Physician’s
Manual

VNS Therapy™ Pulse
Model 102 Generator

and

VNS Therapy™ Pulse Duo
Model 102R Generator

May 2003

Caution: U.S. federal law restricts this device
to sale by or on the order of a physician.

 

 

 

 

 

 


Table of Contents

1... BRIEF DEVICE DESCRIPTION.. 1

1.1.    VNS Therapy System Compatibility. 2

1.2.    Symbols and Definitions 3

2... INTENDED USE / INDICATIONS. 4

3... CONTRAINDICATIONS. 5

4... Warning. 7

5... PRECAUTIONS. 10

5.1.    Sterilization, Storage, and Handling. 13

5.2.    Lead Evaluation and Connection. 15

5.3     Environmental and Medical Therapy Hazards 16

6... Adverse events. 25

6.1.    Adverse Events Observed in Studies 25

6.2.    Potential Adverse Events 27

7... CLINICAL STUDIES. 30

7.1.    Long-Term Data from Uncontrolled Follow Up. 36

7.2.    Other Information. 40

7.3.    Bibliography. 41

8... INDIVIDUALIZATION OF TREATMENT.. 42

9... PATIENT COUNSELING INFORMATION.. 45

10. CONFORMANCE TO STANDARDS. 46

11. HOW SUPPLIED.. 47

12. OPERATOR’S MANUAL. 48

12.1.  Directions for Use. 48

12.2   Physician Training/Information. 132

12.3   Mechanism of Action. 133

12.4   Detailed Device Description. 135

13. Cyberonics’ Limited Replacement Warranty.. 139

14. TROUBLESHOOTING. 142

14.1.  Troubleshooting in the OR. 142

14.2.  Troubleshooting at Follow-Up Visits 150

15. Information and Support.. 161

16. GLOSSARY.. 162


Tables

Table 1. Observed Adverse Events 26

Table 2. Description of Clinical Studies 30

Table 3. Description of Patients 32

Table 4. Principal Efficacy and Safety Results 33

Table 5. Principal Effectiveness Statistics (E05) 35

Table 6. Patient Summary Chart 37

Table 7. Patients Used for Efficacy Analysis 38

Table 8. High Stimulation Parameters (Optimal) 42

Table 9. Specifications and Product Information. 48

Table 10. DC-DC Converter Codes and Lead Impedance
          (Models 102 and 102R)
60

Table 11. Duty Cycles for Various ON and OFF. 65

Table 12. Estimated Battery Life - Nominal Longevity Estimates
          Beginning of Life (BOL) to End of Service (EOS)
67

Table 13. Estimated Battery Life - Worst Case Longevity Estimates
          BOL to ERI
76

Table 14. Estimated Battery Life -  Nominal ERI
          to EOS Time Estimates
113

Table 15. Estimated Battery Life - Worst Case ERI
          to EOS Time Estimates
122

 


Figures

Figure 1. ECG Artifact Produced by Pulse Generator Communication. 24

Figure 2. Change in Seizure Frequency, Patient Distribution. 34

Figure 3. Median Percentage Change in Seizure Frequency. 39

Figure 4. Stimulation (All Duty Cycles Except Low-Output £10 Hz) 53

Figure 5. Magnet Styles 55

Figure 6. Initiating Magnet Activation. 56

Figure 7. Typical Waveforms Obtained from Skin Electrodes 62

Figure 8. Relationship of Lead Impedance to Maximum
          Deliverable Output Current
63

Figure 9. Relationship of Programmed Output Current to
          Lead Impedance
. 64

Figure 10. Placement of Pulse Generator and Lead. 90

Figure 11. Use of Tie-downs in Electrode Placement 93

Figure 12. Vagus Nerve Anatomy and Placement of the Lead. 96

Figure 13. Lead Connector(s) Prior to Insertion and Fully Inserted. 98

Figure 14. Connecting the Resistor Assembly. 106

Figure 15. Pulse Generator Circuitry. 136

Figure 16. X-ray Identification. 137


1.         BRIEF DEVICE DESCRIPTION

The Cyberonics® VNS Therapyä System, used for vagus nerve stimulation (VNSä), consists of the implantable VNS Therapy Generator, a Lead, and the external programming system used to change stimulation settings[1]. The Pulse Generator is an implantable, multiprogrammable, pulse generator that delivers electrical signals to the vagus nerve. The Pulse Generator is housed in a hermetically sealed titanium case and is powered by a single battery. Electrical signals are transmitted from the Pulse Generator to the vagus nerve by the Lead. The Lead and the Pulse Generator make up the implantable portion of the VNS Therapy System.

The external programming system includes the Model 201 Programming Wand, the Model 250 Software, and a compatible computer. (See the Model 250 Physician’s Manual for a list of compatible computers.) The Software allows a physician to place the Programming Wand over the Pulse Generator to read and change device settings.

1.1.            VNS Therapy System Compatibility

The VNS Therapy Pulse, Model 102 Generator, and the VNS Therapy Pulse Duo, Model 102R Generator, are compatible with different Lead types as follows:

¨        Model 102 Generator:

Compatible with Model 302 Lead

¨        Model 102R Generator:

Compatible with Model 300 Lead (dual pin)

Except for Leads, both Models 102 and 102R are compatible with the following system components:

Pulse Generator

Model

Component

Model

102

102R

Lead

300

 

x

302

x

 

Wand

200

x

x

201

x

x

Software

250 v.4.6, 6.1, or higher

x

x

Tunneler

402

x

x

Accessory Pack

502

x

x

Magnets

220

x

x

 


1.2.            Symbols and Definitions

Symbols and definitions used in this manual include the following:

      Notice for reader to pay special attention to the following details

SN        Serial Number

        Expiration Date (Use-Before Date)

     Single Use Only / Do Not Reuse

    Date of Manufacture (Date Product is Labeled)

  Contents Sterilized by Ethylene Oxide

     Storage Temperature

2.         INTENDED USE / INDICATIONS

The VNS Therapy System is indicated for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications.

3.         CONTRAINDICATIONS

*   The VNS Therapy System cannot be used in patients after a bilateral or left cervical vagotomy.

*   Do not use shortwave diathermy, microwave diathermy or therapeutic ultrasound diathermy (hereafter referred to as diathermy) on patients implanted with a VNS Therapy System. Diagnostic ultrasound is not included in this contraindication.

Energy delivered by diathermy may be concentrated into or reflected by implanted products such as the VNS Therapy System. This concentration or reflection of energy may cause heating.

Testing indicates that diathermy can cause heating of the VNS Therapy System well above temperatures required for tissue destruction. The heating of the VNS Therapy System resulting from diathermy can cause temporary or permanent nerve or tissue or vascular damage. This damage may result in pain or discomfort, loss of vocal cord function, or even possibly death if there is damage to blood vessels.


Because diathermy can concentrate or reflect its energy off any size-implanted object, the hazard of heating is possible when any portion of the VNS Therapy System remains implanted, including just a small portion of the Lead or electrode. Injury or damage can occur during diathermy treatment whether the VNS Therapy System is turned “on” or “off”.

            Diathermy is further prohibited because it may also damage the VNS Therapy System components resulting in loss of therapy, requiring additional surgery for system explantation and replacement. All risks associated with surgery or loss of therapy (loss of seizure control) would then be applicable.

Advise your patients to inform all their health care professionals that they should not be exposed to diathermy treatment.

4.      Warning

Physicians should inform patients about all potential risks and adverse events discussed in the VNS Therapy System physician’s manuals.

      The safety and efficacy of the VNS Therapy System has not been established for uses not covered in the “Intended Use/ Indications” section of this manual.

      The safety and efficacy of the VNS Therapy System treatment have not been established for stimulation of the right vagus nerve or of any other nerve, muscle, or tissue.

      Excessive stimulation at an excess duty cycle (that is, one that occurs when ON time is greater than OFF time) has resulted in degenerative nerve damage in laboratory animals. An excess duty cycle can be produced by continuous or frequent magnet activation (> 8 hours), as determined by animal studies. Cyberonics recommends against stimulation at these combinations of ranges.

      Aspiration may result from the increased swallowing difficulties reported by some patients during stimulation. Patients who have pre-existing swallowing difficulties are at greater risk for aspiration.


      Device malfunction could cause painful stimulation or direct current stimulation. Either event could cause nerve damage and other associated problems. Patients should be instructed to use the magnet to stop stimulation if they suspect a malfunction, and then to contact their physician immediately for further evaluation. Prompt surgical intervention may be required if a malfunction occurs.

      Susceptible patients with predisposed dysfunction of cardiac conduction systems (re-entry pathway) have not been studied as part of controlled clinical trials to establish the safety of VNS Therapy System treatment in these patients. Evaluation by a cardiologist is recommended if the family history, patient history, or electrocardiogram suggests an abnormal cardiac conduction pathway. Serum electrolytes, magnesium, and calcium should be documented before implantation. Post-implant electrocardiograms and Holter monitoring are recommended if clinically indicated.

      Sudden unexplained death in epilepsy (SUDEP): Through August 1996, 10 sudden and unexplained deaths (definite, probable, and possible) were recorded among the 1,000 patients implanted and treated with the VNS Therapy device. During this period, these patients had accumulated 2,017 patient‑years of exposure.

           


Some of these deaths could represent seizure‑related deaths in which the seizure was not observed, at night, for example. This number represents an incidence of 5.0 definite, probable, and possible SUDEP deaths per 1,000 patient‑years.

            Although this rate exceeds that expected in a healthy (nonepileptic) population matched for age and sex, it is within the range of estimates for epilepsy patients not receiving vagus nerve stimulation, ranging from 1.3 SUDEP deaths for the general population of patients with epilepsy, to 3.5 (for definite and probable) for a recently studied antiepileptic drug (AED) clinical trial population similar to the VNS Therapy System clinical cohort, to 9.3 for patients with partial onset epilepsy.

*      Patients with obstructive sleep apnea (OSA) may have an increase in apneic events during stimulation. Cyberonics recommends care when treating patients with preexisting OSA. Lowering stimulus frequency or prolonging OFF time may prevent exacerbation of OSA.

*      The VNS Therapy device is not curative: Physicians should warn patients that the VNS Therapy System is not a cure for epilepsy and that since seizures may occur unexpectedly, patients should consult with a physician before engaging in unsupervised activities, such as driving, swimming, and bathing, and in strenuous sports that could harm them or others.

5.      PRECAUTIONS

Physicians should inform patients about all potential risks and adverse events discussed in the VNS Therapy System Physician’s Manuals.

      Laryngeal irritation may result from stimulation. Patients who smoke may have an increased risk of laryngeal irritation.

      Dyspnea may result from stimulation. Patients with chronic obstructive pulmonary disease may have an increased risk of dyspnea.

*      It is important to follow recommended implantation procedures and intraoperative product testing described in this manual. During the intraoperative Lead Test, rare incidents of bradycardia and/or asystole have occurred. As of October 1998, approximately 3,000 patients had been implanted with the VNS Therapy System. Four of these patients were reported to have experienced bradycardia and/or asystole during the intraoperative Lead Test. All four patients recovered without sequelae. One of the four patients was implanted with the VNS Therapy System. There were no postoperative or VNS Therapy treatment-related cardiac adverse events later reported for that patient. No similar events were reported to have occurred during the clinical studies at the time of implantation or during treatment.


The safety of this therapy has not been systematically established for patients experiencing bradycardia or asystole during VNS Therapy System implantation.

      Reversal of Lead polarity has been associated with an increased chance of bradycardia in animal studies. It is important to make sure that the Lead connector pins are correctly inserted (white marker band/serial number to + connection) into the Lead receptacle(s).

      Do not program the VNS Therapy System to an ON or periodic stimulation treatment for at least 14 days after the initial or replacement implantation. Failure to observe this precaution may result in patient discomfort or adverse events.

      Resetting the Pulse Generator turns the device OFF (output current = 0 mA), and all device history information is lost. The device history information should be printed out before resetting.

      Do not use frequencies of 5 Hz or below for long-term stimulation. Because these frequencies generate an electromagnetic trigger signal, their use results in excessive battery depletion of the implanted Pulse Generator and, therefore, should be used for short periods of time only.


      It is important to follow infection control procedures. Infections related to any implanted device are difficult to treat and may require that the device be explanted. Cyberonics recommends that the patient be given antibiotics preoperatively. The surgeon should ensure that all instruments are sterile prior to the operation.

            Cyberonics recommends frequent irrigation of both incision sites with generous amounts of bacitracin or equivalent solution prior to closure. (To minimize scarring, these incisions should be closed with cosmetic closure techniques.) Also, antibiotics should be administered postoperatively at the discretion of the physician.

      The VNS Therapy System is indicated for use only in stimulating the left vagus nerve in the neck area inside the carotid sheath.

      The VNS Therapy System is indicated for use only in stimulating the left vagus nerve below where the superior and inferior cervical cardiac branches separate from the vagus nerve.

      Physicians who implant the VNS Therapy System should be experienced performing surgery in the carotid sheath; physicians should be familiar with vagal anatomy, particularly the cardiac branches; and they should be trained in the surgical technique relating to implantation of the VNS Therapy System. See the section “Physician Training/Information” in this manual.

      A neck brace can be used by the patient for the first week to help ensure proper Lead stabilization.

*      Appropriate physician training is very important:

Ø       Prescribing physicians should be experienced in the diagnosis and treatment of epilepsy and should be familiar with the programming and use of the VNS Therapy System.

Ø       Physicians who implant the VNS Therapy System should be experienced performing surgery in the carotid sheath and should be trained in the surgical technique relating to implantation of the VNS Therapy System. (See the “Physician Training/Information” section of this manual for more information.)

5.1.      Sterilization, Storage, and Handling

The Pulse Generator and accessories have been sterilized using ethylene oxide gas (EO) and are supplied in a sterile package to permit introduction into the operating field. A process indicator is included in the package; devices should be implanted only if the indicator is green. An expiration (or use-before) date is marked on each package.

The implantable portions of the VNS Therapy System are nonpyrogenic.

      Store the Pulse Generator between -20°C (-4°F) and +55°C (+131°F). Temperatures outside this range can damage components.

      Do not store the Pulse Generator where it is exposed to water or other liquids. Moisture can damage the seal integrity of the package materials.

      Do not implant a device if any of the following has occurred:

Ø    The device has been dropped, because dropping it could damage Pulse Generator components.

Ø    The process indicator within the inner package is not green for product sterilized by EO.

Ø    The storage package has been pierced or altered, because this could have rendered it nonsterile.

Ø    The expiration (use-before) date has expired, because this can adversely affect the Pulse Generator’s longevity and sterility.

      Do not ultrasonically clean the Pulse Generator, because doing so may damage Pulse Generator components.

      Do not re-sterilize the Pulse Generator. Return any opened devices to Cyberonics.

      The Pulse Generator is a single-use-only device. Do not reimplant an explanted Pulse Generator for any reason, because infections may occur.


            Explanted generators should be returned to Cyberonics for examination and proper disposal, along with a completed Returned Product Report form. Before returning the Pulse Generator, disinfect the device components with Betadine®, Cidex® soak, or other similar disinfectant, and double-seal them in a pouch or other container properly labeled with a biohazard warning.

      Do not incinerate the Pulse Generator; it contains a sealed chemical battery, and an explosion could result.

5.2.      Lead Evaluation and Connection

      Do not use a lead other than the Model 300 Lead with the Model 102R Generator or a Model 302 Lead with the Model 102 Generator because such use may damage the Pulse Generator or injure the patient.

      Exercise extreme caution if testing the Lead using line-powered equipment because leakage current can injure the patient.

*      Do not insert a Lead in the Pulse Generator Lead receptacle(s) without first visually verifying that the setscrew(s) is sufficiently retracted to allow insertion. Avoid backing the setscrew(s) out further than needed for Lead insertion.


*      Ensure that the hex screwdriver is fully inserted in the setscrew, and then push in on the hex screwdriver and turn it clockwise until it clicks. To avoid damaging (stripping) the setscrew(s) and/or dislodging the setscrew plug(s), insert the hex screwdriver into the center of the setscrew plug, keeping it perpendicular to the Pulse Generator.

5.3       Environmental and Medical Therapy Hazards

      Patients should exercise reasonable caution in avoiding devices that generate a strong electric or magnetic field. (For examples, see the “Other Environmental Hazards” section of this manual.) If a Pulse Generator ceases operation while in the presence of electromagnetic interference (EMI), moving away from the source may allow it to return to its normal mode of operation.

5.3.1.      Hospital and Medical Environments

      VNS Therapy System operation should always be checked by performing device diagnostics after any of the procedures mentioned in this manual. Additional precautions for these procedures are described below.

      For clear imaging, patients may need to be specially positioned for mammography procedures because of the location of the Pulse Generator in the chest. (Most routine diagnostic procedures, such as fluoroscopy and radiography, are not expected to affect system operation.)

      Therapeutic radiation may damage the Pulse Generator’s circuitry, although no testing has been done to date and no definite information on radiation effects is available. Sources of such radiation include therapeutic radiation, cobalt machines, and linear accelerators. The radiation effect is cumulative, with the total dosage determining the extent of damage. The effects of exposure to such radiation can range from a temporary disturbance to permanent damage, and may not be detectable immediately.

*      External defibrillation may damage the Pulse Generator. Attempt to minimize current flowing through the Pulse Generator and Lead system by following these precautions:

Ø       Position defibrillation paddles perpendicular to the Pulse Generator and Lead system and as far from the Pulse Generator as possible.

Ø       Use the lowest clinically appropriate energy output (watt-seconds).

Ø       Confirm Pulse Generator function after any internal or external defibrillation.


*      Use of electrosurgery (electrocautery or radio frequency (RF) ablation devices) may damage the Pulse Generator. Attempt to minimize the current flowing through the Pulse Generator and Lead system by following these precautions:

Ø       Position the electrosurgery electrodes as far as possible from the Pulse Generator and Lead.

Ø       Avoid electrode placement that puts the Pulse Generator or Lead in the direct path of current flow or within the part of the body being treated.

Ø       Confirm Pulse Generator functions as programmed after electrosurgery.

      Magnetic resonance imaging (MRI) should not be performed with a magnetic resonance body coil in the transmit mode. The heat induced in the Lead by an MRI body scan can cause injury.

If an MRI should be done, use only a transmit and receive type of head coil. Magnetic and RF fields produced by MRI may change the Pulse Generator settings (change to reset parameters) or activate the device. Stimulation has been shown to cause the adverse events reported in the “Adverse Events” section of this manual. MRI compatibility was demonstrated using a 1.5T General Electric Signa Imager with a Model 100 only. The Model 102 and Model 102R are functionally equivalent to the Model 100. Testing on this imager as performed on a phantom[2]  indicated that the following Pulse Generator and MRI procedures can be used safely without adverse events:

Ø    Pulse Generator output programmed to 0 mA for
the MRI procedure, and afterward, retested by performing the Lead Test diagnostics and reprogrammed to the original settings

Ø    Head coil type: transmit and receive only

Ø    Static magnetic field strength: £ 2.0 tesla

Ø    Specific-rate absorption (SAR): < 1.3 W/kg
for a 154.5-lb (70-kg) patient

Ø    Time-varying intensity: < 10 tesla/sec

Use caution when other MRI systems are used, since adverse events may occur because of different magnetic field distributions.

*      Procedures in which the RF is transmitted by a body coil should not be done on a patient who has the VNS Therapy System. Thus, protocols must not be used that utilize local coils that are RF-receive only, with RF-transmit performed by the body coil. Note that some RF head coils are receive-only, and that most other local coils, such as knee and spinal coils, are also RF receive-only. These coils must not be used in patients with the VNS Therapy System.


*      Extracorporeal shockwave lithotripsy may damage the Pulse Generator. If therapeutic ultrasound therapy is required, avoid positioning the Pulse Generator part of the body in the water bath or in any other position that would expose it to ultrasound therapy. If that positioning cannot be avoided, program the Pulse Generator output to 0 mA for the treatment, and then after therapy, reprogram the Pulse Generator to the original parameters.

*    If the patient receives medical treatment for which electric current is passed through the body (such as from a TENS unit) either the Pulse Generator output should be set to 0 mA or function of the Pulse Generator should be monitored during initial stages of treatment.

*    Therapeutic ultrasound. Routine therapeutic ultrasound could damage the Pulse Generator and may be inadvertently concentrated by the device, causing harm to the patient.

5.3.2.      Home Occupational Environments

Properly operating microwave ovens, electrical ignition systems, power transmission lines, theft-prevention devices, and metal detectors are not expected to affect the Pulse Generator. Similarly, most routine diagnostic procedures, such as fluoroscopy and radiography, are not expected to affect system operation. However, because of their higher energy levels, sources such as transmitting antennas may interfere with the VNS Therapy System. It is suggested that the Pulse Generator be moved away from equipment—typically at least six feet (1.8 meters)—that may be causing interference.

*      The patient should seek medical advice before entering environments that are protected by a warning notice preventing entry by patients implanted with a cardiac pacemaker or defibrillator.

5.3.3.      Cellular Phones

Based on testing to date, cellular phones have no effect on Pulse Generator operation. Unlike an implanted pacemaker or defibrillator, the Pulse Generator does not sense physiologic signals.

5.3.4.      Other Environmental Hazards

*      Strong magnets, hair clippers, vibrators, loudspeaker magnets, Electronic Article Surveillance (EAS) System tag deactivators, and other similar electrical or electro-mechanical devices, which may have a strong static or pulsing magnetic field, can cause accidental magnet activation. Patients should be cautioned to keep such devices away from the Pulse Generator, typically at least six inches (15 centimeters) away.

5.3.5.         Programming Software

The Pulse Generator can be programmed using the Model 250 Software, Version 4.6, Version 6.1, or higher. The Software should be used on a laptop or handheld computer dedicated only to programming the VNS Therapy System. (For more information, see the Model 250 Software Physician’s Manual for Version 4.6, Version 6.1, or higher, including a list of computers that have been qualified for use with this Software.)


5.3.6.         Pulse Generator and EMI Effects on Other Devices

During stimulation, the Pulse Generator may interfere with devices operating in the 30 kHz to 100 kHz range, such as pocket transistor radios and hearing aids. This interference is a theoretical possibility, and no effects on hearing aids have yet been reported, although the Pulse Generator can interfere with a transistor radio when held directly over one. No specific testing has been done to date, and no definite information on effects is available.

The Pulse Generator should be moved—typically at least six feet (1.8 meters)—away from equipment with which it may be interfering.

Programming or interrogating the Pulse Generator may momentarily interfere with other sensitive electronic equipment nearby. The Pulse Generator is not expected to trigger airport metal detectors or theft-protection devices that are closer than about six feet (1.8 meters).

*      The Pulse Generator may affect the operation of other implanted devices, such as cardiac pacemakers and implantable defibrillators. Possible effects include sensing problems and inappropriate Pulse Generator responses. If the Pulse Generator patient requires concurrent implantable pacemaker and/or defibrillator therapy, careful programming of each system is necessary to optimize the patient’s benefit from each device.

      The magnet provided for activation or inhibition of the Pulse Generator may damage televisions, computer disks, credit cards, and other items affected by strong magnetic fields.


5.3.7.      Effects on ECG Monitors

Pulse Generator data communication produces an ECG artifact, an example of which is shown in the ECG tracings in Figure 1:

Figure 1. ECG Artifact Produced by
Pulse Generator Communication

5.3.8.      Pulse Generator Disposal

      Do not incinerate the Pulse Generator, because it can explode if subjected to incineration or cremation temperatures.

      Return all explanted Pulse Generators to Cyberonics for examination and safe disposal.

*      Do not implant an explanted Pulse Generator in another patient, because sterility, functionality, and reliability cannot be ensured.

6.                  Adverse events

The VNS Therapy System was implanted in 454 patients in five clinical studies involving 611 devices (some patients had Pulse Generator replacements). As of August 1996, total VNS Therapy exposure in these 454 patients was 901 device-years. Individual patient exposure averaged 24 months, with a range of eight days to 7.4 years.

A total of nine patients died during these five studies. One patient died from each of the following: thrombotic thrombocytopenic purpura, drowning, aspiration pneumonia, pneumonia, and renal failure associated with drug and alcohol ingestion. No cause of death was apparent for the other four deaths, which may be classified as sudden unexpected death in epilepsy (SUDEP). None of these deaths were attributed by the investigators to the VNS Therapy System.

6.1.      Adverse Events Observed in Studies

Included among the five clinical trials were two randomized, blinded, active control trials (Study E03 and E05), which involved 314 patients and the implantation of 413 devices, yielding a total VNS Therapy System exposure (inclusive of long-term follow up) of 591 device years. These trials form the basis of the rates of observed adverse events. Table 1 contains only a partial list of the more common and expected observed adverse events associated with the VNS Therapy System. A comprehensive listing of adverse events observed in studies is available by study from the Clinical Research department at Cyberonics.


Table 1 reports the adverse events from these studies during
the randomized phase (approximately a 14-week observation period) and randomized phase plus long-term follow up (
> 3 months) through August 1996. The most common side effect associated with stimulation was hoarseness (voice alteration), which, depending on device settings, can be severe to barely perceptible. Hoarseness is reported to occur primarily during the ON period of stimulation.

Table 1. Observed Adverse Events

N=413 devices in 314 patients,
152 patients in the HIGH treatment group, 591 device years

Randomized + Long-Term Follow Up
(
> 3 Months)
N=314 Patients, 591 Device-Years

Randomized Phase, HIGH Only, N=152 Pts

 

Adverse Event
(AE)

No.
of Patients*

%
of
Patients

No.
of
Events

Events/
Device-Year

No.
of Patients

%
of Patients

Serious AEs

 

 

 

 

 

 

Surgically related

13

4.1

13

0.022

N/A

N/A

Stimulation related

4

1.2

4

0.007

1

0.7

Non-serious AEs

 

 

 

 

 

 

Voice alteration

156

50

720

1.228

91

60

Increased coughing

129

41

456

0.772

57

38

Pharyngitis

84

27

182

0.308

36

24

Paresthesia

87

28

377

0.638

32

21

Dyspnea

55

18

55

0.093

32

21

Dyspepsia

36

12

98

0.166

22

15

Nausea

59

19

154

0.261

21

14

Laryngismus

10

3.2

30

0.051

9

5.9

*   Number of patients reporting the event at least once.

  Percentage of patients reporting the event at least once.

  Included infection, nerve paralysis, hypesthesia, facial paresis, left vocal cord paralysis, left facial paralysis, left hemidiaphragm paralysis, left recurrent laryngeal nerve injury, urinary retention, and low-grade fever.


Status epilepticus: Valid estimates of the incidence of treatment-emergent status epilepticus among VNS Therapy System treated patients are difficult to obtain because Investigators participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, two of 441 adult patients had episodes that could be described unequivocally as “status.” In addition, a number of reports were made of variably defined episodes of seizure exacerbation (for example, seizure clusters and seizure flurries).

Rebound after stimulation was stopped: Seizure frequency was monitored for one to four weeks after stimulation was stopped because of battery depletion in 72 instances (68 patients) in Study E03. Of these instances, 11 of the 72 (15%) had a greater than 25 percent increase above baseline, and 42 of the 72 (58%) had a greater than 25 percent decrease in seizure rate. The seizure rate increased by more than 1.5 standard deviations above baseline in 10 percent of instances (compared with the 7 percent expected).

6.2.      Potential Adverse Events

Adverse events reported during clinical studies as statistically significant are listed below in alphabetical order[3]:

¨        Ataxia (muscle movements or twitching, generally associated with stimulation)

¨        Dyspepsia (indigestion)

¨        Dyspnea (difficulty breathing, shortness of breath)

¨        Hypesthesia (impaired sense of touch)

¨        Increased coughing

¨        Infection

¨        Insomnia (inability to sleep)

¨        Laryngismus (throat, larynx spasms)

¨        Nausea

¨        Pain

¨        Paresthesia (prickling of the skin)

¨        Pharyngitis (inflammation of the pharynx, throat)

¨        Voice alteration (hoarseness)

¨        Vomiting

Other potential adverse events possibly associated with surgery or stimulation include, but are not limited to, the following:

¨        Aspiration (fluid in the lungs)

¨        Blood clotting

¨        Choking sensation

¨        Damage to nerves or vasculature in the surgical area, including the carotid artery and jugular vein

¨        Device (Generator and/or Lead) migration or extrusion

¨        Dizziness

¨        Dysphagia (difficulty swallowing)

¨        Duodenal ulcer, gastric ulcer

¨        Ear pain

¨        Facial flushing

¨        Facial paralysis, paresis

¨        Foreign body reaction to implants, including possible tumor formation

¨        Formation of fibrous tissue, pockets of fluid

¨        Heart rate and rhythm changes

¨        Hiccuping

¨        Incision site pain

¨        Irritability

¨        Laryngeal irritation (sore, painful throat)

¨        Left hemidiaphragm paralysis

¨        Left recurrent laryngeal nerve injury

¨        Left vocal cord paralysis

¨        Low-grade fever

¨        Muscle pain

¨        Neck pain

¨        Nerve injury

¨        Painful or irregular stimulation

¨        Skin, tissue reaction

¨        Stomach discomfort

¨        Tinnitus (ringing in the ears)

¨        Tooth pain

¨        Unusual scarring at the incision site

¨        Urinary retention

¨        Vagus nerve paralysis

¨        Weight change

¨        Worsening of asthma and bronchitis

      Patients who manipulate the Pulse Generator and Lead through the skin may damage or disconnect the Lead from the Pulse Generator and/or possibly cause damage to the vagus nerve.

7.         CLINICAL STUDIES

Five acute-phase clinical studies involving the VNS Therapy System have been conducted (see Table 2). These studies enrolled 537 patients, of whom 454 were implanted with the VNS Therapy System. A total of 611 devices were implanted, and patient exposure totaled 901 device-years, with an individual mean patient exposure of 24 months (ranging from eight days to 7.4 years). A total of 45 centers participated in these studies: 40 in the United States, 2 in Germany, and 1 each in Canada, Holland, and Sweden.

Table 2. Description of Clinical Studies

All patients enrolled in all clinical studies, N=537

Description of Clinical Studies

 

 

Longitudinal

Parallel

 

Study

E01

E02

E04

E03

E05

Total

Type of study

pilot
longitudinal

pilot
longitudinal

open
longitudinal

randomized parallel
high/low

randomized parallel, high/low

-

No. of patients enrolled

11

5

133

126

262

537

No. of
centers*

3

2

24

17

20

45

Reference period (baseline)

weeks 2–4

weeks 3–6

weeks -4–0

weeks -12–0

weeks -12–0

-

Seizure type

partial

partial

all types

partial

partial

-

No. of AEDs

1–2

1–2

not specified

0–3

1–3

-

* Total includes non-U.S. centers (Canada, Holland, Germany-2, and Sweden); several U.S. centers participated in more than one study.

Purpose: The purpose of the studies was to determine whether adjunctive use of optimal stimulation of the left vagus nerve could reduce seizure frequency in patients with refractory seizures.


Methods: In the two randomized, blinded, active control trials (E03 and E05), patients were randomly assigned to either of two treatment groups: HIGH (believed to be therapeutic) or LOW (believed to be less therapeutic). Patients enrolled in the study were seen every four weeks during the baseline period (weeks -12 to 0). Patients meeting eligibility were implanted with the Pulse Generator and Lead (see Table 3).

Two weeks after implantation, patients were randomized to the HIGH or LOW stimulation group, and the Pulse Generator was activated. Patients in the HIGH groups received a higher frequency, greater pulse width, and higher duty cycle of stimulation. The randomized treatment period that followed activation of the Pulse Generator lasted 14 weeks (the last 12 weeks of which were used in the efficacy analysis—the first two weeks for a treatment ramp-up period).

Table 3. Description of Patients

All patients implanted in all clinical studies, N=454

Description of Patients

 

Longitudinal

Parallel

 

Study

E01

E02

E04

E03

E05

Total

No. of patients implanted

11

5

124

115

199

454

No. of patients stimulated

10

5

123

115

198

451

Age (range)

32 (20–58)

33 (18–42)

24 (3–63)

33 (13–57)

33 (13–60)

32 (3–63)

No. of females (%)

4 (36%)

2 (40%)

57 (46%)

43 (37%)

104 (52%)

210 (46%)

Years with epilepsy (range)

22 (13-32)

20 (5-36)

17 (0.8-48)

21 (4-47)

23 (2-52)

21 (0.8-52)

No. of AEDs (av)

1.0

1.0

2.2

2.1

2.1

2.1

Median no. of seizures per day at baseline

0.6

0.42

0.65

0.70 high/           0.85 low

0.58 high/             0.51 low

-

 

Results: The primary efficacy endpoint (percent reduction in seizure rate) was measured over 12 weeks (see Table 4). Adverse events were assessed at each patient visit.


Table 4. Principal Efficacy and Safety Results

All patients in efficacy analyses in all clinical studies, N=441

Principal Efficacy Results

 

Longitudinal

Parallel

 

Study

E01

E02

E04

E03

E05

Total

No. of patients in efficacy analysis

10

5

116

114

196

441

Median reduction in seizures/day

32%*

48%

22%*

23% high*/           6% low

23% high/           21% low

-

Mean reduction
in seizures/day

24%

40%

7%

24% high/          6% low

28% high/           15% low

-

Difference in mean (high/low)

-

-

-

17%§ (3%/31%)

13%|| (2%/23%)

-

% with > 50% response

30%

50%

29%

30% high/          14% low

23% high/          16% low

-

Principal Safety Results Through Long-term Follow Up

Exposure
(pt-yr)

45

20

245

456

135

901

SAEs (high/low)

9%/ -

0%/ -

6%/ -

5%/0%

7%/9%

-

Discontinued (LOE/AE) #

0/1

0/0

2/3

0/2

1/3

3/9

No. of explants**

2

2

15

9

5

33

Deaths: SUDEP/total††

0/0

0/0

3/4

0/3

1/2

4/9

Within group broad analyses:

*     P £ 0.05, by Wilcoxon sign rank.

    P < 0.0001, by anova.

    P £ 0.05, by Student’s t-test.

Between group broad analyses:

§    P £ 0.02, by Wilcoxon rank sum; P £ 0.02, by Student’s t-test.

||   P < 0.04, by aligned ranks test; P < 0.02, by Student’s t-test; P < 0.03, by anova.

Safety information:

    SAEs = serious adverse events.

#   Discontinuing for lack of efficacy (LOE)/adverse events (AE) at one year, excluding deaths.

**  Number of explants through August 1996, excluding deaths.

††         All deaths occurred by the long-term follow-up closing date of August 1996.


    For completeness, Study E04 data—which included patients younger than 12 and those with generalized seizures—are presented in Tables 3 and 4.

Figure 2 and Table 5, which follow, show the results from Study E05, the largest and most recent of the randomized, blinded, active control studies:

Figure 2. Change in Seizure Frequency,
Patient Distribution

(With Corresponding Table)

All E05 patients completing effectiveness evaluation, N=196

 

Table 5. Principal Effectiveness Statistics (E05)

All patients in E05 effectiveness analyses, N=196

Percentage Change (Seizures/Day) from Baseline

Statistics

High (94)

Low (102)

Difference

Median

-23%

-21%

N/A

25%, 75% Quartiles

-8.9%, -49%

4.0%, -43%

N/A

95% Confidence intervals

-35%, -21%

-23%, -7.7%

-23%, -2.3%

Range (min, max)

Mean ± SD

-100%, 52%

- 89%, 171%

-23%, -2.3%

-28% ± 34%

-15% ± 39%

-13%* ± 37%

* Difference is statistically significant (P < 0.05) by analysis of variance (P=0.032) and by Cochran-Mantel-Haenszel aligned ranks (P=0.040).

Patient response to VNS Therapy was examined using statistical modeling (examining group characteristics) and an evaluation of individual patients. No useful predictors were found of an increase or a decrease in seizure frequency.

Conclusions: Patients with refractory partial onset seizures treated with HIGH VNS Therapy had a statistically significant decrease in frequency of seizures, compared with the baseline and compared with patients treated with LOW (active control) VNS Therapy. As indicated in Figure 2, most patients had a reduction in seizure frequency; some, however, had either no change or an increase in seizure frequency. The most common treatment-related adverse events were voice alteration and dyspnea. Treatment was well tolerated, with 97 percent (306 of 314) of the implanted patients continuing into the long-term follow-up phase of the study.


7.1.      Long-Term Data from Uncontrolled Follow Up

Long-term data (> 3 months’ stimulation) were collected on all available E01 through E04 study patients (see Table 6). At the time the VNS Therapy System Premarket Approval Application was considered by the U. S. Food and Drug Administration, long-term data on most Study E05 patients were not available. These long-term follow-up data are uncontrolled because they come from an open-label protocol in which both the antiepileptic drug medications and the VNS Therapy device settings were allowed to be changed.

Ninety-five percent (95%) of patients were continuing one year after their original implant; 82 percent were still receiving stimulation at two years; and 69 percent were receiving stimulation at three years. Some E04 patients had not yet had the opportunity to reach two or three years of stimulation and therefore were not used in the calculations. Additionally, 28 E03 patients were implanted outside the United States in countries that later received commercial approval, and data were available through one year of stimulation only.

 

Table 6. Patient Summary Chart

Patients continuing treatment as of 8/22/96

Study

E01

E02

E03

E04

Total

No. of patients randomized/stimulated

10

5

115

123

253

No. of patients entering long-term phase

10

5

113

123

251

No. of continuing patients being treated for up to 1 year/No. started

10/10

5/5

111/115

112/121*

238/251

No. of continuing patients being treated for up to 2 years/No. started

9/10

4/5

71/87

58/70

142/172

No. of continuing patients being treated for up to 3 years/No. started

7/10

3/5

57/87

21§24

88/126

 

*  Two E04 Study patients had not been implanted long enough to reach the one-year date after implantation.

  Twenty-eight (N=28) commercial European patients were excluded from follow up after one year of treatment due to the commercial release of the VNS Therapy System in those countries.

  As of 8/22/96, only 70 patients had been implanted long enough to reach the two-year treatment period; 58 of the 70 were continuing.

§  As of 8/22/96, only 24 patients had been implanted long enough to reach the three-year treatment period; 21 of the 24 were continuing.

Table 7 shows the number of patients included in the efficacy analysis. It is apparent from the table that not all continuing patients were used in the efficacy analysis. This difference was mostly because of missing data (some patients kept only sporadic records over the long term), although two patients were not used because they had had lobectomy surgery, which had affected their seizure rates.

Table 7. Patients Used for Efficacy Analysis

Study

E01

E02

E03

E04

Total

 

No. of patients randomized/stimulated

10

5

115

123

253

 

No. of patients entering long-term phase

10

5

113

123

251

 

No. of patients used in
1-year efficacy analysis/
No. Stimulated

10/10

4/5

102/111

86/112

202/238

 

No. of patients used in
2-year efficacy analysis/
No. Stimulated

8/9

2/4

51/71*

34/58

95/142

 

No. of patients used in
3-year efficacy analysis/
No. Stimulated

4/7

2/3

49/57

0

55/67

 

*   Of the 71 patients continuing, efficacy data were available for only 51.

  Of the 58 patients, efficacy data were available for only 34.

  No data were available at the three-year time for the E04 patients.

7.1.1.      Long-Term Results

Available long-term data from uncontrolled, open-label protocols during which antiepileptic drug and VNS Therapy device setting changes were allowed suggest improved efficacy over the first 24 months of treatment, with stabilization of this improvement after two years (see Figure 3). As evident from Table 7, these long-term data are limited at years two and three, with no patients being represented in the three-year analysis from Studies E04 or E05. There can be no assurances that the efficacy of the VNS Therapy treatment will continue to improve or will not decline over time, nor can there be assurances that additional long-term data will not reveal new adverse information presently unknown to Cyberonics. However, currently available long-term data do not suggest an increase or a worsening of adverse events, or a decline in efficacy.


Figure 3. Median Percentage Change
in Seizure Frequency

 

*  The acute phase results include seizure frequencies of the E03 Study LOW stimulation group, which included one-half the E03 patients, N=57.

    Patients were permitted to change their AEDs during these long-term follow-up studies, and these changes may have contributed to the change in seizure frequency.

7.2.            Other Information

In the United States, the VNS Therapy System is approved for use in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications. Unlike the two randomized studies, Study E04, an open-label safety study, included patients 12 years old and younger, and patients with generalized seizures. Sixteen patients under age 12, ranging from 3.6 to 12 years old, were evaluated. (Two additional patients had unevaluable seizure data.) These patients were found to have a 17.9 percent median decrease in seizures during the acute phase, with 31 percent of the patients experiencing a greater than 50 percent decrease.

Additionally, 25 patients with generalized seizures were evaluated. (Two additional patients had unevaluable seizure data.) These patients were found to have a 46.6 percent median decrease in seizures during the acute phase, with 44 percent experiencing a greater than 50 percent decrease. The E04 results (N=116 analyzed), including patients younger than 12 and those with generalized seizures, showed a 22 percent median decrease during the acute phase, with 29 percent of the patients experiencing a greater than 50 percent decrease.

The E04 results (N=86 analyzed), excluding patients younger than 12 and those with generalized seizures, showed an 18.3 percent median decrease in seizures during the acute phase, with 27.9 percent of the patients experiencing a greater than
50 percent decrease.

7.3.      Bibliography

A bibliography of animal and clinical studies is available from Cyberonics on request.

8.         INDIVIDUALIZATION OF TREATMENT

Patients should be started on stimulation at a low current setting (0.25 mA), and the current should be increased gradually to allow accommodation to the stimulation. For patient comfort, the output current should be increased in 0.25 mA increments until a comfortable tolerance level is reached. Physicians should appreciate that some patients will accommodate to stimulation levels over time and should therefore allow further increases (in 0.25 mA steps) in output current, if needed. (See the Model 250 Software Physician’s Manual.)

Table 8 lists the stimulation parameters used in the randomized, blinded, active control trials.

Table 8. High Stimulation Parameters (Optimal)

Stimulation Parameters

Normal Mode

Magnet Mode

Output current

0–3.5 mA

0–3.5 mA

Frequency

30 Hz

30 Hz<