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| Name | Class |
|---|---|
| Society for Reproductive Investigation | UNKNOWN |
| American Society for Reproductive Medicine | UNKNOWN |
| University of Wisconsin, Madison | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Letrozole | Active Comparator | 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 + Clomiphene Citrate | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Letrozole | Drug | Letrozole tablet |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Corpora Lutea | Number of corpora lutea on ultrasound | Cycle day 21-24 of 1st treatment cycle |
| Number of Corpora Lutea | Number of corpora lutea on ultrasound |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rachel Mejia, DO | University of Iowa Hospitals & Clinics | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Iowa Hospitals & Clinics - Davenport Clinic | Davenport | Iowa | 52807 | United States | ||
| University of Iowa Hospitals & Clinics |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 2, 2023 |
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| Clomiphene Citrate | Drug | Clomiphene Citrate tablet |
|
|
| Cycle day 21-24 of 2nd treatment cycle |
| Number of Corpora Lutea | Number of corpora lutea on ultrasound | Cycle day 21-24 of 3rd treatment cycle |
| Endometrial Thickness | Endometrial thickness assessed by ultrasound | Cycle day 21-24 of 1st treatment cycle |
| Endometrial Thickness | Endometrial thickness assessed by ultrasound | Cycle day 21-24 of 2nd treatment cycle |
| Endometrial Thickness | Endometrial thickness assessed by ultrasound | Cycle day 21-24 of 3rd treatment cycle |
| Conception | positive serum or urinary test of hCG | 5 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation) |
| Clinical Pregnancy | intrauterine pregnancy with fetal heart motion determined by ultrasound | 6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation) |
| Multiple Gestation | intrauterine pregnancy with more than one fetal heart motion determined by ultrasound | 6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation) |
| Live Birth | delivery of a live born infant determined by medical record abstraction | 9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation) |
| Multiple Birth | delivery of more than one infant determined by medical record abstraction | 9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation) |
| Pregnancy Loss | biochemical pregnancy, miscarriage, or ectopic pregnancy determined by ultrasound or medical record abstraction | Through study completion, an average of 1 year |
| 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 |
| FG001 | 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 |
| Completed 1st Treatment Cycle |
|
| Ongoing Pregnancy Resulting From Cycle 1 | Participants with ongoing pregnancy resulting from cycle 1 did not complete cycle 2 or 3 per protocol and were considered as completing study participation. |
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| Completed 2nd Treatment Cycle | Participants with ongoing pregnancy resulting from cycle 1 did not complete additional treatment cycles. |
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| Ongoing Pregnancy Resulting From Cycle 2 | Participants with an ongoing pregnancy from cycle 2 did not complete cycle 3 per protocol and were considered as completing study participation. |
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| Completed 3rd Treatment Cycle | Participants with ongoing pregnancy resulting from cycle 1 or 2 did not complete additional treatment cycle |
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| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
| ||||||||||||||||
| BMI | Mean | Standard Deviation | kg/m^2 |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Count of Participants | Participants | 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. |
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| Secondary | Number of Corpora Lutea | Number of corpora lutea on ultrasound | Participants who completed study ultrasound during c1st study treatment cycle. | Posted | Mean | Standard Deviation | number of corpora lutea | Cycle day 21-24 of 1st treatment cycle |
| ||||||||||||||||||||||||||||||
| Secondary | Number of Corpora Lutea | Number of corpora lutea on ultrasound | Participants who completed a study ultrasound in their 2nd study treatment cycle. | Posted | Mean | Standard Deviation | number of corpora lutea | Cycle day 21-24 of 2nd treatment cycle |
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| Secondary | Number of Corpora Lutea | Number of corpora lutea on ultrasound | Participants who completed a study ultrasound during their 3rd treatment cycle. | Posted | Mean | Standard Deviation | number of corpora lutea | Cycle day 21-24 of 3rd treatment cycle |
| ||||||||||||||||||||||||||||||
| Secondary | Endometrial Thickness | Endometrial thickness assessed by ultrasound | Participants completing study ultrasound during their first study treatment cycle | Posted | Mean | Standard Deviation | mm | Cycle day 21-24 of 1st treatment cycle |
| ||||||||||||||||||||||||||||||
| Secondary | Endometrial Thickness | Endometrial thickness assessed by ultrasound | Participants who completed study ultrasound during their 2nd study treatment cycle | Posted | Mean | Standard Deviation | mm | Cycle day 21-24 of 2nd treatment cycle |
| ||||||||||||||||||||||||||||||
| Secondary | Endometrial Thickness | Endometrial thickness assessed by ultrasound | Participants who completed study ultrasound during their 3rd study treatment cycle | Posted | Mean | Standard Deviation | mm | Cycle day 21-24 of 3rd treatment cycle |
| ||||||||||||||||||||||||||||||
| Secondary | Conception | positive serum or urinary test of hCG | Not Posted | 5 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation) | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Clinical Pregnancy | intrauterine pregnancy with fetal heart motion determined by ultrasound | Not Posted | 6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation) | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Multiple Gestation | intrauterine pregnancy with more than one fetal heart motion determined by ultrasound | Not Posted | 6 to 7 weeks after treatment in treatment cycles 1, 2, and 3 (treatment cycle is 24-35 days depending on ovulation) | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Live Birth | delivery of a live born infant determined by medical record abstraction | Not Posted | 9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation) | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Multiple Birth | delivery of more than one infant determined by medical record abstraction | Not Posted | 9-10 months following final treatment cycle (treatment cycle is 24-35 days depending on ovulation) | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Pregnancy Loss | biochemical pregnancy, miscarriage, or ectopic pregnancy determined by ultrasound or medical record abstraction | Not Posted | Through study completion, an average of 1 year | Participants |
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 98 | 2 | 98 | 68 | 98 |
| EG001 | 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 | 0 | 92 | 2 | 92 | 69 | 92 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mood changes | Psychiatric disorders | Systematic Assessment |
| ||
| Back pain | General disorders | Systematic Assessment |
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| Abdominal pain | General disorders | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Food borne illness | Gastrointestinal disorders | Systematic Assessment | Nausea, vomiting, diarrhea and fever. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hot flash | Reproductive system and breast disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Abdominal bloating | Reproductive system and breast disorders | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Upset stomach | Gastrointestinal disorders | Systematic Assessment |
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| Mood changes | Psychiatric disorders | Systematic Assessment |
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| Visual changes | Eye disorders | Systematic Assessment |
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| Fatigue | General disorders | Systematic Assessment |
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| Dark Urine | Renal and urinary disorders | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Arthritic pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Dizziness | Nervous system disorders | Systematic Assessment |
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| Breast discomfort | Reproductive system and breast disorders | Systematic Assessment |
| ||
| Abdominal pain | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Rachel Mejia, DO | University of Iowa | 319-356-3143 | rachel-mejia@uiowa.edu |
| Dec 3, 2024 |
| Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D011085 | Polycystic Ovary Syndrome |
| D007246 | Infertility |
| ID | Term |
|---|---|
| D010048 | Ovarian Cysts |
| D003560 | Cysts |
| D009369 | Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 | Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000077289 | Letrozole |
| D002996 | Clomiphene |
| ID | Term |
|---|---|
| D009570 | Nitriles |
| D009930 | Organic Chemicals |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013267 | Stilbenes |
| D001597 | Benzylidene Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
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| Black non-hispanic |
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| Asian |
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| Hispanic |
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| Multiple |
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