Bariatric Embolization of Arteries With Imaging Visible Embolics (BEATLES) (BAE2)

Obesity is defined as a body mass index (BMI) ≥30 kg/m2 and with a subclass of obesity known as morbid or severe obesity (BMI of ≥40 kg/m2). These are major issues in medicine for both participants and medical providers with >36% of the US population affected. Obesity is one of the biggest causes of preventable chronic diseases and healthcare costs in the USA. Obese adults spend 42% more on direct healthcare costs and morbidly obese adults overall have 81% higher healthcare costs than non-obese adults. Obesity is currently treated with dietary, pharmacological, and/or surgical approaches that are often unsuccessful or are associated with additional risks. As the incidence and prevalence of obesity and obesity-related diseases are steadily increasing, there is a growing need to detect the key risk factors involved in disease development and modify standard treatment procedures and protocols. The most successful long-term strategy continues to be bariatric and metabolic surgeries, such as sleeve gastrectomy and Roux-en-Y gastric bypass (RYGBP). The NIH recommends bariatric surgery for participants with a BMI of 40 kg/m2 or greater or a BMI of 35 kg/m2 or greater and obesity related comorbidities. These surgeries enable participants to lose between 50% and 75% of excess body weight. Despite this success, participants are apprehensive and do not undergo bariatric surgery with the biggest fear being the many complications that come with the procedure. Studies have shown that 57-77% of participants are not interested in bariatric surgery although the participants qualify.(16) With the concern of complications from bariatric surgery, interest in endoscopic bariatric techniques has increased over the years. The techniques have been shown to be efficacious, reversible, relatively safe, and cost effective. Further, these techniques offer a therapeutic window for some participants who may otherwise be unable to undergo bariatric surgery. The American Society for Gastrointestinal Endoscopy have approved endoscopic procedures, such as balloon therapy, for participants with BMI in the 30-40 kg/m2 range.(17,18) However, the products used in these therapies also have several limitations primarily the inability to provide long term weight loss given the temporary nature of these balloons.(19) Common adverse events following intragastric balloon insertion include abdominal pain (33.7%), gastroesophageal reflux disease (18.3%), anorexia, and nausea (29%). Severe complications such as gastric ulcers (2%), small bowel obstruction (0.3%), perforation (0.1%), balloon migration (1.4%), and death (0.08%) are less common. Early balloon removal occurred in 9.1% of the study participants due to participant intolerance.(20) In a pilot study to assess safety and efficacy (BEAT Obesity), 20 morbidly obese participants with a BMI of ≥40 kg/m2 with no other comorbid conditions underwent bariatric embolization and were followed for 12 months. Participants were embolized with 300-500 µm Embospheres. None of the 20 participants in the BEAT Obesity trial (the largest prospective trial to date) had any major adverse events. Any gastric ulcers that occurred (40%) were asymptomatic and were completely healed by three months after the procedure.(21) There were many limitations of this study including the absence of a control cohort and non-compliance amongst study participants. A target population of participants with a BMI of 40 kg/m2 and above was too high considering the bariatric embolization procedure is comparable to endoscopic bariatric therapies rather than bariatric surgery. BEAT Obesity excluded participants with comorbidities, such as those who suffer from diabetes, who may greatly benefit from this procedure and are often the target population for endoscopic/surgical bariatric therapies. A larger bead size of 300-500 µm was specifically chosen compared to preclinical data and prior clinical reports due to concerns of gastric ischemia and ulceration. However, smaller bead size produces greater weight loss and hormonal shifts.(22) Investigators hypothesize that transvascular bariatric embolization results in safe and effective weight loss in obese participants compared to control subjects.

The BEATLES study is an investigator-initiated, prospective, double-blinded, randomized, sham-controlled study that will assess the impact of bariatric embolization on the systemic levels of obesity-related hormones and, as a consequence, on weight loss. The goal of this study is to help treat obesity combining a lifestyle program and a minimally invasive, angiographic (i.e., through blood vessels) approach.

All procedure images and reports, regardless of the randomization arm, will be kept with the unblinded member of the study team, and will not be housed centrally. All participants will adhere to the same follow-up schedule, meeting with blinded members of the study team only. The procedural team will not have further contact with the participant, the participant will only be followed by the blinded study team. Once the study is closed, all reports and images will be entered into the clinical record.

27 participants enrolled in the procedure arm. Participants randomized to the control arm will follow the same screening. Pre-procedure assessment will take the same pre-procedure meds. Procedure day, interventional radiologist will determine radial or groin access. After the participant and procedure area are prepped, participants will be under standard moderate sedation medications; all participants will receive lidocaine & a skin nick to their groin or their wrist as determined by the operating physician. Participant will have a blind fold placed & their hearing damped either with ear plugs or noise cancelling headphones. Participants randomized to the control arm will not receive other procedural intervention. Procedural team will follow a prescribed simulated protocol. Participants randomized to the control arm will be given under skin lidocaine and receive a skin nick on the wrist or groin.

27 subjects will be enrolled in the bariatric embolization(BM) procedure arm. BM procedure will be performed under moderate sedation. Procedure will take 1.5 hr to 3 hr subject will be placed on the X-ray fluoroscopy table. Radial or femoral vascular access will be achieved using a small gauge needle, dilated over a guidewire to accommodate a 5 French vascular sheath. Standard catheters, 3 dimensional imaging will be acquired of the stomach, the arteries supplying the fundus arising off the celiac vessel. Microcatheter into the left gastric and/or gastroepiploic arteries supplying the fundus and small calibrated spheres will be infused until stasis of anterograde arterial flow is achieved, with particular care to avoid infusion of non-target arteries. The left gastric and/or gastroepiploic arteries will be embolized. Repeat 3 dimensional imaging: assess bead distribution and fundal coverage. Subject will be monitored in the recovery room and will be observed overnight.

The BEATLES study is an investigator-initiated, prospective, doubleblind, randomized, sham-controlled study that will assess the impact of bariatric embolization on the systemic levels of obesity related hormones and, as a consequence, on weight loss. The goal of this study is to help treat obesity combining a lifestyle program and a minimally invasive, angiographic (i.e., through blood vessels) approach.

Participants randomized to the control arm will follow the same screening and pre-procedure assessment, and will also take the same pre-procedure medications. The procedural team instead will follow a prescribed simulated protocol that will mimic an actual embolization procedure.

Inclusion Criteria: Male or female, aged ≥21 and ≤70 years Willing, able, and mentally competent to provide written informed consent Obese patients with a BMI ≥35 kg/m2 Weight ≤400 lb Vascular anatomy (including celiac, hepatic, and gastric arteries) that in the opinion of the interventional radiologist is amendable to bariatric embolization, as assessed via 3D CT angiography Suitable for protocol therapy, as determined by the interventional radiology investigator Adequate hematologic (neutrophils>1.5x109/L, platelets>70x109/L, international normalized ratio (INR<1.5), hepatic (bilirubin≤2.0mg/dL, albumin≥2.5g/L), and renal (estimated glomerular filtration rate (GFR)>60milliliter mL/min. 1.73m2) function For females of reproductive potential: agreement to use of highly effective contraception for duration of study participation Patients who have failed conservative weight loss therapies such as supervised low calorie diets combined with behavior therapy and exercise Live or work within 65 miles of the enrolling institution in case a catastrophic post embolization event occurs Exclusion Criteria: hemoglobin A1c greater than 8% Patients who are currently taking either Insulin or sulfonylurea (medication changes are allowed) Prior history of gastric, pancreatic, hepatic, and/or splenic surgery Prior radiation therapy to the upper abdomen Prior embolization to the stomach, spleen, or liver Cirrhosis Known portal venous hypertension Active peptic ulcer disease Significant risk factors for peptic ulcer disease, including daily NSAID use Large hiatal hernia, defined as >5 cm in size Active H. Pylori infection Known aortic pathology, such as aneurysm or dissection Renal insufficiency, as evidenced by an estimated glomerular filtration rate of <60 milliliter(mL)/min Major comorbidity, such as active cancer, significant cardiovascular disease, or peripheral arterial disease Pregnancy Pre-existing chronic abdominal pain Positive stool occult blood study GI bleeding or bleeding diathesis within 5 years Weight loss (intentional or unintentional) of more than or equal to 5% of body weight in the 6 months prior to randomization A weight loss greater than 6lb during the weight management run- in Use of anti-obesity medications in the 12 months prior to screening Endoscopic findings that would preclude bariatric embolization (at the discretion of the study team) History of gastric motility disorders or an abnormal nuclear gastric motility examination (to be performed in diabetic subjects only) American Society of Anesthesiologists Class 4 or 5 (very high risk surgical candidates: class 4=incapacitating disease that is a constant threat to life) at the time of screening for enrollment into the study - this exclusion criterion exists, because of the possibility that surgical intervention will be needed if the study intervention subsequently leads to severe adverse effects Inflammatory bowel disease Autoimmune disease or HIV+ History of allergy to iodinated contrast media Failure to comply with pre-procedure weight management "run-in", or other pre-procedural visits (specifically, participants must complete 80% of weight management and Lose It! Food tracking, and 100% of one-time visits, i.e. MRI, computed tomography angiography (CTA), endoscopy) Applicability of any contraindication regarding patient's vasculature as per Instruction for Use Inability to have an MRI scan (i.e., metal implants or claustrophobia) Smokers/vape users/tobacco use Active or new-onset endocrine disorders (stable disease acceptable) Other unforeseen conditions that may make patients unsuitable for the procedure (study team discretion) Exclusion Criteria (Psychiatric): As determined by clinical judgment based on Clinical Interview, psychological/behavioral measures, medical records, previous mental health records/other collateral information (as available) and consistent with diagnostic and statistical manual of mental disorders (DSM) -5 criteria: Diagnosis of severe mental illness (i.e., chronic psychotic spectrum disorders, clinically significant mood disorders) AND/OR one or more of the following: Evidence of active relapse or active impairing symptoms (e.g., suicidal ideation, audio or visual hallucinations, paranoia, thought disturbance, severe impairment) Evidence of minimal supports or limited adherence to ongoing mental health care Failure to provide comprehensive aftercare plan that includes emergency plan for addressing future mental health relapse History of treatment refractory mental illness/recurrent relapse (multiple suicide attempts or inpatient psychiatric hospitalizations in the past 5 years) Within past 3 years: Inpatient psychiatric hospitalization Within past 5 years: Suicide attempt Declining to provide mental health records, a letter of support from mental health professionals, or consent for verbal consultation with mental health professionals when determined to be essential to evaluation. Cognitive impairment, if judged to have Limited capacity to make informed decision about procedure and inability to verbalize an understanding of the surgical procedure, risks and benefits. Inability to demonstrate an understanding of the permanency of lifestyle change required History of Anorexia or History of/Active Bulimia: If determined to be of low enough severity not to be a clear contraindication, minimum of 5 years abstinence from bulimia, current moderate to severe binge eating or night eating syndrome Active or History of Substance Abuse with less than 5 years of abstinence Current use of anti-tricyclic anti-depressants or steroids, psychiatric medications associated with weight gain.

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