Ovulation Induction in Women With Clomiphene Citrate Resistant PCOS

• Sponsor: Cairo University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01909141
• Collaborator: (none)
• Enrollment: 100
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 12.5

Study Details

Study Description

Brief Summary

Polycystic ovary syndrome (PCOS) affects 5-10% of women in childbearing age. Hyperinsulinemia contributes to chronic anovulation commonly encountered in women with PCOS. The first choice therapy is clomiphene citrate (CC). In CC resistant cases, the American College of Obstetrics and Gynecology (ACOG) recommends the use of insulin sensitizer metformin. Other insulin sensitizing agents include rosiglitazone and pioglitazone. Pioglitazone is said to improve fertility and ovulation in patients with PCOS.CC may be associated with poor endometrial thickening due to its antiestrogenic effect. Letrozole may improve this condition. In this study we will compare the effect of combined letrozole-metformin-pioglitazone with that of combined CC-metformin-pioglitazone in ovulation induction in CC-resistant PCOS women.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome; Infertility	Drug: induction of ovulation using letrozole-pioglitazone-metformin; Drug: induction of ovulation using clomiphene citrate-pioglitazone-metformin; Radiation: transvaginal ultrasound; Other: body mass index (BMI) calculation; Other: day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone; Other: pretreatment blood urea and serum creatinine; Other: serum estradiol (E2) on day 12; Other: serum progesterone on day 21; Other: blood urea and serum creatinine every month	Early Phase 1

Detailed Description

Polycystic ovary syndrome (PCOS) affects 5-10% of women in childbearing age. Hyperinsulinemia contributes to chronic anovulation commonly encountered in women with PCOS. The first choice therapy is clomiphene citrate (CC). In CC resistant cases, the ACOG recommends the use of insulin sensitizer metformin. Other insulin sensitizing agents include rosiglitazone and pioglitazone. Pioglitazone is said to improve fertility and ovulation in patients with PCOS.CC has a long half-life (2 weeks), and this may have a negative effect on the cervical mucus and endometrium, leading to discrepancy between ovulation and conception rates. There has been a search for a compound capable of inducing ovulation but devoid of the adverse antiestrogenic effects of CC. recent studies have suggested that letrozole, an aromatase inhibitor, does not possess the adverse antiestrogenic effects of CC and is associated with higher pregnancy rates than CC treatment in patients with PCOS.

In this study we shall compare the effect of combined letrozole-metformin-pioglitazone with that of combined CC-metformin-pioglitazone in ovulation induction in CC-resistant PCOS women.This will be a prospective comparative clinical trial in which 2 groups of women will be generated (groups A and B) using the sealed envelopes randomization method.Group A (40 women) will receive: letrozole 2.5 mg/day from 3rd day of the cycle for 5 days and (pioglitazone 15 mg + metformin 850 mg) once daily from 1st day of the cycle for 10 days. Group B (40 women) will receive clomiphene citrate 100 mg/day from 3rd day of the cycle for 5 days and (pioglitazone 15 mg + metformin 850 mg) once daily from 1st day of the cycle for 10 days. Ovulation will be monitored by vaginal ultrasound and serum estrogen and progesterone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Combined Letrozole-metformin-pioglitazone Versus Combined Clomiphene Citrate-metformin-pioglitazone in Clomiphene Citrate-resistant Women With Polycystic Ovary Syndrome
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: arm 1:letrozole-pioglitazone -metformin group Arm 1 will receive letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days.	Drug: induction of ovulation using letrozole-pioglitazone-metformin; induction of ovulation will be done for arm 1 for 3 consecutive cycles unless pregnancy occured.; Radiation: transvaginal ultrasound; transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle; Other: body mass index (BMI) calculation; BMI will be calculated for all women by dividing the weight in kilograms by the height in meters squared; Other: day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone; baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) will be done for all women.; Other: pretreatment blood urea and serum creatinine; blood urea and serum creatinine will be assayed before stating induction of ovulation to have baseline levels.; Other: serum estradiol (E2) on day 12; serum E2 will be assayed on day 12 of the cycle for all women.; Other: serum progesterone on day 21; serum progesterone will be assayed on day 21 for all women to monitor ovulation.; Other: blood urea and serum creatinine every month; blood urea and serum creatinine will be assayed every month during the treatment period to find out any hazards on kidney functions
Active Comparator: arm 2: clomiphene citrate-pioglitazone-metformin Arm 2 will receive clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days.	Drug: induction of ovulation using clomiphene citrate-pioglitazone-metformin; induction of ovulation for arm 2 will be done in 3 consecutive cycles unless pregnancy occured.; Radiation: transvaginal ultrasound; transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle; Other: body mass index (BMI) calculation; BMI will be calculated for all women by dividing the weight in kilograms by the height in meters squared; Other: day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone; baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) will be done for all women.; Other: pretreatment blood urea and serum creatinine; blood urea and serum creatinine will be assayed before stating induction of ovulation to have baseline levels.; Other: serum estradiol (E2) on day 12; serum E2 will be assayed on day 12 of the cycle for all women.; Other: serum progesterone on day 21; serum progesterone will be assayed on day 21 for all women to monitor ovulation.; Other: blood urea and serum creatinine every month; blood urea and serum creatinine will be assayed every month during the treatment period to find out any hazards on kidney functions

Outcome Measures

Primary Outcome Measures

1. Ovulation Rate [3 months]

Secondary Outcome Measures

1. Number of Follicles>18mm. [3 months]

2. Endometrial Thickness [3 months]

3. Pregnancy Rate [3 months]

Other Outcome Measures

1. Safety of Pioglitazone as Regards Serum Creatinine [3 months]

   serum creatinine was measured at the end of the study period (after 3 months) in both groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 20-40 years old

• PCOS infertile women resistant to CC for3 cycles

Exclusion Criteria:

• presence of medical disorders as diabetes, hypertension, cardiac problems, liver or kidney diseases, hyperprolactinemia or thyroid dysfunction.

• use of gonadotropins before

• previous ovarian drilling

• presence of urinary symptoms especially bloody urine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cairo University	Cairo		Egypt

Sponsors and Collaborators

• Cairo University

Investigators

• Principal Investigator: Ghada Abdel Fattah Abdel Moety, lecturer, Cairo University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ghada Abdel Fattah, lecturer of Obstetrics and Gynecology-Cairo University, Cairo University
• ClinicalTrials.gov Identifier: NCT01909141
• Other Study ID Numbers: fem2013
• First Posted: Jul 26, 2013
• Last Update Posted: Oct 20, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Ghada Abdel Fattah, lecturer of Obstetrics and Gynecology-Cairo University, Cairo University: letrozole; clomiphene citrate; pioglitazone; metformin; ovulation induction; PCOS
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Infertility; Syndrome; Metformin; Pioglitazone; Carbamide Peroxide; Letrozole; Clomiphene; Enclomiphene; Zuclomiphene; Hormones; Estradiol; Testosterone; Progesterone; Follicle Stimulating Hormone

Study Results

Participant Flow

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
Period Title: Overall Study
STARTED	50	50
COMPLETED	50	50
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin	Total
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 will received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occured. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Total of all reporting groups
Overall Participants	50	50	100
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.8 (3.62)	26.58 (2.9)	26.19 (3.29)
Sex: Female, Male (Count of Participants)
Female	50 100%	50 100%	100 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Egypt	50 100%	50 100%	100 100%
infertility period (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.67 (1.62)	3.07 (1.46)	2.87 (1.5)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.45 (2.84)	26.57 (2.7)	26.51 (2.75)
waist/hip ratio (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	0.838 (0.02)	0.837 (0.04)	0.837 (0.037)
systolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	106.08 (8.81)	107.04 (8.97)	106.56 (8.86)
diastolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	69.6 (5.31)	68.44 (5.89)	69.02 (5.61)
hirsutism (participants) [Number]
Number [participants]	11 22%	10 20%	21 21%
acne (participants) [Number]
Number [participants]	7 14%	4 8%	11 11%
ovarian volume (ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml]	14.17 (0.76)	14.58 (1.42)	14.19 (0.98)
FSH (mIU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mIU/L]	5.71 (1.34)	5.68 (1.38)	5.7 (1.35)
LH (mIU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mIU/L]	9.81 (3.16)	10.55 (3.25)	10.18 (3.21)
E2 (Pmol/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Pmol/dL]	49.83 (7.31)	47.75 (10.02)	48.24 (8.56)
prolactin (ng/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/ml]	15.52 (4.84)	14.3 (5.6)	14.9 (5.24)
total testosterone (nmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/L]	1.19 (0.25)	1.13 (0.2)	1.16 (0.23)
free testosterone (Pmol/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Pmol/dL]	3.87 (0.61)	4.12 (1.17)	3.99 (0.94)
TSH (mIU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mIU/L]	3.42 (0.61)	3.51 (0.44)	3.47 (0.53)
free T4 (nmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/L]	13.78 (0.84)	13.58 (0.45)	13.68 (0.68)

Outcome Measures

1. Primary Outcome

Title	Ovulation Rate
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 receivde letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was be done for arm 1 for 3 consecutive cycles unless pregnancy occured. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was caculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occured. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
Measure Participants	50	50
Number [percentage of all cycles]	93	108

2. Secondary Outcome

Title	Number of Follicles>18mm.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
Measure Participants	50	50
Mean (Standard Deviation) [follicles]	1.44 (0.16)	1.5 (0.86)

3. Secondary Outcome

Title	Endometrial Thickness
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
Measure Participants	50	50
Mean (Standard Deviation) [mm]	10.56 (1.79)	9.68 (1.39)

4. Secondary Outcome

Title	Pregnancy Rate
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
Measure Participants	50	50
Number [participants]	28 56%	24 48%

5. Other Pre-specified Outcome

Title	Safety of Pioglitazone as Regards Serum Creatinine
Description	serum creatinine was measured at the end of the study period (after 3 months) in both groups.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group	Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.	Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
Measure Participants	50	50
Mean (Standard Deviation) [mg/dL]	0.62 (0.04)	0.57 (0.03)

Adverse Events

Arm/Group Title	Arm 1:Letrozole-pioglitazone -Metformin Group		Arm 2: Clomiphene Citrate-pioglitazone-metformin
Arm/Group Description	Arm 1 received letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.		Arm 2 received clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occurred. transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle body mass index (BMI) calculation: BMI was calculated. day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women. serum estradiol (E2) was done on day of hCG administration for all women. serum progesterone on day 21 was done for all women.
All Cause Mortality
	Arm 1:Letrozole-pioglitazone -Metformin Group		Arm 2: Clomiphene Citrate-pioglitazone-metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1:Letrozole-pioglitazone -Metformin Group		Arm 2: Clomiphene Citrate-pioglitazone-metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1:Letrozole-pioglitazone -Metformin Group		Arm 2: Clomiphene Citrate-pioglitazone-metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/50 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.