Letrozole + Clomiphene Citrate for Anovulation

(CLC II Trial)

Recruiting at 4 trial locations

Overseen By Karen Summers, MPH, CHES

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: Rachel Mejia

Must not be taking: Hormonal contraception

Disqualifiers: Pregnancy, Endometriosis, Diabetes, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 cycles (24-35 days per cycle)

190 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if combining letrozole and clomiphene citrate helps women with PCOS ovulate better than using letrozole alone. Letrozole lowers estrogen to stimulate egg release, and clomiphene citrate boosts hormone production for the same purpose. The study aims to see if this combination increases the chances of ovulation. Clomiphene citrate has been widely used for over 50 years as a first-line therapy for ovulation induction in PCOS, while letrozole is a newer alternative that appears to improve live birth rates compared to clomiphene.

Will I have to stop taking my current medications?

The trial requires that you stop using hormonal contraception and any medications known to affect reproductive function or metabolism within the past month. If you are taking any of these, you will need to stop before participating.

What data supports the effectiveness of the drug combination Letrozole and Clomiphene Citrate for treating anovulation?

Research shows that both Letrozole and Clomiphene Citrate are effective in inducing ovulation in women with polycystic ovarian syndrome (PCOS), a common cause of anovulation. Letrozole may be slightly more effective than Clomiphene Citrate in certain cases, such as unexplained infertility, suggesting that the combination could be beneficial. ^{1 2 3 4 5}

How does the drug combination of Letrozole and Clomiphene Citrate differ from other treatments for anovulation?

The combination of Letrozole and Clomiphene Citrate is unique because it uses two different drugs that work in distinct ways to induce ovulation. Letrozole, an aromatase inhibitor, is often used when Clomiphene Citrate alone is not effective, and combining them may enhance the chances of ovulation in women who do not respond to standard treatments. ^{1 6 7 8 9}

Research Team

Rachel Mejia, DO

Principal Investigator

University of Iowa Hospitals & Clinics

Eligibility Criteria

This trial is for women with polycystic ovary syndrome (PCOS) who are struggling to get pregnant. They should be able to have regular intercourse and their partners must have normal sperm or a history of causing pregnancy. Women under 35 must have tried for a year, those over 35 for six months, without success.

Inclusion Criteria

I am willing and able to follow all study rules and attend all appointments.

I have been diagnosed with polycystic ovary syndrome.

I can have regular intercourse during the study's ovulation phase.

Exclusion Criteria

I have high prolactin levels that haven't been treated.

I am currently using hormonal birth control methods.

I haven't taken medication that affects fertility or metabolism in the last month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letrozole or a combination of letrozole and clomiphene citrate for up to three menstrual cycles, with dose adjustments based on ovulation response

3 cycles (24-35 days per cycle)

Regular visits for ultrasound and progesterone level assessment

Follow-up

Participants are monitored for clinical pregnancy, multiple gestation, and live birth outcomes

9-10 months following final treatment cycle

Treatment Details

Interventions

• Clomiphene Citrate
• Letrozole

Trial Overview The study is testing if adding clomiphene citrate (CC) to letrozole helps treat infertility in women with PCOS better than using letrozole alone. Participants will receive one of these two treatments randomly across two cycles.

Participant Groups

Group I: Letrozole + Clomiphene Citrate Experimental Treatment 2 Interventions

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 II: Letrozole Active Control 1 Intervention

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.

Clomiphene Citrate is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Clomid for:

• Infertility in women with polycystic ovary syndrome (PCOS)
• Male hypogonadism

Approved in Canada as Serophene for:

• Infertility in women with polycystic ovary syndrome (PCOS)
• Male hypogonadism

Approved in European Union as Clomiphene Citrate for:

• Infertility in women with polycystic ovary syndrome (PCOS)
• Male hypogonadism

Who Is Running the Clinical Trial?

Rachel Mejia

Lead Sponsor

Trials

2

Recruited

260+

American Society for Reproductive Medicine

Collaborator

Trials

1

Recruited

190+

University of Wisconsin, Madison

Collaborator

Trials

1,249

Recruited

3,255,000+

Society for Reproductive Investigation

Collaborator

Trials

1

Recruited

190+

Findings from Research

In a study of 92 women with Polycystic Ovarian Syndrome (PCOS), the Letrozole stair-step protocol achieved an ovulation rate of 96%, which is comparable to the 88% ovulation rate seen with Clomiphene Citrate (CC), indicating both treatments are effective for ovulation induction.

Letrozole resulted in a shorter time to ovulation (19.5 days) compared to CC (23.1 days), suggesting it may be a more efficient option for women seeking to conceive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovulation rates in a stair-step protocol with Letrozole vs clomiphene citrate in patients with polycystic ovarian syndrome. Thomas, S., Woo, I., Ho, J., et al.[2022]

References

1. India pubmed.ncbi.nlm.nih.gov

Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: A prospective randomized trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Letrozole Compared With Clomiphene Citrate for Unexplained Infertility: A Systematic Review and Meta-analysis. [2022]

3. India pubmed.ncbi.nlm.nih.gov

A prospective randomized trial comparing the efficacy of Letrozole and Clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. [2022]

4. Australia pubmed.ncbi.nlm.nih.gov

Letrozole versus clomiphene citrate for unexplained infertility: a systematic review and meta-analysis. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Ovulation rates in a stair-step protocol with Letrozole vs clomiphene citrate in patients with polycystic ovarian syndrome. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Letrozole or clomiphene citrate as first line for anovulatory infertility: a debate. [2021]

7. Singapore pubmed.ncbi.nlm.nih.gov

Influence of the conclusion of a recent large cooperative study in changing standard protocol of inducing menses in anovulatory women with oligomenorrhea prior to initiating ovulation induction with anti-estrogens and outcome. [2020]

8. Norway pubmed.ncbi.nlm.nih.gov

[Ovulation induction by means of letrozole]. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial. [2018]