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Active, not recruitingNCT05206448CLC IIUpdated Apr 15, 2025Results posted

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

A Phase 4 interventional study of Letrozole and Clomiphene Citrate in Polycystic Ovary Syndrome, PCOS and Infertility, sponsored by Rachel Mejia. Active, not recruiting at 4 sites in United States. Open to female participants aged 18 Years to 40 Years. Per ClinicalTrials.gov, last updated 2025-04-15.

Sponsored by Rachel Mejia · Phase 4, Interventional, and Treatment

From the registry’s dates

  • Registered 1 year 2 months after the study started (first participant enrolled Oct 2020, registered Dec 2021).
Phase
Phase 4
Study type
Interventional
Enrollment
190
Allocation
Randomized
Ages
18 Years to 40 Years
Sex
Female
01

Study 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.

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.

02

Conditions studied

  • Polycystic Ovary Syndrome
  • PCOS
  • Infertility
03

In context

Polycystic Ovary Syndrome

956 studies on the registry are indexed under Polycystic Ovary Syndrome; 176 are open to participants now.

This study's enrollment of 190 is above the median of 70 across 697 interventional studies indexed under Polycystic Ovary Syndrome.

Browse Polycystic Ovary Syndrome studies →

Lead sponsor

Rachel Mejia is the lead sponsor of 2 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 40 Years
Sexes eligible
Female
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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 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

Exclusion Criteria:

  1. Current pregnancy
  2. Current use of hormonal ; 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. to clomiphene citrate: 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)
Terms in these criteria, in plain language(3)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Contraception

Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.

Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.

Contraindication

A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.

Hypersensitivity

An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.

05

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
190 participants (actual)

Study arms

  • Active comparator
    Letrozole

    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.

    Drug: Letrozole

  • Experimental
    Letrozole + Clomiphene Citrate

    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.

    Drug: Letrozole · Drug: Clomiphene Citrate

Interventions

06

What researchers measure

Primary outcomes

  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

    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 outcomes

  1. Number of Corpora Lutea

    Number of corpora lutea on ultrasound

    Time frame: Cycle day 21-24 of 1st treatment cycle

  2. Number of Corpora Lutea

    Number of corpora lutea on ultrasound

    Time frame: Cycle day 21-24 of 2nd treatment cycle

  3. Number of Corpora Lutea

    Number of corpora lutea on ultrasound

    Time frame: Cycle day 21-24 of 3rd treatment cycle

  4. Endometrial Thickness

    Endometrial thickness assessed by ultrasound

    Time frame: Cycle day 21-24 of 1st treatment cycle

  5. Endometrial Thickness

    Endometrial thickness assessed by ultrasound

    Time frame: Cycle day 21-24 of 2nd treatment cycle

  6. Endometrial Thickness

    Endometrial thickness assessed by ultrasound

    Time frame: Cycle day 21-24 of 3rd treatment cycle

  7. Conception

    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)

  8. Clinical Pregnancy

    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)

  9. Multiple Gestation

    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)

  10. Live Birth

    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)

  11. Multiple Birth

    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)

  12. Pregnancy Loss

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

    Time frame: Through study completion, an average of 1 year

07

Results

Posted Apr 15, 2025

Participant flow

Participant flow — Overall Study
MilestoneLetrozoleLetrozole + Clomiphene Citrate
Started9892
Completed 1st treatment cycle9892
Ongoing pregnancy resulting from cycle 1415
Completed 2nd treatment cycle9375
Ongoing pregnancy resulting from cycle 2108
Completed 3rd treatment cycle7865
Completed9288
Not completed64
Withdrew: Lost to follow-up22
Withdrew: Withdrawal by subject20
Withdrew: Found ineligible after randomization11
Withdrew: Unable to complete study due to personal constraints10
Withdrew: Became pregnant during gap in treatment after pregnancy loss01

Outcome measures

PrimaryOvulation

Number of Participants with Mid-luteal serum progesterone level \>=3 ng/ml Number of cycles with 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.
Reported as:
Count of participants · Participants
Ovulation
ParticipantsLetrozoleLetrozole + Clomiphene Citrate
Ovulation9189
SecondaryNumber of Corpora Lutea

Number of corpora lutea on ultrasound

Time frame:
Cycle day 21-24 of 1st treatment cycle
Reported as:
Mean · number of corpora lutea
Number of Corpora Lutea
number of corpora luteaLetrozoleLetrozole + Clomiphene Citrate
Number of Corpora Lutea0.64 ± 0.681.09 ± 1.02
SecondaryNumber of Corpora Lutea

Number of corpora lutea on ultrasound

Time frame:
Cycle day 21-24 of 2nd treatment cycle
Reported as:
Mean · number of corpora lutea
Number of Corpora Lutea
number of corpora luteaLetrozoleLetrozole + Clomiphene Citrate
Number of Corpora Lutea0.92 ± 0.701.07 ± 0.78
SecondaryNumber of Corpora Lutea

Number of corpora lutea on ultrasound

Time frame:
Cycle day 21-24 of 3rd treatment cycle
Reported as:
Mean · number of corpora lutea
Number of Corpora Lutea
number of corpora luteaLetrozoleLetrozole + Clomiphene Citrate
Number of Corpora Lutea0.99 ± 0.751.22 ± 0.90
SecondaryEndometrial Thickness

Endometrial thickness assessed by ultrasound

Time frame:
Cycle day 21-24 of 1st treatment cycle
Reported as:
Mean · mm
Endometrial Thickness
mmLetrozoleLetrozole + Clomiphene Citrate
Endometrial Thickness8.52 ± 3.089.41 ± 3.10
SecondaryEndometrial Thickness

Endometrial thickness assessed by ultrasound

Time frame:
Cycle day 21-24 of 2nd treatment cycle
Reported as:
Mean · mm
Endometrial Thickness
mmLetrozoleLetrozole + Clomiphene Citrate
Endometrial Thickness9.15 ± 3.099.32 ± 2.81
SecondaryEndometrial Thickness

Endometrial thickness assessed by ultrasound

Time frame:
Cycle day 21-24 of 3rd treatment cycle
Reported as:
Mean · mm
Endometrial Thickness
mmLetrozoleLetrozole + Clomiphene Citrate
Endometrial Thickness9.11 ± 3.119.41 ± 2.79
SecondaryConception

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)

Results for this outcome have not been posted.

SecondaryClinical Pregnancy

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)

Results for this outcome have not been posted.

SecondaryMultiple Gestation

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)

Results for this outcome have not been posted.

SecondaryLive Birth

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)

Results for this outcome have not been posted.

SecondaryMultiple Birth

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)

Results for this outcome have not been posted.

SecondaryPregnancy Loss

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

Time frame:
Through study completion, an average of 1 year

Results for this outcome have not been posted.

Adverse events

Collected over From first day of taking study medication through resolution of that treatment cycle, determined by menses, positive pregnancy test, or random start of next cycle. Typically, 3-6 weeks per cycle. Depending on number of cycles completed could range from 3 (single cycle) to 18 weeks (3 cycles).. Non-serious events are listed at a 2% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Letrozole0/98 (0%)2/98 (2%)68/98 (69.4%)
Letrozole + Clomiphene Citrate0/92 (0%)2/92 (2.2%)69/92 (75%)
Most frequent serious events
Most frequent serious events
EventLetrozoleLetrozole + Clomiphene Citrate
Back painGeneral disorders0/981/92
Abdominal painGeneral disorders0/981/92
NauseaGastrointestinal disorders0/981/92
ConstipationGastrointestinal disorders0/981/92
Mood changesPsychiatric disorders1/980/92
Food borne illnessGastrointestinal disorders1/980/92
Most frequent other events
Showing 10 of 16
Most frequent other events
EventLetrozoleLetrozole + Clomiphene Citrate
HeadacheNervous system disorders41/9847/92
Hot flashReproductive system and breast disorders29/9845/92
FatigueGeneral disorders30/9837/92
NauseaGastrointestinal disorders31/9824/92
Mood changesPsychiatric disorders27/9829/92
Abdominal painGeneral disorders28/9827/90
Abdominal bloatingReproductive system and breast disorders19/9825/92
Upset stomachGastrointestinal disorders19/9821/92
Back painMusculoskeletal and connective tissue disorders15/9821/92
Breast discomfortReproductive system and breast disorders13/9820/92

Baseline characteristics

Age, Continuous
Age, Continuous(years)LetrozoleLetrozole + Clomiphene CitrateTotal
Mean30.7 ± 4.2529.9 ± 4.3130.2 ± 4.28
Sex: Female, Male
Sex: Female, Male(Participants)LetrozoleLetrozole + Clomiphene CitrateTotal
Female9892190
Male000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)LetrozoleLetrozole + Clomiphene CitrateTotal
White non-hispanic7979158
Black non-hispanic314
Asian426
Hispanic10717
Multiple123
Other112
Region of Enrollment
Region of Enrollment(participants)LetrozoleLetrozole + Clomiphene CitrateTotal
United States9892190
BMI
BMI(kg/m^2)LetrozoleLetrozole + Clomiphene CitrateTotal
Mean36.24 ± 7.9736.78 ± 7.9136.50 ± 7.92
08

Study locations

4 sites
  • University of Iowa Hospitals & Clinics - Davenport Clinic
    Davenport, Iowa 52807, United States
  • University of Iowa Hospitals & Clinics
    Iowa City, Iowa 52242, United States
  • University of Iowa Hospitals & Clinics- West Des Moines Clinic
    West Des Moines, Iowa 50266, United States
  • University of Wisconsin
    Madison, Wisconsin 53562, United States
09

References and documents

Study documents

PDFs hosted by the registry, ClinicalTrials.gov.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Apr 15, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT05206448
Lead sponsor
Rachel Mejia
Collaborators
Society for Reproductive Investigation, American Society for Reproductive Medicine, University of Wisconsin, Madison
Responsible party
Rachel Mejia (Clinical Assistant Professor, University of Iowa) — Sponsor-investigator
First posted
Jan 25, 2022
Start date
Oct 26, 2020
Primary completion
Apr 12, 2024
Completion
Dec 2025 (estimated)
Results posted
Apr 15, 2025
Last update
Apr 15, 2025

Study contacts

Rachel Mejia, DO
principal investigator · University of Iowa Hospitals & Clinics

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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