Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE)

• ClinicalTrials.gov Identifier: NCT02432209
• Recruitment Status: Completed
• First Posted: May 4, 2015
• Results First Posted: March 15, 2021
• Last Update Posted: March 15, 2021
• Sponsor: Yale University
• Collaborators: 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
• Information provided by (Responsible Party): Yale University

Tracking Information

• First Submitted Date: March 16, 2015
• First Posted Date: May 4, 2015
• Results First Submitted Date: January 15, 2021
• Results First Posted Date: March 15, 2021
• Last Update Posted Date: March 15, 2021
• Actual Study Start Date: August 2015
• Actual Primary Completion Date: November 30, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 19, 2021)

Rate of Good Birth Outcomes [ Time Frame: 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

Original Primary Outcome Measures (submitted: May 1, 2015)

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). in obese women with unexplained infertility [ Time Frame: 17 months ]

This will be a three phase study involving a preconception intervention of two types of lifeststyle modification (4 mos) followed by up to 3 cycles of standardized infertility treatment (3 mos) followed by pregnancy (9 mos) . The study will examine an intensive lifestyle modification intervention, which includes caloric restriction by using meal replacements, a weight loss medication (over the counter orlistat) and physical activity recommendations versus a standard lifestyle intervention consisting of increasing physical activity alone on improving 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 in obese women with unexplained infertility. Implicit in the primary aim is the goal of tracking safety of our interventions at all Phases of the study (through lifestyle modification to infertility treatment to pregnancy to infant).

Current Secondary Outcome Measures (submitted: February 19, 2021)

• Live Birth Rate [ Time Frame: At time of birth, approximately 17 months into the study ]
  All the live birth for the study
• Time to Pregnancy in Days [ Time Frame: 0-8 months ]
  Days from randomization to the first known date of conception
• Pregnancy Loss Rate [ Time Frame: After conception, 0-13 months into the study ]
  Pregnancy loss (conception without a live birth) among those who achieved pregnancy
• Multiple Pregnancy Rate [ Time Frame: After conception, 1-13 months into the study ]
  Determined by number of multiple pregnancies / number of pregnancies
• Birth Weight in Grams [ Time Frame: at time of birth, approximately 17 months into the study ]
  Birth weight (grams) for infant delivered
• Mode of Delivery-Cesarean Section [ Time Frame: At time of birth, approximately 17 months into the study ]
  Babies by Cesarean Section/Number of participants who delivered baby

Original Secondary Outcome Measures (submitted: May 1, 2015)

• Live Birth Rate [ Time Frame: 17 months ]
• Time to Pregnancy in Days [ Time Frame: 8 months ]
• Pregnancy Loss Rate determined by number of conceptions without a live birth / number of conceptions [ Time Frame: 17 months ]
• Multiple Pregnancy Rate determined by number of multiple pregnancies / number of pregnancies [ Time Frame: 17 months ]
• Pregnancy Complication Rate determined by number of pregnancies with complications / number of pregnancies [ Time Frame: 17 months ]
• Birth Weight in Grams [ Time Frame: 17 months ]
• Mode of Delivery [ Time Frame: 17 months ]
• Neonatal Complication Rate determined by the number of neonatal complications / number of live births [ Time Frame: 17 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility
• Official Title: Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Infertility, Female

Intervention

• Other: Caloric Restriction
  Subjects on Active comparator will have Caloric Restriction to a 1200-1500 kcal/day diet through use of Nutrisystem Meal Plan.
  Other Name: Nutrisystem
• Drug: Orlistat
  Subjects on Active comparator will use an over-the-counter weight loss medication, Orlistat, a gastric lipase inhibitor that limits gut fat absorption.
  Other Name: Alli
• Other: 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.

Study Arms

• Active Comparator: 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.
  Interventions:

  • Other: Caloric Restriction
  • Drug: Orlistat
  • Other: Moderate physical activity
• Placebo Comparator: 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.
  Intervention: Other: Moderate physical activity

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 7, 2018): 379
• Original Estimated Enrollment (submitted: May 1, 2015): 390
• Actual Study Completion Date: May 2020
• Actual Primary Completion Date: November 30, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 40 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02432209
• Other Study ID Numbers: FIT-Plese
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: IPD will be shared with other researchers through the NICHD DASH system. It will be available 6 months after publication of the primary results.

• Responsible Party: Yale University
• Study Sponsor: Yale University

Collaborators

• 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

Investigators

• Study Chair: Nanette Santoro, MD; University of Colorado, Denver
• Study Director: Heping Zhang, PhD; Yale University
• Principal Investigator: Richard Legro, MD; Penn State University
• Study Director: Michael Diamond, MD; Augusta University
• Study Director: Marcelle Cedars, MD; University of California, San Francisco
• Study Director: Anne Steiner, MD MPH; Univeristy of North Carolina
• Study Director: Karl Hansen, MD PhD; University of Oklahoma
• Study Director: Christos Coutifaris, MD PhD; University of Pennsylvania
• Study Director: Esther Eisenberg, MD MPH; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

• PRS Account: Yale University
• Verification Date: February 2021