Infertility, Polycystic Ovary Syndrome
Conditions
Brief summary
This study evaluates the addition of clomid to letrozole for the treatment of infertility in women with polycystic ovary syndrome. Half of the participants will receive letrozole and clomid in combination, while the other half will receive letrozole alone.
Detailed description
Letrozole and Clomid are both used for ovulation induction, but they have different mechanisms of action. Letrozole has been shown to be superior to clomid in achieving live birth rates in women with infertility and polycystic ovary syndrome. However, the combination of these medications has not been studied. This is a pilot study to evaluate if the combination treatment has improved efficacy as measured by ovulation rate. This is a randomized controlled trial of letrozole versus letrozole and clomiphene citrate (CC) for one menstrual cycle. 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 mid cycle and to evaluate number of follicles (\>15 mm), follicle size, endometrial thickness and pattern. Patients will have mid- luteal phase progesterone level drawn to evaluate ovulation. Side effect profile will also be monitored.
Interventions
DRUGClomiphene
DRUGLetrozole
Sponsors
Rachel Mejia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
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 timed unprotected intercourse in women less than 35 years of age; and after 6 months of regular intercourse without use of contraception in women 35 years and older 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. Normal sperm concentration of 15 million/mL and with normal motility of \> 40% according to World Health Organization cutoff points, in at least one ejaculate during the previous year
Exclusion criteria
1. Current pregnancy 2. Current use of hormonal contraception; 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. Contraindications to clomiphene citrate: hypersensitivity to CC 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level | 7 days following LH surge or at cycle day 21 if no LH surge was detected | Ovulation: mid-luteal progesterone \> /=3 ng/mL. No ovulation: mid-luteal progesterone \<3ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Size of Largest Developing Follicle | Cycle day 12-14 | Size of largest follicle on ultrasound |
| Endometrial Thickness | Cycle day 12-14 | Thickness of endometrial lining assessed by ultrasound |
| Conception | 5 weeks after treatment | Conception: a positive serum or urinary test of hCG; No conception: Neither a positive serum or urinary test of hCG |
| Number of Developing Follicles | Cycle day 12-14 | Number of follicles measuring \> 10mm on ultrasound |
| Multiple Gestation | 9-10 months after treatment | Multiple Gestation: an intrauterine pregnancy with multiple fetal heart rates determined by ultrasonography; No Multiple Gestation: either no intrauterine pregnancy, or an intrauterine pregnancy with a single fetal heart rate determined by ultrasonography |
| Live Birth | 9-10 months after treatment | Live Birth: delivery of a live infant; No Live Birth: no delivery of a live infant |
| Pregnancy Loss | 9-10 months after treatment | Pregnancy Loss: any pregnancy loss including biochemical pregnancy, ectopic pregnancy, and miscarriage; No Pregnancy Loss: no pregnancy loss including biochemical pregnancy, ectopic pregnancy, or miscarriage. |
| Clinical Pregnancy | 6-7 weeks after treatment | Clinical Pregnancy: an intrauterine pregnancy with fetal heart motion determined by ultrasonography; No Clinical Pregnancy: no intrauterine pregnancy with fetal heart motion determined by ultrasonography |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Letrozole Letrozole 2.5 mg orally for 5 days on cycle days 3-7
Letrozole | 35 |
| Letrozole + Clomiphene Letrozole 2.5 mg orally for 5 days on cycle days 3-7 AND Clomid 50 mg orally for 5 days on cycle days 3-7
Clomiphene
Letrozole | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineliegible due to tuberculosis | 0 | 1 |
| Overall Study | Pregnancy | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Letrozole | Letrozole + Clomiphene |
|---|---|---|---|
| 2-hr GTT | 110 mg/dL STANDARD_DEVIATION 21.2 | 103 mg/dL STANDARD_DEVIATION 18.5 | 114 mg/dL STANDARD_DEVIATION 23 |
| Age, Continuous | 31 years STANDARD_DEVIATION 4.1 | 31 years STANDARD_DEVIATION 3.9 | 30 years STANDARD_DEVIATION 4.4 |
| BMI | 33 kg/m^2 STANDARD_DEVIATION 7.8 | 33 kg/m^2 STANDARD_DEVIATION 8.7 | 34 kg/m^2 STANDARD_DEVIATION 7 |
| Clomiphene use >6mo before | 21 Participants | 7 Participants | 14 Participants |
| Current tobacco use | 4 Participants | 1 Participants | 3 Participants |
| Duration of Time Attempting to Conceive | 29 months STANDARD_DEVIATION 24.5 | 30 months STANDARD_DEVIATION 29.6 | 28 months STANDARD_DEVIATION 18.5 |
| Fasting Blood Glucose | 93 mg/dL STANDARD_DEVIATION 9.3 | 95 mg/dL STANDARD_DEVIATION 6.7 | 90 mg/dL STANDARD_DEVIATION 10.6 |
| HbA1c | 5.3 mmol/mol STANDARD_DEVIATION 0.61 | 5.3 mmol/mol STANDARD_DEVIATION 0.47 | 5.3 mmol/mol STANDARD_DEVIATION 0.73 |
| Insurance Coverage Full coverage | 25 Participants | 10 Participants | 15 Participants |
| Insurance Coverage No coverage/unsure | 26 Participants | 16 Participants | 10 Participants |
| Insurance Coverage Partial coverage | 19 Participants | 9 Participants | 10 Participants |
| Letrozole use >6 mo before | 16 Participants | 6 Participants | 10 Participants |
| Max dose of Clomiphene | 150 mg | 150 mg | 150 mg |
| Max dose of Letrzole | 5 mg | 5 mg | 5 mg |
| Metformin Use Current Use | 29 Participants | 14 Participants | 15 Participants |
| Metformin Use Never Used | 25 Participants | 15 Participants | 10 Participants |
| Metformin Use Previous Use/Not Current | 16 Participants | 6 Participants | 10 Participants |
| Ovulation on max dose of Clomiphene | 17 Participants | 9 Participants | 8 Participants |
| Ovulation on max dose of Letrozole | 11 Participants | 4 Participants | 7 Participants |
| PCOS Diagnsosis Hyperandrogenism | 41 Participants | 20 Participants | 21 Participants |
| PCOS Diagnsosis Oligomenorrhea | 67 Participants | 34 Participants | 33 Participants |
| PCOS Diagnsosis Polycystic ovaries according to modified Rotterdam | 67 Participants | 35 Participants | 32 Participants |
| Previous Live Birth | 25 Participants | 14 Participants | 11 Participants |
| Previous use of both Letrozole and Clomiphene | 22 Participants | 8 Participants | 14 Participants |
| Previous use of Clomiphene | 40 Participants | 17 Participants | 23 Participants |
| Previous use of Letrozole | 27 Participants | 10 Participants | 17 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic or Latino | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity More than 1 race | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White | 59 Participants | 29 Participants | 30 Participants |
| Region of Enrollment United States | 70 participants | 35 participants | 35 participants |
| Resistance to both Letrozole and Clomid | 11 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 70 Participants | 35 Participants | 35 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 94 kg STANDARD_DEVIATION 26.1 | 94 kg STANDARD_DEVIATION 29.6 | 94 kg STANDARD_DEVIATION 22.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 33 |
| other Total, other adverse events | 21 / 33 | 19 / 32 |
| serious Total, serious adverse events | 1 / 33 | 1 / 32 |
Outcome results
Primary
Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level
Ovulation: mid-luteal progesterone \> /=3 ng/mL. No ovulation: mid-luteal progesterone \<3ng/mL.
Time frame: 7 days following LH surge or at cycle day 21 if no LH surge was detected
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letrozole | Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level | 15 Participants |
| Letrozole + Clomiphene | Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level | 27 Participants |
p-value: 0.00795% CI: [1.18, 2.75]Chi-squared, Corrected
Secondary
Clinical Pregnancy
Clinical Pregnancy: an intrauterine pregnancy with fetal heart motion determined by ultrasonography; No Clinical Pregnancy: no intrauterine pregnancy with fetal heart motion determined by ultrasonography
Time frame: 6-7 weeks after treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letrozole | Clinical Pregnancy | 1 Participants |
| Letrozole + Clomiphene | Clinical Pregnancy | 3 Participants |
Comparison: This study was not powered to detect significant between-group differences for clinical pregnancy.p-value: 0.356Chi-squared
Secondary
Conception
Conception: a positive serum or urinary test of hCG; No conception: Neither a positive serum or urinary test of hCG
Time frame: 5 weeks after treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letrozole | Conception | 3 Participants |
| Letrozole + Clomiphene | Conception | 4 Participants |
Comparison: This study was not powered to detect significant between-group differences for this conception.p-value: 0.709Chi-squared
Secondary
Endometrial Thickness
Thickness of endometrial lining assessed by ultrasound
Time frame: Cycle day 12-14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Endometrial Thickness | 6.2 mm | Standard Deviation 2.2 |
| Letrozole + Clomiphene | Endometrial Thickness | 8.3 mm | Standard Deviation 3.6 |
p-value: 0.006t-test, 2 sided
Secondary
Live Birth
Live Birth: delivery of a live infant; No Live Birth: no delivery of a live infant
Time frame: 9-10 months after treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letrozole | Live Birth | 1 Participants |
| Letrozole + Clomiphene | Live Birth | 3 Participants |
Comparison: This study was not powered to detect significant between-group differences for live birth.p-value: 0.356Chi-squared
Secondary
Multiple Gestation
Multiple Gestation: an intrauterine pregnancy with multiple fetal heart rates determined by ultrasonography; No Multiple Gestation: either no intrauterine pregnancy, or an intrauterine pregnancy with a single fetal heart rate determined by ultrasonography
Time frame: 9-10 months after treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letrozole | Multiple Gestation | 0 Participants |
| Letrozole + Clomiphene | Multiple Gestation | 0 Participants |
Secondary
Number of Developing Follicles
Number of follicles measuring \> 10mm on ultrasound
Time frame: Cycle day 12-14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letrozole | Number of Developing Follicles | 0 follicles |
| Letrozole + Clomiphene | Number of Developing Follicles | 1 follicles |
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Pregnancy Loss
Pregnancy Loss: any pregnancy loss including biochemical pregnancy, ectopic pregnancy, and miscarriage; No Pregnancy Loss: no pregnancy loss including biochemical pregnancy, ectopic pregnancy, or miscarriage.
Time frame: 9-10 months after treatment
Population: Participants who conceived
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letrozole | Pregnancy Loss | 2 Participants |
| Letrozole + Clomiphene | Pregnancy Loss | 1 Participants |
Comparison: This study was not powered to detect significant between-group differences for pregnancy loss.p-value: 0.486Chi-squared, Corrected
Secondary
Size of Largest Developing Follicle
Size of largest follicle on ultrasound
Time frame: Cycle day 12-14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letrozole | Size of Largest Developing Follicle | 10 mm |
| Letrozole + Clomiphene | Size of Largest Developing Follicle | 16 mm |
p-value: 0.004Wilcoxon (Mann-Whitney)