Enterra® Therapy Overview

Defining Gastroparesis Enterra® Therapy Defining Gastroparesis

Anatomical Overview

What is Gastroparesis? A symptomatic chronic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction A stomach disorder in which food is digested more slowly than normal. In a healthy digestive system, strong muscular contractions move food from the stomach through the digestive tract. With gastroparesis, stomach muscles work poorly (or not at all), thus preventing the stomach from emptying properly. Steve: Needs to have the Parkman reference added

Symptoms Most patients present with upper-gastrointestinal symptoms or with symptoms related to disordered gastric motor function. These include: Nausea and vomiting Abdominal bloating Abdominal pain Feelings of fullness after only a few bites of food (early satiety) Heartburn or gastroesophageal reflux disease (GERD) Changes in blood sugar levels Lack of appetite Excessive weight loss Steve: Needs to have the Parkman reference added

Prevalence The true prevalence of gastroparesis is not known; however, it has been estimated that up to 5 million persons in the US may suffer from this condition.* In a survey patients with documented chronic gastroparesis patients, it was found that the origins were about 36 percent idiopathic and 29 percent diabetic, with the remaining amount attributed to several other causes.** * Abell T, et al.. Nutrition in Clinical Practice 2006. ** Soykan I, et al.Dig Dis Sci. 1998.

Enterra® Therapy Etiologies of Gastroparesis (Disease States)

Etiologies In a study of 146 patients, the most common origins were: Idiopathic (35%) Diabetic (29%) Postsurgical (13%) Others: Parkinson’s disease, vascular disease, pseudo-obstruction Soykan I et al. Dig Dis Sci 1998.

Idiopathic Gastroparesis Delayed gastric emptying without apparent cause or underlying abnormality may be the most common form of gastroparesis Symptoms fluctuate: patient may have episodes of pronounced symptoms interspersed with relatively symptom-free intervals Patients are frequently young or middle-aged women Kendall, McCallum. Gastroenterology 1993. Parkman et al. Gastroenterology 2004.

Idiopathic Gastroparesis Symptoms may resolve after months or even years Patients with a viral trigger tend to have slow resolution of their symptoms over several years Patients without a viral trigger tend to show less improvement over time Parkman et al. Gastroenterology 2004.

Idiopathic Gastroparesis In a study of 146 patients, 52 patients had idiopathic gastroparesis: 23% had sudden onset of symptoms after viral syndrome, suggesting a potential viral etiology 48% had severe abdominal pain 19% had gastroesophageal reflux disease and non-ulcerative dyspepsia 23% had depression 8% had onset post-cholecystectomy Soykan I et al. Dig Dis Sci 1998,

Diabetic Gastroparesis Gastroparesis is a recognized complication of diabetes mellitus Primarily among patients with long-standing type 1 diabetes and other associated complications Gastroparesis affects: 40-50% of people with Type 1 diabetes 30-40% of people with Type 2 diabetes Parkman. Gastroenterology 2004. Diabetes Institute Foundation Website. 2005

Diabetic Gastroparesis Likely to result from impaired neural control of gastric motility, possibly at the level of the vagus nerve Problems with blood glucose control may be the first indication that a diabetic patient is developing gastroparesis Gastroparesis contributes to poor glycemic control because of unpredictable delivery of food into the duodenum Delayed gastric emptying with continued insulin administration may produce hypoglycemia Parkman. Gastroenterology 2004.

Post-surgical* Gastroparesis Any surgery of the upper intestinal tract (esophagus, stomach or duodenum) may result in injury to the vagus nerve** Gastroparesis may occur as a complication of a variety of surgical procedures*** Post-vagotomy - Most often peptic ulcer surgery with vagotomy Post-fundoplication - Complication of fundoplication to treat GERD Post-bariatric - Most commonly Roux-en-Y gastric bypass for obesity Post lung and heart-lung transplantation * Use of gastric electrical stimulation for post-surgical gastroparesis is not an approved indication for Enterra® Therapy. **American College of Gastroenterolgy Website. 2005 ***Parkman et al. Gastroenterology 2004.

Enterra® Therapy Diagnosing Gastroparesis

Scintigraphy is the gold standard Diagnosis History and physical examination to assess: Underlying medical condition Duration, severity and frequency of symptoms Assessment for obstruction (X-ray, endoscope) Nuclear medicine study – 4 hour scinotography (gastric emptying test) Scintigraphy is the gold standard Parkman et al. Gastroenterology 2004. Tougas ???

Enterra® Therapy Gastroparesis Treatment Continuum

Treatment Principles Considerations in developing patient treatment plan Reduce symptoms Correct fluid, electrolyte and nutritional deficiencies Glycemic control for diabetic patients Identify and rectify underlying cause, if possible Parkman et al. Gastroenterology 2004

Traditional Management Treatment Continuum Least invasive Most invasive Diet modification Drug therapies Enteral feeding / TPN Surgical procedures Total parental nutrition Enterra Therapy Kendall, McCallum. Gastroenterology 1993.

Diet Modification Oral diet modifications should include adjustments in composition, consistency, size, and frequency of meals Patients should be prescribed meals which are low in fat and fiber, in order to Promote gastric motility Reduce symptoms of nausea, vomiting and abdominal pain If solid foods are not tolerated, a liquid diet can be tried, supplemented with vitamins and minerals Koch. Practical Gastroenterol 1997. Karras, Pfeifer. Curr Ther Endocrinol Ther 1997.

Drug Therapy The commonly used pharmacotherapy for gastroparesis has been a combination of prokinetic agents and antiemetics, such as Metoclopramide Erythromycin Cisapride (no longer on the market) Domperidone (not currently available in US) Side effects are common with both prokinetics and antiemetics Drug therapy options are limited

Drug Therapy Antiemetic agents for nausea and vomiting Phenothiazines commonly prescribed Serotonin receptor antagonists Side effects common, including sedation and extrapyramidal effects Antiemetic drugs act on peripheral and central neural structures Parkman et al. Gastroenterology 2004.

Drug Therapy Prokinetic agents to increase GI motility Metoclopramide: side effects may restrict use in up to 30% of patients Erythromycin: side effects (nausea, vomiting) may mimic those of gastroparesis Cisapride: only available under compassionate use/limited access programs due to link with cardiac arrhythmias and sudden death Prokinetic medications enhance gut contractility and promote the aboral movement of luminal contents. In the stomach, prokinetic agents increase antral contractility, correct gastric dysrhythmias, and improve antroduodenal coordination.

Options for Drug-Refractory Patients Gastrostomy tube For venting or suctioning the stomach Jejunostomy tube Feeding tube inserted into the small intestine Complications include infection, tube dysfunction, and tube dislodgement. Parkman et al. Gastroenterology 2004.

Options for Drug-Refractory Patients Surgical procedures Gastrectomy: Lower stomach is stapled or surgically removed; upper stomach is reattached to small intestine Pyloroplasty: Widening of opening to small intestine Gastrojejunostomy: Creating a passage between stomach and small intestine Roux-en-Y diversion: Gastric bypass Parkman et al. Gastroenterology 2004.

Options for Drug-Refractory Patients Total parenteral nutrition (TPN) Intravenous delivery of nutrition Often utilized as an end-stage option when nutrition is severely compromised and weight loss extensive Should be temporary due to complication risk The cost of TPN is at least ten times greater than enteral feeding, with some patients consuming over $200,000 annually in healthcare costs

Options for Drug-Refractory Patients Gastric electrical stimulation (Enterra® Therapy) is a viable treatment option for patients with chronic, drug refractory nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology. Enterra Therapy uses mild electrical stimulation to stimulate the nerves of the stomach, possibly activating a nausea- and vomiting-control mechanism to relieve the symptoms of gastroparesis. Parkman et al. Gastroenterology 2004.

Enterra® Therapy Overview Gastric Pacing vs. Neurostimulation U. S. Indication / CE Mark Patient Selection Enterra System components Surgical Procedure Programming and Patient Management

Make full life possible for patients with chronic nausea or vomiting secondary to gastroparesis when medication is not effective.

Gastric Pacing vs. Neurostimulation Enterra® Therapy Gastric Pacing vs. Neurostimulation

Gastric Electrical Stimulation (GES) Two different types Low-frequency/Long duration/High energy stimulation: “Gastric pacing” High-frequency/Short duration/Low energy stimulation: “Enterra Therapy” Physiological and clinical effects of GES are determined by specific pulse parameters and the position of electrodes. Soffer et al. Aliment Pharmacol Ther 2009:30;681.

GES with Low-Frequency/Long-Duration Pulses: “Gastric pacing” Stimulation Frequency:  Intrinsic Frequency (3x/min) Drives (entrains) the frequency of the smooth muscle slow wave (intrinsic), at the same frequency of the external stimulus High energy stimulation Requires multiple sets of electrodes Not FDA approved

US & CE Mark Indications Enterra® Therapy US & CE Mark Indications

Enterra Therapy U.S. Indication “Enterra Therapy is indicated for the treatment of patients with chronic, intractable (drug-refractory) nausea and vomiting secondary to gastroparesis of diabetic or idiopathic origin.” Designated as Humanitarian Use Device (HUD) September 1999 by the FDA. Approved as Humanitarian Device Exemption (HDE) March 2000 by the FDA.

Guidelines - Humanitarian Use Device (HUD) Designation Device to treat <4,000 patients/year with rare disorder Safe / probable benefit to patient outweighs risk of injury and/or illness from its use Requires Institutional Review Board (IRB) approval

Humanitarian Device Exemption (HDE) HDE authorizes marketing of a HUD Must have HUD designation Device company completes application for HDE

Enterra Therapy CE Mark Indication Enterra Therapy is indicated for the treatment of patients with chronic, intractable (drug-refractory) nausea and vomiting secondary to gastroparesis. CE Mark granted August 2002

Enterra® Therapy Patient Selection

Key Selection Criteria Idiopathic or diabetic gastroparesis Chronic, severe vomiting or nausea Drug-refractory Parkman et al. Gastroenterology 2004.

Patient Selection Physician weighs all available treatment options Evaluate appropriate patients Educate patient and family about therapy and expectations Discuss surgical procedure of Enterra Therapy with patient and family Define follow-up schedule and expectations Parkman et al. Gastroenterology 2004.

Enterra® Therapy System Components

Gastric Electrical Stimulation (Enterra Device) Neurostimulator

Pulse Generator & Leads Enterra System Components Pulse Generator & Leads Programmer

Enterra® Therapy Surgical Procedure

Surgical Procedure Performed under general anesthesia Surgical procedure lasts 1-2 hours Laparoscopy Laparotomy Neurostimulator activated in OR or anytime after implant based on the surgeon’s medical judgment X-ray post-surgery to document initial lead position Evaluate neurostimulator parameters before discharge Parkman et al. Gastroenterology 2004.

Surgical Procedure Using laparotomy or laparoscopy, two intramuscular leads with electrodes are fixed to the muscle of the lower stomach The leads are attached to the neurostimulator Laparotomy (abdominal incision) Laparoscopy (abdominal visualization via an endoscope) Parkman et al. Gastroenterology 2004.

Enterra® Therapy Programming & Patient Management

Programming Preparation: turn programmer on, place programming head on device box Pre-program following instructions technical manual Check impedance and programming final amplitude Begin stimulation

Documentation Fill out the Device Tracking Registration Form and affix serial number stickers: one IPG and two leads Mail top copy to Medtronic in prepaid, self-addressed envelope This will ensure the patient receives a permanent ID card for the device and is registered with Medtronic in case any product or safety notice must be sent Place two copies in the patient’s chart Place printed parameters (pre-and post-implant) in the progress notes in the patient’s chart

Patient Management Post-op Provide patient with information on: Post-op care Follow-up instructions Make sure the patient receives the temporary registration card and the patient manual, which are provided in the neurostimulator package

Patient Follow-Up Visit within one month Repeat visits: six months/PRN Evaluate symptoms, adverse effects and neurostimulator parameters Be attentive to any possible side effects

Enterra® Therapy Clinical Studies

WAVESS Study (Worldwide Anti-Vomiting Electrical Stimulation Study) Gastric Electrical Stimulation for Medically Refractory Gastroparesis

Study Goals Investigate short-term effect of GES on symptom reduction Assess effectiveness of GES on symptoms, gastric retention and health-related quality of life over 12-month period Evaluate adverse events Abell et al. Gastroenterology 2003.

WAVESS Study (Worldwide Anti-Vomiting Electrical Stimulation Study) N = 33 patients with chronic gastroparesis (17 diabetic, 16 idiopathic) Design: 12 month study conducted in two phases Phase I – two month randomized placebo-controlled double-blind cross-over trial, followed immediately by phase II Phase II – 10 month open-label Duration: July 1997 – March 1999 Abell et al. Gastroenterology 2003.

Study Design Patients received gastric electrical stimulation for 12 months Patients randomized in double-blind crossover design to stimulation ON or OFF for 1-month periods Blind broken; all patients programmed to stimulation ON and evaluated at 6 and 12 months Abell et al. Gastroenterology 2003.

WAVESS: Study Design Multicenter double blind crossover March 14-15, 1997 WAVESS: Study Design Multicenter double blind crossover ON Random Baseline 1/2 Implant 1/2 OFF Phase I Phase II 1 2 6 12 Months N = 33 33 33 27 24 Patients 17 diabetic 16idiopathic Abell et al. Gastroenterology 2003. Study Initiation Meeting USA, Washington 13

WAVESS Outcomes RESULTS – VOMITING Median vomiting frequency significantly decreased from baseline Diabetic group: Decreased from 13.4 episodes/week to 2.6 at 6 months (81%) and 4.9 at 12 months (63%) Idiopathic group: Decreased from 26.8 episodes/week to 3.0 at 6 months (88%) and to 4.5 at 12 months (83%) Combined group: Decreased from 17.3 episodes/week to 2.6 at 6 months (85%) and 4.8 at 12 months (72%) Abell et al. Gastroenterology 2003.

Outcomes as 12-month follow-up post-implant 12-Month Vomiting Frequency Outcomes as 12-month follow-up post-implant % Reduction > 80% > 50% < 25% Diabetic (n=10) 55% 73% 18% Idiopathic (n=13) 54% 85% 15% All (n=23) 52% 79% 17% Abell et al. Gastroenterology. 2003 Aug;125(2):421-8

Results: Quality of Life (QOL) Physical scores significantly improved from baseline: In diabetic, idiopathic and combined groups at six months In diabetic and combined groups at 12 months Mental scores significantly improved from baseline: In combined group at 6 and 12 months Abell et al. Gastroenterology 2003.

SF-36 Results * p < .025 Physical Composite Score Mental Composite Score * p < .025 Abell et al. Gastroenterology 2003.

Mean Hospital Days Etiology Prior Surg Post Diabetic (n=8) 70.5 6.4 41.1 Idiopathic (n=16) 38.1 5.4 21.2 All patients (n=24) 48.9 5.7 27.8 Prior = Hospital days in year prior to implant surgery Surg = Hospital days for implant surgery Post = Hospital days in year after discharge Abell et al. Gastroenterology 2003.

Complications/Adverse Events System removed in four patients due to: Infection of neurostimulator pocket (two patients) Pain related to lead perforation of stomach Erosion of neurostimulator through skin Surgery to reposition and re-anchor neurostimulator in one patient due to discomfort from system migration Abell et al. Gastroenterology 2003.

Conclusions In this group of 33 patients with long-term gastroparesis, gastric electrical stimulation: Significantly reduced vomiting frequency and upper GI symptoms Significantly improved quality of life Represents a major advance in the treatment of medically refractory gastroparesis Abell et al. Gastroenterology 2003.

Enterra Therapy Reimbursement, Coding and Billing Coverage and payment is available and is dependent on individual insurance carriers. Medtronic Gastroenterology Economic Solutions has resources available to help with specific DRG, CPT, and ICD-9 CM codes.

References Abell et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003, Aug;125(2):421-8. American College of Gastroenterology Website. Available at: http://www.acg.gi.org/patients/gihealth/gastroparesis.asp. Accessed Feb. 22, 2005. Baigrie RJ et al. Enteral versus parenteral nutrition after oesophagogastric surgery: a prospective ransomized comparison. Aust. N.Z. J. Surg 1996, 66:668-670. Fontana RJ, Barnett JL. Jejunostomy tube placement in refractory diabetic gastroparesis: a retrospective review. Am J Gastroenterology 1996, 91(10):2174-8. Hornbuckle K, JL Barnett. The diagnosis and work-up of the patient with gastroparesis. J Clin Gastroenterol 2000, Mar;30(2):117-24. Karras PJ, Pfeifer MA. Diabetic gastrointestinal autonomic neuropathy. Curr Ther Endocrinol Metab 1997, 6:462-465. Kendall BJ, McCallum RW. Gastroparesis and the current use of prokinetic drugs. Gastroenterol 1993, 1(2):107-114. Koch KL. Gastroparesis: diagnosis and management. Article eight in the series. Practical Gastroenterol 1997, November. Pp 30-43.

References, Continued McCallum RW. Clinical pharmacology forum: motility agents and the gastrointestinal tract. Am J Med Sci 1996, Jul;312(1):19-26 McCallum RW. Review of current status of prokinetic agents in gastroenterology. American Journal of Gastroenterology 1985 80:1008-16. Parkman HP et al. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004 Nov;127(5):1592-1622. Parkman HP et al. American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology 2004 Nov;127(5):1589-91 Soykan I et al. Demography, clinical characteristics, psychological and abuse profile, treatment and long term follow up of patients with gastroparesis. Dig Dis Sci 1998, 11:2398-2404. Tougas G et al. Assessment of Gastric Emptying Using a Low Fat Meal: Establishment of International Control Values. Am J Gastroenterology 2000, Jun;95(6):1456-62. The Diabetes Institutes Foundation Website. Available at: http://www.dif.org/DiabetesTopics/Gastroparesis.htm. Accessed Feb. 22, 2005.

Enterra Therapy for Gastroparesis: Product technical manual must be reviewed prior to use for detailed disclosure. Indications: The Medtronic Enterra Therapy System for gastric electrical stimulation (GES) is indicated for use in the treatment of chronic, intractable (drug refractory) nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology. Contraindications: The Enterra Therapy System is contraindicated in patients whom the physician determines are not candidates for surgical procedures and/or anesthesia due to physical or mental health conditions. Do not use shortwave diathermy, microwave diathermy or therapeutic ultrasound diathermy (all now referred to as diathermy) on patients implanted with a neurostimulation system. Energy from diathermy can be transferred through the implanted system and can cause tissue damage at the location of the implanted electrodes, resulting in severe injury or death. Diathermy is further prohibited because it can also damage the neurostimulation system components resulting in loss of therapy, requiring additional surgery for system explantation and replacement. Warnings: This system has not been evaluated for pregnancy, pediatric use, or patients under the age of 18, or over the age of 70. Strong sources of electromagnetic interference (EMI) can result in serious injury, system damage, or operational changes to the system. Strong sources of EMI include MRI, electrocautery, radiofrequency (RF)/microwave ablation, external defibrillators, ultrasonic equipment, radiation therapy, and theft detectors. Patients on anticoagulation therapy may be at a greater risk for post-operative complications. The system may be affected by or adversely affect other implantable devices such as cardiac pacemakers and cardioverters/defibrillators. Rupture or piercing of the neurostimulator can result in severe burns. The use of non-Medtronic components with this system may result in damage to Medtronic components, loss of therapy, or patient injury. When possible, identify and treat any infections remote to the implant site prior to surgery. It is recommended that the neurostimulator implant site be irrigated with antibiotic solution during surgery and that IV antibiotics be administered perioperatively. Infections at the implant site almost always require the surgical removal of the implanted system. Avoid excess lead slack in the abdominal cavity. The lead can become entangled with or erode into the bowel, which may result in bowel obstruction, bowel perforation, intra-abdominal infection, bowel resection and may require system revision. Precautions: Clinicians and patients should follow programming guidelines and precautions provided in product manuals. Patients should avoid manipulating or rubbing the neurostimulator system components, which can cause component damage, skin erosion, or stimulation at the implant site. Patients should be detoxified from narcotics prior to implant so that the effects of stimulation can be properly assessed. Patients should avoid activities that may put undue stress on the implanted neurostimulation system components. Patients should not scuba dive below 10 meters of water or enter hyperbaric chambers above 2.0 atmosphere absolute (ATA). Electromagnetic interference, postural changes, and other activities may cause shocking or jolting. Adverse Events: Adverse events related to the system include infection, stomach wall perforation, migration/erosion of the neurostimulator, programming difficulty, undesirable change in stimulation, implant site pain, hemorrhage, hematoma, migration/dislodgement of the lead, extra-abdominal pain, seroma, concomitant muscle stimulation, allergenic or immune system response to implanted materials, loss of therapeutic effect, and gastrointestinal complications including upper and lower gastro-intestinal (GI) symptoms. Humanitarian Device: Authorized by Federal law for use in the treatment of chronic intractable (drug refractory) nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology. The effectiveness of this device for this use has not been demonstrated. For further information, please call Medtronic at 1-800-328-0810 and/or consult Medtronic’s website at www.medtronic.com. USA Rx Only. Rev 0709