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Polycystic Ovary SyndromePhase 4CLC IINCT05206448

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

A Phase 4 study testing Letrozole and Clomiphene Citrate in people with Polycystic Ovary Syndrome and PCOS, run by Rachel Mejia at 4 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 40 years, women only
Conditions the study is for
Polycystic Ovary Syndrome, PCOS, Infertility
What is being tested?
Letrozole and Clomiphene Citrate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
190 participants
Where
4 sitesUnited States
Study dates
26 Oct 2020to Dec 2025
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 10Show fewer
  • 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)

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • University of Iowa Hospitals & Clinics - Davenport Clinic

    Davenport, Iowa, 52807

  • University of Iowa Hospitals & Clinics

    Iowa City, Iowa, 52242

  • University of Wisconsin

    Madison, Wisconsin, 53562

  • University of Iowa Hospitals & Clinics- West Des Moines Clinic

    West Des Moines, Iowa, 50266

Other trials in United States

About this study

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.

Read the 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.

Being tested
Letrozole, Clomiphene Citrate
Medical subject headings
Polycystic Ovary Syndrome, Infertility

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LetrozoleDrug

    Also called femara

    Letrozole tablet

  • Clomiphene CitrateDrug

    Also called Clomid, Clomiphene

    Clomiphene Citrate tablet

Study groups in NCT05206448
Study groupRoleWhat they receive
LetrozoleActive comparatorLetrozole 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.
Receives: Drug: Letrozole
Letrozole + Clomiphene CitrateExperimentalLetrozole 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.
Receives: Drug: Letrozole; Drug: Clomiphene Citrate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Ovulation

    Number of Participants with Mid-luteal serum progesterone level >=3 ng/ml Number of cycles with Mid-luteal serum progesterone level >=3 ng/ml

    Measured: 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 outcomes (12)

  1. Number of Corpora Lutea

    Number of corpora lutea on ultrasound

    Measured: Cycle day 21-24 of 1st treatment cycle

  2. Number of Corpora Lutea

    Number of corpora lutea on ultrasound

    Measured: Cycle day 21-24 of 2nd treatment cycle

  3. Number of Corpora Lutea

    Number of corpora lutea on ultrasound

    Measured: Cycle day 21-24 of 3rd treatment cycle

  4. Endometrial Thickness

    Endometrial thickness assessed by ultrasound

    Measured: Cycle day 21-24 of 1st treatment cycle

  5. Endometrial Thickness

    Endometrial thickness assessed by ultrasound

    Measured: Cycle day 21-24 of 2nd treatment cycle

  6. Endometrial Thickness

    Endometrial thickness assessed by ultrasound

    Measured: Cycle day 21-24 of 3rd treatment cycle

  7. Conception

    positive serum or urinary test of hCG

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

  8. Clinical Pregnancy

    intrauterine pregnancy with fetal heart motion determined by ultrasound

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

  9. Multiple Gestation

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

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

  10. Live Birth

    delivery of a live born infant determined by medical record abstraction

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

  11. Multiple Birth

    delivery of more than one infant determined by medical record abstraction

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

  12. Pregnancy Loss

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

    Measured: Through study completion, an average of 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jan 2022
  2. Study start26 Oct 2020
  3. Primary completion12 Apr 2024
  4. Study completionDec 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
190 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05206448
Sponsor's protocol ID
201906826
Acronym
CLC II
Status last verified
Mar 2025
First submitted
28 Dec 2021
Last updated
15 Apr 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Letrozole and Clomiphene Citrate in people with Polycystic Ovary Syndrome and PCOS, run by Rachel Mejia at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 15 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Apr 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Ovulation (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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05206448.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2025.

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