###### Depression Physician's Manual {#depression-physicians-manual .unnumbered}

**VNS Therapy™ Pulse\
Model 102 Generator**

***and***

**VNS Therapy™ Pulse Duo\
Model 102R Generator**

March 2004

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

![](media/image1.png){width="1.9604166666666667in" height="0.9375in"}

REF 26-0005-6300/1\
 Copyright 2003, 2004 Cyberonics, Inc. Houston, Texas\
All rights reserved

Table of Contents

[1-D. BRIEF DEVICE DESCRIPTION 1](#brief-device-description)

[2-D. INTENDED USE / INDICATIONS 2](#intended-use-indications)

[3-D. CONTRAINDICATIONS 3](#contraindications)

[4-D. Warnings 5](#warnings)

[5-D. PRECAUTIONS 8](#precautions)

[5.1-D. Sterilization, Storage, and Handling
11](#sterilization-storage-and-handling)

[5.2-D. Lead Evaluation and Connection
11](#lead-evaluation-and-connection)

[5.3-D. Environmental and Medical Therapy\
Hazards 11](#environmental-and-medical-therapy-hazards)

[6-D. Adverse events 12](#adverse-events)

[6.1-D. Serious Adverse Events 13](#serious-adverse-events-saes)

[6.2-D. Safety Considerations Specific to\
Depressed Patients
14](#safety-considerations-specific-to-depressed-patients)

[6.3-D. High Rate of Subject Continuation
15](#high-rate-of-subject-continuation)

[6.4-D. AE Relationship to VNS Therapy
16](#ae-relationship-to-vns-therapy)

[6.5-D. AEs Related to Implantation 17](#aes-related-to-implantation)

[6.6-D. High Continuation Rate 25](#high-continuation-rate)

[6.7-D. Conclusion 26](#conclusion)

[7-D. CLINICAL STUDIES of depression
27](#clinical-studies-of-depression)

[7.1-D. Safety and efficacy 27](#safety-and-efficacy)

[7.2-D. Mechanism of Action 27](#mechanism-of-action)

[7.3-D. Feasibility (D-01) Study 28](#feasibility-d-01-study)

[7.4-D. Pivotal (D-02) Study 28](#pivotal-d-02-study)

[7.5-D. Pivotal (D-02) Study,\
Long-term Phase 30](#pivotal-d-02-study-long-term-phase)

[7.6-D. Data Analysis 33](#data-analysis)

[7.7-D. Results 35](#results)

[7.8-D. Results: Comparative (D-04) Study
39](#results-comparative-d-04-study)

[7.9-D. Efficacy Improved and Sustained\
Over Time 43](#efficacy-improved-and-sustained-over-time)

[7.10-D. Clinical Benefit Over Time 43](#clinical-benefit-over-time)

[7.11-D. Antidepressant Treatments 47](#antidepressant-treatments)

[7.12-D. ECT Versus VNS Therapy-Sustained\
Response 49](#ect-versus-vns-therapy-sustained-response)

[7.13-D. Benefits/Clinical Utility of\
VNS Therapy in the Treatment of\
Depression
50](#benefitsclinical-utility-of-vns-therapy-in-the-treatment-of-depression)

[7.14-D. Bibliography 51](#bibliography)

[8-D. INDIVIDUALIZATION OF TREATMENT
52](#individualization-of-treatment)

[9-D. PATIENT COUNSELING INFORMATION
55](#patient-counseling-information)

[10-D. CONFORMANCE TO STANDARDS 56](#conformance-to-standards)

[11-D. HOW SUPPLIED 57](#how-supplied)

[12-D. OPERATOR'S MANUAL 58](#operators-manual)

[12.1-D. Directions for Use 58](#directions-for-use)

[12.2-D. Physician Training/Information
58](#physician-traininginformation)

[12.3-D. Mechanism of Action 58](#mechanism-of-action-1)

[12.4-D. Detailed Device Description 59](#detailed-device-description)

[13-D. Cyberonics' Limited Replacement Warranty
60](#cyberonics-limited-replacement-warranty)

[14-D. TROUBLESHOOTING 61](#troubleshooting)

[15-D. Information and Support 62](#information-and-support)

[16-D. GLOSSARY 63](#glossary)

Tables

[Table D-1. Implantation-Related Adverse Events\
Occurring in ≥5% of Subjects During the\
Acute Phase of the Pivotal (D-02) Study 17](#__RefHeading___Toc54420402)

[Table D-2. Implantation-related Adverse Events \< 5%\
Acute Phase-Pivotal (D-02) study 18](#__RefHeading___Toc54420403)

[Table D-3. Stimulation-Related Adverse Events ≥5% Treatment Versus
Control, Acute Phase -\
Pivotal (D-02) study 20](#__RefHeading___Toc54420404)

[Table D-4. Stimulation-related Adverse Events \<5%\
in the Treatment Group, Acute Phase-\
Pivotal (D-02) Study 22](#__RefHeading___Toc54420405)

[Table D-5. Percentage of Stimulation-related Adverse Events ≥5% By
Quarters of Stimulation -\
Pivotal (D-02) Study 23](#__RefHeading___Toc54420406)

[Table D-6. Stimulation-Related Adverse Events,\
Long-term Phase, \<5% Pivotal (D-02)\
Study 24](#__RefHeading___Toc54420407)

[Table D-7. Description of Subjects in Pivotal (D-02)\
and Comparative (D-04) Studies 32](#__RefHeading___Toc54420408)

[Table D-8. Responders, Remitters, and Percent Change Pivotal (D-02)
Study 12-Month Completer Population 38](#__RefHeading___Toc54420409)

[Table D-9. Stimulation Parameters at 12 months of\
VNS Therapy in the pivotal (D-02) study 52](#__RefHeading___Toc54420410)

Figures

[Figure D-1. Pivotal Study, Long-Term 35](#__RefHeading___Toc54412825)

[Figure D-2. Responder and Remitter Quarterly Results
37](#__RefHeading___Toc54412826)

[Figure D-3. Comparison of IDS-SR Scores of Pivotal\
Versus Comparative (D-04) Study Subjects\
by Study Visit 42](#__RefHeading___Toc54412827)

[Figure D-4. Categories Identifying Degree of Clinical Benefit in D-02
(HRSD~24~) 12-Month\
Completer Population (N=174) 44](#__RefHeading___Toc54412828)

[Figure D-5. 12-Month Outcomes of Extraordinary,\
Highly Meaningful or Meaningful Clinical Benefit At 3 and 12 Months
(N=56) 46](#__RefHeading___Toc54412829)

[Figure D-6. 12-Month Outcomes of Pivotal (D-02)\
Subjects with Minimal or Less Clinical\
Benefit At 3 and 12 Months (N=118) 47](#__RefHeading___Toc54412830)

# BRIEF DEVICE DESCRIPTION

Please refer to Section 1 in the epilepsy part of this manual for a
brief description of the components of the VNS Therapy System,
compatibility, and symbols and definitions used in this manual.

# INTENDED USE / INDICATIONS

The VNS Therapy System is indicated for the adjunctive long-term
treatment of chronic or recurrent depression\* for patients over the age
of 18 who are experiencing a major depressive episode that has not had
an adequate response to two or more adequate antidepressant
treatments\*.

\* See glossary for a definition of terms.

# CONTRAINDICATIONS

![](media/image2.wmf) The VNS Therapy System cannot be used in patients
after a bilateral or left cervical vagotomy.

![](media/image3.wmf) 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.

# Warnings

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

![](media/image4.wmf) **Unapproved uses**\
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.

![](media/image5.wmf) **Unspecified nerve, muscle, or tissue
stimulation**\
The safety and efficacy of the VNS Therapy System have not been
established for stimulation of the **right vagus nerve** or of any other
nerve, muscle, or tissue.

![](media/image6.wmf) **Excessive stimulation**\
**Note: Use of the Magnet to activate stimulation is not recommended for
patients with depression. The Magnet Mode output current should remain
at 0.0mA for patients with depression.**

> 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.

![](media/image7.wmf) **Device manipulation**\
Patients who manipulate the Pulse Generator and Lead through the skin
(Twiddler's Syndrome) may damage or disconnect the Lead from the Pulse
Generator and/or possibly cause damage to the vagus nerve.

![](media/image8.wmf) **Swallowing difficulties**\
**Aspiration** may result from the increased swallowing difficulties
reported by some patients during stimulation. Patients with
**pre-existing swallowing difficulties** are at greater risk for
aspiration.

![](media/image9.wmf) **Device malfunction**\
**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.

![](media/image10.wmf) **Dysfunctional cardiac conduction systems\
**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.

![](media/image11.wmf) **Obstructive sleep apnea**\
Patients with obstructive sleep apnea (OSA) may have an increase in
apneic events during stimulation. Cyberonics recommends care when
treating patients with pre-existing OSA. Lowering stimulus frequency or
prolonging OFF time may prevent exacerbation of OSA.

![](media/image12.wmf) **VNS Therapy device is not curative**\
Physicians should warn patients that VNS Therapy has not been proven to
be a cure for depression.

# PRECAUTIONS

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

![](media/image13.wmf) **Laryngeal irritation** may result from
stimulation. **Patients who smoke** may have an increased risk of
laryngeal irritation.

![](media/image14.wmf) **Dyspnea** may result from stimulation.
**Patients with chronic obstructive pulmonary disease** may have an
increased risk of dyspnea.

![](media/image15.wmf) It is important to follow recommended
implantation procedures and intraoperative product testing described in
this manual. During the intraoperative Lead Test, infrequent incidents
of bradycardia and/or asystole have occurred. If asystole, severe
bradycardia (heart rate \< 40 bpm), or a clinically significant change
in heart rate is encountered during a Lead Test or during initiation of
stimulation, physicians should be prepared to follow guidelines
consistent with Advanced Cardiac Life Support (ACLS).

Additionally, postoperative bradycardia can occur among patients with
certain underlying cardiac arrhythmias. If a patient has experienced
asystole, severe bradycardia (heart rate \< 40 bpm) or a clinically
significant change in heart rate during a Lead Test at the time of
initial device implantation, the patient should be placed on a cardiac
monitor during initiation of stimulation.

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

![](media/image16.wmf) **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).

![](media/image17.wmf) **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.

![](media/image18.wmf) **Resetting the Pulse Generator** turns the
device OFF (output current = 0.0 mA), and all device history information
is lost. The device history information should be printed out before
resetting.

![](media/image19.wmf) **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.

![](media/image20.wmf) 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.

![](media/image21.wmf) The VNS Therapy System is indicated for use only
in stimulating the **left vagus nerve** in the neck area inside the
carotid sheath.

![](media/image22.wmf) 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.**

![](media/image23.wmf) **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 Section 12.2 in
the epilepsy part of this manual.

![](media/image24.wmf) A **neck brace** can be used by the patient for
the first week to help ensure proper Lead stabilization.

![](media/image25.wmf) **Appropriate physician training** is very
important.

-   **Prescribing physicians** should be experienced in the diagnosis
    and treatment of depression and should be familiar with the
    programming and use of the VNS Therapy System.

-   **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 Section 12.2 in the epilepsy part of this
    manual for more information.)

## Sterilization, Storage, and Handling

Please refer to Section 5.1 in the epilepsy part of this manual for
information on sterilization, storage, and handling of the VNS Therapy
System.

## Lead Evaluation and Connection

Please refer to Section 5.2 in the epilepsy part of this manual for
information on evaluating and connecting the Lead component of the VNS
Therapy System.

## Environmental and Medical Therapy Hazards

Please refer to Section 5.3 in the epilepsy part of this manual for
information on environmental and medical therapy hazards that may affect
the VNS Therapy System, devices that may be affected by the VNS Therapy
System, and guidance for disposal of the Pulse Generator.

# Adverse events

The safety profile of VNS Therapy observed in the feasibility (D-01) and
pivotal (D-02) studies is consistent with the known safety profile of
VNS Therapy that has emerged from the epilepsy clinical trials and more
than 56,000 patient-years of commercial use. The adjunctive use of VNS
Therapy among patients with treatment-resistant, chronic or recurrent
depression appears to be associated with similar adverse effects and
safety risks as its use among patients with treatment-refractory
epilepsy.

It is important to note that subjects often had comorbid illnesses and
almost all study subjects were also receiving antidepressant and other
drugs that could have contributed to these events.

## Serious Adverse Events (SAEs)

### Low Number of SAEs Reflects Safety of VNS Therapy

During the pivotal (D-02) study, 13 SAEs were considered related to the
implant procedure (wound infection, asystole, bradycardia, syncope,
abnormal thinking, vocal cord paralysis \[two reports\], aspiration
pneumonia, voice alteration, device site reaction \[two reports\], acute
renal failure, and urinary retention). Investigators did not report any
SAE to be related to stimulation. During the long-term phase of the
pivotal (D-02) study, nine SAEs were considered at least possibly
related to stimulation (sudden death of unknown cause, syncope \[2
reports\], dizziness, a manic depressive reaction in a subject with
bipolar disorder, hemorrhage GI, vocal cord paralysis, paresthesia, and
an incident of worsening depression for which the investigator
considered VNS Therapy a possible but unlikely contributor). These
relatively few reports of SAEs attributable to VNS Therapy implantation
or stimulation reflect the relative safety of VNS Therapy.

### No Direct Role of VNS Therapy in Deaths

Four deaths occurred during the pivotal (D-02) study: one after the
subject had given consent, but before the subject was implanted; the
second, a suicide; the third, a death of unknown cause; and the fourth,
a subject who developed multi-organ failure. No direct role of VNS
Therapy is evident in any of these deaths.

### Unanticipated Adverse Device Effects

Two events in the pivotal (D-02) study met criteria for an unanticipated
adverse device effect (UADE)---see Glossary for definition. Both these
events were non-specific complications of surgery related to the implant
procedure and occurred before stimulation began. One UADE was an episode
of acute renal failure thought to be secondary to antibiotic
administration, and the other was an episode of altered mental status
thought to be due to perioperative narcotic administration.

## Safety Considerations Specific to Depressed Patients

Two specific safety concerns in the use of all antidepressant therapies
are the precipitation of manic or hypomanic episodes and the possible
effect of antidepressant therapy on suicidal ideation and behavior.

### Antidepressant Treatments and Manic or Hypomanic Reaction 

Although patients with bipolar disorder experience manic episodes as the
cardinal feature of their disorder, effective antidepressant therapies
themselves can occasionally precipitate a manic or hypomanic episode.
Antidepressant therapies can also occasionally precipitate a manic or
hypomanic episode in patients without a prior history of mania who are
being treated for a major depressive episode.

#### Manic Reactions Within Expected Range

In the pivotal (D-02) study, six hypomanic or manic reactions were
identified according to DSM IV criteria and the Young Mania Rating Scale
(YMRS). Five were observed in subjects with a known history of prior
hypomanic or manic episodes. Considering that lithium therapy, the
standard drug used to control mania, had not been successful for these
subjects with bipolar disorders, the incidence of hypomanic or manic
reactions in the pivotal (D-02) study seems to be well within the
expected range.

### 56% of VNS Therapy Subjects Showed Decreased Suicidal Ideation Scores

At 12 months of VNS Therapy, 90% of the subjects in the pivotal (D-02)
study showed either improvement (56%) or no change (34%) in their scores
on item 3 of the HRSD~24~, which measures suicidal ideation.

## High Rate of Subject Continuation

### Low Rate of Discontinuations Because of Adverse Events

In the feasibility (D-01) study, no discontinuations were related to
adverse events attributed to VNS Therapy or the implant procedure. By
the time all continuing subjects in the pivotal (D-02) study had at
least 1 year of VNS Therapy, 3% (8/235) of the subjects had discontinued
VNS Therapy for an adverse event-related reason. The reasons for these
eight discontinuations included one case each of suicide,
implant-related infection necessitating device removal, hoarseness,
lightheadedness, post-operative pain, chest and arm pain, sudden death
(of unknown cause), and worsening depression (reported by the
investigator as an adverse event rather than as lack of efficacy).

This low rate of discontinuation attributed to adverse events
demonstrates that VNS Therapy is very well tolerated in subjects with
treatment-resistant depression.

### Implant-Related Adverse Events 

Because all eligible study subjects in the pivotal (D-02) study were
implanted with the VNS Therapy System device, no control was available
to assess whether an adverse event was related to the surgery.
Investigators, therefore, determined which adverse events were related
to implantation. The events reported as related to implantation and
occurring in at least 10% of the subjects who received VNS Therapy
System implants in the pivotal (D-02) study were device site pain,
device site reaction, incision pain, dysphagia, hypesthesia,
pharyngitis, voice alteration, and incision site reaction. Most of the
individual incidences of these events resolved within 30 days.

Hypesthesia (generally described as a localized numbness) and voice
alteration, however, tended to be more persistent in some individuals.
For example, in 17 of 25 reports of implantation-related hypesthesia,
the event continued beyond 3 months. Hypesthesia would be an expected
side effect of nerve injury during surgery. The persistence of voice
alteration in some subjects is difficult to assess because it could
represent surgical injury to the innervation of the larynx, but vagus
nerve stimulation itself can cause voice alteration.

## AE Relationship to VNS Therapy

Investigators determined whether an adverse event (AE) was possibly,
probably, or definitely related to implantation of or stimulation by the
VNS Therapy Pulse Generator and Lead.

## AEs Related to Implantation

Tables D-1 and D-2 list implantation-related adverse events.

1.  []{#__RefHeading___Toc54420402 .anchor}Implantation-Related Adverse
    Events Occurring in ≥5% of Subjects During the Acute Phase of the
    Pivotal (D-02) Study

  -----------------------------------------------------------------------
  **Body System**                      **D-02 Acute Phase Incidence of
                                       Surgery-Related AEs (N=235)**
  ------------------------------------ ----------------------------------
  Body as a Whole                      

  Incision Pain                        36%

  Device Site Pain                     23%

  Device Site Reaction                 14%

  Headache                             8%

  Neck Pain                            7%

  Pain                                 7%

  Cardiovascular System                

  None ≥5% Reported                    

  Digestive System                     

  Dysphagia                            11%

  Nausea                               9%

  Endocrine System                     

  None ≥5% Reported                    

  Hemic and Lymphatic System           

  None ≥5% Reported                    

  Metabolic and Nutritional Disorders  

  None ≥5% Reported                    

  Musculoskeletal                      

  None ≥5% Reported                    

  Nervous System                       

  Hypesthesia                          11%

  Paresthesia                          6%

  Respiratory System                   

  Voice Alteration                     33%

  Pharyngitis                          13%

  Dyspnea                              9%

  Cough Increased                      6%

  Skin and Appendages                  

  Incision Site Reaction               29%

  Special Senses                       

  None\>5% Reported                    

  Urogenital                           

  None \>5% Reported                   
  -----------------------------------------------------------------------

2.  []{#__RefHeading___Toc54420403 .anchor}Implantation-related Adverse
    Events \< 5% Acute Phase-Pivotal (D-02) study

  -----------------------------------------------------------------------
  **Body System**
  -----------------------------------------------------------------------
  Body as a Whole

  Abdominal Pain, Allergic Reaction, Anaphylactic Reaction, Asthenia,
  Back Pain, Chest Pain, Chills, Fever, Infection, Injection Site Pain,
  Neck Rigidity, Photosensitivity Reaction, Surgical Injury, Viral
  Infection, Wound Infection

  Cardiovascular System

  Arrhythmia, Asystole, Bradycardia, Hemorrhage, Migraine, Palpitation,
  Syncope, Tachycardia

  Digestive System

  Anorexia, Constipation, Diarrhea, Dyspepsia, Flatulence,
  Gastrointestinal Disorder, Vomiting

  Endocrine System

  Thyroid Disorder

  Hemic and Lymphatic System

  Ecchymosis, Lymphadenopathy

  Metabolic and Nutritional Disorders

  Edema, Hyperglycemia, Peripheral Edema

  Musculoskeletal

  Arthralgia, Joint Disorder, Myalgia, Myasthenia

  Nervous System

  Abnormal Dreams, Agitation, Ataxia, Dizziness, Hypertonia, Insomnia,
  Nervousness, Neuralgia, Neuropathy, Thinking Abnormal, Tremor,
  Vasodilatation, Vocal Cord Paralysis
  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  **Body System**
  -----------------------------------------------------------------------
  Respiratory System

  Aspiration Pneumonia, Asthma, Atelectasis, Bronchitis, Hiccup, Hypoxia,
  Laryngismus, Laryngitis, Lung Disorder, Respiratory Disorder, Rhinitis,
  Sinusitis, Sputum Increased

  Skin and Appendages

  Application Site Reaction, Maculopapular Rash, Pruritus, Rash, Sweating

  Special Senses

  Ear Disorder, Ear Pain, Tinnitus

  Urogenital

  Acute Kidney Failure, Dysuria, Metrorrhagia, Urinary Retention
  -----------------------------------------------------------------------

### Stimulation-Related Adverse Events

The investigators determined that seven events occurring at a frequency
of 10% or greater among subjects assigned to the treatment group were
stimulation-related: voice alteration (55%), cough increased (24%),
dyspnea (19%), neck pain (16%), dysphagia (13%), laryngismus (11%), and
paresthesia (10%). After 60 days, subjects were no longer reporting most
of the seven events. Laryngismus (7 of 13) and voice alteration (53 of
68), however, tended to be more persistent with subjects continuing to
report the event for more than 3 months.

Tables D-3 and D-4 list stimulation-related adverse events that occurred
during the acute phase of the pivotal (D-02) study.

3.  []{#__RefHeading___Toc54420404 .anchor}Stimulation-Related Adverse
    Events ≥5% Treatment Versus Control,\
    Acute Phase - Pivotal (D-02) study

+---------------------------+-------------------+----------------------+
| **Body System**           | **D-02**          | **D-02 Sham-control  |
|                           |                   | \* (N=116)**         |
|                           | **Treatment       |                      |
|                           | (N=119)**         |                      |
+===========================+===================+======================+
| Body as a Whole           |                   |                      |
+---------------------------+-------------------+----------------------+
| Incision Pain             | 6 (5%)            | 3 (3%)               |
+---------------------------+-------------------+----------------------+
| Neck Pain                 | 19 (16%)          | 1 (\<1%)             |
+---------------------------+-------------------+----------------------+
| Cardiovascular System     |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Digestive System          |                   |                      |
+---------------------------+-------------------+----------------------+
| Dysphagia                 | 15 (13%)          | 0 (0%)               |
+---------------------------+-------------------+----------------------+
| Nausea                    | 8 (7%)            | 1 (\<1%)             |
+---------------------------+-------------------+----------------------+
| Endocrine System          |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Hemic and Lymphatic       |                   |                      |
| System                    |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Metabolic & Nutritional   |                   |                      |
| Disorders                 |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Musculoskeletal System    |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Nervous System            |                   |                      |
+---------------------------+-------------------+----------------------+
| Paresthesia               | 12 (10%)          | 3 (3%)               |
+---------------------------+-------------------+----------------------+

+---------------------------+-------------------+----------------------+
| **Body System**           | **D-02**          | **D-02 Sham-control  |
|                           |                   | \* (N=116)**         |
|                           | **Treatment       |                      |
|                           | (N=119)**         |                      |
+===========================+===================+======================+
| Respiratory System        |                   |                      |
+---------------------------+-------------------+----------------------+
| Cough Increased           | 28 (24%)          | 2 (2%)               |
+---------------------------+-------------------+----------------------+
| Dyspnea                   | 23 (19%)          | 2 (2%)               |
+---------------------------+-------------------+----------------------+
| Laryngitis                | 13 (11%)          | 0 (0%)               |
+---------------------------+-------------------+----------------------+
| Pharyngitis               | 9 (8%)            | 1 (\<1%)             |
+---------------------------+-------------------+----------------------+
| Voice Alteration          | 65 (55%)          | 3 (3%)               |
+---------------------------+-------------------+----------------------+
| Skin and Appendages       |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Special Senses            |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+
| Urogenital                |                   |                      |
+---------------------------+-------------------+----------------------+
| None ≥5%                  |                   |                      |
+---------------------------+-------------------+----------------------+

**\***Note: These subjects were not receiving stimulation during this
phase.

4.  []{#__RefHeading___Toc54420405 .anchor}Stimulation-related Adverse
    Events \<5% in the Treatment Group, Acute Phase-Pivotal (D-02) Study

  -----------------------------------------------------------------------
  **Body System**

  Body as a Whole

  Asthenia, Chest Pain, Device Site Pain, Device Site Reaction, Headache,
  Neck Rigidity, Pain

  Cardiovascular System

  Migraine, Palpitation, Postural Hypotension, Syncope, Tachycardia

  Digestive System

  Anorexia, Constipation, Diarrhea, Dyspepsia, Eructation, Flatulence,
  Increased Appetite, Vomiting

  Endocrine System

  None reported

  Hemic and Lymphatic System

  None reported

  Metabolic and Nutritional Disorders

  Weight Gain

  Musculoskeletal

  Myalgia, Myasthenia

  Nervous System

  Abnormal Dreams, Agitation, Depression, Dizziness, Emotional Lability,
  Hypertonia, Hypesthesia, Insomnia, Manic Reaction, Nervousness, Sleep
  Disorder, Somnolence, Twitching, Vasodilatation

  Respiratory System

  Asthma, Hiccup, Respiratory Disorder, Rhinitis

  Skin and Appendages

  Incision Site Reaction

  Special Senses

  Ear Pain, Tinnitus

  Urogenital

  Amenorrhea
  -----------------------------------------------------------------------

### Stimulation-related Events, Long-term Phase

Tables D-5 and D-6 list adverse events that occurred at an incidence of
≥5% and \<5%, respectively. These adverse events were observed over
quarters of stimulation. Subjects are counted only once within each body
system, preferred descriptive term, eg, neck pain, nausea, or
pharyngitis, and time interval.

5.  []{#__RefHeading___Toc54420406 .anchor}Percentage of
    Stimulation-related Adverse Events ≥5% By Quarters of Stimulation -
    Pivotal (D-02) Study

+-------------------------------+--------+--------+--------+---------+
| **Body System**               | **3    | **6    | **9    | **12    |
|                               | Mos.** | Mos.** | Mos.** | Mos.**  |
|                               |        |        |        |         |
|                               | **N    | **N    | **N    | **      |
|                               | =232** | =225** | =218** | N=209** |
+-------------------------------+--------+--------+--------+---------+
| Body as a Whole               |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Neck Pain                     | 16%    | 11%    | 14%    | 13%     |
+-------------------------------+--------+--------+--------+---------+
| Pain                          | 6%     | 6%     | 5%     | 6%      |
+-------------------------------+--------+--------+--------+---------+
| Headache                      | 5%     | 4%     | 4%     | 4%      |
+-------------------------------+--------+--------+--------+---------+
| Cardiovascular System         |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Digestive System              |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Dysphagia                     | 13%    | 8%     | 7%     | 4%      |
+-------------------------------+--------+--------+--------+---------+
| Nausea                        | 6%     | 2%     | 2%     | 2%      |
+-------------------------------+--------+--------+--------+---------+
| Endocrine System              |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Hemic and Lymphatic System    |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Metabolic & Nutritional       |        |        |        |         |
| Disorders                     |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Musculoskeletal System        |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Nervous System                |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Paresthesia                   | 11%    | 7%     | 4%     | 4%      |
+-------------------------------+--------+--------+--------+---------+
| Respiratory System            |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Voice Alteration              | 58%    | 60%    | 57%    | 54%     |
+-------------------------------+--------+--------+--------+---------+
| Cough Increased               | 24%    | 9%     | 7%     | 6%      |
+-------------------------------+--------+--------+--------+---------+
| Dyspnea                       | 14%    | 16%    | 15%    | 16%     |
+-------------------------------+--------+--------+--------+---------+
| Laryngismus                   | 10%    | 8%     | 7%     | 5%      |
+-------------------------------+--------+--------+--------+---------+
| Pharyngitis                   | 6%     | 4%     | 4%     | 5%      |
+-------------------------------+--------+--------+--------+---------+
| Skin and Appendages           |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Special Senses                |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| Urogenital                    |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+
| None ≥5% Reported             |        |        |        |         |
+-------------------------------+--------+--------+--------+---------+

6.  []{#__RefHeading___Toc54420407 .anchor}Stimulation-Related Adverse
    Events, Long-term Phase, \<5% Pivotal (D-02) Study

  -----------------------------------------------------------------------
  **Body System**

  Body as a Whole

  Abdominal Pain, Asthenia, Chest Pain, Device Site Pain, Device Site
  Reaction, Flu Syndrome, Incision Pain, Neck Rigidity, Viral Infection

  Cardiovascular System

  Bradycardia, Hypotension, Migraine, Palpitation, Postural Hypotension,
  Syncope, Tachycardia

  Digestive System

  Anorexia, Colitis, Constipation, Diarrhea, Dyspepsia, Eructation,
  Flatulence, Gastritis, Gastrointestinal Disorder, Increased Appetite,
  Vomiting

  Endocrine System

  None reported

  Hemic and Lymphatic System

  None reported

  Metabolic and Nutritional Disorders

  Weight Gain, Weight Loss

  Musculoskeletal

  Athralgia, Joint Disorder, Myalgia

  Nervous System

  Abnormal Dreams, Agitation, Amnesia, Anxiety, Confusion, Depression,
  Dizziness, Dry Mouth, Emotional Lability, Hypertension, Hypertonia,
  Hypesthesia, Insomnia, Manic Reaction, Manic Depressive Reaction,
  Nervousness, Sleep Disorder, Somnolence, Speech Disorder, Thinking
  Abnormal, Tremor, Twitching, Vasodilatation, Vocal Cord Paralysis

  Respiratory System

  Asthma, Hiccup, Respiratory Disorder, Rhinitis, Stridor

  Skin and Appendages

  Incision Site Reaction, Sweating

  Special Senses

  Amblyopia, Deafness, Ear Pain, Eye Pain, Tinnitus

  Urogenital

  Amenorrhea, Menstrual Disorder
  -----------------------------------------------------------------------

##  High Continuation Rate

Of the 295 subjects implanted during both the feasibility\
(D-01) and pivotal studies (D-02), 270 subjects (92%) were still
receiving VNS Therapy at 12 months.

### Device safety

The VNS Therapy System performed according to its labeling. Most device
issues were communication difficulties easily resolved by repositioning
the programming wand or replacing the programming wand batteries. One
high lead impedance occurred requiring replacement; a lead break due to
fatigue at the electrode bifurcation was noted. Most device complaints
were resolved on the day of initial complaint.

### Most Adverse Events Decreased Over Time

Subjects who reported adverse events during the first 3 months of
stimulation and continued to report those adverse events were monitored
by 3-month intervals. The largest decreases were noted between the first
and second quarters of stimulation. The most notable exception was voice
alteration. During the first quarter, 135 of 209 subjects (65%) reported
voice alteration. Of those 135 subjects, 90 continued to report it
during the fourth quarter of stimulation.

### Very Few Late-emerging Adverse Events

After the first 3 months of stimulation, the incidence of first-reported
adverse events did not exceed 1.3% of total study subjects for any
event.

### Adverse Events Classification 

Investigators rated adverse events as mild, moderate, or severe
according to the protocol definitions: mild events were transient and
easily tolerated by the subject; moderate events caused discomfort and
interrupted usual activities; severe events caused considerable
interference with the subject's usual activities.

### Most Adverse Events Rated Mild or Moderate

Most adverse events for the feasibility (D-01) study and pivotal (D-02)
study were mild or moderate. Because the pivotal (D-02) study included a
sham-control group, further analysis of severity rating was performed.
At 3 months of VNS Therapy, there were 280 (43%) adverse events that
were categorized as mild, 293 (45%) as moderate, and 73 (11%) as severe
in the pivotal (D-02) study sham-control group. The pivotal (D-02) study
treatment group had 360 (47%) adverse events categorized as mild, 349
(45%) as moderate, and 61 (8%) as severe. The frequency of events rated
as severe during the pivotal (D-02) study was slightly less in the
treatment group than in the sham-control group. Stimulation did not seem
to impose a higher risk for severe events.

## Conclusion

VNS Therapy is a tolerable therapy (92% continuation rate at 1 year
D-01/D-02) that is also safe. The adverse and serious adverse events
reported in the depression studies were similar to those in epilepsy
studies. VNS Therapy is a safe and tolerable therapy for persons with
treatment-resistant depression.

# CLINICAL STUDIES of depression

## Safety and efficacy

Results of clinical trials demonstrated the safety and efficacy of VNS
Therapy for treatment-resistant depression. For most subjects,
antidepressant effectiveness improved over time and was sustained long
term. After 12 months of VNS Therapy, more than one in two subjects
received a meaningful clinical benefit and one in six was essentially
free of depressive symptoms. Of the subjects who showed an initial
benefit, 73% maintained the benefit after 12 months. Almost 50% of
subjects who had no benefit at 3 months had meaningful benefit after 12
months. The treatment was well tolerated as evidenced by 90% of the
study participants remaining in the study after 1 year. Most side
effects, typically related to stimulation, were rated as mild or
moderate and many lessened with time.

## Mechanism of Action

Although the mechanism of action is not completely understood, several
studies have shown that VNS Therapy influences neurotransmitters and
brain structures thought to be involved in
depression.[^1]^,^[^2]^,^[^3]^,^[^4] In addition, brain imaging studies
have shown that VNS Therapy modulates blood flow or metabolism in many
areas of the brain that are implicated in neuropsychiatric
disorders.Error: Reference source not found

Reports of improved mood among patients receiving VNS Therapy for
treatment of epilepsy prompted studies among subjects with
treatment-resistant depression. During the clinical trials that
evaluated VNS Therapy as a treatment for epilepsy, some subjects
experienced an improvement in mood. In some cases these improvements
seemed to exceed what would be expected based on the amount of
improvement observed in the subjects' epilepsy.

## Feasibility (D-01) Study

The primary efficacy measure in the open-label feasibility (D-01) study
was the percent of subjects responding (response was defined as a 50% or
greater improvement in the HSRD~28~ score). Of the 59 subjects with
evaluable data, 18 (31%) responded at acute study exit, which was 12
weeks after implantation. Observation of subjects continued. After 1
year of VNS Therapy, 25 of 55 subjects (45%) responded, and after 2
years, 18 of 42 (43%) responded*.* One in six subjects reached remission
(defined as HRSD~28~ scores less than 10) after 1 and 2 years of
treatment. Other measures of depressive symptoms (CGI, MADRS, BDI,
IDS-SR) and quality of life (MOS-36) supported the HRSD~28~ scores.

## Pivotal (D-02) Study 

The pivotal (D-02) study of VNS Therapy consisted of both an acute and a
long-term phase to collect data regarding the safety and efficacy of VNS
Therapy as an adjunctive treatment for persons with chronic or recurrent
treatment-resistant depression.

### Pivotal Study, Acute Phase (D-02 Acute)

The acute phase was a 12-week (after implantation), double-blind,
randomized, parallel-group sham treatment-controlled, multi-center
study. Subjects were assigned randomly to either the treatment
(stimulation) group or control (sham) group and results of these two
groups were compared. All subjects in both groups meeting the
eligibility criteria for participation in the study were implanted with
the VNS Therapy Pulse Generator and VNS Therapy Lead. The VNS Therapy
System remained OFF for 2 weeks after implantation to allow for recovery
from surgery. Most subjects in the pivotal (D-02) study were being
treated with one or more antidepressant medications at the time of
enrollment. Medications were to remain constant at the pre-implant
baseline dosages throughout the acute phase for both the treatment and
sham-control groups.

**Sham Control:** Sham-control group subjects were treated the same as
the treatment group, except that the output current of the device
remained at 0.0 mA so that it did not deliver stimulation during the
acute phase.

**Treatment Group:** Two weeks after implant, stimulation was initiated
for the treatment group. Over the next 2 weeks, parameters were adjusted
to patient tolerance, then remained constant for the rest of the acute
phase (8 weeks). Decreases in stimulation parameters were permitted to
accommodate patient tolerance.

## Pivotal (D-02) Study, Long-term Phase

All pivotal (D-02) study subjects who completed the acute phase were
eligible to continue into the long-term extension phase, during which
all subjects received active VNS Therapy. During the first 10 weeks of
the extension phase, sham-control subjects (also referred to as the
delayed treatment group for the long-term phase), received stimulation
parameter adjustments. Weekly or every other week clinic visits and
assessments were identical to those experienced by the treatment group
during the acute phase. Otherwise, the protocol specified monthly clinic
visits for both groups through 12 months of active VNS Therapy. Various
assessments, including depression ratings, were performed throughout
this period. During the long-term extension phase, investigational site
programmers were allowed to adjust stimulation parameters as clinically
indicated. Additionally, concomitant antidepressant treatments could be
added, removed, or adjusted as clinically indicated.

### Comparative Assessments

The comparative (D-04) study was a long-term, observational, prospective
study to collect data regarding usual standard-of-care for
treatment-resistant chronic or recurrent depression in persons who were
experiencing a major depressive episode at the time of admission.
Clinical (depression assessments) and quality of life outcomes were
assessed at baseline, 3, 6, 9, and 12 months.

#### Concomitant Therapies

Subjects enrolled in the comparative (D-04) study met the same
enrollment criteria regarding chronicity or recurrence of depression,
previous treatment failures, and severity of depression as subjects in
the pivotal (D-02) study. Because the study was observational in nature,
the protocol did not specify therapies for the treatment of depression;
rather the physician managing the study subject's depression selected
therapy according to clinical judgment. Thus antidepressant therapy in
the comparative (D-04) study comprised "standard of care" treatment
(also known as "treatment as usual"). The entire range of treatment
options available for the comparative (D-04) study subjects was also
available to the pivotal (D-02) study subjects as concomitant treatment
to their VNS Therapy. Thus subjects in both the long-term pivotal (D-02)
extension and the comparative (D-04) study received standard of care
treatment; however, only the pivotal (D-02) study subjects received VNS
Therapy.

The comparative (D-04) study was conducted at 13 investigational sites,
12 of which were also pivotal (D-02) study sites. The similarities in
the key inclusion criteria and study sites provide a basis to expect
that the demographic and disease characteristics of both groups would be
comparable, which was confirmed by the results of the analyses conducted
to examine the comparability. These subjects provided a comparison group
for the pivotal (D-02) study subjects at 12 months.

7.  []{#__RefHeading___Toc54420408 .anchor}Description of Subjects in
    Pivotal (D-02) and Comparative (D-04) Studies

+--------------------------------------------+-----------+-------------+
|                                            | **        | **Co        |
|                                            | Pivotal** | mparative** |
|                                            |           |             |
|                                            | **(D-02)\ | **(D-04)\   |
|                                            | Study**   | Study**     |
+--------------------------------------------+-----------+-------------+
| Number of subjects                         | 205       | 124         |
|                                            |           |             |
| (evaluable population)                     |           |             |
+--------------------------------------------+-----------+-------------+
| Mean age (years)                           | 46.3      | 45.5        |
+--------------------------------------------+-----------+-------------+
| Number of females                          | 131 (64%) | 85 (69%)    |
+--------------------------------------------+-----------+-------------+
| Diagnosis: Unipolar                        | 185 (90%) | 109 (88%)   |
+--------------------------------------------+-----------+-------------+
| Diagnosis: Bipolar                         | 20 (10%)  | 15 (12%)    |
+--------------------------------------------+-----------+-------------+
| Mean duration of illness (years)           | 25.5      | 25.8        |
+--------------------------------------------+-----------+-------------+
| Mean duration of this depressive episode   | 49.9      | 68.6        |
| (months)                                   |           |             |
+--------------------------------------------+-----------+-------------+
| Subjects who previously received ECT\      | 108 (53%) | 32 (26%)    |
| during lifetime                            |           |             |
+--------------------------------------------+-----------+-------------+
| Subjects who previously received ECT\      | 72 (35%)  | 15 (12%)    |
| during current major depressive episode    |           |             |
+--------------------------------------------+-----------+-------------+
| Number of failed adequate trials of        | 3.5       | 3.5         |
| antidepressants during this current major  |           |             |
| depressive episode                         |           |             |
+--------------------------------------------+-----------+-------------+
| Mean age at onset of first symptoms of     | 21.8      | 20.8        |
| depression, mania, hypomania (years)       |           |             |
+--------------------------------------------+-----------+-------------+
| Mean number of previous hospital           | 2.7       | 2.1         |
| admissions for mood disorders in lifetime  |           |             |
+--------------------------------------------+-----------+-------------+

##  Data Analysis

### Pivotal (D-02) study 

The primary efficacy variable for both the acute and the long-term
phases of the pivotal (D-02) study was the Hamilton Rating Scale for
Depression-24 item (HRSD~24~). For the acute-phase analysis, the
HRSD~24~ response rate (percentage of subjects with a ≥50% improvement
from baseline to 3 months, acute phase exit) was compared between the
treatment and the sham-control groups. For the long-term phase, a linear
regression model was used to assess the changes in HRSD~24~ raw scores.
Secondary efficacy analyses included 1) between-group comparisons of the
Inventory of Depressive Symptomatology-Self Report (IDS-SR), 2) the
Clinical Global Impression (CGI), and 3) Medical Outcome Survey 36-Item
Short Form Health Survey (MOS SF-36).

### Comparative (D-04) Study

The primary efficacy variable for the D-02 and D-04 comparative analysis
was the IDS-SR (raw scores). Multiple assessments with the IDS-SR
allowed use of a linear regression model for the analysis. The HRSD~24~
was used as a secondary assessment variable to analyze differences in
response rates and raw score changes between subjects in the pivotal
(D-02) and comparative (D-04) studies. Subjects in the comparative
(D-04) study were assessed with the HRSD~24~ only at baseline and 12
months.

Secondary analyses included IDS-SR average change, IDS-SR response,
IDS-SR complete response, IDS-SR sustained response, HRSD~24~ average
change, and HRSD~24~ response. Other secondary analyses included the
CGI.

### Propensity Scores

To reduce selection bias, propensity scores, defined as the conditional
probability of being treated given the covariates, were used to balance
the covariates between the two groups. Propensity scores provide a
scalar summary of the covariate (eg, age, number of prior depressive
episodes, etc) information. They are not limited by traditional methods
of adjustment, which can only use a limited number of covariates for
adjustment. Propensity scores were calculated for the pivotal (D-02)
study and comparative (D-04) study groups and used in the linear
regression analysis.

### Responder Rate

For each subject, the percentage of improvement in the assessment scores
between baseline and post-treatment was calculated as follows.

{Mean Assessment Score (Visit B1 and Visit B2)-(assessment score at
endpoint)} divided by Mean Assessment Score (Visit B1 and Visit B2) x
100

Response was defined as ≥50% decrease in the endpoint score compared
with the baseline score. Subjects with \<50% reduction in the assessment
were considered non-responders.

All statistical analyses were performed using the updated SAS version
8.2. All statistical tests were two-sided and performed at the 0.050
level of significance. No adjustments were made for multiple outcome
measures.

1.  []{#__RefHeading___Toc54412825 .anchor} Pivotal Study, Long-Term

![](media/image26.wmf)

\*4 subjects did not meet continuation criteria (HRSD~24~ \<18)

\*\*Subjects not included in Efficacy Analysis

6 subjects: did not continue into long-term phase

20 subjects: not evaluable

## Results

Figure D-1 provides a flow chart of subjects from the acute phase
through the long-term phase of the pivotal (D-02) study. Information
describing subjects in the pivotal (D-02) and comparative (D-04) studies
is presented in Table D-7.

### Results: Acute phase, pivotal (D-02) study

In the primary efficacy measure, HRSD~24~ response rate, (the percentage
of subjects achieving a ≥50% improvement in HRSD~24~ total score from
baseline to acute phase exit), 15% of the treatment group and 10% of the
sham-control group were responders (p=0.238). Analyses using a secondary
efficacy parameter, the IDS-SR, did show a statistically significant
advantage for VNS Therapy over sham treatment: 17% response versus 7%
response (p=0.032) using the last observation carried forward (LOCF)
method.

#### Consistent numerical trends supported VNS Therapy effectiveness

Although at 3 months the study did not show a statistically significant
difference between the efficacy of VNS Therapy versus sham treatment in
the population as defined by this study, the consistent numerical trends
and occasional results of statistical significance on secondary outcome
measures did provide supportive evidence of the effectiveness of VNS
Therapy for subjects with treatment-resistant depression.

2.  []{#__RefHeading___Toc54412826 .anchor} Responder and Remitter
    Quarterly Results

![](media/image27.wmf)

### Results: Long-Term Phase, Pivotal Study (D-02)

During long-term VNS Therapy, the D-02 subjects exhibited statistically
significant and clinically meaningful improvement. The primary analysis
found statistically significant improvement in HRSD~24~ scores averaged
over 12 months (p\<0.001). Additionally, clinical significance was
shown, using HRSD~24~, in numbers and proportions of subjects achieving
response (30%), remission (complete response; 17%). This improvement was
consistent and seen across multiple assessments; the results of the
IDS-SR, MADRS, and CGI corroborated the HRSD~24~ analyses (Figure D-2,
evaluable population, and Table D-8, 12-month completer population).

8.  []{#__RefHeading___Toc54420409 .anchor}Responders, Remitters, and
    Percent Change Pivotal (D-02) Study\
    12-Month Completer Population

  ---------------------- ----------------- ---------------- ------------------
                         **HRSD~24~^a^**   **IDS-SR^b^**    **MADRS**

                         12-Month Visit    12-Month Visit   12-Month Visit

  Responders -- N (%)                                       

  Treatment              34/103 (33%)^2^   25/102 (25%)     34/103 (33%)^2^

  Delayed treatment      18/71 (25%)       13/71 (18%)      22/71 (31%)^1^

  All 12-Month           52/174^a^         38/173 (22%)^1^  56/174 (32%)^3^
  Completers             (30%)^3^                           

  Remitters -- N (%)                                        

  Treatment              19/103 (18%)^2^   16/102 (16%)^1^  25/103 (24%)^2^

  Delayed treatment      10/71 (14%)       10/71 (14%)      16/71(23%)^1\ c^

  All 12-Month           29/174 (17%)^2^   26/173 (15%)^2^  41/174 (24%)^3^
  Completers                                                

  Percent Change                                            

  Treatment              31.9% ^3^         28% ^3^          33% ^3^

  Delayed treatment      26.5% ^3^         17% ^3^          26% ^3^

  All 12-Month           29.7% ^3^         24% ^3^          30% ^3^
  Completers                                                
  ---------------------- ----------------- ---------------- ------------------

^1^ p\<0.05; ^2^ p\<0.01; ^3^ p\<0.001; Response and Remitter used the
Exact McNemar's test compared with 3 months; Percent Change used the
paired t-test (change from pre-stimulation baseline); Median percent
change used the Wilcoxon Signed Rank test to determine whether the
median was different from zero.

^a^ Three subjects did not have 12-month HRSD~24~ assessments. (These 3
subjects did have 11-month assessments).

^b^ One subject did not have a baseline IDS-SR assessment and several
others did not have 12-month assessments, which accounts for the varying
Ns in the comparison of HRSD~24~ with IDS-SR data.

^c^ Two delayed-treatment subjects did not have 12-month MADRS
assessments.

**Treatment Group:** Subjects who received VNS Therapy during the
pivotal trial (D-02) acute phase

**Control Group (Delayed Treatment Group):** Subjects who received no
VNS Therapy during the pivotal trial (D-02) acute phase, then began
receiving VNS Therapy at the beginning of the pivotal trial (D-02)
long-term phase

### Improved Quality of Life 

The observed improvement in depression among subjects in the pivotal
(D-02) study long-term phase was supported by improved quality of life
as measured by the MOS SF-36. Significant improvement was observed in
several of the MOS SF-36 subscales: Vitality, Social Functioning, Role
Functioning -- Emotional, Mental Health (p\<0.01), and the Physical and
General Health Perceptions (p\<0.05).

### Tolerability - Subjects Continuing VNS Therapy at 12 months

Of the 295 subjects implanted during both the Feasibility (D-01) and
pivotal Studies (D-02), 270 subjects (92%) were still receiving VNS
Therapy after 12 months.

## Results: Comparative (D-04) Study

The D-04 study provided a control group of similarly ill subjects who
received usual standard-of-care therapies for 12 months but were not
implanted with the VNS Therapy device. See Table D-7.

### Well-Matched Populations

This comparison analyzed evaluable populations of 205 VNS Therapy
subjects (D-02) and 124 usual standard-of-care subjects (D-04). Groups
were well matched, with similar demographic, psychiatric, and mood
disorder treatment histories. The only relevant significant differences
between groups were in duration of current episode (with more months
found in the D-04 group) and previous ECT history (with higher usage of
ECT found in the D-02 group). These differences likely counter each
other regarding the degree of treatment resistance of these two groups,
and are handled within the efficacy analysis by use of a propensity
adjustment. Clearly, the D-04 group was a similarly ill subject
population.

### Statistically Significant Improvement with Adjunctive VNS Therapy

The primary and secondary analyses comparing subjects treated with
adjunctive VNS Therapy and usual standard of care (pivotal, D-02) with
subjects treated with usual standard of care alone (comparative, D-04)
showed that adjunctive VNS Therapy and usual standard of care produces
statistically significantly greater improvement in depressive symptoms
over 1 year of treatment. The primary efficacy analysis, a repeated
measures linear regression analysis of the IDS-SR over 1 year, showed a
statistically significant (p\<0.001 evaluable; p\<0.001 intent to treat)
difference at a very robust level favoring adjunctive VNS Therapy and
usual standard of care. (See Figure D-3.)

#### Secondary Analyses

Additionally, essentially all secondary analyses were statistically
significant and showed VNS Therapy improved depressive symptoms more
than usual standard-of-care after 12 months of therapy. IDS average
change, IDS response, IDS complete response, IDS sustained response,
HRSD~24~ average change, and HRSD~24~ response were all statistically
significant. Last observation carried forward (LOCF) analyses supported
the *a-priori* analyses.

### Efficacy for Depressive Symptoms

These results indicate that adjunctive VNS Therapy provides significant
benefit (efficacy) for depressive symptoms in a chronically ill or
recurrent, treatment-resistant depression population, when compared with
usual standard-of-care.

3.  []{#__RefHeading___Toc54412827 .anchor} Comparison of IDS-SR Scores
    of Pivotal Versus Comparative (D-04) Study Subjects by Study Visit

![](media/image28.wmf)

## Efficacy Improved and Sustained Over Time 

Subjects in the long-term phase of the pivotal (D-02) study continued to
show improvement throughout 12-months of VNS Therapy (Figure D-3). At 12
months, 30% of subjects met criteria as responders or remitters, using
HRSD~24~, compared with 16% of subjects who were responders or remitters
at 3 months. Although the regression models consistently indicated the
greatest improvement during the first 3 months of treatment, proportions
of subjects achieving response and remission at 12 months were
consistently greater than at 3 months of treatment. For example,
HRSD~24~ scores improved 19.7% from 3 to 12 months of VNS Therapy.
Additionally, when subjects were assigned to categories according to
improvement, almost 50% of subjects who had no improvement at 3 months
had some degree of benefit at 12 months of VNS Therapy.

## Clinical Benefit Over Time 

To explore whether these subjects were receiving benefit that was not
fully reflected in the response rates, they were assigned to categories
according to "clinical benefit." Clinical benefit was categorized as
extraordinary (≥75% improvement in HRSD~24~), highly meaningful (50% to
\<75%), meaningful (25% to \<50%), minimal (0% to \<25%), and worsened
(less than 0%). This scale is consistent with studies in many chronic
illnesses that define less than a 50% improvement as a clinically
meaningful response (eg, schizophrenia, obsessive compulsive disorder).

At 12 months of VNS Therapy, 30% of subjects experienced either an
extraordinary or a highly meaningful clinical benefit and 25% had a
meaningful benefit (55% had at least a meaningful benefit). This benefit
was greater at 12 months compared with 3 months (Stuart-Maxwell test,
p\<0.001) (Figure D-4).

4.  []{#__RefHeading___Toc54412828 .anchor} Categories Identifying
    Degree of Clinical Benefit in D-02 (HRSD~24~)\
    12-Month Completer Population (N=174)

![](media/image29.wmf)The clinical benefit categorization can also be
analyzed to further characterize benefit over time. Both those who had
early benefit and those who did not were assessed later (12 months). Of
the 56 subjects who had benefit at 3 months, 41 (73%) continued to have
benefit at 12 months (Figure D-5). The results of this analysis show
that most of the subjects in the pivotal (D-02) study maintained or
increased their improvement: 34 of 56 subjects (61%) who exhibited
extraordinary, highly meaningful or meaningful clinical benefit at 3
months of VNS Therapy exhibited the *same* or *more* improvement at 12
months of VNS Therapy. Of the 118 subjects who were without at least a
meaningful benefit at 3 months, 56 (47%) had at least meaningful benefit
at 12 months of VNS Therapy (Figure D-6). This indicates that a large
portion of those who do not benefit early will receive meaningful
benefit over time. More importantly for a treatment-resistant
population, most subjects who have early meaningful benefit continue to
maintain this meaningful benefit at 12 months.

5.  []{#__RefHeading___Toc54412829 .anchor} 12-Month Outcomes of
    Extraordinary, Highly Meaningful or Meaningful Clinical Benefit At 3
    and 12 Months (N=56)

![](media/image30.wmf)

6.  []{#__RefHeading___Toc54412830 .anchor} 12-Month Outcomes of Pivotal
    (D-02) Subjects with Minimal or Less Clinical Benefit\
    At 3 and 12 Months (N=118)

![](media/image31.wmf)

## Antidepressant Treatments

Electroconvulsive therapy (ECT) use was similar among the pivotal (D-02)
and comparative (D-04) subjects (7% and 6%, respectively).

### Antidepressant Drugs and Response

Antidepressant drug use was greater among pivotal (D-02) study subjects
who were non-responders and comparative (D-04) study subjects overall
than among the pivotal (D-02) study subjects who achieved a response.
During the 12 months, 77% of the pivotal (D-02) study non-responders and
81% of all comparative (D-04) study subjects either added a new
antidepressant treatment or increased an existing antidepressant dose by
an antidepressant resistance rating (ARR) level of one or more.

In contrast, only 56% of the pivotal (D-02) study subjects who were
responders to VNS Therapy either added a new antidepressant treatment or
increased an existing antidepressant dose by an antidepressant
resistance rating (ARR) level of one or more.

Twice as many pivotal (D-02) study responders (44%) had no ARR changes
or removed or decreased medications by at least one ARR level or were
not taking medications as compared with non-responders (23%). These
findings strongly support the conclusion that the VNS Therapy responders
derived their benefit from VNS Therapy (or an augmentation effect of VNS
Therapy) rather than from the concomitant antidepressant treatments.

Although medication changes were examined above and implied that
medication changes in the subjects was not a consequential determinant
of outcome, the possibility that only the D-02 subjects who showed
improvement had *meaningful* medication sensitivity changes remains
(though highly improbable). To address this possibility an additional
medication analysis was performed using the primary D-02 vs D-04
repeated measures linear regression methods. This approach uses a
missing data paradigm to calculate the difference between the D-02 and
D-04 groups that would have been observed under conditions where no
inter-current changes in medications would have occurred in the D-02
group. This approach censors the D-02 IDS-SR scores after the point
where a subject had a significant medication increase (ARR increase) or
ECT treatment (all subsequent data points are carried forward and
replace all subsequent non-missing IDS measurements). Therefore, all
improvement for the D-02 group would be attributable to VNS Therapy
alone and not to other treatment changes. Note that this approach is
asymmetric, no censoring was performed on the D-04 data. Though this is
a conservative approach, since D-04 treatment is akin to \"best flexible
medication (and/or ECT) management\", it would be inappropriate to
censor ratings after a treatment change. This extremely conservative
analysis approached significance in the D-02 group as compared to D-04
(p = 0.052; 95% CI -0.37, 0.00) for the evaluable population.

## ECT Versus VNS Therapy-Sustained Response

As a point of reference, the acute effect of ECT diminishes over time. A
recent ECT study[^5] shows that within 6 months of achieving remission
(HRSD\<=10), the relapse rate was 64%. Sackeim et al[^6] reported that
relapse after ECT response was almost twice as likely among patients who
were medication-resistant: only 32% of such patients maintained their
response during the year after ECT. The proportion of VNS
Therapy-treated subjects maintaining their response compares favorably
with that of patients who received ECT.

## Benefits/Clinical Utility of VNS Therapy in the Treatment of Depression

Clinical trials supported the use of VNS Therapy as an adjunctive
long-term treatment of chronic or recurrent depression for subjects
experiencing a major depressive episode that had not had an adequate
response to two or more adequate antidepressant treatments.

Expected results of adjunctive VNS Therapy for treatment-resistant
depression

-   a response (ie, at least a 50% improvement in depressive symptoms)
    in at least 15% to 17% of patients after 10 weeks of treatment

-   a response in at least 21% to 37% of patients after 12 months of
    treatment

-   remission (complete response) of depressive symptoms in at least 15%
    to 17% of patients after 12 months of treatment

-   a sustained response in 13% to 27% of patients during 12 months of
    treatment

-   successful maintenance of the initial improvement in a high
    percentage of patients (eg, 73% to 77% of patients who had
    meaningful or greater benefit at 3 months of treatment maintained at
    least meaningful benefit after 12 months of treatment)

Benefits of non-systemic mechanism of action

-   a very well-tolerated therapy as indicated by the high continuation
    rate for therapy after 12 months (92%)

-   adverse effects essentially limited to those related to stimulation
    of the vagus nerve, ie, an absence of the systemic effects
    associated with drug therapy; many of the common adverse effects
    only occur when stimulation of the vagus nerve is actually occurring

-   the ability to halt acute stimulation-related adverse effects
    immediately through the use of magnet deactivation of stimulation

-   an absence of adverse cognitive and psychomotor effects

-   an absence of overdose toxicity

-   favorable findings in animal reproductive studies

-   ability to add VNS Therapy to antidepressant drug therapy without
    producing drug-drug interactions

-   assured compliance with the ability to turn off stimulation to
    control side effects, if desired, because VNS Therapy is programmed
    to work automatically without the need for patient action (ie, no
    pills to take)

## Bibliography

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

# INDIVIDUALIZATION OF TREATMENT

Patients should be started on stimulation at a low current output
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 D-9 lists the stimulation parameters reported at 12 months of VNS
Therapy in the pivotal (D-02) study.

9.  []{#__RefHeading___Toc54420410 .anchor}Stimulation Parameters at 12
    months of VNS Therapy in the pivotal (D-02) study

  -------------------------- ---------------------- ----------------------
  **Stimulation Parameters** **Median Value at 12   **Range**
                             months**               

  Output current             1.0                    0 to 2.25

  Frequency                  20 Hz                  2 to 30 Hz

  Pulse width                500 μsec               130 to 750 μsec

  ON time                    30 sec                 7 to 60 sec

  OFF time                   5 min                  0.3 to 180 min
  -------------------------- ---------------------- ----------------------

The magnet output current should be set to 0 mA.

![](media/image32.wmf) The safety and efficacy of this therapy have not
been systematically established for uses not covered in the "Intended
Use / Indications" section of this manual or in patients with the
following conditions:

-   Cardiac arrhythmias or other abnormalities

-   History of dysautonomias

-   History of previous therapeutic brain surgery

-   History of respiratory diseases or disorders, including dyspnea and
    asthma

-   History of ulcers (gastric, duodenal, or other)

-   History of vasovagal syncope

-   Neurological diseases other than epilepsy or depression

-   Only one vagus nerve

-   Other concurrent forms of brain stimulation

-   Pre-existing hoarseness

-   Pregnancy or nursing\*

\*Pre-clinical Study, Teratogenic Effects: There are no adequate and
well-controlled studies of VNS Therapy in pregnant women. Reproduction
studies have been performed using female rabbits stimulated with the
commercially available VNS Therapy System at stimulation dose settings
similar to those used for humans. These animal studies have revealed no
evidence of impaired fertility or harm to the fetus due to VNS Therapy.
Because animal reproduction studies are not always predictive of human
response and animal studies cannot address developmental abnormalities,
VNS should be used during pregnancy only if clearly needed. Although the
operating ranges of the VNS Therapy System and fetal monitors are
dissimilar and no interaction would be expected, testing has not been
performed. Therefore, the potential may exist for interaction between
the VNS Therapy System and fetal monitoring systems.

# PATIENT COUNSELING INFORMATION

In the unlikely event of uncomfortable adverse events, continuous
stimulation, or other malfunction, the patient must be advised to hold
or tape the magnet directly over the implanted Pulse Generator to
prevent additional stimulation. If patients or caregivers find this
procedure necessary, they should immediately notify the patient's
physician.

# CONFORMANCE TO STANDARDS

The VNS Therapy System conforms to the following standards:

-   American National Standards Institute (ANSI) and Association for the
    Advancement of Medical Instrumentation (AAMI) NS15 --- Implantable,
    peripheral nerve stimulators

-   EN 45502-1 --- Active Implantable Medical Devices: Requirements for
    the safety, marking, and information to be provided by the
    manufacturer

# HOW SUPPLIED

Implantable portions of the VNS Therapy System have been sterilized
using ethylene oxide gas (EO), and are supplied in a sterile package for
direct 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 date is marked on the outer package.

If the package has been exposed to extreme temperatures or moisture (see
Section 5.1 in the epilepsy part of this manual) or if there is any
indication of external damage, the package should be left unopened and
returned to Cyberonics.

# OPERATOR'S MANUAL

## Directions for Use

Please refer to Section 12.1 in the epilepsy part of this manual. The
Directions for Use are equivalent for epilepsy and depression with the
following exceptions.

-   For patients with depression, the Magnet Mode output current should
    always be programmed at 0.0 mA, the setting at which the Pulse
    Generator is shipped from Cyberonics.

-   Use of the Magnet Mode is limited to patients with epilepsy.
    Patients with epilepsy or their caregivers pass the magnet over the
    implanted Pulse Generator to activate on-demand delivery of a single
    train of vagus nerve stimulation and help abort or diminish a
    seizure.

-   Magnet Mode is not used for patients with depression.

## Physician Training/Information

Please refer to Section 12.2 in the epilepsy part of this manual.

## Mechanism of Action

Studies examining the central nervous system effects of vagus nerve
stimulation contributed to the rationale for VNS Therapy's use as an
antidepressant. Given the known projections of the vagus nerve within
the brain and preliminary work examining the effect of vagus nerve
stimulation on neurotransmitters, it seems that stimulating the vagus
nerve produces effects on norepinephrine and serotonin, the two
principal neurotransmitters implicated in the therapeutic effect of
antidepressant drugs.[^7]

Additionally, neuroimaging studies show that VNS Therapy modulates
activity in regions of the brain believed to be involved in mood
regulation, including limbic structures and specific cortical areas such
as the orbitofrontal cortex. Finally, Kral recently demonstrated that
VNS Therapy produces effects in the rat forced swim test (FST) paradigm
that are comparable to those of the tricyclic antidepressant drug
desipramine. The FST is a behavioral model commonly used to identify
potential antidepressant drugs.

Harden[^8] and Elger[^9] both reported improvements in the depression
scores of patients receiving VNS Therapy for the treatment of epilepsy
based on the use of standardized depression rating scales. These
improvements were not dependent on improvement in the patients'
seizures, and provided a basis for further investigation into the
antidepressant role of VNS Therapy.

## Detailed Device Description

Please refer to Section 12.4 in the epilepsy part of this manual for a
detailed device description.

# Cyberonics' Limited Replacement Warranty

Please refer to Section 13 in the epilepsy part of this manual.

# TROUBLESHOOTING

Please refer to Section 14 in the epilepsy part of this manual for
assistance in troubleshooting the VNS Therapy System.

# Information and Support

If there are questions regarding use of the VNS Therapy System or any of
its accessories, please contact Cyberonics:

**USA**\
Cyberonics, Inc.\
100 Cyberonics Boulevard\
Houston, Texas 77058

Telephone: (281) 228-7200\
Fax: (281) 218-9332

**For 24-hour support, please call:**\
**Telephone: (800) 332-1375** General Operator

> **Ext 7330** Technical Support\
> **Ext 7337** Clinical Support

**Europe**\
Cyberonics Europe, S.A.\
Belgicastraat 9\
1930 Zaventem\
Belgium

Telephone: 32 2 720 95 93\
Fax: 32 2 720 60 53

**Internet\
**www.cyberonics.com

# GLOSSARY

+-----------------------+----------------------------------------------+
| **ACLS**              | Advanced Cardiac Life Support                |
+-----------------------+----------------------------------------------+
| **AE (Adverse         | Any symptom, sign, illness, or experience    |
| Event)**              | that develops or worsens in severity and/or  |
|                       | frequency during the course of the study     |
|                       | (ie, any changes from baseline)              |
+-----------------------+----------------------------------------------+
| **ARR**               | Antidepressant Resistance Rating             |
+-----------------------+----------------------------------------------+
| **Baseline Periods**  |                                              |
+-----------------------+----------------------------------------------+
| > **D-02 Acute        | Two pre-implantation visits (Visits B1 and   |
| > Phase**             | B2) for both groups                          |
+-----------------------+----------------------------------------------+
| > **D-02 Long-Term    | For the evaluation of efficacy, the period   |
| > Phase**             | just before initiation of VNS Therapy;       |
|                       | during the long-term phase, the baseline     |
|                       | period of subjects who had been assigned to  |
|                       | the acute treatment group during the acute   |
|                       | phase differed from that of the subjects who |
|                       | had been assigned to the acute sham-control  |
|                       | group; because this baseline period is just  |
|                       | before treatment initiation for both groups, |
|                       | it is more comparable for analysis purposes  |
+-----------------------+----------------------------------------------+
| > **Treatment Group** | During the long-term phase, the baseline for |
|                       | the subjects who had been assigned to the    |
|                       | acute treatment group during the acute phase |
|                       | was the pre-implantation baseline (B1 & B2)  |
+-----------------------+----------------------------------------------+
| > **Delayed Treatment | During the long-term phase, the baseline for |
| > Group (Acute        | the subjects who had been assigned to the    |
| > Sham-control        | acute sham-control group during the acute    |
| > Group)**            | phase was the final two acute study visits,  |
|                       | V8 and V9 (acute study exit)                 |
+-----------------------+----------------------------------------------+
| > **D-04**            | The visit occurring after obtaining informed |
|                       | consent                                      |
+-----------------------+----------------------------------------------+
| **BOL**               | Beginning of Life                            |
+-----------------------+----------------------------------------------+
| **CGI (Clinical       | Two 7-point scales completed by the clinical |
| Global Impression)**  | rater to assess the subject's condition      |
|                       | regarding the severity of illness (CGI-S)    |
| Chronic or Recurrent  | and global improvement (CGI-I); the severity |
| Depression            | scale ranges from 1 -- "normal, not at all   |
|                       | ill" to 7 -- "among the most extremely ill   |
|                       | patients;" the improvement scale ranges from |
|                       | 1 -- "very much improved" to 7 -- "very much |
|                       | worse;" the CGI was developed by the NIMH to |
|                       | provide a standardized assessment with       |
|                       | clinically relevant anchors; it is one of    |
|                       | most widely used brief assessment tools in   |
|                       | psychiatry.                                  |
|                       |                                              |
|                       | A current major depressive episode that is   |
|                       | of at least two years in duration or a       |
|                       | current major depressive episode in a        |
|                       | patient with a history of multiple prior     |
|                       | episodes of depression.                      |
+-----------------------+----------------------------------------------+
| **Clinical Benefit**  | Degree of improvement in depression as       |
|                       | measured by the HRSD~24~; physician expert   |
|                       | consultants to the Sponsor developed this    |
|                       | designation                                  |
|                       |                                              |
|                       | -   extraordinary clinical benefit, at least |
|                       |     a 75% reduction from baseline            |
|                       |                                              |
|                       | -   highly meaningful clinical benefit, at   |
|                       |     least a 50% but less than a 75%          |
|                       |     reduction from baseline                  |
|                       |                                              |
|                       | -   meaningful clinical benefit, at least a  |
|                       |     25% but less than a 50% reduction from   |
|                       |     baseline                                 |
|                       |                                              |
|                       | -   minimal or no clinical benefit, at least |
|                       |     no change or less than a 25% reduction   |
|                       |     from baseline                            |
|                       |                                              |
|                       | -   worsened: increase in HRDS~24~ compared  |
|                       |     with baseline                            |
+-----------------------+----------------------------------------------+
| **Complete Response   | Subjects who scored less than a pre-defined  |
| (Complete Responder   | score were considered to have achieved a     |
| or Remitter)**        | complete response; scores representing       |
|                       | complete response were an HRSD~24~ raw score |
|                       | of 9 or less, a MADRS raw score of 10 or     |
|                       | less, or an IDS-SR raw score of 14 or less;  |
|                       | this corresponds to the concept of           |
|                       | remission, where the illness, in this case   |
|                       | depression, has few to no residual symptoms  |
|                       | present                                      |
+-----------------------+----------------------------------------------+
| **Duty Cycle**        | Percentage of time during which stimulation  |
|                       | occurs; stimulation time (programmed ON time |
|                       | plus 2 seconds of ramp-up time and 2 seconds |
|                       | of ramp-down time) divided by the sum of     |
|                       | signal ON and OFF times                      |
+-----------------------+----------------------------------------------+
| **EAS**               | Electronic article surveillance              |
+-----------------------+----------------------------------------------+
| **ECT                 | A treatment for depression and other         |
| (Electroconvulsive    | indications using electrodes on the surface  |
| Therapy)**            | of the head to direct electrical current     |
|                       | into the brain to induce generalized         |
|                       | seizures in a patient                        |
+-----------------------+----------------------------------------------+
| **EMI**               | Electromagnetic interference                 |
+-----------------------+----------------------------------------------+
| **EOS**               | End of service                               |
+-----------------------+----------------------------------------------+
| **ERI**               | Elective replacement indicator               |
+-----------------------+----------------------------------------------+
| **Excess Duty Cycle** | Duty cycle for which the ON time is greater  |
|                       | than the OFF time                            |
| **Failed Adequate     |                                              |
| Treatment**           | Failure to respond to electroconvulsive      |
|                       | therapy or an established antidepressant     |
|                       | drug administered at an adequate dose for an |
|                       | adequate duration.                           |
+-----------------------+----------------------------------------------+
| **FDA**               | United States Food and Drug Administration   |
+-----------------------+----------------------------------------------+
| **HRSD (Hamilton      | The HRSD is the most widely used rating      |
| Rating Scale for      | scale to assess symptoms of depression; a    |
| Depression)**         | multi-dimensional, observer-rated scale for  |
|                       | assessing overall depression severity; the   |
|                       | 28-item version of the scale was             |
|                       | administered to subjects in this study; per  |
|                       | protocol for the feasibility (D-01) study,   |
|                       | all 28 items were used for rating purposes;  |
|                       | per protocol for the pivotal (D-02) study,   |
|                       | only the first 24 items were used for rating |
|                       | purposes                                     |
+-----------------------+----------------------------------------------+
| **High Lead           | DC-DC Converter Codes greater than\          |
| Impedance**           | four on a device diagnostic test; not a sole |
|                       | determinant of a need for Lead replacement   |
+-----------------------+----------------------------------------------+
| **IDS-SR (Inventory   | A 30-item patient self-report rating of the  |
| of Depressive         | symptoms of mood and depression; this        |
| Symptomatology        | validated scale is becoming more widely used |
| Self-Report)**        | in clinical studies for assessing depression |
|                       | symptoms                                     |
+-----------------------+----------------------------------------------+
| **LIMIT Output        | Output current other than that which was     |
| Current**             | programmed; not a sole indicator of a device |
|                       | malfunction                                  |
+-----------------------+----------------------------------------------+
| **LOCF (Last          | This analysis technique uses the last        |
| Observation Carried   | available data point for subsequent time     |
| Forward)**            | points where data is missing                 |
+-----------------------+----------------------------------------------+
| **Long-term Phase**   | The portion of the pivotal (D-02) study      |
|                       | comprising follow-up after the acute portion |
|                       | of the study (after Visit 9); the long-term  |
|                       | portion included longitudinal follow-up by a |
|                       | blinded rater; the analysis of the long-term |
|                       | data included a repeated measures            |
|                       | within-subjects analysis of changes in       |
|                       | depressive symptoms at 12 months of VNS      |
|                       | Therapy                                      |
+-----------------------+----------------------------------------------+
| **MADRS (Montgomery   | A 10-item scale completed by the clinical    |
| Asberg Depression     | rater for assessing overall depression       |
| Rating Scale)**       | severity; this rating scale is common in     |
|                       | Europe                                       |
+-----------------------+----------------------------------------------+
| **Magnet Activation** | Brief magnet application and removal, which  |
|                       | initiates a stimulation                      |
+-----------------------+----------------------------------------------+
| **Microcoulomb**      | Product of current and time, or output       |
|                       | current (in mA) multiplied by the pulse      |
|                       | width (in msec)                              |
+-----------------------+----------------------------------------------+
| **MOS SF-36 (Medical  | A quality of life (QOL) tool that assesses   |
| Outcome Survey        | overall QOL and subscales of physical        |
| 36-Item Short Form    | functioning, role functioning-physical,      |
| Health Survey)**      | bodily pain, general health perceptions,     |
|                       | vitality, social functioning, role           |
|                       | functioning-emotional, mental health, and    |
|                       | overall change in health                     |
+-----------------------+----------------------------------------------+
| **Nominal             | Specific preset parameters available with    |
| Parameters**          | the software; Cyberonics suggests that the   |
|                       | Pulse Generator be set to these parameters   |
|                       | when patients are first stimulated (see      |
|                       | Section 12.1.1 in the epilepsy part of this  |
|                       | manual for specific nominal parameters)      |
+-----------------------+----------------------------------------------+
| **Output Current**    | Amount of electrical current delivered in a  |
|                       | single pulse of a stimulation, measured in   |
|                       | mA                                           |
+-----------------------+----------------------------------------------+
| **Patient Code**      | Any three-digit combination assigned by the  |
|                       | treating physician; generally programmed at  |
|                       | time of implantation; often patient's        |
|                       | initials: first, middle, last (or with a     |
|                       | hyphen for no known middle initial)          |
+-----------------------+----------------------------------------------+
| **Pulse Width**       | Duration of a single pulse within a          |
|                       | stimulation, measured in μsec                |
+-----------------------+----------------------------------------------+
| **Ramp-down**         | Gradual decrease over approximately 2        |
|                       | seconds in output current at the end of      |
|                       | stimulation greater than 10 Hz in signal     |
|                       | frequency                                    |
+-----------------------+----------------------------------------------+
| **Ramp-up**           | Gradual increase over approximately 2        |
|                       | seconds in output current at the beginning   |
|                       | of stimulation greater than 10 Hz in signal  |
|                       | frequency                                    |
+-----------------------+----------------------------------------------+
| **Refractory**        | Resistant to previous treatment alternatives |
|                       | defined by the treating physician; generally |
|                       | refers to the depressive symptoms of         |
|                       | patients who have tried and failed two or    |
|                       | more antidepressant treatments               |
+-----------------------+----------------------------------------------+
| **Remission           | See Complete Response                        |
| (Remitter)**          |                                              |
+-----------------------+----------------------------------------------+
| **Reset Parameters**  | Parameters to which the Pulse Generator      |
|                       | internally programs when it is reset (see    |
|                       | Section 12.1.1 in the epilepsy part of this  |
|                       | manual for specific reset parameters)        |
+-----------------------+----------------------------------------------+
| **Responder**         | At a given point, a subject with a ≥50%      |
|                       | reduction in HRSD, MADRS, or IDS-SR scores   |
|                       | at 12 months of stimulation compared with    |
|                       | baseline (see Baseline Period definition)    |
+-----------------------+----------------------------------------------+
| **Response            | A subject with at least a 50% reduction in   |
| (Responder)**         | depression assessment (ie, HRSD~24~, MADRS,  |
|                       | or IDS-SR) compared with the baseline        |
+-----------------------+----------------------------------------------+
| **SAE (Serious        | Any adverse event that resulted in any of    |
| Adverse Event)**      | the following outcomes: death, a life        |
|                       | threatening adverse experience, in-patient   |
|                       | hospitalization or prolongation of existing  |
|                       | hospitalization, a persistent or significant |
|                       | disability/incapacity, a congenital          |
|                       | anomaly/birth defect or any medical          |
|                       | intervention that prevents one of the above; |
|                       | the sponsor also included cancer and         |
|                       | pregnancy as SAEs                            |
+-----------------------+----------------------------------------------+
| **Signal Frequency**  | Repetition rate of pulses in a stimulation;  |
|                       | measured in number of pulses per second (Hz) |
+-----------------------+----------------------------------------------+
| **Signal OFF Time**   | Interval between stimulations when there is  |
|                       | no stimulation; measured in minutes          |
+-----------------------+----------------------------------------------+
| **Signal ON Time**    | Length of time the programmed output current |
|                       | is delivered (not including ramp-up and      |
|                       | ramp-down times); measured in seconds        |
+-----------------------+----------------------------------------------+
| **Statistically       | Results are considered statistically         |
| Significant**         | significant if p-values for the appropriate  |
|                       | statistical tests are less than or equal to  |
|                       | 0.050                                        |
+-----------------------+----------------------------------------------+
| **Stimulation         | For the treatment group, a 2-week period     |
| Adjustment Period**   | between Visit 2 and Visit 4 during the acute |
|                       | portion of the study. For the delayed        |
|                       | treatment group, a 2-week period between     |
|                       | Visit 9 and Visit 11 at the start of the     |
|                       | long-term study. The output current was      |
|                       | progressively increased to a comfortably     |
|                       | tolerable level during this period. After    |
|                       | this period, output current was held         |
|                       | constant for an 8-week period unless         |
|                       | reduction was necessary for tolerance        |
+-----------------------+----------------------------------------------+
| **Stimulation         | Programmed output current, signal frequency, |
| Parameters**          | pulse width, signal ON time, and signal OFF  |
|                       | time                                         |
+-----------------------+----------------------------------------------+
| **Stimulation Time**  | Therapeutic output of the VNS Therapy Pulse  |
|                       | Generator; consists of the signal ON time,   |
|                       | plus 2 seconds of ramp-up time and 2 seconds |
|                       | of ramp-down time                            |
+-----------------------+----------------------------------------------+
| *                     | Adverse events that occurred on or after the |
| *Treatment-Emergent** | implant and were not present during the      |
|                       | baseline period or events that were present  |
|                       | during baseline that worsened in severity    |
|                       | after the implant                            |
+-----------------------+----------------------------------------------+
| **Treatment           | Subjects who, after the randomization        |
| Failures**            | procedure, 1) exited the acute study before  |
|                       | Visit 9 due to treatment-related adverse     |
|                       | events, or a lack of efficacy 2) met the     |
|                       | suicide exclusion criteria, 3) attempted     |
|                       | suicide resulting in hospitalization of more |
|                       | than 3 days, or 4) developed mania or more   |
|                       | than three mood episodes as defined by       |
|                       | DSM-IV. Subjects who were treatment failures |
|                       | during the acute study were also considered  |
|                       | treatment failures for long-term analysis    |
|                       | purposes                                     |
+-----------------------+----------------------------------------------+
| **UADE (Unanticipated | Any serious adverse effect on health or      |
| Adverse Device        | safety or any life-threatening problem or    |
| Effect)**             | death caused by, or associated with, a       |
|                       | device, if that effect, problem, or death    |
|                       | was not previously identified in nature,     |
|                       | severity, or degree of incidence in the      |
|                       | investigational plan or application          |
|                       | (including a supplementary plan or           |
|                       | application); also, any other unanticipated  |
|                       | serious problem associated with a device     |
|                       | that relates to the rights, safety, or       |
|                       | welfare of patients                          |
+-----------------------+----------------------------------------------+
| **Vagus Nerve**       | Either of the pair of tenth cranial nerves   |
|                       | arising from the medulla and supplying       |
|                       | mainly the viscera, especially with          |
|                       | autonomic sensory and motor fibers; in this  |
|                       | document, vagus nerve always refers to the   |
|                       | *left* vagus nerve                           |
+-----------------------+----------------------------------------------+
| **VNS**               | Vagus Nerve Stimulation                      |
+-----------------------+----------------------------------------------+
| **VNS Therapy^™^**    | VNS delivered by Cyberonics' Neurocybernetic |
|                       | Prosthesis                                   |
+-----------------------+----------------------------------------------+
| **Within-Group**      | A statistical comparison including only      |
|                       | subjects in the same group assignment        |
+-----------------------+----------------------------------------------+
| **YMRS (Young Mania   | An 11-item scale completed by the clinical   |
| Rating Scale)**       | rater to assess the symptoms of mania        |
+-----------------------+----------------------------------------------+

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