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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
Sponsored by
Rachel Mejia
About
Eligibility
Locations
Arms
Outcomes
Full info

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:

  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)

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

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
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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
No
Product Manufactured in and Exported from the U.S.
No
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
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.
Arm Title
Letrozole + Clomiphene Citrate
Arm Type
Experimental
Arm Description
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.
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
No
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
Email
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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