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

Primary Purpose

Infertility, Female

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Caloric Restriction

Orlistat

Moderate physical activity

About this trial

This is an interventional treatment trial for Infertility, Female

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

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.
BMI ≥ 30 kg/m2.
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.
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.
Normal or corrected thyroid function within one year of study initiation.
Normal or corrected prolactin level within one year of study initiation.
In general good health, not taking any medications which could interfere with the study (e.g., FSH, insulin sensitizers).
Ability to have inseminations following hCG administration.
Male partner with total motile sperm in the ejaculate of at least 5 million sperm, within one year of study initiation.
Able to comply with intercourse instructions and collection of semen for insemination.

Exclusion Criteria:

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.
Undiagnosed abnormal uterine bleeding.
Suspicious ovarian mass.
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.
Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal hyperplasia.
Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.
Known significant anemia (Hemoglobin <10 g/dL).
History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.
Known heart disease (New York Heart Association Class II or higher).
Known Liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5 mg/dL).
Known Renal disease (defined as BUN >30 mg/dL or serum creatinine > 1.4 mg/dL).
History of, or suspected cervical carcinoma, endometrial carcinoma or breast carcinoma.
History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks at one time).
Known Cushing's disease.
Known or suspected adrenal or ovarian androgen secreting tumors.
Allergy or contraindication to the treatment medications: CC or hCG.
Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation) whether or not it has been reversed.
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.
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).
Known moderate or severe endometriosis.
Anovulation or oligo-ovulation including hypothalamic amenorrhea, polycystic ovary syndrome, etc.
Donated semen.
Couples in which either partner is legally married to someone else.
Medical conditions that are contraindications to pregnancy.
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.
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.)
Any contraindication to study requirements including diet recommendations and activity requirements.
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.
History of Gout.

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Intensive Lifestyle Mod. Intervention

Standard Lifestyle Intervention

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Live Birth Rate

All the live birth for the study

Time to Pregnancy in Days

Days from randomization to the first known date of conception

Pregnancy Loss Rate

Pregnancy loss (conception without a live birth) among those who achieved pregnancy

Multiple Pregnancy Rate

Determined by number of multiple pregnancies / number of pregnancies

Birth Weight in Grams

Birth weight (grams) for infant delivered

Mode of Delivery-Cesarean Section

Babies by Cesarean Section/Number of participants who delivered baby

Full Information

NCT ID

NCT02432209

First Posted

March 16, 2015

Last Updated

February 1, 2022

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

1. Study Identification

Unique Protocol Identification Number

NCT02432209

Brief Title

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

Acronym

FIT-PLESE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Completed

Study Start Date

August 2015 (Actual)

Primary Completion Date

November 30, 2019 (Actual)

Study Completion Date

May 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Yale University

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Infertility, Female

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

379 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intensive Lifestyle Mod. Intervention

Arm Type

Active Comparator

Arm Description

Arm Title

Standard Lifestyle Intervention

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Other

Intervention Name(s)

Caloric Restriction

Other Intervention Name(s)

Nutrisystem

Intervention Description

Subjects on Active comparator will have Caloric Restriction to a 1200-1500 kcal/day diet through use of Nutrisystem Meal Plan.

Intervention Type

Drug

Intervention Name(s)

Orlistat

Other Intervention Name(s)

Alli

Intervention Description

Subjects on Active comparator will use an over-the-counter weight loss medication, Orlistat, a gastric lipase inhibitor that limits gut fat absorption.

Intervention Type

Other

Intervention Name(s)

Moderate physical activity

Intervention Description

All subjects in both arms will be encouraged to engage in moderate physical activity with target of 10,000 steps a day.

Primary Outcome Measure Information:

Title

Rate of Good Birth Outcomes

Description

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

Secondary Outcome Measure Information:

Title

Live Birth Rate

Description

All the live birth for the study

Time Frame

At time of birth, approximately 17 months into the study

Title

Time to Pregnancy in Days

Description

Days from randomization to the first known date of conception

Time Frame

0-8 months

Title

Pregnancy Loss Rate

Description

Pregnancy loss (conception without a live birth) among those who achieved pregnancy

Time Frame

After conception, 0-13 months into the study

Title

Multiple Pregnancy Rate

Description

Determined by number of multiple pregnancies / number of pregnancies

Time Frame

After conception, 1-13 months into the study

Title

Birth Weight in Grams

Description

Birth weight (grams) for infant delivered

Time Frame

at time of birth, approximately 17 months into the study

Title

Mode of Delivery-Cesarean Section

Description

Babies by Cesarean Section/Number of participants who delivered baby

Time Frame

At time of birth, approximately 17 months into the study

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. BMI ≥ 30 kg/m2. 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. 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. Normal or corrected thyroid function within one year of study initiation. Normal or corrected prolactin level within one year of study initiation. In general good health, not taking any medications which could interfere with the study (e.g., FSH, insulin sensitizers). Ability to have inseminations following hCG administration. Male partner with total motile sperm in the ejaculate of at least 5 million sperm, within one year of study initiation. Able to comply with intercourse instructions and collection of semen for insemination. Exclusion Criteria: 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. Undiagnosed abnormal uterine bleeding. Suspicious ovarian mass. 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. Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal hyperplasia. Type I or Type II diabetes mellitus, or if receiving antidiabetic medications. Known significant anemia (Hemoglobin <10 g/dL). History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event. Known heart disease (New York Heart Association Class II or higher). Known Liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5 mg/dL). Known Renal disease (defined as BUN >30 mg/dL or serum creatinine > 1.4 mg/dL). History of, or suspected cervical carcinoma, endometrial carcinoma or breast carcinoma. History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks at one time). Known Cushing's disease. Known or suspected adrenal or ovarian androgen secreting tumors. Allergy or contraindication to the treatment medications: CC or hCG. Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation) whether or not it has been reversed. 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. 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). Known moderate or severe endometriosis. Anovulation or oligo-ovulation including hypothalamic amenorrhea, polycystic ovary syndrome, etc. Donated semen. Couples in which either partner is legally married to someone else. Medical conditions that are contraindications to pregnancy. 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. 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.) Any contraindication to study requirements including diet recommendations and activity requirements. 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. History of Gout.

Overall Study Officials: