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

Primary Purpose

Polycystic Ovary Syndrome, PCOS, Infertility

Status

Recruiting

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Letrozole

Clomiphene Citrate

About this trial

This is an interventional treatment trial for Polycystic Ovary Syndrome

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept 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)

Sites / Locations

University of Iowa Hospitals & Clinics - Davenport ClinicRecruiting
University of Iowa Hospitals & ClinicsRecruiting
University of Iowa Hospitals & Clinics- West Des Moines ClinicRecruiting
University of WisconsinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Letrozole

Letrozole + Clomiphene Citrate

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Ovulation

Mid-luteal serum progesterone level >=3 ng/ml

Secondary Outcome Measures

Number of corpora lutea

Number of corpora lutea on ultrasound

Number of corpora lutea

Number of corpora lutea on ultrasound

Number of corpora lutea

Number of corpora lutea on ultrasound

Endometrial thickness

Endometrial thickness assessed by ultrasound

Endometrial thickness

Endometrial thickness assessed by ultrasound

Endometrial thickness

Endometrial thickness assessed by ultrasound

Conception

positive serum or urinary test of hCG

Clinical pregnancy

intrauterine pregnancy with fetal heart motion determined by ultrasound

Multiple gestation

intrauterine pregnancy with more than one fetal heart motion determined by ultrasound

Live birth

delivery of a live born infant determined by medical record abstraction

Multiple birth

delivery of more than one infant determined by medical record abstraction

Pregnancy Loss

biochemical pregnancy, miscarriage, or ectopic pregnancy determined by ultrasound or medical record abstraction

Full Information

NCT ID

NCT05206448

First Posted

December 28, 2021

Last Updated

December 19, 2022

Sponsor

Rachel Mejia

Collaborators

Society for Reproductive Investigation, American Society for Reproductive Medicine, University of Wisconsin, Madison

1. Study Identification

Unique Protocol Identification Number

NCT05206448

Brief Title

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

Acronym

CLC II

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 26, 2020 (Actual)

Primary Completion Date

April 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Rachel Mejia

Collaborators

Society for Reproductive Investigation, American Society for Reproductive Medicine, University of Wisconsin, Madison

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Polycystic Ovary Syndrome, PCOS, Infertility

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

184 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Letrozole

Arm Type

Active Comparator

Arm Description

Arm Title

Letrozole + Clomiphene Citrate

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Letrozole

Other Intervention Name(s)

femara

Intervention Description

Letrozole tablet

Intervention Type

Drug

Intervention Name(s)

Clomiphene Citrate

Other Intervention Name(s)

Clomid, Clomiphene

Intervention Description

Clomiphene Citrate tablet

Primary Outcome Measure Information:

Title

Ovulation

Description

Mid-luteal serum progesterone level >=3 ng/ml

Time Frame

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.

Secondary Outcome Measure Information:

Title

Number of corpora lutea

Description

Number of corpora lutea on ultrasound

Time Frame

Cycle day 21-24 of 1st treatment cycle

Title

Number of corpora lutea

Description

Number of corpora lutea on ultrasound

Time Frame

Cycle day 21-24 of 2nd treatment cycle

Title

Number of corpora lutea

Description

Number of corpora lutea on ultrasound

Time Frame

Cycle day 21-24 of 3rd treatment cycle

Title

Endometrial thickness

Description

Endometrial thickness assessed by ultrasound

Time Frame

Cycle day 21-24 of 1st treatment cycle

Title

Endometrial thickness

Description

Endometrial thickness assessed by ultrasound

Time Frame

Cycle day 21-24 of 2nd treatment cycle

Title

Endometrial thickness

Description

Endometrial thickness assessed by ultrasound

Time Frame

Cycle day 21-24 of 3rd treatment cycle

Title

Conception

Description

positive serum or urinary test of hCG

Time Frame

5 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation)

Title

Clinical pregnancy

Description

intrauterine pregnancy with fetal heart motion determined by ultrasound

Time Frame

6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation)

Title

Multiple gestation

Description

intrauterine pregnancy with more than one fetal heart motion determined by ultrasound

Time Frame

6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation)

Title

Live birth

Description

delivery of a live born infant determined by medical record abstraction

Time Frame

9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation)

Title

Multiple birth

Description

delivery of more than one infant determined by medical record abstraction

Time Frame

9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation)

Title

Pregnancy Loss

Description

biochemical pregnancy, miscarriage, or ectopic pregnancy determined by ultrasound or medical record abstraction

Time Frame

Through study completion, an average of 1 year

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Karen Summers, MPH, CHES

Phone

319-356-8862

CLC-PCOS@uiowa.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rachel Mejia, DO

Organizational Affiliation

University of Iowa Hospitals & Clinics

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Iowa Hospitals & Clinics - Davenport Clinic

City

Davenport

State/Province

Iowa

ZIP/Postal Code

52807

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jessica Kresowik, MD

Facility Name

University of Iowa Hospitals & Clinics

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242

Country

United States

Individual Site Status

Recruiting

Facility Name

University of Iowa Hospitals & Clinics- West Des Moines Clinic

City

West Des Moines

State/Province

Iowa

ZIP/Postal Code

50266

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Abigail Mancuso, MD

Facility Name

University of Wisconsin

City

Madison

State/Province

Wisconsin

ZIP/Postal Code

53562

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Laura Cooney, MD, MSCE

12. IPD Sharing Statement

Learn more about this trial

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

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