Trial Information

Comparison of the Effects of Monotherapy With Exenatide or Metformin to Combined Exenatide and Metformin Therapy on Menstrual Cyclicity in Overweight Women With Polycystic Ovary Syndrome

Objectives: The objective of the present proposal is to compare the clinical, endocrine and
metabolic effects of therapy with exenatide and metformin alone, to combination therapy in
women with PCOS. This study will serve as a pilot investigation to open perspectives for
future investigations combining insulin-sensitizing drugs with different mechanisms of
action in patients with PCOS, especially ones for whom standard treatment with metformin is
less effective.

Subjects : 60 oligomenorrheic overweight/obese (BMI >27) women meeting criteria for PCOS
(age 18-40)· six or fewer menses /year or amenorrheic· clinical or laboratory evidence of
hyperandrogenism (hirsutism or elevated testosterone (T))· PCOS ovary on ultrasound(need to
meet criteria 1 and either 2 or 3 [or both]) Inclusion/Exclusion Criteria: Major EXCLUSION
CRITERIA – FEMALE1) other uncorrected endocrinopathy- hyperprolactinemia, hyper- or
hypothyroidism, congenital adrenal hyperplasia2) presence of overt diabetes or impaired
glucose tolerance3) alterations in hepatic or renal function4) use of hormonal medications,
insulin sensitizers or medications that interfere with carbohydrate metabolism for at least
8 weeks5) Any medical condition which, in the judgment of the investigator may interfere
with the absorption, distribution, metabolism or excretion of the drug6) Simultaneous
participation in another clinical trial7) Known active substance abuse including tobacco and
alcohol. (> 10 cigarettes/day)8) Refusal or inability to comply with protocol9) patient
desiring pregnancy, pregnant, or breastfeeding Study Design: Balanced randomized parallel
group clinical study with 3 treatment arms: metformin (1000 mg BID); exenatide (10 mcg BID)
or combined (metformin 1000 mg BID; exenatide 10 mcg BID) therapy for 24 weeks.

Efficacy Measures: Primary- Menstrual Cyclicity ( # menses/ 24 weeks)Secondary-BMI, WHR,
FAI (T/SHBG), DHEAS, lipids, insulin resistance-(HOMA and composite insulin sensitivity
index [ SIOGTT), and pancreatic ß-cell function (corrected insulin response [CIRgp] and
insulinogenic index [IGI] ).

Safety: For safety, all subjects who enter the study are evaluable. Subjects will be
monitored for safety by assessment of adverse events, physical exams, vital signs and
laboratory values.

Statistical methods/analysis: The measurement of menstrual frequency involves nominal data (
patients with/without regular cycles pre vs post-treatment and will be analyzed using the
McNemar test (complex chi square for paired data). For all other analyses, in which the
data are interval, parameters, such as androgens, lipids, insulin sensitivity, etc. will
be evaluated using a SS/Treatment x Trials (pre/post) analyses of variance (ANOVA). This
repeated measures design will allow us to determine if each of the treatment drugs had an
effect and if they are significantly different from each other while controlling for
individual patient differences Study Drug Regimens: Exenatide5 ug bid - 4 weeks10 ug bid -
20 weeks (end of study)Metformin500 mg qd 2 weeks500 mg bid 2 weeks 500 mg am, 1000 mg pm- 2
weeks1000 mg bid –18 weeks (end study) Exenatide plus MetforminExenatide- 5 ug bid-4
weeksMetformin 500 qd for 2 weeks, 500 mg bid 2 weeksExenatide- 10 ug –20 weeks (to end of
study)Metformin-500 mg am, 1000 mg pm- 2 weeks – 1000 bid for 18 weeks (end of study)**
Metformin may be adjusted at the discretion of the physician to a level that is tolerable in
patients who cannot tolerate the full dose of metformin in combination with exenatide
(combination therapy only )