Letrozole + Clomiphene Citrate for Anovulation

(CLC II Trial)

Not currently 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)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether adding clomiphene citrate to letrozole can enhance fertility treatment for women with polycystic ovary syndrome (PCOS). Researchers will divide participants into two groups: one will receive both letrozole and clomiphene citrate, while the other will receive only letrozole. Women who have tried to conceive for a year or more without success, or who have irregular periods due to PCOS, might be suitable for this study. As a Phase 4 trial, it involves treatments already FDA-approved and proven effective, helping to determine how they can benefit more patients.

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 is the safety track record for these treatments?

Research has shown that combining letrozole and clomiphene citrate (CC) is generally safe for women with polycystic ovary syndrome (PCOS) who have trouble getting pregnant. One study found that this combination increased pregnancy and ovulation rates without causing significant side effects. Another study reported that using both medications nearly doubled the ovulation rate compared to letrozole alone, again without major safety concerns.

Studies have also shown that letrozole alone is safe for treating infertility. No evidence suggests that letrozole increases the risk of birth defects or pregnancy loss. Overall, both treatments appear to be safe options for women with infertility related to PCOS. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the combination of Letrozole and Clomiphene Citrate for treating anovulation because it offers a new approach by using two medications together, which is different from the standard treatments that typically use either one or the other. Letrozole works by blocking estrogen production, which can stimulate the ovaries, while Clomiphene Citrate increases the release of hormones that trigger ovulation. By combining these mechanisms, there's potential for higher ovulation rates compared to using each drug alone. This combination could improve the chances of ovulation and pregnancy for women who haven't responded to traditional treatments.

What evidence suggests that this trial's treatments could be effective for infertility in women with polycystic ovary syndrome?

This trial will compare the effectiveness of using letrozole together with clomiphene citrate (CC) versus letrozole alone for women with polycystic ovary syndrome (PCOS) who are having trouble getting pregnant. Research has shown that the combination of letrozole and CC can increase the chances of pregnancy and ovulation more than letrozole alone, and it may also lower the risk of miscarriage. Letrozole alone has also proven effective, with higher rates of live births and ovulation compared to clomiphene alone. Both treatments are promising, but the combination of letrozole and CC appears to improve fertility outcomes more for women with PCOS. ^{3 6 7 8 9}

Who Is on the Research Team?

Rachel Mejia, DO

Principal Investigator

University of Iowa Hospitals & Clinics

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

Citations

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clinicaltrials.gov/study/NCT05206448

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2.

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Effects of letrozole combined with clomiphene in the treatment ...

The results demonstrated that the combination therapy significantly improved pregnancy rates, ovulation rates, miscarriage rates, and estradiol ...

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S0015028218322258

A randomized controlled trial of combination letrozole and ...

The combination of letrozole and CC was associated with a higher ovulation rate compared with letrozole alone in women with infertility and PCOS.

4.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1313517

Letrozole versus Clomiphene for Infertility in the Polycystic ...

As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.

5.

cnyfertility.com

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Clomid Vs Letrozole: Which Fertility Drug Works Best?

Researchers concluded that there is no significant statistical difference in the effectiveness of Clomid or Letrozole to improve clinical ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8245002/

Letrozole for Female Infertility - PMC - PubMed Central

A systematic review and meta-analysis in 2019 showed no difference in terms of clinical pregnancy, live birth, spontaneous miscarriage, or twin gestation ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12249453/

Scoping Review of Letrozole in Assisted Reproductive ...

In patients with endometriosis, letrozole resulted in a higher implantation rate (47.53%) compared to conventional protocols (25.8%), although ...

8.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0301211525008073

Does the use of letrozole in infertility treatment increase ...

Altough current evidence does not suggest an increased risk of congenital malformations or pregnancy loss associated with the use of LTZ for timed intercourse, ...

9.

mdpi.com

mdpi.com/2227-9059/13/9/2051

Letrozole at the Crossroads of Efficacy and Fetal Safety in ...

Emerging data from large, randomized trials and meta-analyses demonstrate no increase in congenital anomalies, miscarriage, or adverse perinatal outcomes in ...