Pilot Study of the Safety and Efficacy of Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Using an Active Implantable Vagal Nerve Stimulation Device in Patients With Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a devastating disease which affects approximately
1% of the population causing pain, and limiting physical activity and
employment. RA leads to permanent physical deformity and disability from
incompletely controlled inflammation and resultant structural damage to the
joints. In the last decade, the emergence of antagonists of tumor necrosis
factor (TNF)-alpha and other biological response modifiers as treatments for RA
has greatly improved the course and prognosis. Despite these advances, there
remains a great medical need as current treatments have significant safety and
cost disadvantages (McInnes, 2010).

The Cholinergic Anti-inflammatory Pathway (CAP) is an important physiological
regulator of inflammation. A wealth of preclinical evidence suggests that
activation of this pathway through electrical stimulation of the vagus nerve
(VNS) can also be a feasible and effective means of reducing pathological
systemic inflammation, and thus may represent a novel approach to treating RA
and other human inflammatory diseases (Tracey, 2009; van Maanen, 2009a).

The aim of the current protocol is to begin to test this hypothesis in a pilot
study in which RA patients will be surgically implanted with a commercially
available vagal nerve stimulation device and the clinical safety and efficacy
of neurostimulation of the cholinergic anti-inflammatory pathway (NCAP) will be
assessed using standard clinical measures and surrogate biomarkers of RA.

The primary efficacy objective is to determine the effect of NCAP on the
clinical signs and symptoms of rheumatoid arthritis as assessed by the 28 Joint
Disease Activity Score (DAS28).

The secondary efficacy objectives are to determine the effect of NCAP on:
* clinical signs and symptoms of rheumatoid arthritis as assessed by Americn
College of Rheumatology (ACR) response criteria and European League Against
Rheumatism (EULAR) response and remission criteria;
* health status and quality-of-life as assessed by the Euro-QoL EQ 5D
instrument;
* biomarkers of inflammation as assessed by serum cytokine and mediator levels,
changes in expression of circulating cell surface markers by FACS, and changes
in LPS-inducible cytokine release in whole blood assays; and
* joint inflammation as assessed by changes in gene and protein expression of
relevant inflammatory mediators in synovial biopsy tiss

The exploratory efficacy objectives are to:

* assess the clinical and biomarker response to a 14 day withdrawal of
stimulation following 42 consecutive days of active treatment, and;

* assess the clinical and biomarker response at visits other than the Day 42
primary endpoint visit

The safety objectives are to determine the safety of NCAP as assessed by
Adverse Events, Serious Adverse Events, 12 Lead ECG, Vital Signs, and Safety
Laboratory Studies

This will be an open-label multicenter study of the safety, efficacy and
anti-inflammatory biological activity of NCAP using vagal nerve stimulation
with a Cyberonics VNS implantable medical device.

Patients will sign informed consent and then will be screened, and if eligible
will be enrolled in the study and admitted for surgical implantation of the
device. After the implantation procedure and prior to hospital discharge the
device will be set in inactive mode and the patient will recuperate from
surgery for at least 14 days. The patients who consent to synovial biopsy will
have the biopsy procedure done either at the time of device implantation, or a
minimum of 4 days before the Day 0 Visit.
On Day 0, patients will visit the clinic, have baseline clinical assessments,
safety laboratory studies, and biomarker studies performed, and will be given a
single 60 second active stimulation at a frequency of 10Hz, with a 250
microsecond pulse duration, and an output current as maximally tolerated
between a minimum of 0.25 mA to a maximum of 2.0 mA. Following the single 60
second stimulation on day 0, the time course of the biological response will be
assessed with follow-up biomarker studies at several times thereafter. The
patients will return on days 1 and 4 for biomarker assessments.
On day 7, the patient will return to clinic, will be given another in-clinic
stimulation, and be instructed in the use of the device actuation magnet in
order to self-administer treatments at home once daily thereafter. Attempts
will be made at this and subsequent visits to increase the delivered output
current to the maximally tolerated level. The patient will return to clinic on
days 14, 21, and 28 for follow-up assessments. At the Day 28 Visit, if the
patient has not achieved a moderate or good EULAR clinical response (i.e., a
DAS28 level of 3.2 or better), the stimulation frequency will be increased from
once daily to four times daily.
On day 42, all subjects will have their device inactivated, and will enter a 14
day treatment withdrawal period. On the Day 56 Visit, following clinical and
biomarker assessments, the device will be reactivated and the treatment will be
re-initiated at the same level and on the same schedule as the patient was
receiving at the Day 42 Visit. This schedule will continue through the final
study visit at day 84.

Patients who meet any of the following criteria are not to be enrolled in this
study:
* Inability to provide informed consent
* Significant psychiatric disease or substance abuse
* History of unilateral or bilateral vagotomy
* History of recurrent vaso-vagal syncope episodes
* Known obstructive sleep apnea
* Known history of cardiac rhythm disturbances, atrio-ventricular block of
greater than first degree, or cardiac conduction pathway abnormalities other
than isolated right bundle branch block or isolated left anterior fascicle block
* Significant pharyngeal dysfunction or swallowing difficulties
* Pre-existing clinically significant vocal cord damage or hoarseness
* Previously implanted electrically active medical devices (e.g., cardiac
pacemakers, automatic implantable cardioverter-defibrillators)
* Asthma or chronic obstructive pulmonary disease not controlled by
medications, or any other disease causing clinically significant dyspnea at
time of screening
* Active peptic ulcer disease
* Intra-articular or parenteral corticosteroid treatment within 3 months of
enrollment
* Any investigational small molecule drug within 30 days of enrollment, or any
investigational monoclonal antibody or investigational soluble receptor within
3 months of enrollment

What are the general risks of participating in this research study?
Surgical placement of the device or stimulation of your vagus nerve with the
device may cause all, some or none of the adverse events listed below.
The most common side effects reported in patients who had the device placed to
treat their epilepsy or depression are symptoms of the throat including
hoarseness, voice changes, throat pain, and swallowing difficulties, as well as
shortness of breath, nausea, and indigestion. These symptoms happen almost only
during the time the device is actually delivering electrical stimulation.

Other uncommon side effects reported include:
* slowing or other alterations of the heart rate,
* scarring or infections of the tissues around where the device is placed,
* worsening of certain lung and breathing diseases such as asthma, chronic
obstructive pulmonary disease and sleep apnea in patients who already had these
diseases when the device was placed.
* The device itself can move from where it was placed by the surgeon, and this
might do damage to the vagus nerve, other nerves, blood vessels or other
structures of the body.
* The device or any of its parts can break, in which case it may not deliver
stimulation correctly.

Risks Relating to Surgical Placement of the Device
The surgical placement of the device (called *implantation*) can uncommonly
cause damage to the vagus nerve, which typically improves with time, but in
rare cases can be permanent. The most significant symptoms from damage to the
vagus nerve are hoarseness or other voice, breathing or swallowing changes that
occur because some of nerves that go to the muscles of the throat come from the
vagus. During the surgery for device placement other muscles, nerves, blood
vessels or tissues in the area can also rarely be damaged. Infections occur
uncommonly after placement of the device. These can usually be treated with
antibiotics, but uncommonly they will require the device to be removed. In rare
cases, when the device function is first being checked during the implantation
surgery, significant slowing of the heart rate can occur. This will be closely
monitored and treated should it happen.

Risks Relating toSurgical Removal of the Device
At the end of the study the device can be left in place and turned off so it
does not deliver electrical stimulation. If you wish to participate in a
longer term study, it can also be left on to continue to deliver stimulation.
However, at any time during this study or the longer term study, you can decide
to have it surgically removed. Uncommonly the device might also need to be
removed if it becomes infected and the infection does not respond to
antibiotics, or if the device malfunctions in a way that might be dangerous to
you. The kinds of complications listed above for surgical implantation can also
occur during removal. However, because some scarring around the components of
the device usually happens over time, removal carries a higher risk of
complications than implantation.

Chest X-ray
You will need to have a chest x-ray performed if you have not had one within
the last 6 months. The amount of radiation received during a chest x-ray is
about equivalent to 7-10 days of naturally occurring background radiation from
sun, soil, food and water to which a person is exposed.

Blood Draws
You will need to have blood samples obtained throughout the study. The total
amount of blood volume which will be taken during the course of the study is
about 315 milliliters. Possible side effects of the blood draws are pain,
bruising or bleeding at the site of needle puncture. Giving blood can
occasionally cause headache, nausea or light-headedness.