Long Term Observational Study Of The Safety And Efficacy Of 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).
This hypothesis was tested in a pilot study (SPM-005) in which RA patients were
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) was assessed using standard
clinical measures and surrogate biomarkers of RA.
The aim of the current protocol is to determine the long term safety and
efficacy of NCAP in the patients who previously enrolled in study SPM-005.
The SPM-006 substudy has the aim to investigate the effect of vagal nerve
stimulation on the hormonal balance. These hormones play an important role in
humans f.i. the regulation of inflammation. The vagal nerve stimulation can
affect the secretion of those hormones and via this pathway inhibiting
inflammation.

Primary Efficacy Objective
The primary efficacy objective is to determine the long term efficacy of vagal
nerve stimulation as assessed by the DAS28 score.

Secondary Efficacy Objectives
The secondary efficacy objectives are to determine the long term efficacy of
vagal nerve stimulation as assessed by:
• the American College of Rheumatology (ACR) 20, 50 and 70 response rate,
• the European League Against Rheumatism (EULAR) response rate, and
• changes in the Euro-QoL EQ-5D quality of life instrument score.

Safety Objectives
The safety objectives are to determine the long term safely of vagal nerve
stimulation as assessed by the subject incidence rates of:
• Adverse events
• Serious adverse events
• Device deficiencies

In this hormone and metabolic substudy the effect of vagal nerve stimulation on
the secretion of neuroendocrine and metabolic hormones will be studied. Also
the effect of food intake will be investigated.

This will be an open label multicenter study of the safety and efficacy of an
active implantable VNS device in patients with rheumatoid arthritis.
Patients who complete study SPM-005 will be enrolled in this study at the time
of the last visit of the preceding study. The assessments at the last visit of
the preceding study will also be used as baseline measures for the current
study. If the patient has previously discontinued SPM-005 and greater than 30
days have elapsed since the final visit in SPM-005, baseline measures for the
current study will be repeated, and an interim medical history will be taken to
assess whether any new medical conditions were diagnosed in the time between
studies.

Visit assessments for the current study:
• Physical Exam
• Vital signs
• RA Disease Assessment
• Euro-QOL Instrument
• Adverse Events
• Concomitant Medications

Custom Diagnostics should be performed prior to discharge from the clinic.
Prior to discharge from clinic the patient*s device settings and daily
frequency of stimulation sessions (i.e., QD or QID) should be set to the same
as those which were being used at the final visit of study SPM-005. The Normal
Mode Output Current should remain at 0.0 mA. Throughout the current study, the
patient will self-deliver stimulations.

From visit 3 onwards and at the discretion of and after discussion between the
Investigator and the Medical Monitor, based on level of RA activity at the
visit, stimulation parameters that may be increased or decreased. Allowable
ranges for new parameters are as follows:
• Magnet Mode Output Current: Minimum 0.250 mA, maximum 2.0 mA
• Pulse width 250 microseconds, frequency 10 Hz
• Magnet Mode stimulation time one minute, with a maximum of 5 one minute
magnet mode activations per stimulation session, these individual activations
to be given over 10-15 minutes
• Stimulation session frequency: Minimum once every two weeks, maximum ten
times daily
.

The study will continue until the last patient entered has completed 24 months
in this study.

Hormone and metabolic sunstudy:
Patients will fast overnight and will have two visits. One visit with vagal
nerve stimulation and food intake and the other without stimulation. The
following samples/measurements will be performed:
- blood samples will be drawn on several time points
- resting energy expenditure
- heart rate variability and core temperature

The patients will continue to use their previously implanted Cyberonics device
for this study.

What are the general risks of participating in this research study?

Stimulation of your vagus nerve with the device may cause all, some or none of
the adverse events listed below:
symptoms of the throat including hoarseness, voice changes, throat pain, and
swallowing difficulties, as well as shortness of breath, nausea, and
indigestion. In those patients, these symptoms generally occurred only during
the time the device was 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 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. However, at any time during this study
you can decide to have it surgically removed. 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.

Due to the vena puncture a bruise can occur, which will resolve spontaneously.