Trial Outcomes & Findings for Randomized Controlled Trial of Combined Letrozole and Clomid (CLC II) Versus Letrozole Alone for Women With Anovulation (NCT NCT05206448)

Results Overview

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

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE4

Target enrollment

190 participants

Primary outcome timeframe

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.

Results posted on

2025-04-15

Participant Flow

Participant milestones

Participant milestones
Measure	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. Letrozole: Letrozole tablet	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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Overall Study STARTED	98	92
Overall Study Completed 1st Treatment Cycle	98	92
Overall Study Ongoing Pregnancy Resulting From Cycle 1	4	15
Overall Study Completed 2nd Treatment Cycle	93	75
Overall Study Ongoing Pregnancy Resulting From Cycle 2	10	8
Overall Study Completed 3rd Treatment Cycle	78	65
Overall Study COMPLETED	92	88
Overall Study NOT COMPLETED	6	4

Reasons for withdrawal

Reasons for withdrawal
Measure	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. Letrozole: Letrozole tablet	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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Overall Study Lost to Follow-up	2	2
Overall Study Withdrawal by Subject	2	0
Overall Study found ineligible after randomization	1	1
Overall Study unable to complete study due to personal constraints	1	0
Overall Study Became pregnant during gap in treatment after pregnancy loss	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Letrozole n=98 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=92 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet	Total n=190 Participants Total of all reporting groups
Age, Continuous	30.7 years STANDARD_DEVIATION 4.25 • n=5 Participants	29.9 years STANDARD_DEVIATION 4.31 • n=7 Participants	30.2 years STANDARD_DEVIATION 4.28 • n=5 Participants
Sex: Female, Male Female	98 Participants n=5 Participants	92 Participants n=7 Participants	190 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White non-hispanic	79 Participants n=5 Participants	79 Participants n=7 Participants	158 Participants n=5 Participants
Race/Ethnicity, Customized Black non-hispanic	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Asian	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	98 participants n=5 Participants	92 participants n=7 Participants	190 participants n=5 Participants
BMI	36.24 kg/m^2 STANDARD_DEVIATION 7.97 • n=5 Participants	36.78 kg/m^2 STANDARD_DEVIATION 7.91 • n=7 Participants	36.50 kg/m^2 STANDARD_DEVIATION 7.92 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Letrozole n=98 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=92 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Ovulation	91 Participants	89 Participants

SECONDARY outcome

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

Population: Participants who completed study ultrasound during c1st study treatment cycle.

Number of corpora lutea on ultrasound

Outcome measures

Outcome measures
Measure	Letrozole n=97 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=91 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Number of Corpora Lutea	0.64 number of corpora lutea Standard Deviation 0.68	1.09 number of corpora lutea Standard Deviation 1.02

SECONDARY outcome

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

Population: Participants who completed a study ultrasound in their 2nd study treatment cycle.

Number of corpora lutea on ultrasound

Outcome measures

Outcome measures
Measure	Letrozole n=89 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=74 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Number of Corpora Lutea	0.92 number of corpora lutea Standard Deviation 0.70	1.07 number of corpora lutea Standard Deviation 0.78

SECONDARY outcome

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

Population: Participants who completed a study ultrasound during their 3rd treatment cycle.

Number of corpora lutea on ultrasound

Outcome measures

Outcome measures
Measure	Letrozole n=75 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=64 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Number of Corpora Lutea	0.99 number of corpora lutea Standard Deviation 0.75	1.22 number of corpora lutea Standard Deviation 0.90

SECONDARY outcome

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

Population: Participants completing study ultrasound during their first study treatment cycle

Endometrial thickness assessed by ultrasound

Outcome measures

Outcome measures
Measure	Letrozole n=97 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=91 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Endometrial Thickness	8.52 mm Standard Deviation 3.08	9.41 mm Standard Deviation 3.10

SECONDARY outcome

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

Population: Participants who completed study ultrasound during their 2nd study treatment cycle

Endometrial thickness assessed by ultrasound

Outcome measures

Outcome measures
Measure	Letrozole n=89 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=74 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Endometrial Thickness	9.15 mm Standard Deviation 3.09	9.32 mm Standard Deviation 2.81

SECONDARY outcome

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

Population: Participants who completed study ultrasound during their 3rd study treatment cycle

Endometrial thickness assessed by ultrasound

Outcome measures

Outcome measures
Measure	Letrozole n=75 Participants 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=64 Participants 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Endometrial Thickness	9.11 mm Standard Deviation 3.11	9.41 mm Standard Deviation 2.79

Adverse Events

Letrozole

Serious events: 2 serious events

Other events: 68 other events

Deaths: 0 deaths

Letrozole + Clomiphene Citrate

Serious events: 2 serious events

Other events: 69 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Letrozole n=98 participants at risk 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. Letrozole: Letrozole tablet	Letrozole + Clomiphene Citrate n=92 participants at risk 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. Letrozole: Letrozole tablet Clomiphene Citrate: Clomiphene Citrate tablet
Psychiatric disorders Mood changes	1.0% 1/98 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.	0.00% 0/92 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.
General disorders Back pain	0.00% 0/98 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.	1.1% 1/92 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.
General disorders Abdominal pain	0.00% 0/98 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.	1.1% 1/92 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.
Gastrointestinal disorders Nausea	0.00% 0/98 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.	1.1% 1/92 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.
Gastrointestinal disorders Constipation	0.00% 0/98 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.	1.1% 1/92 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.
Gastrointestinal disorders Food borne illness	1.0% 1/98 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.	0.00% 0/92 • 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). Participants reported if they had experienced any side effects on daily logs, identifying the side effects they experienced from a list of known medication side effects. They also had the option to enter free text. For each reported side effect, they were asked to rank the severity. Serious adverse events included visits to the Emergency room and those which caused marked limitation in activity.

Other adverse events

Additional Information

Rachel Mejia, DO

University of Iowa

Phone: 319-356-3143

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place