Lifestyle Intervention and Metformin for Women With Polycystic Ovary Syndrome (PCOS)

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00151411
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 114
• Location: 1
• Arms: 2
• Duration (Months): 41
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the combination therapy of lifestyle intervention and use of Metformin together will improve ovulation induction and hyperandrogenemia in women with polycystic ovary syndrome, by gathering data from adult and adolescent females.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: Metformin; Drug: Placebo; Behavioral: Lifestyle Intervention	Phase 2

Detailed Description

PCOS is characterized by excess circulating androgen levels and chronic anovulation. PCOS is also characterized by insulin resistance and hyperinsulinemia. Several recent studies in a variety of non-hospital based populations have provided evidence that the incidence of hyperandrogenic chronic anovulation is in the range of 4-6% of the female population. Improvements in insulin sensitivity in women with PCOS, either through lifestyle changes or through pharmaceutical intervention, have consistently resulted in a marked improvement in the reproductive and metabolic abnormalities in PCOS. The primary objective in the adult female population is to determine that combination therapy will improve ovulatory frequency. Secondary objective is to improve circulating hyperandrogenemia and insulin sensitivity then single agent therapy. The primary objective of the adolescent population is to determine that the combination therapy will improve hyperandrogenemia. Secondary objective is to improve ovulatory frequency and insulin sensitivity than just the use of a single agent therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 114 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The Effect of Combination Therapy With Lifestyle Intervention and Metformin in Females With Polycystic Ovary Syndrome
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Metformin	Drug: Metformin; Medication was initiated in a step-up fashion every five days, from one tablet per day to four (500 mg per tablet).; Behavioral: Lifestyle Intervention; A combined intervention of diet and exercise was employed with the goal of achieving an average weight loss of at least 7% of initial body weight over six months with a prescription of 150 min/week of exercise combined with a low-calorie diet.
Placebo Comparator: Placebo Placebo	Drug: Placebo; Placebo; Behavioral: Lifestyle Intervention; A combined intervention of diet and exercise was employed with the goal of achieving an average weight loss of at least 7% of initial body weight over six months with a prescription of 150 min/week of exercise combined with a low-calorie diet.

Outcome Measures

Primary Outcome Measures

1. Change in Testosterone After 6 Months of Treatment [baseline and 6 months]

Secondary Outcome Measures

1. Ovulation Rate [6 months]

   Count of ovulations per subject during the treatment period.

2. Change in Insulin Sensitivity Index After 6 Months of Treatment [baseline and 6 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 39 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Spontaneous intermenstrual periods of greater than or equal to 45 days or a total of 8 or less periods per year

• Elevated testosterone levels

• General good health

• Off of current medications which may confound response to study medications

Exclusion Criteria:

• Pregnancy

• Lactose Intolerance

• Medical Contraindications

• Elevated Prolactin, 17hydroxyprogesterone, or Follicle stimulating hormone blood tests

• Diabetes, liver, heart, kidney or uncorrected thyroid disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033

Sponsors and Collaborators

• Milton S. Hershey Medical Center
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Richard Legro, M.D., Milton S. Hershey Medical Center

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: NCT00151411
• Other Study ID Numbers: 2003-172; HD-02-012
• First Posted: Sep 9, 2005
• Last Update Posted: Mar 21, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Richard S. Legro, M.D., Professor, Obstetrics and Gynecology and Public Health Sciences, Milton S. Hershey Medical Center: Polycystic Ovary Syndrome (PCOS); Anovulation; Elevated Testosterone
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Syndrome; Metformin

Study Results

Participant Flow

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 2000mg/d (2 500mg tablets taken twice a day) initiated in a step-up fashion	Placebo (2 tablets twice a day) initiated in a step-up fashion
Period Title: Overall Study
STARTED	55	59
COMPLETED	22	16
NOT COMPLETED	33	43

Baseline Characteristics

Arm/Group Title	Metformin	Placebo	Total
Arm/Group Description	Metformin 2000mg/d (2 500mg tablets taken twice a day) initiated in a step-up fashion	Placebo (2 tablets twice a day) initiated in a step-up fashion	Total of all reporting groups
Overall Participants	55	59	114
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	55 100%	59 100%	114 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29 (4.5)	28.8 (4.6)	28.9 (4.6)
Sex: Female, Male (Count of Participants)
Female	55 100%	59 100%	114 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	55 100%	59 100%	114 100%

Outcome Measures

1. Primary Outcome

Title	Change in Testosterone After 6 Months of Treatment
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 2000mg/d (2 500mg tablets taken twice a day) initiated in a step-up fashion	Placebo (2 tablets twice a day) initiated in a step-up fashion
Measure Participants	55	59
Least Squares Mean (95% Confidence Interval) [ng/dL]	-2.1	-6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -9.9 to 18.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Ovulation Rate
Description	Count of ovulations per subject during the treatment period.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

A total of 76 patients with daily urine collections.

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 2000mg/d (2 500mg tablets taken twice a day) initiated in a step-up fashion	Placebo (2 tablets twice a day) initiated in a step-up fashion
Measure Participants	37	39
0 ovulations	10 18.2%	19 32.2%
1 ovulation	6 10.9%	5 8.5%
2 ovulations	4 7.3%	7 11.9%
3 ovulations	7 12.7%	3 5.1%
4 ovulations	4 7.3%	2 3.4%
5 ovulations	1 1.8%	0 0%
6+ ovulations	5 9.1%	3 5.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	This statistical analysis models the probability of ovulation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Zero-altered negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 0.9 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Placebo is the reference group, i.e. for the rate ratio, Metformin represents the numerator and Placebo the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	This statistical analysis models the count of ovulations provided a woman actually ovulated.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Zero-altered negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Placebo is the reference group, i.e. for the rate ratio, Metformin represents the numerator and Placebo the denominator.

3. Secondary Outcome

Title	Change in Insulin Sensitivity Index After 6 Months of Treatment
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 2000mg/d (2 500mg tablets taken twice a day) initiated in a step-up fashion	Placebo (2 tablets twice a day) initiated in a step-up fashion
Measure Participants	55	59
Least Squares Mean (95% Confidence Interval) [index]	1.9	-2.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95%; 0.1 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Metformin		Placebo
Arm/Group Description	Metformin 2000mg/d (2 500mg tablets taken twice a day) initiated in a step-up fashion		Placebo (2 tablets twice a day) initiated in a step-up fashion
All Cause Mortality
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/55 (0%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/55 (69.1%)		33/59 (55.9%)
Gastrointestinal disorders
Diarrhea	19/55 (34.5%)	78	6/59 (10.2%)	22
stomach/abdominal pain or discomfort	6/55 (10.9%)	9	7/59 (11.9%)	16
nausea and/or vomiting	9/55 (16.4%)	27	7/59 (11.9%)	18
flatulence	2/55 (3.6%)	5	3/59 (5.1%)	3
flu	8/55 (14.5%)	12	4/59 (6.8%)	4
General disorders
hair loss	3/55 (5.5%)	3	0/59 (0%)	0
allergic reaction	0/55 (0%)	0	3/59 (5.1%)	3
dental issues	3/55 (5.5%)	4	1/59 (1.7%)	2
Infections and infestations
common cold/respiratory tract infection	12/55 (21.8%)	23	13/59 (22%)	19
Musculoskeletal and connective tissue disorders
musculoskeletal	5/55 (9.1%)	7	9/59 (15.3%)	17
Nervous system disorders
dizziness	3/55 (5.5%)	5	3/59 (5.1%)	3
headache/migraine	12/55 (21.8%)	42	11/59 (18.6%)	16
fatigue	2/55 (3.6%)	2	4/59 (6.8%)	4
altered mood/mood swings	0/55 (0%)	0	5/59 (8.5%)	6
Renal and urinary disorders
bladder infection	1/55 (1.8%)	2	3/59 (5.1%)	9
Reproductive system and breast disorders
dysmenorrhea/cramps	7/55 (12.7%)	14	9/59 (15.3%)	19
vaginal infection	3/55 (5.5%)	3	3/59 (5.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.