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

Sponsor

Rachel Mejia (Other)

Overall Status

Recruiting

CT.gov ID

NCT05206448

Collaborator

Society for Reproductive Investigation (Other), American Society for Reproductive Medicine (Other), University of Wisconsin, Madison (Other)

184

Enrollment

Locations

Arms

37.2

Anticipated Duration (Months)

Patients Per Site

2.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome PCOS Infertility	Drug: Letrozole Drug: Clomiphene Citrate	Phase 4

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

184 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 26, 2020

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Letrozole Letrozole tablet Other Names: femara
Experimental: 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.	Drug: Letrozole Letrozole tablet Other Names: femara Drug: Clomiphene Citrate Clomiphene Citrate tablet Other Names: Clomid Clomiphene

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Letrozole

Letrozole tablet

Other Names:

femara

Experimental: 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.

Drug: Letrozole

Letrozole tablet

Other Names:

femara

Drug: Clomiphene Citrate

Clomiphene Citrate tablet

Other Names:

Clomid

Clomiphene

Outcome Measures

Primary Outcome Measures

Ovulation [Tested 6 to 8 days following patient reporting a positive ovulation test (LH surge). If no surge is detected, progesterone lab will be drawn on Cycle day 21-24.]
Mid-luteal serum progesterone level >=3 ng/ml

Secondary Outcome Measures

Number of corpora lutea [Cycle day 21-24 of 1st treatment cycle]
Number of corpora lutea on ultrasound
Number of corpora lutea [Cycle day 21-24 of 2nd treatment cycle]
Number of corpora lutea on ultrasound
Number of corpora lutea [Cycle day 21-24 of 3rd treatment cycle]
Number of corpora lutea on ultrasound
Endometrial thickness [Cycle day 21-24 of 1st treatment cycle]
Endometrial thickness assessed by ultrasound
Endometrial thickness [Cycle day 21-24 of 2nd treatment cycle]
Endometrial thickness assessed by ultrasound
Endometrial thickness [Cycle day 21-24 of 3rd treatment cycle]
Endometrial thickness assessed by ultrasound
Conception [5 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation)]
positive serum or urinary test of hCG
Clinical pregnancy [6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation)]
intrauterine pregnancy with fetal heart motion determined by ultrasound
Multiple gestation [6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation)]
intrauterine pregnancy with more than one fetal heart motion determined by ultrasound
Live birth [9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation)]
delivery of a live born infant determined by medical record abstraction
Multiple birth [9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation)]
delivery of more than one infant determined by medical record abstraction
Pregnancy Loss [Through study completion, an average of 1 year]
biochemical pregnancy, miscarriage, or ectopic pregnancy determined by ultrasound or medical record abstraction

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Willing to comply with all study procedures and be available for the duration of the study
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.
Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria.
Ability to have regular intercourse during the ovulation induction phase of the study.
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:

Current pregnancy
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
Other known cause of infertility: endometriosis, tubal factor, uterine abnormalities
Uncorrected thyroid disease
Untreated hyperprolactinemia
Medical conditions in which avoiding pregnancy is recommended until under improved control: poorly controlled Type 1 or Type 2 diabetes, poorly controlled hypertension
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
Contraindications to letrozole: hypersensitivity to letrozole or any of its components
Use of medications known to affect reproductive function or metabolism or that are an absolute contraindication during pregnancy within the past month
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)