Electrical Stimulation of the Sphenopalatine Ganglion for the Treatment of Migraine Headaches

This application proposes a clinical study of electrical stimulation of the sphenopalatine
ganglia (SPG) as a treatment for up to three individuals with episodic migraine headache.
The present study is aimed at obtaining pilot data to guide a future controlled trial of
this treatment modality. The study population will include individuals suffering from
episodic migraine headaches with chronic severe disability, as demonstrated by the Migraine
Disability Assessment Questionnaire (Lipton, 2000) and Headache Impact Test short form
(HIT-6™) (Kosinski, 2003).

The treatment involves implantation of an electrode into the SPG. The electrode is connected
subcutaneously to an infraclavicular stimulator (PrimeAdvanced™ 37702 Multi-program
Neurostimulator System, Medtronic Inc., Minneapolis MN). Proper electrode placement will be
verified using anatomic and physiologic techniques. Participants will receive the Medtronic
Model 3389 or 3387 lead, or Medtronic subcompact lead Model 3776-45, 3776-60, or 3776-75.
Stimulation will be delivered in a range of frequencies from 20 to 130 Hz, and pulse width
from 60 to 450 μsec, and a titrated voltage. The voltages used for chronic stimulation may
range up to the pulse generator maximum of 10.5 volts but are anticipated to generally be
below 3 volts, keeping below the 30 µcoulomb/cm² charge density safety limit, and below the
threshold for adverse stimulation-related effects. The minimum number of contacts on the
quadripolar leads will be activated as necessary to produce a response.

The Prime Advanced neurostimulator to be used in this study allows the clinician to set all
stimulation parameters including the maximum allowable amplitude. It is our responsibility
to assure that appropriate stimulation parameters are used to result in appropriate
electrical exposure charge density) below a 30 µC/cm2/phase limit. As is done with
commercially available neurostimulators, during this study, we will utilize the charts
presented in Figures 1 and 2 below to assist in selection of programming parameters, and
this programming will be maintained by software controls within the neurostimulator.

For this exploratory study of 3 patients, the maximum electrical stimulating parameters,
resulting electrical exposure (e.g., charge density), will be determined using the methods
described above. It is our responsibility to assure that safe stimulation parameters are
used at all times and that the maximum settings do not exceed the safety limits. Our plan is
to begin with lead 3776 if possible, because it does not require an extra extension, but we
would use 3387 or 3389 if clinically indicated.

The proposed study is a physician-sponsored research investigation of three patients, and
the attention to stimulation parameters will be much greater than can be expected for a
commercially released product. It is our responsibility within this investigational study to
insure the selected stimulation parameters do not exceed the safety limit of 30μC/cm2/phase.
Patients participating in the study will only be able to lower stimulation amplitudes,
thereby keeping stimulation parameters BELOW any clinician set maximum. The only programs
available to or accessible by the patients will maintain the previously described parameter
set limitations. Thus, the programming of the Implantable Programmable Generator (IPG) will
keep the three patients from stimulating outside or above the set and safe parameters.

The primary outcome measures for assessing the efficacy of migraine treatment will be a
subject reported daily diary noting frequency and intensity of headaches. During this
investigation we will obtain preliminary controlled data on the safety and efficacy of SPG
stimulation for migraine treatment.

Inclusion Criteria:

1. Age ≥18 years.

2. Subject has onset of migraine headache occurring before age 60.

3. Subject has been diagnosed with migraine headache with or without aura, according to
the 2004 IHS criteria 1.1 and 1.2.

4. Subject reports a HIT-6 score of >56, a MIDAS score of >20 and/or a failure of
adequate and appropriate previous migraine treatment.

5. Subject has carried the diagnosis of migraine for at least 6 months prior to
enrollment.

6. Subject has had at least three migraine headache attacks per month.

7. Subject has had at least three headache days (migraine or non-migraine) per month and
maintains this requirement during the baseline period on diary.

8. Subject is able to distinguish migraine headache attacks as discrete from other
headaches (i.e., tension-type headaches).

9. Subject has the ability to read, comprehend and legibly and reliably record
information as required by the protocol.

10. Subject is able to provide written informed consent prior to participation in the
study.

11. Subject agrees to not participate in supplemental or alternative therapy during the
baseline or treatment phases of the clinical study. This includes: acupuncture,
spinal manipulation, TENS, and magnetic field treatments.

12. Subject agrees to maintain current preventative headache medication regimens (no
change in type, frequency, or dose) from baseline screening visit to the end of the
Phase 2 treatment phase.

Exclusion Criteria:

1. Subject currently has Medication Overuse Headache (MOH) in the judgment of the
investigator or by ICHD-II criteria.

2. Subject has a history of headaches days ≥ 15 per month.

3. Subject has a history of trigeminal autonomic cephalalgias.

4. Subject has any medical condition or disorder that:

1. Is considered to be clinically significant and may pose a safety concern

2. Could interfere with the accurate assessment of safety or efficacy

3. Could potentially affect a subject's safety or study outcome.

5. Subject has had a major infection or surgery in the past month.

6. Subject has undergone facial surgery in the area of sphenopalatine ganglia for
cosmetic, corrective, therapeutic, or traumatic reasons.

7. Subject has been treated with radiation to the face.

8. Subject was diagnosed with any major infectious processes, primary or secondary
malignancies involving the face that have been active or required treatment in the
past six (6) months.

9. Subject currently meets criteria as defined by the Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV-TR) for an active major depressive episode or for active
significant psychiatric disorders, including dementia, uncontrolled general anxiety
disorder, psychotic disorders or uncontrolled bipolar disorder. Exclusion criteria
include: suicidality, active psychosis, untreated severe depression and/ or anxiety
disorder, litigation, addiction, homicidal ideation, significant Axis II disorders
and untreated sleep disorder.

10. Subject currently has clinically significant drug or alcohol abuse as defined by
DSM-IV-TR or is unable to refrain from substance abuse throughout the study.

11. Subject is currently participating or has participated in the last month in another
clinical study in which the subject has, is, or will be exposed to an investigational
or non-investigational drug or device.

12. Subject is felt to be at risk of non-compliance (e.g. for completing the diary or
maintaining a stable headache medicine regimen) in the investigator's opinion.

13. Subject is woman of childbearing age who is pregnant, nursing, or not using
contraception.

14. Subject has had previous radio-frequency ablation of the SPG.

15. Subject has had blocks of the SPG in last 3 months.

16. Subject has undergone botulinum toxin injections of the head and/or neck in the last
3 months.

17. Subject has an implantable stimulator or any implanted devices in the head and/or
neck.

18. Subject has H/O bleeding disorders or coagulopathy, or is on anticoagulation,
antiplatelet, or GP IIb IIIa inhibitor medication.

19. Subject has H/O malignancy or any other condition that requires MRI monitoring.

20. Subject has or requires pacemaker/defibrillator.

21. Subject is not suitable for the study, in the judgment of the Investigators, due to
social, co-morbid psychological, and/or medical considerations.

22. Subject has H/O stroke, cardiovascular disease, and/or epilepsy.

23. Subject was on antipsychotic or antidepressant medications (except for migraine
prevention) in the past 3 months prior to the study.

24. Subject is allergic or has shown hypersensitivity to materials of the Medtronic
components which come in contact with the body.