Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility

Study Objective An intensive lifestyle modification intervention (which includes caloric
restriction, use of an over-the-counter weight loss medication, and moderate physical
activity with tracking) designed to promote a weight loss of approximately 7% of initial body
weight is more likely to achieve a good perinatal outcome (i.e. a healthy term normal weight
infant) than a recommendation to standard lifestyle modification with moderate physical
activity with tracking (based on publically available activity recommendations) in obese
women with unexplained infertility.

Patient Population The population will consist of 380 obese women with unexplained
infertility, age 18-40 years old. Subjects must have normal ovulatory function and normal
ovarian reserve. Additionally, the couple will have no other major infertility factor: the
subject will have at least one patent fallopian tube and a normal uterine cavity, and a
partner total motile sperm count of at least 5 million in at least one ejaculate.

Study Design This will be a two-arm, multicenter, prospective, randomized clinical trial of a
lifestyle modification program with tracked increased physical activity and weight loss
(intensive) compared to recommendations to tracking of increased physical activity alone with
weight maintenance (standard) in women with obesity and unexplained infertility. This 16 week
period of lifestyle modification will be followed by an open label empiric infertility
treatment regimen consisting of three cycles of ovarian stimulation with oral medication
(clomiphene citrate (CC)), triggering of ovulation with human chorionic gonadotropin (hCG)
and intrauterine insemination (IUI).

Treatment The intensive lifestyle modification intervention will consist of caloric
restriction (consumption of approximately 1200-1500 kcal/d), use of an over-the-counter
weight loss medication (Alli, which is brand name Orlistat, a gastric lipase inhibitor that
limits gut fat absorption), and moderate physical activity (goal of reaching 10,000 steps a
day). The pretreatment intervention will last 16 weeks and is designed to promote a weight
loss of approximately 7% of total body weight. Women in the standard lifestyle intervention
(standard) will receive publicly available written materials that promote engagement in
moderate physical activity with target of 10,000 steps a day. Detailed instruction of
physical activity will not be provided. Participants in both groups will receive activity
tracking devices (Fitbit Wireless Activity Tracker) and wireless scales (Fitbit Aria Wireless
Activity Scale) to promote adherence to the inventions and to allow monitoring for compliance
by study personnel. The pretreatment intervention will last 16 weeks. Both groups will aim
for activity levels of 10,000 steps/day, with a recommendation to increase steps from
baseline by 500 steps/per week. The investigators will monitor subjects monthly during this
preconception intervention. After 16 weeks of lifestyle modification, all subjects randomized
will receive a standardized empiric infertility treatment, regardless of adherence or success
in achieving treatment goals. This treatment will consist of ovarian stimulation with CC
followed by ultrasound follicular monitoring, hCG trigger of ovulation, and a single partner
intrauterine insemination (IUI) per treatment cycle for up to three treatment cycles. The
goal for both treatment groups will be to maintain levels of physical activity and weight
achieved during the pretreatment phase during the empiric infertility treatment phase.
Subjects who conceive will be followed throughout pregnancy with the wireless activity
monitor and wireless scale. Additionally there will be three brief onsite visits during
pregnancy (per trimester at 16, 24, and 32 weeks) for onsite determination of weight,
glycemic, and blood pressure changes and collection of biospecimens. All pregnancy outcomes
will be tracked. Subjects who deliver will be encouraged to donate placenta and cord blood to
the study repository and then to enroll in our Pregnancy Registry for continued infant
follow-up. The investigators will also expand the number and variety of specimens that are
collected for the repository from both partners including urine and serum, semen, saliva,
placenta and cord blood.

Inclusion Criteria:

1. Women ≥18 to ≤ 40 years of age, with one or more years infertility history, desirous
of conceiving, regularly ovulating (defined as 9 or more menses per year), at
initiation of participation.

2. BMI ≥ 30 kg/m2.

3. Normal uterine cavity and at least one open fallopian tube confirmed by
hysterosalpingography (HSG), sonohysterography (SHG), or laparoscopy/hysteroscopy in
the last three years preceding enrollment into the study. An uncomplicated
intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum course
resulting in live birth within the last three years will also serve as sufficient
evidence of a patent tube and normal uterine cavity as long as the subject did not
have, during the pregnancy or subsequently, risk factors for Asherman's syndrome or
serious pelvic infection or other disorder leading to an increased suspicion for
intrauterine abnormality or tubal occlusion.

4. Evidence of ovarian function/reserve as assessed by menstrual cycle day 3 (+/-2 days)
FSH ≤10 IU/L with estradiol ≤ 70 pg/mL OR AMH ≥ 1 ng/mL within one year prior to study
initiation.

5. Normal or corrected thyroid function within one year of study initiation.

6. Normal or corrected prolactin level within one year of study initiation.

7. In general good health, not taking any medications which could interfere with the
study (e.g., FSH, insulin sensitizers).

8. Ability to have inseminations following hCG administration.

9. Male partner with total motile sperm in the ejaculate of at least 5 million sperm,
within one year of study initiation.

10. Able to comply with intercourse instructions and collection of semen for insemination.

Exclusion Criteria:

1. Currently pregnant or successful pregnancies within 12 months of initiating
participation. Clinical intrauterine miscarriages prior to initiating participation,
within ASRM guidelines: subjects over 35 must wait six months, while subjects under 35
must wait 12 months. No exclusion for biochemical pregnancies.

2. Undiagnosed abnormal uterine bleeding.

3. Suspicious ovarian mass.

4. Subjects on oral contraceptives, depo-progestins, or hormonal implants (including
Implanon). A two month washout period will be required prior to screening for patients
on these agents. Longer washouts may be necessary for certain depot contraceptive
methods or implants, especially when the implants are still in place. A one-month
washout will be required for patients taking oral cyclic progestins.

5. Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal
hyperplasia.

6. Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.

7. Known significant anemia (Hemoglobin <10 g/dL).

8. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.

9. Known heart disease (New York Heart Association Class II or higher).

10. Known Liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5
mg/dL).

11. Known Renal disease (defined as BUN >30 mg/dL or serum creatinine > 1.4 mg/dL).

12. History of, or suspected cervical carcinoma, endometrial carcinoma or breast
carcinoma.

13. History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks
at one time).

14. Known Cushing's disease.

15. Known or suspected adrenal or ovarian androgen secreting tumors.

16. Allergy or contraindication to the treatment medications: CC or hCG.

17. Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation)
whether or not it has been reversed.

18. Subjects with untreated poorly controlled hypertension defined as a systolic blood
pressure ≥ 160 mm Hg or a diastolic ≥ 100 mm Hg obtained on two measures at least 60
minutes apart.

19. Subjects who have undergone a bariatric surgery procedure in the past or are in a
period of acute weight loss (defined as a weight loss of greater than 5 kgs in the
last 6 months).

20. Known moderate or severe endometriosis.

21. Anovulation or oligo-ovulation including hypothalamic amenorrhea, polycystic ovary
syndrome, etc.

22. Donated semen.

23. Couples in which either partner is legally married to someone else.

24. Medical conditions that are contraindications to pregnancy.

25. Presence of severe, untreated psychiatric illness (major depression, substance abuse,
eating disorder, etc.) that would, in the opinion of the site investigator, interfere
with the patient's ability to successfully complete the study.

26. Any additional medical conditions that would be a contraindication to orlistat. (This
includes patients with chronic malabsorption syndrome or cholestasis or known
hypersensitivity to any of the drugs used in this study.)

27. Any contraindication to study requirements including diet recommendations and activity
requirements.

28. Currently participating in a lifestyle intervention program (such as Weight Watchers,
Atkins Diet, Curves) or lost more than 5% body weight within the last 6 months.

29. History of Gout.