Effects of Vagus Nerve Cryoablation on Glycemic Control and Weight Loss in Obese Patients With Type 2 Diabetes
Phase: NA
Conditions: Diabetes Type 2, Diabetes Mellitus, Obesity
Sponsor: Emory University

Cryovagotomy Trial 
February 22. 2021 
 
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Effects of vagus nerve cryoablation on glycemic control and weight loss in 
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obese patients with type 2 diabetes 
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NCT Number: NCT04276051 
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Protocol Date: February 22, 2021 
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Emory University School of Medicine 
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Department of Medicine, Endocrinology 
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Correspondence to:  
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Alexandra Migdal, M.D. 
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Assistant Professor of Medicine  
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Emory University School of Medicine 
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Director, Diabetes and Endocrinology Section 
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Grady Health System 
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69 Jesse Hill Jr Dr. 
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Atlanta, Georgia 30303 
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USA 
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Cryovagotomy Trial 
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I. BACKGROUND/RATIONALE AND PURPOSE: 
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Obesity is a growing epidemic, currently affecting over 1/3 of the adult US population1 and is a 
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well-established risk factor for the development of diabetes and cardiovascular disease.2 Given 
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that the majority of patients with type 2 diabetes (T2D) are obese, weight loss is the cornerstone 
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of treatment, and has been shown to decrease risk of long term complications3, lead to 
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improvements in A1c and lipid levels4,5, as well as decreased need for medications and 
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improvements in quality of life6. Unfortunately, lifestyle intervention is often ineffective at 
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achieving long-term sustainable, clinically significant weight loss7. Bariatric surgery is a 
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successful intervention, leading to 20-30% weight loss with remission of diabetes in 30-65% of 
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patients 1-5 years post surgery8,9. However, this invasive procedure is associated with high rates 
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of short- and long-term complications, including need for reoperations, vitamin/mineral 
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deficiencies, anemia, and osteoporosis10-12. It is clear that the current management options for 
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obese patients, including lifestyle changes, medications and surgery, are suboptimal and 
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innovative strategies are necessary to optimize diabetes control and weight management.     
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Energy balance and glycemic control are mediated largely by the gut-brain axis, specifically the 
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vagus nerve. The vagus nerve can stimulate or inhibit food intake depending on nutritional 
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status. Vagal nerve signaling is disrupted in the setting of obesity and thought to contribute to 
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overeating behaviors13. Vagus nerve blockade has the potential to be a highly efficacious, 
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minimally invasive intervention to address current obesity treatment limitations. Clinical studies 
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evaluating the efficacy of an implantable electric vagus nerve blockade device found that 
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subjects lost on average 8.8% of total body weight at 1 year; patients with T2D experienced 
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improved glycemic control, with an average A1c improvement of 1.0% at 12 months14. 
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Unfortunately, nearly 40% of subjects experienced side effects related to the device15. A recent 
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pilot study from our group at Emory University (see preliminary results) reported weight loss 
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efficacy of a minimally invasive CT guided cryoablation of the vagus nerve in obese, non-
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diabetic subjects. Patients lost 5.6% of total body weight and 22.7% excess body weight at 6 
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months with no significant side effects16. We propose to evaluate the feasibility and efficacy of 
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this procedure through a randomized control trial in obese patients with T2D. We hypothesize 
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that those patients undergoing the cryoablation procedure will experience improvement in 
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glycemic control and enhanced weight loss at 6 months follow-up compared to the control group. 
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Impact of weight loss on diabetes control and complications: Over 12% of adults in the 
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United States are affected by type 2 diabetes (T2D), the majority (>90%) of whom are 
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overweight or obese. Weight loss, through lifestyle intervention, medications or bariatric 
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surgery, is recommended for all overweight/obese individuals with T2D. Patients who are able to 
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achieve >5% weight loss at 12 months experience improvement in HbA1c, total cholesterol, 
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LDL, HDL, triglycerides, systolic blood pressure and diastolic blood pressure7. Intensive 
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lifestyle interventions, glycemic control and weight loss have also been shown to decrease the 
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risk of development of chronic kidney disease17 and other microvascular diseases18. 
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Unfortunately, many studies have shown that long-term maintenance of weight loss is 
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tremendously difficult19,20. 
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Current weight management options: medication and bariatric surgery: Weight loss 
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medication and bariatric surgery are approved when adequate weight loss is not achieved with 
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lifestyle interventions alone. Medications lead to clinically significant weight loss of >5% in 
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approximately 50% of patients for whom they are prescribed, while the other half have 
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suboptimal weight response21. Furthermore, weight loss effects are durable only while patients 
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take the medications, with regain after cessation of drug therapy22. Bariatric surgery has proven 
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superior efficacy over lifestyle interventions with regards to weight management, diabetes 
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remission and reduction of comorbidities8,23. However, due to the invasive nature of surgery, 
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concerns about long-term complications, and limited patient access to accredited centers, 
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bariatric surgery is underutilized. Up to 5% of patients experience a surgical complication 
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following the procedure24, and rates of vitamin and mineral deficiency can reach >60%25. As 
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such, options for long-term effective weight loss are limited and alternative strategies are needed 
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to improve outcomes for obese patients. 
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Gut-brain axis is an important regulator of diet induced obesity: In a lean, healthy milieu, 
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intake of food triggers vagal nerve afferent neurons to relay information about gastric 
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distension26 and satiety hormones to the hindbrain27, which responds appropriately to decrease 
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food intake and stimulate the hedonic reward system28. In the setting of chronic overeating and 
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obesity, the release of satiety-inducing neuropeptides is decreased, while orexigenic signaling 
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(hunger promoting) is preserved29, which may contribute to further hyperphagia. This data has 
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been replicated in several animal models30-32 and provides a compelling argument that aberrant 
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vagal nerve signaling promotes weight gain. Neuromodulation of the vagus nerve, therefore, is 
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an attractive therapeutic intervention for obesity management.  
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Historical utilization of vagotomy: The rationale behind the procedure is rooted in historical 
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surgical treatments of duodenal ulcer disease, namely the evolution of selective and highly 
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selective surgical vagotomies33-35. Although these procedures have been largely supplanted by 
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the medical management of Helicobacter Pylori, their safety and ancillary value for the 
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management of obesity – and even subsequent heart disease and diabetes – have long been 
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investigated.36-41 of particular relevance to this proposal is the development and study of an 
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implanted vagal nerve stimulator for purposes of managing obesity, the Vbloc® device. 
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Investigators have shown that by modifying the afferent and efferent signaling pathways of the 
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distal vagal fibers, significant positive effects are manifested via weight loss, anthropometric 
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variables, cholesterol levels, blood glucose levels, quality of life, and blood pressure values.42 
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Said another way, subdiaphragmatic vagotomies have a long history in humans without 
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associated cardiac or sympathetic complications. 
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Vagus nerve blockade using an implantable device leads to weight loss and improvement in 
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glycemic control and blood pressure: A small, prospective, open label trial evaluated the 
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efficacy of an implantable electric vagus blocking device (VBLOC) on glycemic control and 
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blood pressure in obese subjects with T2D. Patients were implanted with VBLOC and followed 
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prospectively for 12 months. Excess weight loss at 12 months was 25± 4%, with improvement in 
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HbA1c from 7.8% ±0.2% at baseline to 6.8%. Decreases were also seen in fasting plasma 
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glucose values and blood pressure14. Other studies using the same device for weight management 
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have reported pain at the VBLOC site in nearly 40% of subjects 15 which may limit the 
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widespread applicability of this device despite promising efficacy data, and supports the notion 
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of cryovagotomy as an alternative approach. 
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Efficacy of CT guided cryoablation of the vagus nerve for weight loss: Pilot data from 
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investigators at Emory University has demonstrated the safety and feasibility of percutaneous CT 
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guided cryoablation of the posterior vagal trunk in patients with mild to moderate obesity (BMI 
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30-37 kg/m2). This small and uncontrolled study enrolled twenty subjects for a cryoablation of 
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the vagus nerve along the distal esophagus. This rapid, minimally invasive procedure was found 
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to be 100% technically successful. There were no procedure related complications or adverse 
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events during a 6 month follow up period. In an extension of this protocol, patients were brought 
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back after the 6 month study to be evaluated for gastroparesis. One subject was found to have 
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delayed gastric emptying on imaging but was asymptomatic clinically. It is unclear if this was 
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related to the study procedure since baseline gastric emptying studies were not performed. 
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Patients lost an average of 5.6% total body weight, with 22.7% excess BMI lost [delta BMI/ 
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(initial BMI-25)] over the 6-month monitoring period. Participants reported decreases in appetite 
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following the procedure at all time points, with 15.8% reporting “somewhat less appetite”, 
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68.4% reporting “much less appetite”, and 10.5% reporting “very much less appetite.”16  
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II. SIGNIFICANCE AND INNOVATION: 
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 Pilot data from investigators at Emory University has demonstrated the safety and feasibility of 
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percutaneous CT guided cryoablation of the posterior vagal trunk in patients with mild to 
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moderate obesity (BMI 30-40 kg/m2). This small and uncontrolled study enrolled ten subjects 
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for a cryoablation of the vagus nerve along the distal esophagus. This rapid, minimally invasive 
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procedure was found to be 100% technically successful. There were no procedure related 
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complications or adverse events during a 6 month follow up period. Patients lost an average of 
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5.6% total body weight, with 22.7% excess BMI lost [delta BMI/(initial BMI-25)] over the 3-
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month monitoring period. Participants reported decreases in appetite following the procedure at 
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all time points, with 15.8% reporting “somewhat less appetite”, 68.4% reporting “much less 
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appetite”, and 10.5% reporting “very much less appetite.”43  
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In addition to weight loss, we anticipate that the cryovagotomy procedure will result in 
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significant improvement in glycemic control and cardiovascular risk factors, which may result in 
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long-term benefit is reducing diabetic complications. We propose a prospective, randomized 
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controlled trial to determine if a minimally invasive cryoablation procedure of the vagus nerve 
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will lead to greater weight loss and improvements in glycemic control, metabolic profile, and 
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cardiovascular risk factors compared to lifestyle intervention in obese patients with T2D. Our 
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data will provide preliminary data to support application for an NIH grant to further investigate 
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manipulation of the gut-brain axis for management of type 2 diabetes and obesity. 
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III. DESCRIPTION OF STUDY PROTOCOL 
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A. SPECIFIC OBJECTIVES: 
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Cryovagotomy Trial 
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Objective 1. To compare glycemic control of patients undergoing vagus nerve cryoablation 
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plus lifestyle intervention at 6 and 12 months compared to lifestyle intervention alone in 
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obese patients with T2D. Patients with T2D, BMI 30-40 kg/m2, A1c 7.5-10.5% on stable doses 
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of oral antidiabetic agents will be randomized to cryoablation plus lifestyle or lifestyle 
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intervention alone and will be followed prospectively for 12 months in a controlled randomized 
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trial. We will compare changes in A1c levels between groups at 3, 6 and 12-months of follow up.  
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Objective 2. To determine changes in weight and anthropometric metrics among patients 
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receiving cryoablation plus lifestyle intervention versus lifestyle intervention only. Changes 
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in body weight, BMI, waist circumference, and BIA measured at baseline, 3 and 6 months after 
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intervention will be assessed.  
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Objective 3. To determine safety of the cryoablation of the vagus nerve. We will monitor 
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rates of AEs and SAEs related to the procedure which develop during the duration of the trial.  
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B. ENDPOINTS: 
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The primary endpoint of the trial is difference in glycemic control, defined as A1c, fasting 
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glucose and insulin sensitivity (HOMA-IR), at 3, 6 and 12 months between the vagus nerve 
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cryoablation group and the lifestyle intervention monotherapy group. 
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The primary safety endpoint of the trial is occurrence of death and all procedure related 
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complications, such as bleeding, infection, pneumothorax, hemothorax, pulmonary injury, 
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complications of sedation, pain requiring hospital admission or treatment, dysphagia, 
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gastroparesis, nausea and vomiting, and gastrointestinal ulceration for the duration of the study.  
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Secondary outcomes include differences between treatment groups in any of the following 
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measures:  
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1. Body mass index (BMI), waist circumference, and waist-to-hip ratio at 3 and 6 months     
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compared to baseline 
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2. 
Lipids (total cholesterol, LDL, triglycerides) at 6 months compared to baseline 
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3. 
Systolic and diastolic blood pressure at 3 and 6 months compared to baseline 
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4. 
Daily caloric intake as measured by 3-day food recall compared to baseline at 3 and 6 
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months. 
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5. 
Changes in antihyperglycemic medication regimen compared to baseline at 3 and 6 
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months. 
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6. 
Appetite, hunger and satiety scoring by visual analog scale at baseline, 1 week, 1 month, 
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3 months and 6 months 
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7. 
Physical activity questionnaire (IPAQ) at baseline, 3 and 6 months  
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8. 
Fasting glucose and insulin levels at 3 and 6 months compared to baseline 
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C. STUDY DESIGN: 
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This is a randomized, controlled, unblinded clinical study in obese adult patients with T2D, 
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HbA1c 7.5-10.5%, BMI 30-40 kg/m2 treated with non-insulin antidiabetic medications with 
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February 22. 2021 
 
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stable doses for at least 3 months. 
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Subjects will be pre-screened with the relevant questions from the Three Factor Food 
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Questionnaire by phone or in person to determine eligibility prior to consent. Following consent 
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and screening for trial eligibility, subjects will be randomized to treatment group. The primary 
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endpoint, glycemic control, will be assessed at 6 months post-procedure. Patients will be 
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recruited from the diabetes clinic at Grady Memorial Hospital and Emory University Clinics. 
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We will be screen up to 40 participants to be able to randomized 30 patients, they will be 
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enrolled in this pilot exploratory study. Patients will be randomly allocated to undergo either CT 
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guided cryoablation of the vagus nerve plus lifestyle intervention or lifestyle intervention alone.   
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Group 1: CT guided cryoablation of the vagus nerve plus lifestyle intervention (n=15).   
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Group 2: Lifestyle intervention by trained RD/CDE (n=15).  
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All subjects will have the procedure performed at Grady Memorial Hospital or Emory University 
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Hospital Midtown or Johns Creek by trained study personnel.  
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The study schema is shown below. Both groups will undergo screening for eligibility followed 
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by randomization. If the subject is not fasting at time of initial consent and screening, he/she will 
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be brought back for a subsequent visit with fasting blood work. Subjects must be randomized 
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within 4 weeks of the screening visit. If the randomization visit falls outside of the 4 week time 
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frame, the subject must undergo repeat screening procedures. In- person lifestyle counseling will 
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be provided at baseline visit for both groups. Those undergoing cryoablation will receive a phone 
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call 24 hour post-procedure to evaluate for any immediate complications, 1 week in person 
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follow up visit, as well as a safety call at 2 months. Subjects in both groups will have weekly 
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contact with RD and in person follow up visits at 4 weeks, 3 months, and 6 months. Blood work, 
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anthropometric data and questionnaires will be administered at baseline, 3 months, and 6 months. 
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Safety follow up appointments will be scheduled at 9 months and 12 months, though no further 
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lifestyle counseling will be provided after 6 months. Questioning regarding adverse events and 
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side effects will occur at all visits, as well as assessment of glycemic control. Anti-
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hyperglycemic medications will be adjusted at visits under the direction of the endocrinologist, 
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or as needed for clinically significant hypo- or hyperglycemic events.  
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Blood work will be as follows: For all lab parameters, subject results must be within the 
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reference range unless otherwise specified by inclusion/exclusion criteria or if assessed by study 
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physician to be not clinically significant.  
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Lab test 
Baseline 
3 months 
6 months 
9 months 
12 months 
Complete 
metabolic 
panel 
X 
X 
X 
X 
X 
Pregnancy test 
X 
X 
X 
X 
 
HbA1c 
X 
X 
X 
X 
X 
Lipid panel 
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X 
 
 
Insulin level 
X 
X 
X 
 
X 
TSH 
X 
 
 
 
 
 
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D. STUDY PROCEDURE: 
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Cryoablation procedure (to be performed by Dr. Prologo or Dr. Dariushnia): Subjects will 
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be NPO for 12 hours prior to the ablation procedure. Metformin and sulfonylureas will be held 
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the evening prior to the procedure. Subjects will present to the Interventional Radiology pre-
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procedure holding area at 8:00 AM on the morning of the procedure and will have a peripheral 
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IV placed by nursing staff. Point of care blood glucose level will be checked; the procedure will 
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be deferred for BG >250 mg/dl until diabetes control can be better optimized. Low doses of 
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sedation will be used with IV versed and fentanyl. An Interventional Radiology nurse will 
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monitor the subject while sedation is being administered. Skin will be numbed using lidocaine. 
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The procedure will be done under CT guidance and involves a 4-5 mm scalpel incision followed 
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by percutaneous probe placement about the posterior gastroesophageal junction (the location of 
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the posterior vagal trunk). The probe will create a zone of decreased temperature (-20 to -40oC) 
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involving the posterior vagal nerve fibers/plexus. The cryoablation process will include a 3-
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minute freeze, followed by a 1-minute thaw, and a second 3-minute freeze and 1 minute thaw. 
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After the procedure, a sterile dressing will be applied, and subjects will be monitored for 12 
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hours. 
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Lifestyle Intervention: All subjects will receive standardized dietary and exercise counseling 
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from a registered dietitian and exercise physiologist (Dr. Frediani). Participants will be counseled 
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to follow a low carbohydrate diet providing a moderate amount of carbohydrates per day (~100 
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g). Focus will be on increasing fruits and vegetables and decreasing refined sugars and processed 
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foods. Dietary counseling will include motivational interviewing, goal setting and nutrition 
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education.44 Subjects will also be encouraged to slowly increase physical activity to at least 150 
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minutes weekly. The lifestyle intervention structure will include detailed counseling sessions at 
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baseline, 3 and 6 months. These sessions ideally will occur face-to-face, although telemedicine 
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visit (via zoom) will be permitted on case-by-case basis due to the COVID-19 pandemic. In 
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addition, there will be weekly phone calls or texts (participants’ choice) providing a total of 26 
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points of contact recommended by the USPSTF (United States Preventive Services Task 
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Force).45  
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Surveys: Subjects will complete a number of surveys as part of participation in the trial. at 
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baseline, 3 months, 6 months and 12 months. Three-day food records are a validated method of 
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assess food intake46 and will be administered at baseline, 3 months, 6 months and 12 
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months.Subjects will also complete visual analogue scale ratings of appetite at baseline, 1 week, 
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1 month, 3 month, 6 month and 12 month.47 The International Physical Activity Questionnaires 
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(IPAQ) is to provide a set of well-developed instruments that can be used internationally to 
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obtain comparable estimates of physical activity.48 Subjects will also complete the relevant 
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questions from the Three Factor Eating questionnaire during pre-screening and must have an 
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average score ≥3 on questions 4, 8, 9, 13, and 14 to be eligible. The entire questionnaire will be 
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administered after subjects have been consented. The Three Factor Eating Questionnaire is a 
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self-assessment scale used in studies of eating behavior in overweight and normal individuals, 
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designed to assess cognitive restraint, disinhibition, and hunger.49 Preliminary investigation of 
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this cryovagotomy procedure has identified subjects who score ≥3 on the aforementioned 
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questions to be those who respond best to the intervention.16 
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Blinding. The trial design is an unblinded, randomized control trial. By nature of the study 
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design, participants and study personnel must be aware of which arm participants are enrolled. 
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E. POTENTIAL RISKS AND BENEFITS: 
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Risk to Human Subjects: Specific to this procedure, a 20 subject pilot was recently completed 
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that demonstrated no procedure related complications or adverse events during 6 months of 
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follow up. During the 12 month extension, 1/20 patients was found to have a prolonged gastric 
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emptying time, though it is unclear if this was related to the study procedures as no baseline 
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measurements were performed and the subject was asymptomatic. The Visual–Ice Cryoablation 
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System is intended for cryoablative tissue destruction using a minimally invasive procedure. As 
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described in the Icesphere 1.5 Needle user manual on page 14, there are no known adverse 
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events related to the specific use of the cryoablation needles50. The procedure is CT guided 
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which allows for real-time visualization of the process to ensure efficacy and avoid damage to 
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any adjacent tissue or structures. Percutaneous CT-guided cryoneurolysis is well established and 
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routinely performed clinically. Specifically, Dr. Prologo’s group has conducted three other 
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independent studies of peripheral nerve cryoablation, with procedural methods and outcome 
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measures that parallel the methods described herein51-53. Perhaps more importantly though, 
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the device is routinely used in clinical practice for the ablation of nerves as part of 
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percutaneous procedures that are very similar to the percutaneous cryovagotomy proposed 
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for this study, including cryoablation for treatment of trigeminal neuralgia in the setting of 
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cancer54,  celiac plexus cryoablation,55 as well as obturator nerve cryoablation, genitofemoral 
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nerve cryoablation, cryoablation of medial branch nerves in the setting of facetogenic lumbar 
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spine pain, and cryoablation of the inferior alveolar nerve. 
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Regarding the mechanism of cryoneurolysis, the premise upon which nerve cryoablation 
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procedures have been founded is the induction of a specific, reversible nerve injury.56-58 Nerve 
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injury classifications are classically described and correlated with clinical course following 
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trauma (crush, stretch, laceration, etc.), the most widely cited of which are the Seddon and 
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Sunderland classifications.59,60  it has been shown that temperatures induced by cryoablation 
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devices correspond with Sunderland 2 injuries in peripheral nerves.56,57 This precise neural injury 
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results in several well described events that lead to favorable clinical outcomes – cessation of 
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conduction, induced Wallerian degeneration, and predictable regeneration of axons upon an 
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intact connective tissue scaffold. 57,58,61 the translation of these events (beyond conduction 
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cessation) has been documented as nerve function recovery in animal studies and in humans62-65. 
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62-66 
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Please see below with more details on the identified potential risks of procedures performed 
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percutaneously in interventional radiology: 
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1.  Bleeding: The risk of bleeding is estimated to be <2%, and is specifically localized to 
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the site of the skin incision (4-5 mm). The risk of any internal bleeding is negligible since 
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it is a CT guided procedure and direct visualization of the probe during the procedure 
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limits any inadvertent involvement of vascular structures. After the procedure, patients 
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will have a sterile bandage placed on the incision and will be monitored for 12 hours. 
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2. Pneumothorax: Estimated risk is <1%. We feel that the risk of pneumothorax is non-
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significant given that this is a CT guided procedure, which will minimize any off target 
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risk. Should any complications arise, this will be visualized in real time on the CT scan 
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and immediate treatment will be provided. 
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3. Sedation associated risks: <0.5% risk. Conscious sedation using fentanyl and versed 
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will be used at standard procedural doses. Should any excess sedation occur, this will be 
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reversed immediately in the procedural suite. 
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4. Off target ablation: This refers to any inadvertent ablation of other nerves, estimated to 
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be <1.0% risk. This would be seen in real-time on CT guidance, and ablation could be 
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halted immediately to prevent complete nerve resection. 
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Protection against risks: Our strict inclusion and exclusion criteria for entry will help to 
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minimize risks. In addition, we will carefully monitor patients with a phone call 24 hours, and 2 
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months after the procedure, and a clinic visit at 1 week, 1 month, 3 months, 6 and 12 months. 
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Subjects will be monitored for specific procedure related complications or adverse events at each 
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visit. Subjects will also be provided with contact information for study personnel should any 
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events occur in between visits. Unscheduled events can be arranged to assess any urgent matters. 
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All AEs, regardless of whether or not they are related to the procedure and use of the device, will 
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be documented and reported to the IRB, DSMB, and FDA in a timeline as specified by the FDA 
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Code of Federal Regulations Title 21, section 812.150 reporting (21CFR812.150(b)).Outcomes 
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regarding hypo- and hyper- glycemia will also be collected and reported for safety monitoring. 
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Subjects with poorly controlled diabetes (A1c >10.5%) or a history of DKA will be excluded 
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from enrollment. Subjects will be educated on the potential for development of hypoglycemia. 
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Diabetic medications will be adjusted in event of hypoglycemia/hyperglycemia under the 
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direction of Dr. Alexandra Migdal (Endocrinologist). Self-monitoring of blood glucose (BG) 
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levels will be recommended twice daily and any time symptoms of hypo/hyperglycemia occur. 
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In the setting of hyperglycemia (average BG >250 mg/dl x 1 week), medication doses will be 
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adjusted. Subjects on metformin will have the dose titrated to a maximum of 2000 mg/d if 
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tolerated. Sulfonylureas can be titrated to maximal doses per manufacturer instruction. Subjects 
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may be prescribed rescue therapy with insulin in the event of significant hyperglycemia 
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unresponsive to titration of oral agents.  In the setting of BG <100 mg/dl, sulfonylurea doses will 
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be decreased by 50% and discontinued if necessary. If BG <55 mg/dl, sulfonylureas will be 
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stopped. Metformin will be stopped if hypoglycemia persists. 
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Technical success rate of the procedure and procedure related complications: 
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Discontinuation of the trial will occur if 3 participants within the first 8 of 30 planned experience 
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significant adverse events (AEs) (Grade 3 procedure-related AE or procedure-related serious 
366 
AE) at any point during follow-up and if 4 participants experience significant AEs (Grade 3 
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procedure-related serious AE) at any time. The trial will be stopped at any point if a Grade 4 or 
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Grade 5 AE occurs until determination can be made regarding its potential relationship to study 
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involvement.  
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Grading of AEs: 
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Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
of prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE67 
 
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Specific clinical signs or symptoms that will qualify for the above criterial include (amongst 
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other potential Grade 3-5 AEs not listed here): constitutional symptoms (severe fatigue 
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interfering with ADLs, fever > 40°C, prolonged and/or severe rigors), endocrine (uncontrolled 
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hyperglycemia, ketoacidosis), gastrointestinal (inadequate caloric intake requiring TPN or IV 
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fluids, diarrhea requiring IV fluids and/or manifesting as >7 stools/day, symptomatic abdominal 
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distention or bloating, severe abdominal pain requiring narcotics, ileus, severe nausea requiring 
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hospitalization, bowel obstruction or perforation), hemorrhage requiring intervention, infection 
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requiring antibiotics, or pain interfering with ADLs.   
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Withdrawal Criteria: The subject may withdraw at any time during the study by the primary 
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care provider or his/her own decision. 
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The subject may be withdrawn at the investigator’s discretion due to a safety concern or for 
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contravention to the inclusion and/or exclusion criteria. Any subjects experiencing a Grade 3-5 
388 
AE as described will be withdrawn from the study. Reasons for study withdrawal will be tracked 
389 
and documented. 
390 
 
391 
If a subject is withdrawn prior to completion of the 12 month study period, the subject will be 
392 
encouraged to keep follow up appointments with the study team for monitoring of adverse events 
393 
or until resolution of any adverse events related to the procedure.  
394 
Data Safety Monitoring: In addition, an independent data safety monitoring committee 
395 
(DSMC) will be established to serve as the primary data and safety monitoring group for the 
396 
trial. The DSMC will review unblinded interim safety data, evaluate whether the study should be 
397 
stopped or amended for safety or other reasons, and make such recommendations to the 
398 
investigators. In addition, the DSMC will provide input to the investigators concerning the study 
399 
protocol, statistical analysis plan, administrative conduct of the trial, and interpretation of the 
400 
final safety and efficacy data. The DSMC will meet every 6 months, and as needed in the event 
401 
of an unanticipated adverse device effect. At each meeting, the DSMC will review the incidence 
402 
of adverse events, severity of each, statistical considerations, and safety concerns (including 
403 
information on hypo- or hyper-glycemia)– as well as conduct of the trial and accrual goals.  
404 
f. Potential benefits to the subject. We believe that subjects receiving the interventional 
405 
treatment will benefit from modest weight loss and improvement in glycemic control. Subjects 
406 
who receive the lifestyle counseling are expected to achieve modest weight loss as well. 
407 
Furthermore, enrollment in clinical research studies and enhanced focus on glucose monitoring 
408 
has been shown to reduce complications associated with hyperglycemia.   
409 
 
410 
F. STUDY SUBJECT SELECTION: 
411 
Inclusion criteria:  
412 
1. Males and females between the ages of 22-65 
413 
2. Diagnosis of T2DM for <10 years 
414 
3. HbA1c between ≥7.5% and ≤10.5% 
415 
4. Treatment with non-insulin antidiabetic medications with stable doses for at least 3 
416 
months, with failed prior attempts at dietary interventions to optimize diabetes control 
417 
5. BMI 30-40 kg/m2 
418 

Cryovagotomy Trial 
February 22. 2021 
 
12
6. Willing to comply with study requirements 
419 
7. Documented negative pregnancy test in women of child bearing potential and use of an 
420 
effective birth control method 
421 
8. Average score of ≥3 on questions 4, 8, 9, 13, and14 from the Three Factor Eating 
422 
Questionnaire, to be assess prior to consent via phone screen or in person.  
423 
 
424 
Exclusion criteria:  
425 
1. Diagnosis of type 1 diabetes or history of diabetic ketoacidosis 
426 
2. Use of insulin therapy 
427 
3. Significant kidney disease (eGFR < 60 ml/min/1.73m2) 
428 
4. Current drug or alcohol addiction 
429 
5. Thyroid disease unless underlying diagnosis is primary hypothyroidism on stable 
430 
medications for >3 months with TSH in reference range at time of screening visit 
431 
6. Systemic steroid use within 30 days prior to randomization 
432 
7. Use of prescription or over the counter weight loss medications within 6 months prior to 
433 
randomization 
434 
8. Weight gain/loss >5% over the past 6 months 
435 
9. Previous GI surgery or abnormal GI anatomy which may limit technical feasibility of the 
436 
procedure 
437 
10. Recent diagnosis of cardiovascular disease requiring PCI or CABG within the past 6 
438 
months 
439 
11. Abnormal pathologies or conditions of the GI tract, including peptic ulcers, hiatal hernia, 
440 
active gallbladder disease, pancreatitis, cirrhosis, inflammatory bowel disease, upper GI 
441 
bleed within 6 months of randomization 
442 
12. Any condition or major illness that places the subject at undue risk by participating in the 
443 
study 
444 
13. Psychiatric condition rendering the subject unable to understand the possible 
445 
consequences of the study 
446 
14. Inability to provide informed consent 
447 
15. Female subjects who have been pregnant within 6 months or breast-feeding at time of 
448 
enrollment into the study, or women who plan to become pregnant within the next 12 
449 
months  
450 
16. Diagnosis of anemia, RBC transfusion in the preceding 3 months or expectation to 
451 
receive transfusion within the next 12 months, or hemaglobinopathies that would affect 
452 
HbA1c reliability  
453 
17. Active or recent infection 
454 
18. Immunosupression 
455 
19. History of coagulopathy or high risk for development of deep vein thrombosis (including 
456 
congestive heart failure, those who are non-ambulatory, active leukemia/lymphoma, prior 
457 
thrombotic events, family history of thrombosis) 
458 
20. History of blood pressure instability (systolic BP ≤100 or ≥160 mmHg) 
459 
21. History of autonomic dysfunction, including amyloidosis, Parkinson’s disease, 
460 
autoimmune disease, spinal cord injury 
461 
 
462 
G. STATISTICAL CONSIDERATIONS: 
463 

Cryovagotomy Trial 
February 22. 2021 
 
13
The primary outcome is the difference in glycemic control (as measured by HbA1c) at 6 and 12 
464 
months between the vagus nerve cryoablation group and the lifestyle intervention group. 
465 
Summary statistics including mean, median, and standard deviations for the changes in HbA1c  
466 
at 3, 6, 9 and 12 months will be computed. We will then compare the changes at 6 months 
467 
between the two treatment groups by a nonparametric Wilcoxon test or a two-sample t-tests 
468 
(with appropriate data transformation if needed).  We will conduct one-way ANOVA to estimate 
469 
the mean difference in glycemic parameters at 6 and 12 months month between the two 
470 
treatment groups. We may further adjust for some important confounders by using linear 
471 
regression models. We will also assess the glycemic control outcomes simultaneously across 
472 
different follow-up visits (i.e.  12, 24 weeks) through repeated measures ANOVA models, which 
473 
appropriately account for within-subject correlations in the measurements. In addition, we will 
474 
consider repeated measures linear regression model with visits incorporated as a continuous time 
475 
variable. We may include other covariates in the model when feasible.  
476 
The primary safety endpoint of the trial is the occurrence of death and all procedure related 
477 
complications, such as bleeding, infection, pneumothorax, hemothorax, pulmonary injury, 
478 
complications of sedation, pain requiring hospital admission or treatment, dysphagia, 
479 
gastroparesis, nausea and vomiting, and gastrointestinal ulceration for the duration of the study. 
480 
We will first use the Chi-square test (or Fisher’s exact test) to compare the occurrence of this 
481 
primary safety endpoint between the two treatment groups. We will perform logistic regression 
482 
to evaluate the group difference while adjusting for other potential confounders such as age, 
483 
gender, and BMI. In addition, we will compare the number of procedure related complications 
484 
by using Poisson regression or Negative Binomial regression between the two treatment groups. 
485 
Standard model selection (e.g. forward, backward variable selection) and model checking 
486 
procedures (e.g. deviance residual plot and Hosmer- Lemeshow test) will be performed to ensure 
487 
the adequacy of the final models. 
488 
 
489 
Secondary outcomes will be compared between the two treatment groups. For continuous 
490 
secondary outcomes, we will follow the plan proposed for primary outcome. For discrete 
491 
secondary outcomes, we will first conduct cross-sectional comparisons based on Chi-squared 
492 
tests or Fisher’s exact test.  If the discrete outcome is measured at multiple visits, we will fit 
493 
repeated measures generalized linear models to simultaneously assess the difference in the 
494 
longitudinal discrete outcome between the two treatment groups. Other covariates may be 
495 
included in the models if feasible. 
496 
 
497 
Sample Size Calculation and Power Analysis:  
498 
This study is generating pilot data for utilization of this procedure in a novel patient population. 
499 
Given the 15 patients per group, taking into account 20% attrition rate, we would have 12 
500 
patients per group. In this case, we would have 80% power to detect a difference in glycemic 
501 
control outcome change that equals 1.2 times the standard deviation of the glycemic control 
502 
outcome change. The data generated from this study will provide useful relevant preliminary 
503 
data for planning larger randomized studies.  
504 
 
505 
 
506 
IV. DATA HANDLING AND RECORD KEEPING: 
507 

Cryovagotomy Trial 
February 22. 2021 
 
14
Data collection records with personal identifiers will be stored in locked file cabinets.  Blood 
508 
samples drawn in conjunction with this study will not be labeled with information that could 
509 
directly identify study subjects.  De-identified serum samples will be stored.  We may use the 
510 
samples collected and stored in this study for future studies without a separate IRB consent for 
511 
the subjects. This will be explained to the study subjects at the time of consent. If we use the 
512 
samples in future studies, coded identifiers will be used. The informed consent will make it clear 
513 
that subjects can request their samples to be destroyed at any time. Presentation of the study 
514 
results at regional or scientific meetings or in publications will not identify subjects.  Access to 
515 
research and confidential records will be limited to clinical investigators, research coordinators, 
516 
and the IRB at Emory University.  
517 
 
518 
Study coordinators and/or investigators will collect baseline and follow up data, complete the 
519 
CRF (case report form) and enter data into RedCap (electronic database provided by the Emory 
520 
Research Information Technology Department). Baseline data will include demographics 
521 
(gender, age, ethnicity), duration of diabetes, comorbid conditions, medications, BMI, screening 
522 
labs, QOL assessment scores, appetite score, three-day food records analyzed using Nutrition 
523 
Database System for Research (NDSR) and physical activity questionnaire (IPAQ).48 Follow up 
524 
data will include medications, BMI, body measurements, follow-up labs, QOL assessment 
525 
scores, appetite score, three-day food record, IPAQ, and adverse events.  
526 
 
527 
 
528 
V. ETHICS: 
529 
A. INFORMED CONSENT 
 
530 
After identification of eligible patients these individuals will be provided basic information 
531 
regarding the study and, if interested, a member of the research staff using inclusion/exclusion 
532 
criteria delineated elsewhere in the protocol will then screen patients.  Informed consent will be 
533 
obtained before any trial related procedures including screening procedures. The consent form, 
534 
potential risks and benefits, and the rights of research participants will be explained to the 
535 
participant by the investigators or research coordinator.  Individuals will be asked if they have 
536 
questions, and a member of the research staff will answer questions.  The principal investigator 
537 
(PI) will also be available at all times to answer questions that participants may have during the 
538 
consent procedure or during the time a participant is enrolled in the study.  The consent form will 
539 
be completed only by trained research personnel familiar with the study protocol procedures, 
540 
informed consent process, who have undergone CITI training in accordance with the IRB 
541 
guidelines of Emory University.  A signed copy of the consent form will be provided to the 
542 
participant and a copy will be placed in the file that is maintained for each participant in the 
543 
study office. Adults who speak any of the following languages (English, Spanish) will be 
544 
approached for participation in the study.   
545 
 
546 
 
547 
B. RECRUITMENT AND RANDOMIZATION 
548 
Subjects will be recruited from the Diabetes Clinic at Grady Memorial Hospital and Emory 
549 
Healthcare clinics. Patients with diabetes will be identified electronically. Once a potential 
550 
candidate is identified, we will approach the primary clinician as well as the patient for consent.  
551 

Cryovagotomy Trial 
February 22. 2021 
 
15
 
552 
Patients will be randomized consecutively using a computer-generated randomization table 
553 
provided by Dr. Limin Peng at the Emory School of Public Health.  
554 
 
555 
 
556 
VI. LIABILITY AND SUBJECT INSURANCE: 
557 
A. FINANCIAL OBLIGATION 
 
558 
No additional cost to patients or to the institution will be incurred for research purposes. Patients 
559 
will not be billed for the laboratory work or any test that is being done only for study purposes.  
560 
Patients will be responsible for the cost of their usual ongoing medical care, including 
561 
procedures and/or non-study medications that their doctor requires as part of their usual medical 
562 
care. 
563 
 
564 
B. PAYMENT FOR PARTICIPATION 
    
565 
Participation in this study is voluntary.  Patients will receive $25 for the screening visit, $75 for 
566 
the enrollment visit, $30 for the 1 month, 3 month, 6 month, 9 month and 12 month visit to 
567 
compensate for time and effort. Total compensation will be two hundred and fifty dollars 
568 
($250.00). 
569 
 
570 
C. RESEARCH INJURIES 
 
571 
If a patient is injured because of taking part in this study, Dr. Migdal and investigators at each 
572 
institution, along with the medical facilities will make medical care available.  Emory University, 
573 
however, has not set aside any money to pay participants or to pay for their medical treatment. 
574 
The only exception is if it is proved that the injury or illness is directly caused by the negligence 
575 
of an Emory/Grady employee.  “Negligence” is the failure to follow a standard duty of care. 
576 
Financial compensation for such things as lost wages, disability or discomfort due to an injury 
577 
related to the study is not available.   
578 
 
579 
 
580 
VII. 
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581 
 
582 
1. 
Ogden CL CM, Fryar CD, Flegal KM.  . Prevalence of obesity among adults and youth: 
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United States, 2011–2014. NCHS data brief, no 219. Hyattsville, MD: National Center 
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2. 
Centers for Disease Control and Prevention. National Diabetes Statistics Report A, GA: 
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Baum A, Scarpa J, Bruzelius E, Tamler R, Basu S, Faghmous J. Targeting weight loss 
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644 
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646 
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647 
24. 
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649 
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gastrointestinal function. Auton Neurosci. 2011;161(1-2):6-13. 
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30. 
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37. 
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severance and decreased risk of subsequent type 2 diabetes in peptic ulcer patients: An 
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38. 
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Improvements in Obesity, Cardiovascular Risk Factors, and Glycemic Control in Patients 
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with Type 2 Diabetes Mellitus: 2-Year Results of the VBLOC DM2 Study. Obes Surg. 
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39. 
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loss improved by vagotomy. World J Surg. 1993;17(1):75-78; discussion 79. 
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42. 
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746 
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