Endobarrier Treatment in Women With PCOS
Endobarrier Treatment in Women With PCOS
Women with Polycystic ovary syndrome (PCOS) experience multiple fertility treatments, a long
 treatment duration and a low pregnancy prevalence. This syndrome is frequently accompanied by
 overweight and insulin resistance which can mediate the limited response to fertility
 treatment. The Endobarrier device was shown to be efficient in weight and glucose lowering.
 The aim of this study is to investigate the ability of the Endobarrier device to improve the
 outcome of fertility treatments in women with PCOS.
1. PCOS Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of
 reproductive age, associated with reproductive and metabolic dysfunction with a
 prevalence of 5-10% of reproductive aged women.

 Diagnostic criteria vary and according to the Rotterdam ESHRE/ASRM- Sponsored PCOS
 Consensus Workshop Group PCOS is defined when at least two of the following three
 criteria are present: [i] polycystic ovaries, by ultrasound [ii] oligo and/or
 anovulation, and [iii] clinical and/or biochemical signs of hyperandrogenism.

 The clinical presentation varies from amenorrhea and a sonographic picture of polycystic
 ovaries but with subtle phenotypic abnormalities or signs of hyperandrogenism, to
 advanced Stein and Leventhal syndrome with clinical heterogeneity as the rule. Moreover,
 women with PCOS might exhibit features of the metabolic syndrome, including impaired
 glucose tolerance (IGT), obesity and dyslipidaemia ,with their associated long- term
 sequelae, namely endometrial carcinoma, hypertension, type 2 diabetes (T2D) and
 cardiovascular disease.

 Impaired Glucose Intolerance (IGT) and PCOS Impaired glucose tolerance, or insulin
 resistance, are defined as decreased insulin-mediated glucose utilization. It has long
 been recognized as a major risk factor for diabetes. Moreover, it was shown that
 lifestyle intervention or metformin in patients with IGT, may reduce the prevalence of
 T2D. Several dynamic invasive tests and calculated indices are currently available for
 detecting IGT. While the euglycemic clamp technique is considered the most accurate test
 for the assessment of insulin resistance, this cumbersome test is frequently replaced by
 the simple measurement of the ratio of fasting glucose to fasting insulin, or the 2-hour
 glucose level after a 75-g oral glucose tolerance test (OGTT) (WHO criteria, impaired
 glucose tolerance [IGT] >140 mg/dL to 199 mg/dL). As a result, reports of the prevalence
 on IGT in women with PCOS vary depending on the sensitivity and specificity of the tests
 employed and the heterogenic phenotypes of PCOS.

 Obesity - definition, significance and prevalence among women with PCOS:

 Obesity, a common clinical manifestation of PCOS patients, is linked to insulin
 resistance and failure or delayed response to the various COH treatments.The associated
 health detriments of this major health problem are increased with increasing body mass
 index (BMI). Data regarding the impact of obesity on IVF cycles outcome is
 controversial, ranging from studies reporting on no effect of increasing BMI on IVF
 success rates to those demonstrating a lower cumulative live birth rates in overweight
 patients. PCOS and assisted reproduction PCOS women with insulin resistance undergoing
 ovulation induction with gonadotropin have a longer duration of treatment, use a higher
 total FSH dose, have an elevated cancellation rate and a lower conception rate.
 Improving insulin sensitivity through both lifestyle and pharmacological intervention
 were suggested to ameliorate the aforementioned abnormalities, restore ovulation and
 enhance pregnancy in women with PCOS.

 In vitro fertilization (IVF) and embryo transfer (ET) is an effective therapy for PCOS
 patients and results in pregnancy rates that are comparable with those for women with
 tubal factor infertility. Moreover, because the number of multiple pregnancies can be
 kept to a minimum by transferring small numbers of embryos, IVF-ET became a reasonable
 option to PCOS patients who are refractory to conventional infertility modalities or who
 have coexisting infertility factors.

 Many controlled ovarian hyperstimulation (COH) strategies have been offered for the
 treatment of patients with PCOS undergoing IVF.

 In an attempt to examine the influence of BMI on IVF outcome in patients undergoing COH
 with either GnRH-agonist or antagonist, the investigators found that while in patients
 with BMI>25 kg/m2, COH with either GnRH-agonist or antagonist achieved a comparable
 outcome, in those with BMI<25 kg/m2, the use of GnRH-agonist suppressive protocol
 revealed a significantly higher pregnancy rates.

 Moreover, in another study of PCOS patients undergoing IVF-ET cycles, the investigators
 demonstrated that COH utilizing the midluteal long GnRH-agonist suppressive protocol was
 the protocol of choice in lean patients, probably due to its ability to lower the high
 basal LH milieu and its detrimental effect of oocytes' quality and implantation
 potential.

 2. Device Description ENDOBARRIER The EndoBarrier Gastrointestinal Liner system received CE
 Mark on 11 December 2009 and is indicated for the treatment of obesity and Type 2
 diabetes. The implant is indicated for a maximum implant duration period of twelve
 months. The intent of the EndoBarrier is to facilitate glycemic control and weight loss
 by mimicking portions of the Roux-en-Y bypass procedure. The device consists of 3
 components: the implant, the delivery system, and the removal system.

 The procedure entails bypassing the duodenum and the proximal jejunum with a 60 cm
 non-permeable polymeric sleeve which is attached to the duodenal wall. This sleeve prevents
 the contact of food with the duodenal wall, thereby re-capitulating one of the major
 properties of the RYGB operation. With this technique, control of diabetes is accompanied by
 weight loss, with no need for medications that may cause weight gain / hypoglycemia and may
 serve to replace or postpone surgery.

 In a recent paper by de Moura et al, Twenty-two subjects with uncontrolled type 2 diabetes
 and a body mass index between 40- 60 kg/m ² were implanted with the EndoBarrier and followed
 prospectively for 1 year.

 The authors found statistically significant reductions in fasting blood glucose (- 30.3 ±
 10.2 mg/dL), fasting insulin (- 7.3 ± 2.6 lU/mL), and HbA1c ( - 2.1±0.3%) in patients
 undergoing the procedure.

 The study conclusions were that EndoBarrier improves glycemic status in obese subjects with
 diabetes and therefore represents a non-surgical, reversible alternative to bariatric
 surgery. Internal data from GI Dynamics reveals that obese subject (average BMI of 44 kg/m²)
 and uncontrolled diabetes ( average A1c of 8.4 %) who were implanted with EndoBarrier for one
 year showed the following:

 1. A reduction of 2.1% of the A1c level, with a value of less than 7% in 80% of the
 subjects.

 2. An average reduction of 20 Kg (representing 16% of the excess weight).

 3. A 29% reduction in the triglyceride level and a 14% reduction in LDL-c. After 12 months
 the EndoBarrier was removed and the subjects remained in follow up for additional 18
 months. During this period, the achievement was maintained.

 3. Study Design: This is a two arm open-label three phase trail investigating the effect of
 an EndoBarrier device on fertility and metabolic parameters in obese insulin resistant (IR)
 PCOS women Arm 1: women seeking pregnancy after failed IVF treatment cycle/s. Arm 2: women
 seeking pregnancy after failure to ovulate in response to clomiphene citrate (CC) -
 clomiphene resistant.

 Phase 1: (treatment phase) - Six months with Endobarrier Phase 2: (follow-up phase) - Twelve
 months after Endobarrier retrieval Phase 3: (long term observation phase) - to see whether
 and when a pregnancy was achieved within the second year after retrieval.

 4. Methods and assessments: 4.1 Visit 1- screening All potential patients will be screened
 for eligibility at visit 1. Informed consent (ICF) will be explained to the patient prior to
 conducting any study procedures. A discussion in which the patient is explained about the
 advantage and disadvantage of the trail and the trail procedures will be taken. If
 participation is agreed to by the patient after they read the ICF, the patient will sign and
 date the ICF, and get a copy of the signed and dated form.

 The following activities will occur on Visit 1:

 The patient signs the ICF form A patient number will be assigned to the patient. Inclusion /
 Exclusion criteria will be reviewed. Demographic data : Age. Medical history evaluation and
 concomitant medication record. A physical and gynecological examination (including Ultrasound
 of Ovaries) will be conducted.

 An oral OGTT 75g will be performed. Fasting Laboratory measurements will be performed A date
 for visit 2 will be scheduled.

 4.2 visit 2 - Gastro screening

 The following activities will occur on Visit 2:

 The patient will be referred to the Gastroenterology department for Gastroscopy.

 The patient will be instructed to start 40 mg Omeprazole twice daily 3 days prior to visit 4
 (Implantation of the Endobarrier).

 The patient will be instructed to start contraceptive from now on. Diet consultation will be
 performed The patient will be asked to answer the "Visual analog scale" (VAS) questionnaire.

 A date for visit 3 will be scheduled.

 4.3 visit 3 - Endobarrier implantation The patient will arrive in a fasting state. The
 patient will be asked about any AE's and change in medications. Vital signs, weight, waist
 circumferences will be measured. Fasting Laboratory measurements will be performed Under full
 anesthesia (in order to achieve the best conditions for the accurate positioning of the
 device) gastroscopy will be performed and a guide wire will be inserted to the jejunum.

 The Endobarrirer device will be inserted over the guide wire and introduced into the duodenal
 bulb. The correct location of the device will be evaluated by the endoscope.

 Under fluoroscopy the device will be operated and the sleeve will be released from its
 capsule. Contrast material will be injected thorough the sleeve to insure full opening.

 After full expansion of the sleeve, the anchoring mechanism will be operated and the sleeve
 will be anchored by small hooks to the duodenal bulb.

 Correct hooking will be visualized endoscopically.

 4.4 visits 4-9 The patient will be asked about any AE's and change in medications. Vital
 signs, weight, waist circumferences will be measured. Fasting Laboratory measurements will be
 performed Diet consultation will be performed. The patient will be asked to answer the
 "Visual analog scale" (VAS) questionnaire.

 4.5 visit 10- pre-retrieval visit The patient will be asked about any AE's and change in
 medications. Vital signs, weight, waist circumferences will be measured. Fasting laboratory
 measurements will be performed The patient will be asked to answer the "Visual analog scale"
 (VAS) questionnaire

 4.6 visit 11- Endobarrier retrieval The retrieval procedure will be performed after sedation.
 A retrieval hood will be connected to the endoscope tip. A scope will be introduced to the
 duodenum. A retrieval grasper will be inserted through the scope. By pulling the drawstring
 the anchoring hook will collapse and when all hooks are within the plastic retrieval hood the
 endoscope will be withdrawn safely out.

 The patients will be referred to the infertility Clinic for treatment.

 4.7 visit 12-19 - once in 3M follow up Patient will come to a visit once every 3 months,
 until pregnancy is achieved or until the end of the study period.

 Patient will be asked about any AE's and change in medications. Gynecological exam (may
 include Ultrasound of Ovaries) may be performed. Fasting laboratory measurements will be
 performed The patient will be asked to answer the "Visual analog scale" (VAS) questionnaire.

 Patient will be required to provide the site will data regarding last fertility treatment

 **In case pregnancy is achieved patient is requested to inform the site within 1 week.

 Relevant information regarding the fertility treatment will be collected
Inclusion criteria:

 1. Women willing to comply with study requirements and have signed an informed consent
 form.

 2. Age 20-35

 3. BMI ≥ 35 kg/m²

 4. A history of failed IVF treatment cycle/s or resistance to ovulation induction with
 clomiphene citrate.

 5. Documented negative pregnancy test.

 6. Women agree to remain on contraceptives as long as the Endobarrier is intact.

 7. PCOS as defined by at least two of the following criteria:

 A. Polycystic ovaries. B. Oligo and/or anovulation C. Clinical (i.e acne, hirsutism)
 and/or biochemical signs of hyperandrogenism (i.e high levels of Testosterone,
 Androstendione, 17-hydroxyprogesterone, DHEA-S) and exclusion of other etiologies
 (congenital adrenal hyperplasia androgen-secreting tumors, Cushing's syndrome).

 8. IGT as defined by: the ratio of fasting glucose to fasting insulin <4.5, and/or 2-hour
 glucose level after a 75-g oral glucose tolerance test between 140-199 mg/dL.

 9. Documented FSH levels below 12 IU/L, from any source taken no longer than 3 months
 before screening.

 Exclusion Criteria:

 1. Subjects taking systemic corticosteroids or drugs known to affect GI motility within
 30 days prior to randomization

 2. Subjects receiving any prescription or over the counter weight loss medication within
 30 days prior to the Endobarrier insertion procedure (including GLP-1 analogs).

 3. Known Diabetes as defined by: fasting plasma glucose ≥126 mg/dL or any plasma glucose
 ≥200 mg/dL or HbA1c level ≥6.5% .

 4. Previous GI surgery that could preclude the ability to place the EndoBarrier device,
 liner or affect the function of the implant

 5. Subjects with a history of abnormal GI anatomical findings documented on imaging
 study, which in the opinion of the Investigator, may impair implantation of the
 EndoBarrier device

 6. Subjects with active GERD not taking a Proton Pump Inhibitor (PPI), which in the
 investigator's opinion might interfere with the Endobarrier.

 7. Subjects with symptomatic kidney stones within 6 months prior to randomization.

 8. Known abnormal pathologies or conditions of the gastrointestinal tract, including
 ulcers or Crohn's disease, atresias or stenoses, upper gastro-intestinal bleeding
 conditions

 9. Subjects with symptomatic gallstones within 6 months prior to randomization

 10. Coagulopathy defined as hgb <10g/dl and platelet < 100,000/ml or diagnosis of
 hemophilia, factor X deficiencies or fibrinogen abnormalities

 11. Any documented history of acute or chronic pancreatitis

 12. Subjects requiring prescription antithrombotic therapy (i.e. anticoagulant or
 antiplatelet agent)

 13. Subjects unable to discontinue Aspirin or any other NSAIDs (non-steroidal
 anti-inflammatory drugs) or any other drugs with bleeding as a potential side effect
 (i.e coumadin) during the study duration

 14. Known diagnosis of systemic lupus erythematosus, scleroderma or other autoimmune
 connective tissue disorder

 15. Subject is or has been enrolled in another investigational study within 3 months of
 participation into the EndoBarrier study

 16. Subjects with poor dentition who cannot completely chew their food.

 17. Subjects with thyroid disease unless controlled with a therapeutic dose of medication
 and have normal thyroid function tests for a minimum of 6 months prior to
 randomization

 18. Subjects not residing within a 3 hour driving distance of the study center.

 19. Subjects with an abnormal laboratory or ECG abnormality which the investigators deems
 clinically significant and makes the patient a poor candidate for the study

 20. Subjects with known allergies or hypersensitivity to ceftrixone, cephalosporins or
 penicillin.

 21. The investigator may decide to exclude the participation of a subject due to medical,
 safety or any other reason (i.e; behavioral issues, etc.) at any point before the
 implantation procedure.