedure and then placed in a dish for fertilization by sperm to form embryos. The embryos are grown in the laboratory then replaced into the woman's uterus 3-5 days later.

The stimulation of the ovaries is important. Some patients undergo ovarian stimulation for IVF but do not respond to the treatment. This is a very difficult situation because even though several ovarian stimulation protocols have been used for poor responder patients, it is not clear which protocol works best. In fact, two of the most commonly used protocols have not been directly compared.

This study will randomize (like flipping a coin) couples with a history of low response who are going to start IVF treatment into two groups. In one group the female partner will use a protocol called "E2 patch/antagonist". These women will use an estrogen patch and injected antagonist for several days before starting injectable fertility medications. The other group will use a protocol called "OCP/microdose". This group of women will use oral contraceptive pills (OCPs) and small doses of lupron along with the other injectable fertility medications. We will then follow their progress to see how many eggs they produce and how many women get pregnant.

Study Overview

• Status: Withdrawn
• Conditions: Infertility
• Intervention / Treatment: Drug: Oral contraceptive pill and microdose lupron; Drug: E2 patch/antagonist

Detailed Description

Patients who have difficulty conceiving naturally often seek medical advice. These patients often undergo initial treatment with insemination using oral or injectable medications. However, if this fails to achieve a pregnancy, patients often undergo in vitro fertilization (IVF). IVF is a process which involves a protocol of injectable medications to stimulate the ovary to produce several eggs at once. These eggs are retrieved under ultrasound guidance and fertilized in the laboratory. After 3-5 days of growth in the laboratory, the appropriate number of embryos is then transferred back to the patient's uterus.

Sometimes, patients who go through ovarian stimulation and IVF do not respond well. These patients have low estrogen levels, few eggs retrieved, and fewer embryos to transfer back to the uterus. Overall, they have lower pregnancy rates than other patients. It is not clear which medication protocol would give them the highest chance of pregnancy. Two protocols, one called the "E2/antagonist" protocol and the other called the "OCP/microdose" protocol, are routinely used in poor responder patients. But, they have never been prospectively compared so it is not possible to say whether one approach is better.

In order to determine which medication protocol results in more pregnancies, we propose to randomize poor responder patients who are scheduled to undergo treatment with IVF to one of these two protocols. These two protocols are already standard care in IVF centers around the world. Following randomization, the clinical care of study participants will be the same as all other IVF patients. Specifically, the adjustment of medication, egg retrieval, and embryo transfer procedures will be identical to non-study patients undergoing IVF.

HYPOTHESIS We hypothesize that the poor responder patients undergoing ovarian stimulation for IVF with the E2/antagonist protocol will have a higher pregnancy rate than those in the OCP/microdose group.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • The Ronald O. Perlman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Females of couples with an indication for IVF who have a history of poor response as defined by one of the following:
• Cancellation of IVF due to inadequate follicular development
• Peak estradiol < 1000 pg/mL
• < 6 oocytes retrieved
• Age ≥18 years at the time of signing informed consent
• Availability of ejaculatory sperm (use of donated and/or cryopreserved sperm is allowed)
• Willing and able to sign informed consent

Exclusion Criteria:

• Prior use of the E2/ganirelix or OCP/microdose protocol
• Less than 2 ovaries or any other ovarian abnormality
• Presence of uncorrected unilateral or bilateral hydrosalpinx
• Presence of any clinically relevant pathology affecting the uterine cavity or intramural fibroid ≥ 5cm
• Contraindications for the use of gonadotropins (e.g. tumors, pregnancy/lactation, undiagnosed vaginal bleeding, hypersensitivity, clinically significant ovarian cysts)
• Contraindications for the use of oral contraceptive pills (h/o thromboembolism, breast cancer, undiagnosed vaginal bleeding)
• Contraindications for the use of estrogen patches (h/o thromboembolism, breast cancer, undiagnosed vaginal bleeding)
• Abnormal karyotyping of the patient or her partner (if karyotyping is performed)
• Hypersensitivity to any of the concomitant medication prescribed as part of the treatment regimen in this protocol
• Transfer of embryos to the patient not planned (i.e. gestational carrier use planned, embryos to be frozen)
• Unable to give informed consent

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: OCP/MDL; Oral contraceptive pills/microdose lupron	Drug: Oral contraceptive pill and microdose lupron; Desogestrel/ethinyl estradiol tablets, 0.15 mg/0.03 mg, one tablet by mouth daily for 14 days Leuprolide acetate 40 µg by subcutaneous injection twice a day during ovarian stimulation (approximately 14 days); Other Names: Lupron; Ortho-Cept®; Desogen®; Reclipsen™; Apri®; Leuprorelin; Leuprorelin Acetate
Experimental: E2/antagonist; Estradiol patch/gonadotropin-releasing hormone antagonist	Drug: E2 patch/antagonist; Estradiol transdermal system 0.1 mg/day (25 cm2 patch. Patch changed every other day x 3. Final patch left on for about 7 days. Total duration of therapy approximately 14 days. Gonadotropin-releasing hormone antagonist 0.25 mg subcutaneously every other day for 3 total doses.; Other Names: Climara®; Ganirelix acetate injection®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pregnancy rate	7 weeks gestation

Secondary Outcome Measures

Outcome Measure	Time Frame
Cycle cancellation rate	Cycle completion
Peak estradiol level	Cycle completion
Ampules of gonadotropins required during ovarian stimulation	Cycle completion
Number of days of ovarian stimulation	Cycle completion
Number of oocytes retrieved	Cycle completion
Number of embryos transferred	Cycle completion
Number of embryos frozen	Cycle completion
Embryo grade	Cycle completion
Implantation rate	7 weeks gestation
Miscarriage rate	20 weeks gestation
Pregnancy outcome	Following delivery

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Investigators: Principal Investigator: Zev Rosenwaks, M.D., Weill Medical College of Cornell University

Publications and helpful links

Helpful Links

• The Ronald O. Perlman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medical College

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: January 21, 2009
• First Submitted That Met QC Criteria: January 21, 2009
• First Posted (Estimate): January 22, 2009

Study Record Updates

• Last Update Posted (Estimate): June 25, 2013
• Last Update Submitted That Met QC Criteria: June 21, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Randomized clinical trial; In vitro fertilization; Poor responder patients; Estrogen patch; Gonadotropin-releasing hormone antagonist; Oral contraceptive pill; Microdose lupron
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Reproductive Control Agents; Contraceptive Agents, Female; Fertility Agents, Female; Fertility Agents; Leuprolide; Contraceptive Agents; Contraceptives, Oral; Contraceptives, Oral, Combined; Ganirelix
• Other Study ID Numbers: 0810010037

Drug and device information, study documents

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