OWL-PCOS: Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (PCOS) Women

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00704912
• Collaborator: University of Pennsylvania (Other)
• Enrollment: 217
• Locations: 2
• Arms: 3
• Duration (Months): 65.9
• Patients Per Site: 108.5
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The goal of this three-armed randomized controlled trial is to establish the relative roles of treatment of hyperandrogenism versus obesity (as the largest modifiable factor contributing to insulin resistance) in treating infertility and improving pregnancy outcomes among obese PCOS women. The investigators hypothesize that the key to restoring ovulation leading to live birth is to correct hyperandrogenism with oral contraceptive pills, but the key to avoiding later pregnancy complications is to improve insulin sensitivity with weight loss.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: Orlistat/Meal Replacement/Lifestyle Modification; Drug: Loestrin 1/20; Drug: Combination of treatments	Phase 2

Detailed Description

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility among women, and women with PCOS are at increased risk for pregnancy complications such as gestational diabetes and pre-eclampsia. Both hyperandrogenism (HA) and obesity exacerbated insulin resistance (IR) are characteristics of the syndrome, and are targets for treatment, but which should be the predominant focus is still unknown. Phase 1 of this study will be a randomized trial of three preconception interventions in infertile women with PCOS. The first arm will be a combined intervention of medication, meal replacements, and lifestyle modification to improve IR. Orlistat is a gastric lipase inhibitor that reduces the absorption of fat contained in a meal by about 30%. The second arm will be the use of a continuous OCP for 4 months to improve HA. Lo-Estrin 1/20 will be used in a continuous method for 4 months to suppress the ovary. The third arm is the combination of both to improve HA an IR. Phase II of this study will involve ovulation induction with clomiphene citrate with hopeful outcome of pregnancy. Finally, Phase III involve following the pregnancies for outcomes and complications.

Study Design

• Study Type: Interventional
• Actual Enrollment: 217 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lifestyle intervention Orlistat/Meal Replacement/Lifestyle Modification	Drug: Orlistat/Meal Replacement/Lifestyle Modification; Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.; Other Names: Orlistat Alli Lifestyle Intervention Weight Loss
Active Comparator: Oral Contraceptives (OCP) Loestrin 1/20	Drug: Loestrin 1/20; Patients will be started on a low dose containing OCP for a continuous 4 month period.; Other Names: OCP Oral Contraceptive
Active Comparator: Lifestyle/OCP Combined Combination of treatments	Drug: Combination of treatments; Medications will be administered as described for the other 2 arms.; Other Names: Orlistat Alli OCP Oral Contraceptive Weight Loss Lifestyle Intervention

Outcome Measures

Primary Outcome Measures

1. Live Birth Rate [Participants were followed for 4 months of attempted conception and those who conceived were then followed for the duration of their pregnancy, approximately 9 months.]

Secondary Outcome Measures

1. Ovulation Rate [Up to 4 months]

2. Change in Weight [Baseline, 4 months]

   Change from baseline to end of the 4-month intervention.

3. Prevalence of Metabolic Syndrome [Baseline, 4 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Couples Inclusion Criteria:

• Partner with sperm concentration of >=14 million/mL in at least one ejaculate with motile sperm.

• Ability to have regular intercourse 2-3 times per week during the ovulation induction phase of study.

• At least one patent tube and normal uterine cavity as determined by sonohysterogram, hysterosalpingogram, or hysteroscopy/laparoscopy within the last 3 years, or confirmation of a intrauterine pregnancy within the past 2 years.

• No previous sterilization procedures(vasectomy, tubal ligation) that have been reversed.

• Wanting to seek pregnancy.

Inclusion Criteria:

• Chronic anovulation or oligomenorrhea defined as intermenstrual periods of >= 45 days or a total of <=8 periods per year.

• Hyperandrogenism will be an elevated total testosterone >=50 ng/dL.

• Hirsutism determined by a modified Ferriman-Gallwey Score >8.

• PCO on ultrasound (12 or more follicles measuring 2-9 mm in diameter).

• BMI >=27 to <=42.

• Normal EKG to rule out any abnormalities with the heart.

Exclusion Criteria:

• Current pregnancy.

• Patients on oral contraceptives, depo progestins, or hormonal implants.

• Patients with hyperprolactinemia defined as two prolactin levels at least one week apart >30 ng/mL.

• Patients with known 21-hydroxylase deficiency by a fasting 17-hydroxyprogesterone (17-OHP) level <2 ng/mL and ACTH stimulation test as needed, or other enzyme deficiency.

• Patients with menopausal FSH levels >20 mIU/mL.

• Patients with uncorrected thyroid disease (TSH <0.45 mIU/ML or >4.5 mIU/ML).

• Patients diagnosed with Type1 or Type II diabetes.

• Patients with liver disease defined as AST or ALT >2 times normal or total bilirubin

2.5 mg/dL.

• Patients with renal disease defined as BUN >30 mg/dL or serum creatinine >1.4 mg/dL.

• Patients with significant anemia (Hemoglobin <10 mg/dL).

• Patients with a history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident.

• Patients with known heart disease that is likely to be exacerbated by pregnancy.

• Patients with a history of , or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma. A normal PAP smear or reassuring colposcopy based on current ACOG guidelines will be required.

• Patient with current history of alcohol abuse.

• Patients enrolled simultaneously into other investigative studies.

• Patients taking other medications know to affect reproductive function or metabolism.

• Patients with a suspected adrenal or ovarian tumor secreting androgens.

• Patients with suspected Cushing's syndrome.

• Patients who have undergone a bariatric surgery procedure in the recent past (<12 months).

• Patients with untreated poorly controlled hypertension defined as systolic blood pressure >=150 mm Hg or average diastolic >=100 mm Hg on three measurements obtained 5 minutes apart. If treated, average systolic blood pressure >= 140 mm Hg or average diastolic >= 90 mm Hg.

• Patients with medical conditions that represent contraindications to orlistat, OCP, clomiphene, and/or pregnancy.

• Patients currently participating in lifestyle intervention program (Weight Watchers, Atkins Diet, Curves) or lost more than 5% body weight within the last 6 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penn State College of Medicine, Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
2	University of Pennsylvania, Department of Obstetrics and Gynecology	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Milton S. Hershey Medical Center
• University of Pennsylvania

Investigators

• Principal Investigator: Richard S Legro, M.D., Penn State College of Medicine, Penn State Milton S. Hershey Medical Center
• Principal Investigator: Christos Coutifaris, M.D., Ph.D., Universtiy of Pennsylvania, Department of Obstetrics and Gynecology

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about this study.

Publications

None provided.

• Responsible Party: Richard S. Legro, M.D., Professor, Obstetrics and Gynecology and Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00704912
• Other Study ID Numbers: 27184
• First Posted: Jun 25, 2008
• Last Update Posted: Nov 6, 2016
• Last Verified: Nov 1, 2016

• Keywords provided by Richard S. Legro, M.D., Professor, Obstetrics and Gynecology and Public Health Sciences, Milton S. Hershey Medical Center: Polycystic Ovary Syndrome
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Hyperandrogenism; Insulin Resistance; Syndrome; Orlistat; Contraceptive Agents; Norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; Contraceptives, Oral

Study Results

Participant Flow

Pre-assignment Detail	217 subjects consented for the study, of which 149 were randomized to one of the 3 treatment groups. Sixty-eight subjects were not randomized because they withdrew prior to randomization or were determined ineligible during the screening process.

Arm/Group Title	Lifestyle Intervention	Oral Contraceptives (OCP)	Lifestyle/OCP Combined
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.	Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.	Combination of treatments: Medications will be administered as described for the other 2 arms.
Period Title: Overall Study
STARTED	50	49	50
COMPLETED	44	45	43
NOT COMPLETED	6	4	7

Baseline Characteristics

Arm/Group Title	Lifestyle Intervention	Oral Contraceptives (OCP)	Lifestyle/OCP Combined	Total
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.	Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.	Combination of treatments: Medications will be administered as described for the other 2 arms.	Total of all reporting groups
Overall Participants	50	49	50	149
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.6 (3.4)	29.8 (3.7)	28.7 (4.2)	29.0 (3.8)
Gender (Count of Participants)
Female	50 100%	49 100%	50 100%	149 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 12%	6 12.2%	5 10%	17 11.4%
Not Hispanic or Latino	44 88%	43 87.8%	45 90%	132 88.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	2 4%	0 0%	1 2%	3 2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	7 14%	7 14.3%	14 28%	28 18.8%
White	35 70%	40 81.6%	31 62%	106 71.1%
More than one race	5 10%	2 4.1%	4 8%	11 7.4%
Unknown or Not Reported	1 2%	0 0%	0 0%	1 0.7%
Parity (participants) [Number]
0 births	41 82%	38 77.6%	45 90%	124 83.2%
>0 births	9 18%	11 22.4%	5 10%	25 16.8%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	96.0 (15.8)	94.6 (14.4)	95.2 (14.5)	95.3 (14.8)
Body Mass Index (BMI) (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	35.1 (4.6)	35.1 (4.2)	35.5 (4.4)	35.2 (4.4)
Metabolic Syndrome (participants) [Number]
Yes	18 36%	14 28.6%	21 42%	53 35.6%
No	31 62%	34 69.4%	29 58%	94 63.1%
Unknown	1 2%	1 2%	0 0%	2 1.3%

Outcome Measures

1. Primary Outcome

Title	Live Birth Rate
Time Frame	Participants were followed for 4 months of attempted conception and those who conceived were then followed for the duration of their pregnancy, approximately 9 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lifestyle Intervention	Oral Contraceptives (OCP)	Lifestyle/OCP Combined
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.	Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.	Combination of treatments: Medications will be administered as described for the other 2 arms.
Measure Participants	50	49	50
Number [participants]	13 26%	5 10.2%	12 24%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Oral Contraceptives (OCP)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Log-binomial model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 1.0 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Contraceptives (OCP), Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Log-binomial model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; 0.9 to 6.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Log-binomial model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.5 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Ovulation Rate
Time Frame	Up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lifestyle Intervention	Oral Contraceptives (OCP)	Lifestyle/OCP Combined
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.	Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.	Combination of treatments: Medications will be administered as described for the other 2 arms.
Measure Participants	50	49	50
Measure Clomiphene Treatment Cycles	136	154	140
Number [total number of ovulations]	82	71	94

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Oral Contraceptives (OCP)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Log-binomial model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; 1.0 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Contraceptives (OCP), Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log-binomial model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 1.1 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Log-binomial model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Weight
Description	Change from baseline to end of the 4-month intervention.
Time Frame	Baseline, 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lifestyle Intervention	Oral Contraceptives (OCP)	Lifestyle/OCP Combined
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.	Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.	Combination of treatments: Medications will be administered as described for the other 2 arms.
Measure Participants	50	49	50
Least Squares Mean (95% Confidence Interval) [kg]	-6.2	-1.1	-6.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Oral Contraceptives (OCP)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Change
	Estimated Value	-5.0
	Confidence Interval	(2-Sided) 95%; -6.3 to -3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Lifestyle vs. OCP

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Contraceptives (OCP), Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Change
	Estimated Value	-5.0
	Confidence Interval	(2-Sided) 95%; -6.2 to -3.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Combined vs. OCP

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Change
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Lifestyle vs. Combined

4. Secondary Outcome

Title	Prevalence of Metabolic Syndrome
Time Frame	Baseline, 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lifestyle Intervention	Oral Contraceptives (OCP)	Lifestyle/OCP Combined
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.	Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.	Combination of treatments: Medications will be administered as described for the other 2 arms.
Measure Participants	50	49	50
Metabolic Syndrome at Baseline	18 36%	14 28.6%	21 42%
Metabolic Syndrome at End of Intervention	18 36%	21 42.9%	16 32%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention
	Comments	Comparing change in prevalence of metabolic syndrome from baseline to the end of intervention.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.6 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	End of intervention compared to baseline.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Contraceptives (OCP)
	Comments	Comparing change in prevalence of metabolic syndrome from baseline to the end of intervention.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 1.4 to 4.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	End of intervention compared to baseline

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lifestyle/OCP Combined
	Comments	Comparing change in prevalence of metabolic syndrome from baseline to the end of intervention.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	GEE
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	End of intervention compared to baseline

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Oral Contraceptives (OCP)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	GEE
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Oral Contraceptives (OCP), Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	GEE
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lifestyle Intervention, Lifestyle/OCP Combined
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	GEE
	Comments

Adverse Events

Arm/Group Title	Lifestyle Intervention		Oral Contraceptives (OCP)		Lifestyle/OCP Combined
Arm/Group Description	Orlistat/Meal Replacement/Lifestyle Modification: Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.		Loestrin 1/20: Patients will be started on a low dose containing OCP (20 mcg ethinyl estradiol/1 mg norethindrone acetate daily) for a continuous 4 month period.		Combination of treatments: Medications will be administered as described for the other 2 arms.
All Cause Mortality
	Lifestyle Intervention		Oral Contraceptives (OCP)		Lifestyle/OCP Combined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lifestyle Intervention		Oral Contraceptives (OCP)		Lifestyle/OCP Combined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/50 (6%)		0/49 (0%)		1/50 (2%)
Gastrointestinal disorders
Perforated appendix	0/50 (0%)	0	0/49 (0%)	0	1/50 (2%)	1
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy	1/50 (2%)	1	0/49 (0%)	0	0/50 (0%)	0
Preterm delivery	1/50 (2%)	1	0/49 (0%)	0	0/50 (0%)	0
Reproductive system and breast disorders
Abnormal uterine bleeding	1/50 (2%)	1	0/49 (0%)	0	0/50 (0%)	0
Other (Not Including Serious) Adverse Events
	Lifestyle Intervention		Oral Contraceptives (OCP)		Lifestyle/OCP Combined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/50 (64%)		37/49 (75.5%)		43/50 (86%)
Gastrointestinal disorders
Steatorrhea/Diarrhea	6/50 (12%)		0/49 (0%)		12/50 (24%)
Constipation	6/50 (12%)		1/49 (2%)		4/50 (8%)
Gas/Bloating	2/50 (4%)		2/49 (4.1%)		5/50 (10%)
Dyspepsia	2/50 (4%)		0/49 (0%)		3/50 (6%)
Gas/Bloating	4/44 (9.1%)		1/44 (2.3%)		3/43 (7%)
Constipation	2/44 (4.5%)		2/44 (4.5%)		3/43 (7%)
General disorders
Headache	15/50 (30%)		14/49 (28.6%)		18/50 (36%)
Nausea/Vomiting	6/50 (12%)		7/49 (14.3%)		9/50 (18%)
Abdominal Pain	5/50 (10%)		1/49 (2%)		10/50 (20%)
Dry Mouth	4/50 (8%)		0/49 (0%)		1/50 (2%)
Dizziness/Vertigo	3/50 (6%)		2/49 (4.1%)		0/50 (0%)
Fatigue	1/50 (2%)		2/49 (4.1%)		3/50 (6%)
Insomnia	2/50 (4%)		0/49 (0%)		3/50 (6%)
Tachycardia	1/50 (2%)		0/49 (0%)		3/50 (6%)
Headache	4/44 (9.1%)		6/44 (13.6%)		12/43 (27.9%)
Nausea/Vomiting	5/44 (11.4%)		3/44 (6.8%)		5/43 (11.6%)
Fatigue	2/44 (4.5%)		1/44 (2.3%)		3/43 (7%)
Abdominal Pain	2/44 (4.5%)		3/44 (6.8%)		1/43 (2.3%)
Visual Changes	1/44 (2.3%)		0/44 (0%)		3/43 (7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	1/50 (2%)		3/49 (6.1%)		4/50 (8%)
Back Pain	1/50 (2%)		1/49 (2%)		3/50 (6%)
Pregnancy, puerperium and perinatal conditions
Nausea/Vomiting	4/16 (25%)		0/8 (0%)		1/14 (7.1%)
Fatigue	3/16 (18.8%)		0/8 (0%)		1/14 (7.1%)
Pelvic Pain	3/16 (18.8%)		0/8 (0%)		1/14 (7.1%)
Breast Pain	1/16 (6.3%)		0/8 (0%)		2/14 (14.3%)
Headache	2/16 (12.5%)		0/8 (0%)		1/14 (7.1%)
Mood Swings	1/16 (6.3%)		0/8 (0%)		1/14 (7.1%)
Constipation	1/16 (6.3%)		0/8 (0%)		1/14 (7.1%)
Hot flushes	2/16 (12.5%)		0/8 (0%)		0/14 (0%)
Spotting in pregnancy	1/16 (6.3%)		0/8 (0%)		1/14 (7.1%)
Hypertension	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Vaginitis/Vulvitis	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Vaginal Dryness/Pain	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Hyperemesis	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Urinary tract infection in pregnancy	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Dizziness/Vertigo	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Rash	0/16 (0%)		1/8 (12.5%)		0/14 (0%)
Gas/Bloating	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Abdominal Pain	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Dyspepsia	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Pre-eclampsia	4/16 (25%)		1/8 (12.5%)		2/14 (14.3%)
Gestational Diabetes	3/16 (18.8%)		1/8 (12.5%)		2/14 (14.3%)
Preterm Delivery	3/16 (18.8%)		0/8 (0%)		0/14 (0%)
Premature Rupture of Membranes	3/16 (18.8%)		0/8 (0%)		0/14 (0%)
Upper Respiratory Infections	3/16 (18.8%)		0/8 (0%)		0/14 (0%)
Placental Abnormalities	1/16 (6.3%)		1/8 (12.5%)		0/14 (0%)
Dental abscess	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Dental, other	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Other specified disorders of biliary tract	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Breast lump	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Vaginitis/Vulvitis	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Urinary tract infection in pregnancy	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Incompetent cervix	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Infection of amniotic cavity	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Pruritus	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Dizziness/Vertigo	0/16 (0%)		1/8 (12.5%)		0/14 (0%)
Sleep disturbance	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Sleep apnea	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Edema localized	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Glycosuria	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Headache	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Musculoskeletal Pain	0/16 (0%)		0/8 (0%)		1/14 (7.1%)
Pregnancy-induced Hypertension	2/16 (12.5%)		0/8 (0%)		0/14 (0%)
Pulmonary collapse	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Postpartum depression	0/16 (0%)		1/8 (12.5%)		0/14 (0%)
Postpartum infection	1/16 (6.3%)		0/8 (0%)		0/14 (0%)
Neonatal Jaundice	2/12 (16.7%)		1/5 (20%)		4/12 (33.3%)
Intrauterine growth restriction	1/12 (8.3%)		0/5 (0%)		1/12 (8.3%)
Neonatal infection	0/12 (0%)		0/5 (0%)		1/12 (8.3%)
Other complication of infant after delivery	0/12 (0%)		0/5 (0%)		1/12 (8.3%)
Psychiatric disorders
Mood Swings	3/50 (6%)		3/49 (6.1%)		3/50 (6%)
Mood Swings	3/44 (6.8%)		3/44 (6.8%)		2/43 (4.7%)
Reproductive system and breast disorders
Breast Pain	1/50 (2%)		10/49 (20.4%)		6/50 (12%)
Dysmenorrhea	1/50 (2%)		8/49 (16.3%)		3/50 (6%)
Abnormal uterine bleeding	0/50 (0%)		4/49 (8.2%)		6/50 (12%)
Vaginitis/Vulvitis	1/50 (2%)		4/49 (8.2%)		1/50 (2%)
Pelvic Pain	2/50 (4%)		3/49 (6.1%)		1/50 (2%)
Pelvic Pain	7/44 (15.9%)		12/44 (27.3%)		13/43 (30.2%)
Breast Pain	5/44 (11.4%)		7/44 (15.9%)		9/43 (20.9%)
Hot flushes	4/44 (9.1%)		6/44 (13.6%)		3/43 (7%)
Dysmenorrhea	1/44 (2.3%)		6/44 (13.6%)		1/43 (2.3%)
Vaginal Dryness/Pain	0/44 (0%)		3/44 (6.8%)		0/43 (0%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infections	8/50 (16%)		8/49 (16.3%)		13/50 (26%)
Upper Respiratory Infections	2/44 (4.5%)		5/44 (11.4%)		5/43 (11.6%)

Limitations/Caveats

[Not Specified]

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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.