Infertility, Female
Conditions
Brief summary
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).
Detailed description
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.
Interventions
OTHERCaloric Restriction
Subjects on Active comparator will have Caloric Restriction to a 1200-1500 kcal/day diet through use of Nutrisystem Meal Plan.
DRUGOrlistat
Subjects on Active comparator will use an over-the-counter weight loss medication, Orlistat, a gastric lipase inhibitor that limits gut fat absorption.
All subjects in both arms will be encouraged to engage in moderate physical activity with target of 10,000 steps a day.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Penn State University
Augusta University
University of California, San Francisco
University of North Carolina
University of Oklahoma
University of Pennsylvania
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Good Birth Outcomes | At time of birth, approximately 17 months into the study | Defined as a live birth of an infant born at ≥ 37 weeks, with a birth weight between 2500 and 4000g and without a major congenital anomaly |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Pregnancy in Days | 0-8 months | Days from randomization to the first known date of conception |
| Pregnancy Loss Rate | After conception, 0-13 months into the study | Pregnancy loss (conception without a live birth) among those who achieved pregnancy |
| Live Birth Rate | At time of birth, approximately 17 months into the study | All the live birth for the study |
| Birth Weight in Grams | at time of birth, approximately 17 months into the study | Birth weight (grams) for infant delivered |
| Mode of Delivery-Cesarean Section | At time of birth, approximately 17 months into the study | Babies by Cesarean Section/Number of participants who delivered baby |
| Multiple Pregnancy Rate | After conception, 1-13 months into the study | Determined by number of multiple pregnancies / number of pregnancies |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intensive Lifestyle Mod. Intervention 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.
Caloric Restriction: Subjects on Active comparator will have Caloric Restriction to a 1200-1500 kcal/day diet through use of Nutrisystem Meal Plan.
Orlistat: Subjects on Active comparator will use an over-the-counter weight loss medication, Orlistat, a gastric lipase inhibitor that limits gut fat absorption.
Moderate physical activity: All subjects in both arms will be encouraged to engage in moderate physical activity with target of 10,000 steps a day. | 188 |
| Standard Lifestyle Intervention 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.
Moderate physical activity: All subjects in both arms will be encouraged to engage in moderate physical activity with target of 10,000 steps a day. | 191 |
| Total | 379 |
Baseline characteristics
| Characteristic | Standard Lifestyle Intervention | Total | Intensive Lifestyle Mod. Intervention |
|---|---|---|---|
| Age, Continuous | 32 years | 32 years | 32 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 12 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 177 Participants | 356 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 37 Participants | 82 Participants | 45 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) White | 140 Participants | 266 Participants | 126 Participants |
| Sex: Female, Male Female | 191 Participants | 379 Participants | 188 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 188 | 0 / 191 |
| other Total, other adverse events | 157 / 188 | 157 / 191 |
| serious Total, serious adverse events | 12 / 188 | 13 / 191 |
Outcome results
Primary
Rate of Good Birth Outcomes
Defined as a live birth of an infant born at ≥ 37 weeks, with a birth weight between 2500 and 4000g and without a major congenital anomaly
Time frame: At time of birth, approximately 17 months into the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Rate of Good Birth Outcomes | 23 Participants |
| Standard Lifestyle Intervention | Rate of Good Birth Outcomes | 29 Participants |
p-value: 0.40495% CI: [0.48, 1.34]Chi-squared
Secondary
Birth Weight in Grams
Birth weight (grams) for infant delivered
Time frame: at time of birth, approximately 17 months into the study
Population: For the live-born infants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Birth Weight in Grams | 3217.7 gram |
| Standard Lifestyle Intervention | Birth Weight in Grams | 3189.3 gram |
Secondary
Live Birth Rate
All the live birth for the study
Time frame: At time of birth, approximately 17 months into the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Live Birth Rate | 38 Participants |
| Standard Lifestyle Intervention | Live Birth Rate | 42 Participants |
Secondary
Mode of Delivery-Cesarean Section
Babies by Cesarean Section/Number of participants who delivered baby
Time frame: At time of birth, approximately 17 months into the study
Population: For those who delivered baby(babies)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Mode of Delivery-Cesarean Section | 19 Participants |
| Standard Lifestyle Intervention | Mode of Delivery-Cesarean Section | 23 Participants |
Secondary
Multiple Pregnancy Rate
Determined by number of multiple pregnancies / number of pregnancies
Time frame: After conception, 1-13 months into the study
Population: For those with clinical pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Multiple Pregnancy Rate | 7 Participants |
| Standard Lifestyle Intervention | Multiple Pregnancy Rate | 3 Participants |
Secondary
Pregnancy Loss Rate
Pregnancy loss (conception without a live birth) among those who achieved pregnancy
Time frame: After conception, 0-13 months into the study
Population: For those who achieved pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Pregnancy Loss Rate | 24 Participants |
| Standard Lifestyle Intervention | Pregnancy Loss Rate | 14 Participants |
Secondary
Time to Pregnancy in Days
Days from randomization to the first known date of conception
Time frame: 0-8 months
Population: For those who achieved pregnancy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intensive Lifestyle Mod. Intervention | Time to Pregnancy in Days | 160 days |
| Standard Lifestyle Intervention | Time to Pregnancy in Days | 163 days |