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

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).

Study Overview

• Status: Completed
• Conditions: Infertility, Female
• Intervention / Treatment: Other: Caloric Restriction; Drug: Orlistat; Other: Moderate physical activity

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
• Enrollment (Actual): 379
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • University of California San Francisco
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Michigan
    • Southfield, Michigan, United States, 48034
      • Wayne State University
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Atrium Health Carolinas Healthcare System
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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 Names: 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 Names: 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.
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At time of birth, approximately 17 months into the study

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Pennsylvania; University of Oklahoma; University of California, San Francisco; Penn State University; Augusta University; University of North Carolina
• Investigators: Study Chair: Nanette Santoro, MD, University of Colorado, Denver; 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)

Publications and helpful links

General Publications

• Legro RS, Hansen KR, Diamond MP, Steiner AZ, Coutifaris C, Cedars MI, Hoeger KM, Usadi R, Johnstone EB, Haisenleder DJ, Wild RA, Barnhart KT, Mersereau J, Trussell JC, Krawetz SA, Kris-Etherton PM, Sarwer DB, Santoro N, Eisenberg E, Huang H, Zhang H; Reproductive Medicine Network. Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial. PLoS Med. 2022 Jan 18;19(1):e1003883. doi: 10.1371/journal.pmed.1003883. eCollection 2022 Jan.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): November 30, 2019
• Study Completion (Actual): May 1, 2020

Study Registration Dates

• First Submitted: March 16, 2015
• First Submitted That Met QC Criteria: May 1, 2015
• First Posted (Estimate): May 4, 2015

Study Record Updates

• Last Update Posted (Actual): February 3, 2022
• Last Update Submitted That Met QC Criteria: February 1, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Infertility, Female; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Lipid Regulating Agents; Anti-Obesity Agents; Orlistat
• Other Study ID Numbers: FIT-Plese

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.