What is the mechanism of action of this treatment?

Clomiphene Citrate and Letrozole are common treatments for infertility that work by different mechanisms to induce ovulation. Clomiphene Citrate, a Selective Estrogen Receptor Modulator (SERM), blocks estrogen receptors in the hypothalamus, leading to increased release of gonadotropins (FSH and LH) which stimulate ovulation. Letrozole, an Aromatase Inhibitor, reduces estrogen production by inhibiting the enzyme aromatase, resulting in increased FSH secretion from the pituitary gland, which also promotes ovulation. Understanding these mechanisms is important for infertility patients as it helps tailor treatment to their specific hormonal needs and underlying causes of infertility.

What side effects are associated with this type of intervention?

Clomiphene Citrate, a selective estrogen receptor modulator, is commonly associated with side effects such as endometrial thinning, hot flashes, ovarian hyperstimulation, and a higher incidence of multiple pregnancies. Letrozole, an aromatase inhibitor, generally has fewer side effects but can include fatigue, dizziness, and joint pain. Notably, Letrozole is less likely to cause endometrial thinning compared to Clomiphene Citrate.

What prior FDA approvals exist?

Clomiphene Citrate, a Selective Estrogen Receptor Modulator, has been FDA-approved for the treatment of infertility in women with ovulatory dysfunction since the 1960s. It works by stimulating ovulation through increased release of gonadotropins. Letrozole, an Aromatase Inhibitor, is primarily approved for the treatment of breast cancer but is used off-label for ovulation induction in women with polycystic ovary syndrome (PCOS) who are resistant to Clomiphene Citrate. Both drugs are commonly used in clinical practice to induce ovulation and improve fertility outcomes.

What other types of research exist?

Promising novel alternatives to Clomiphene Citrate and Letrozole for infertility treatment include: 1) Gonadotropins, which are used for controlled ovarian hyperstimulation and have shown efficacy in combination with intrauterine insemination (IUI) or in vitro fertilization (IVF). 2) Aromatase inhibitors combined with other agents, such as norethisterone acetate or GnRH analogs, which have shown potential in reducing endometriosis-related pain and improving fertility outcomes. 3) Dopamine agonists like cabergoline for hyperprolactinemic anovulation, which can effectively induce ovulation. These alternatives offer different mechanisms of action and may be suitable for patients who do not respond to or cannot tolerate Clomiphene Citrate or Letrozole.

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Selective Estrogen Receptor Modulator (SERM)

Letrozole + Clomiphene Citrate for Anovulation (CLC II Trial)

Phase 4

Waitlist Available

Led By Rachel Mejia, DO

Research Sponsored by Rachel Mejia

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria.

Partner with a normal sperm concentration and motility or total motile sperm count, or has fathered a pregnancy in the past

Must not have

Untreated hyperprolactinemia

Current use of hormonal contraception or implants

Timeline

Screening 3 weeks

Treatment Varies

Follow Up through study completion, an average of 1 year

Awards & highlights

All Individual Drugs Already Approved

Drug Has Already Been Approved

No Placebo-Only Group

Pivotal Trial

Approved for 10 Other Conditions

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Letrozole and clomiphene can cause hot flashes, stomach upset, headaches, breast tenderness, mood swings, blurred vision and rarely increase the chance of having twins or more.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with polycystic ovary syndrome.

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My partner has normal sperm or has fathered a child before.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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I am currently using hormonal birth control methods.

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I have a known cause of infertility such as endometriosis, tubal issues, or uterine abnormalities.

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I have a thyroid condition that hasn't been treated.

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I cannot take clomiphene citrate or letrozole due to health reasons.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ through study completion, an average of 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~through study completion, an average of 1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and through study completion, an average of 1 year for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Ovulation

Secondary study objectives

Clinical pregnancy

Conception

Endometrial thickness

+5 more

Side effects data

From 2018 Phase 4 trial • 79 Patients • NCT02137538

10%

Fracture

Acne

Scoliosis

Hair loss

Sacroiliitis

Neuro event

100%

80%

60%

40%

20%

Study treatment Arm

Anastrozole

Letrozole

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

Drug Has Already Been Approved

The FDA has already approved this drug, and is just seeking more data.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Approved for 10 Other Conditions

This treatment demonstrated efficacy for 10 other conditions.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Letrozole + Clomiphene CitrateExperimental Treatment2 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: LetrozoleActive Control1 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Letrozole

FDA approved

Clomifene

FDA approved

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Clomiphene Citrate and Letrozole are common treatments for infertility that work by different mechanisms to induce ovulation. Clomiphene Citrate, a Selective Estrogen Receptor Modulator (SERM), blocks estrogen receptors in the hypothalamus, leading to increased release of gonadotropins (FSH and LH) which stimulate ovulation. Letrozole, an Aromatase Inhibitor, reduces estrogen production by inhibiting the enzyme aromatase, resulting in increased FSH secretion from the pituitary gland, which also promotes ovulation. Understanding these mechanisms is important for infertility patients as it helps tailor treatment to their specific hormonal needs and underlying causes of infertility.

Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.Metabolic syndrome in obesity: treatment success and adverse pregnancy outcomes with ovulation induction in polycystic ovary syndrome.