Randomized Controlled Trial of Combined Letrozole and Clomid (CLC II) Versus Letrozole Alone for Women With Anovulation

NCT ID: NCT05206448

Last Updated: 2025-04-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 190 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-26
• Study Completion Date: 2025-12-31

Brief Summary

This study evaluates the addition of clomiphene citrate (CC) to letrozole for the treatment of infertility in women with polycystic ovary syndrome across a course of two treatment cycles with stair step dosing of letrozole similar to standard of care. Half of the participants will receive letrozole and CC in combination, while the other half will receive letrozole alone.

Detailed Description

Letrozole and Clomid are both used for ovulation induction, but they have different mechanisms of action. In a pilot study we found that the combination of letrozole 2.5 mg and CC 50 mg nearly doubled the ovulation rate as compared to use of letrozole monotherapy (77% vs. 43%, P=0.007; rate ratio for ovulation (95% CI) 1.80 (1.18 to 2.75), with similar endometrial thickness and number of follicles across treatment arms among those who ovulated. Additional data is needed to evaluate escalating dosages, multiple cycles, live birth and multiple gestation with this novel treatment combination.

This is a randomized controlled trial of letrozole versus letrozole and clomiphene citrate (CC) for up to three menstrual cycles. Women will be randomized in a 1:1 ratio to receive letrozole 2.5 mg or combination of letrozole 2.5 mg and clomiphene 50 mg for 5 days on days 3-7 of menstrual cycle. The women and their partners will be instructed to have regular intercourse with the intent to conceive during the cycle. Patients will have an transvaginal ultrasound in the mid-luteal phase of cycle to assess corpora lutea number and endometrial thickness. Patients will have mid- luteal phase progesterone level drawn to evaluate ovulation. Patients in both study arms who do not ovulate will have their Letrozole dose increased by 2.5 mg in the next study cycle to a max of 7.5 mg. Patients in the combination arm who do not ovulate will only have their Letrozole dose increased and will continue to receive the same dose of clomiphene across the three study treatment cycles. Side effect profile will also be monitored.

Conditions

Polycystic Ovary Syndrome; PCOS; Infertility

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Letrozole

Letrozole 2.5 mg orally for 5 days on cycle days 3-7 in first study treatment cycle. Participants who ovulate and do not become pregnant will repeat the same treatment protocol for their next study cycle. Participants who do not ovulate will repeat the protocol with Letrozole dose increase of 2.5 mg daily in the next treatment cycle, to a maximum dose of 7.5 mg in the 3rd cycle.

Group Type: ACTIVE_COMPARATOR

Letrozole

Intervention Type: DRUG

Letrozole tablet

Letrozole + Clomiphene Citrate

Letrozole 2.5 mg orally for 5 days on cycle days 3-7 AND Clomiphene Citrate 50 mg orally for 5 days on cycle days 3-7. Participants who ovulate and do not become pregnant will repeat the same treatment protocol for their next study cycle. Participants who do not ovulate will repeat the protocol with Letrozole dose increase of 2.5mg daily in the next treatment cycle to a maximum dose of 7.5 mg in the 3rd cycle, while maintaining the same dose of Clomiphene Citrate.

Group Type: EXPERIMENTAL

Letrozole

Intervention Type: DRUG

Letrozole tablet

Clomiphene Citrate

Intervention Type: DRUG

Clomiphene Citrate tablet

Interventions

Letrozole

Letrozole tablet

Intervention Type: DRUG

Clomiphene Citrate

Clomiphene Citrate tablet

Intervention Type: DRUG

Other Intervention Names

femara; Clomid; Clomiphene

Eligibility Criteria

Inclusion Criteria

1. Willing to comply with all study procedures and be available for the duration of the study

2. Diagnosis of infertility: Inability of couple to achieve successful pregnancy after 12 months of regular time unprotected intercourse in women less than 35 years of age; and after 6 months of regular intercourse without use of contraception in women 35 years and older. Women that have anovulation or oligomenorrhea are also considered to meet diagnosis of infertility, without meeting the time constraints described above.

3. Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria.

4. Ability to have regular intercourse during the ovulation induction phase of the study.

5. Partner with a normal sperm concentration of 15 million/mL and with normal motility of >40% according to World Health Organization cutoff points or greater than 10 million total motile sperm count OR has fathered a pregnancy in the past.

Exclusion Criteria

1. Current pregnancy

2. Current use of hormonal contraception; use of any type of combined contraceptive or oral progestins within the past month; or use of hormonal implants or depo progestins within the past 3 months

3. Other known cause of infertility: endometriosis, tubal factor, uterine abnormalities

4. Uncorrected thyroid disease

5. Untreated hyperprolactinemia

6. Medical conditions in which avoiding pregnancy is recommended until under improved control: poorly controlled Type 1 or Type 2 diabetes, poorly controlled hypertension

7. Contraindications to clomiphene citrate: hypersensitivity to clomiphene citrate or any of its components, history of liver disease or known liver disease, unknown cause of abnormal uterine bleeding, or intracranial lesion

8. Contraindications to letrozole: hypersensitivity to letrozole or any of its components

9. Use of medications known to affect reproductive function or metabolism or that are an absolute contraindication during pregnancy within the past month

10. If patients are suspected based on clinical findings for other etiologies that mimic PCOS, work up must be completed to exclude other etiologies prior to enrollment (i.e. Cushing's syndrome, androgen-secreting tumor)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Society for Reproductive Investigation

UNKNOWN

Sponsor Role: collaborator

American Society for Reproductive Medicine

UNKNOWN

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: collaborator

Rachel Mejia

OTHER

Sponsor Role: lead

Responsible Party

Rachel Mejia

Clinical Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Rachel Mejia, DO

Role: PRINCIPAL_INVESTIGATOR

University of Iowa Hospitals & Clinics

Locations

University of Iowa Hospitals & Clinics - Davenport Clinic

Davenport, Iowa, United States

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States

University of Iowa Hospitals & Clinics- West Des Moines Clinic

West Des Moines, Iowa, United States

University of Wisconsin

Madison, Wisconsin, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

201906826

Identifier Type: -

Identifier Source: org_study_id