Intra-Arterial Injection of Lidocaine and Glucocorticoid in the Treatment of Intractable Headaches: A Non-Randomized, Open-Label Phase 1 Clinical Trial
Phase: PHASE1
Conditions: Refractory Migraine
Sponsor: The Cooper Health System

Cover Page for ClinicalTrials.gov 
 
Document: 
Study Protocol with Statistical Analysis Plan 
 
Brief Title:  
Localized Injection of Lidocaine and Glucocorticoid for Headache Treatment Phase 1 (LIGHT 1) 
 
Official Title: 
Intra-Arterial Injection of Lidocaine and Glucocorticoid in the Treatment of 
Intractable Headaches: A Non-Randomized, Open-Label Phase 1 Clinical Trial 
 
Unique Protocol ID:  
23-267 
 
NCT:  
NCT06462781 
 
Document Latest Approved Date: 
02/21/2025 
 

Investigational Drug: lidocaine/methylprednisolone 
 
Sponsor: Daniel A. Tonetti, MD 
Confidential 
Version #: 0.1.4 
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Clinical Research Protocol 
 
Intra-Arterial Injection of Lidocaine and Glucocorticoid in the Treatment of 
Intractable Headaches: A Non-Randomized, Open-Label Phase 1 Clinical Trial 
 
 
Protocol Number: 
0.1.4 
Version Date: 
02/21/2025 
Investigational Drug(s): 
Xylocaine®-MPF (lidocaine hydrochloride) 
SOLU-MEDROL® (methylprednisolone sodium succinate) 
IND Number: 
170099 
Development Phase: 
Phase 1 
Sponsor-Investigator: 
Daniel A Tonetti, MD, MS 
Cooper University Health Care 
101 Haddon Avenue, Suite 407 
Camden, New Jersey, USA 08103 
Funding Organization: 
Society of Vascular and Interventional Neurology 
Principal Investigator: 
Name: Daniel A Tonetti, MD, MS 
Telephone: 855-306-3876 
Fax: 856-546-8527 
E-mail: tonetti-daniel@cooperhealth.edu 
Coordinating Center: 
Cooper University Health Care 
 
This confidential information about an investigational product is provided for the exclusive use of investigators of 
this product and is subject to recall at any time. The information in this document may not be disclosed unless 
federal or state law or regulations require such disclosure. Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
TABLE OF CONTENTS 
 
1. 
Table of Contents ........................................................................................................ 2 
2. 
Protocol Summary ...................................................................................................... 3 
3. 
Study Rationale ........................................................................................................... 4 
3.1. 
Intractable Migraine ............................................................................................ 4 
3.2. 
Rationale of Evaluating Study Drug for Treatment Indication ........................... 5 
3.3. 
Alternatives to Study Drug ................................................................................. 5 
3.4. 
Risk / Benefit Assessment .................................................................................. 6 
3.4.1. 
Drug-Related Risks ..................................................................................... 6 
4. 
Study Objectives ......................................................................................................... 7 
4.1. 
Primary Objective ............................................................................................... 7 
4.2. 
Secondary Objectives .......................................................................................... 7 
5. 
Study Design ............................................................................................................... 7 
5.1. 
General Approach for Evaluation of Treatment ................................................. 7 
5.2. 
Description of First Year Trial(s) ....................................................................... 8 
5.3. 
Number of Subjects to be Evaluated ................................................................... 8 
5.4. 
Duration of Trial and Subject Involvement ........................................................ 8 
5.5. 
Administrative Organization ............................................................................... 8 
6. 
Subject Selection ......................................................................................................... 9 
6.1. 
Inclusion Criteria ................................................................................................ 9 
6.2. 
Exclusion Criteria ............................................................................................. 10 
6.3. 
Recruitment ....................................................................................................... 11 
6.4. 
Screening ........................................................................................................... 11 
7. 
Study Treatment, Procedures, and Guidelines .......................................................... 11 
7.1. 
Study Intervention ............................................................................................. 11 
7.2. 
Study Assessment and Activities ...................................................................... 12 
7.2.1. 
Visit 1 (Screening) .................................................................................... 13 
7.2.2. 
Visit 2 (Administration) ............................................................................ 14 
7.2.3. 
Visit 3 (Week 1 ± 2 days) ......................................................................... 14 
7.2.4. 
Visit 4 (Week 6 ± 2 days) ......................................................................... 14 
7.2.5. 
Visit 5 (Week 12 ± 2 days) ....................................................................... 14 
8. 
Data Safety Monitoring ............................................................................................. 14 
8.1. 
Safety Monitoring Plan ..................................................................................... 14 
9. 
Statistical Methods and Considerations .................................................................... 17 
9.1. 
Analysis Plan .................................................................................................... 17 
9.2. 
Interim Analysis ................................................................................................ 17 
10. Administrative, Ethical, Regulatory Considerations ................................................ 17 
10.1. 
Informed Consent .......................................................................................... 17 
10.2. 
Investigator and Facilities Data .................................................................... 17 
11. APPENDICES .......................................................................................................... 19 
11.1. 
Appendix A: The Migraine Disability Assessment Test (MIDAS) .............. 20 
11.2. 
Appendix B: 4-Point Verbal Pain Scale ........................................................ 21 
11.3. 
Appendix C: 11-Point Numeric Pain Scale .................................................. 22 
 
 

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2. 
PROTOCOL SUMMARY 
 
Name of Drug(s) 
Lidocaine hydrochloride (Xylocaine®-MPF); 
methylprednisolone sodium succinate (SOLU-MEDROL®) 
Treatment Group/Sample Size 
10 total subjects 
Design 
Open-label, non-randomized study 
Estimated Length of Subject 
Involvement 
90 days 
Route of Administration 
Intra-arterial 
Regimen 
40 mg lidocaine/20mg methylprednisolone co-administered 
into each middle meningeal artery (left and right side) once 
Primary Objective 
This study will evaluate the safety of a co-administration of 
intra-arterial lidocaine and methylprednisolone for patients 
with intractable migraine. In addition, an examination of 
pain-related symptomatic relief per pain score scales will be 
assessed. 
Study Population 
10 adults over the age of 18 with a diagnosis of intractable 
migraine without aura, defined as failure of four treatment 
trials, will be enrolled in the study if they meet inclusion and 
exclusion criteria and are willing to participate in the study. 
Multicenter 
No 
Blinding 
None/Open-label 
Randomization 
None/Non-randomized 
Primary Safety Variable 
Adverse Events  
Primary Efficacy Variable  
Difference in pre- and post-drug MIDAS, 4-point verbal 
pain scale, and 11-point numeric pain scale scores.  

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3. 
STUDY RATIONALE 
3.1. 
Intractable Migraine 
Treatment-refractory intractable migraine is a challenging clinical condition. The 
Refractory Headache Survey estimated intractable migraine prevalence to be on average between 
5-10% of the neurologic specialists’ patient consensus.1 Failure of adequate control of symptoms 
under standard therapy causes significant pain burden, migraine-related disability, and impaired 
quality of life.1 Consequently, new approaches to intractable migraine treatment have potential to 
improve patient outcomes. 
Previous case reports describe positive clinical experiences from initial attempts at intra-
arterial lidocaine administration into the middle meningeal artery, including reduced migraine-
related disability, subjective reports of pain improvement, and reduced pain scores.2,3 Two severe 
migraine patients received intra-arterial doses of 40 mg lidocaine and 20 mg methylprednisolone 
in the middle meningeal artery, and reported subjective improvement in headache intensity after 
24 hours.3 Qureshi et al. (2021) found that in a study of four patients, intra-arterial lidocaine 
administered in 2 mg/ml increments up until 50 mg to bilateral middle meningeal arteries resulted 
in large decrease in pain score (from greater than 5/10 to less than 5/10) and subjective reports of 
decreased headache intensity in four patients.2 Moreover, these initial experiences have not 
reported any serious adverse effects associated with intra-arterial lidocaine administration. This is 
in concordance with the safety profile of intra-arterial lidocaine administration in the peripheral 
circulation.4,5,6 However, the patient sample was limited, and a formal phase 1 trial is yet to be 
conducted.  
Results of this study will demonstrate the safety profile of this drug co-administration, 
and it will serve as the basis for future larger-scale investigations to evaluate efficacy. Safety and 
efficacy of the administration will expand available treatment options for intractable migraine 
patients.  
We propose to conduct a pilot, non-randomized, open-label phase 1 clinical trial to 
characterize the safety of intra-arterial injection of lidocaine and methylprednisolone into the 
middle meningeal artery for treatment of intractable migraine.  
The primary objective is to evaluate the safety of intra-arterial co-administration of 
lidocaine and methylprednisolone into the middle meningeal artery for intractable migraine 
patients. The secondary objective is to evaluate the effectiveness of lidocaine and 
methylprednisolone administration for modifying migraine-related symptom burden in intractable 
migraine patients.  
 
1 D'Antona L, Matharu M. Identifying and managing refractory migraine: barriers and opportunities? J Headache Pain. 2019;20(1):89. 
Epub 20190823. 
2 Qureshi AI, Pfeiffer K, Babar S, Huang W, Lobanova I, Ishfaq MF, et al. Intra-arterial injection of lidocaine into middle meningeal 
artery to treat intractable headaches and severe migraine. J Neuroimaging. 2021;31(6):1126-34. 
3 Qureshi AI, Qureshi MH, Khan AA, Suri MF. Effect of intra-arterial injection of lidocaine and methyl-prednisolone into middle 
meningeal artery on intractable headaches. J Vasc Interv Neurol. 2014;7(5):69-72. 
4 Duvnjak S, Andersen PE. Intra-arterial lidocaine administration during uterine fibroid embolization to reduce the immediate 
postoperative pain: a prospective randomized study. CVIR Endovasc. 2020;3(1):10. 
5 Keyoung JA, Levy EB, Roth AR, Gomez-Jorge J, Chang TC, Spies JB. Intraarterial lidocaine for pain control after uterine artery 
embolization for leiomyomata. J Vasc Interv Radiol. 2001;12(9):1065-9. 
6 Lee SH, Hahn ST, Park SH. Intraarterial lidocaine administration for relief of pain resulting from transarterial chemoembolization of 
hepatocellular carcinoma: its effectiveness and optimal timing of administration. Cardiovasc Intervent Radiol. 2001;24(6):368-71.  
 

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3.2. 
Rationale of Evaluating Study Drug for Treatment Indication 
Treatment-refractory intractable migraine is a challenging clinical condition, and causes 
severely impaired quality of life due to subpar control of symptoms.7 Anesthetic agents, such as 
lidocaine, administered within the blood circulation have been shown in prior investigations to be 
beneficial for severe headache patients.8,9 Steroidal agents, such as methylprednisolone, 
administered within the blood circulation have also been previously studied as viable agents for 
headache treatment, including as a stand-alone measure and in combination with anesthetic 
agents.10,11 
 
Mechanistically, lidocaine inhibits ionic fluxes across the neuronal membrane necessary 
for initiating and propagating electrical impulses conducting pain signals.12 Consequently, 
inhibited neuronal signaling blocks the pain sensation associated with migraines. Steroids exert a 
multi-organ anti-inflammatory response, including within the brain, through cell signaling 
inhibition of inflammatory markers.13 Hence, steroids likely are therapeutic for migraines, since 
they counteract the neurogenic inflammation associated with migraines.10,11 
 
Prior case reports in six patients describe initial clinical experiences following intra-
arterial lidocaine and methylprednisolone administration into the middle meningeal artery.14,15 
These patients reported favorable symptomatic relief, including reduced disability and subjective 
pain improvement, following the drug co-administration. Moreover, there were no serious 
adverse events reported in both investigations.  
 
Consequently, the co-administration of two commercially-available drugs demonstrates 
potential to provide patients relief for a clinically-challenging diagnosis. Although early 
experience suggests favorable safety and efficacy, formal analysis in this phase 1 study and other 
subsequent investigations will evaluate the drug as a potentially viable treatment option for 
patients with treatment-resistant migraines, and thus improve their pain and qualify of life. 
Additionally, this phase 1 study will facilitate global assessment of practices, research 
procedures, and recruitment practices, with the intention of use as the basis for multicenter 
support for future clinical trial phases.  
3.3. 
Alternatives to Study Drug 
The alternative for not taking part in this study is to continue current course of care, 
which may include continuing current medications (oral or infusion) for intractable migraine. 
Other medications are available for this condition, including antiepileptic drugs, beta-blockers, 
antidepressants, angiotensin receptor blockers/angiotensin-converting enzyme inhibitors, 
nonsteroidal anti-inflammatory agents (NSAIDS), ergots, triptans, analgesics (i.e., 
acetaminophen), botulinum toxin injections, or calcitonin gene-related peptide monoclonal 
antibodies.  
 
7 D'Antona L, Matharu M. Identifying and managing refractory migraine: barriers and opportunities? J Headache Pain. 2019;20(1):89. 
Epub 20190823. 
8Krusz JC, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable migraine. Headache. 2000;40:224–
30. 
9 Sheridan DC, Spiro DM, Nguyen T, Koch Tk, Meckler GD. Low-dose propofol for the abortive treatment of pediatric migraine in 
the emergency department. Pediatric Emergency Care. 2012;28:1293. 
10 Rowe BH, Colman I, Edmonds ML, Blitz S, Walker A, Wiens S. Randomized controlled trial of intravenous dexamethasone to 
prevent relapse in acute migraine headache. Headache. 2008;48:333–40.  
11 Fiesseler FW, Shih R, Szucs P, et al. Steroids for migraine headaches: a randomized double-blind, two-armed, placebo-controlled 
trial. The Journal of Emergency Medicine. 2011;40:463–8. 
12 NDA 006488 lidocaine hydrochloride injection, solution. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba082c2f-64f4-419d-9c88-74f203316e17  
13 NDA 011856 methylprednisolone sodium succinate for injection, USP. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd99be87-c8d9-48d6-a8e5-e081052e3f19 
14 Qureshi AI, Pfeiffer K, Babar S, Huang W, Lobanova I, Ishfaq MF, et al. Intra-arterial injection of lidocaine into middle meningeal 
artery to treat intractable headaches and severe migraine. J Neuroimaging. 2021;31(6):1126-34. 
15 Qureshi AI, Qureshi MH, Khan AA, Suri MF. Effect of intra-arterial injection of lidocaine and methyl-prednisolone into middle 
meningeal artery on intractable headaches. J Vasc Interv Neurol. 2014;7(5):69-72. 

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3.4. 
Risk / Benefit Assessment 
Risks associated with intra-arterial administration route includes rare adverse events 
related to intravascular access, including allergic response to contrast agents, vessel injury, access 
site hematoma, and infection. Risks will be mitigated by implementation of institutional standard 
practices protocol, including standardized procedures in the event of an interventional access-
related complication.  
 
For example:  
• 
Protocols are in place to obtain an ultrasound study if access site hematoma is suspected 
post-administration of the study drug.  
• 
In case of unexpected, severe contrast allergy, a combination of intravenous fluids, 
diphenhydramine, hydrocortisone, and/or adrenaline will be administered.  
 
Risks associated with sedative mediations used for “twilight anesthesia”/monitored anesthesia 
care (MAC) include the risk of excessive or prolonged sedation, potentially requiring intubation. 
Risks will be mitigated by using minimal sedation necessary to safely obtain interventional 
access.  
Risks associated with methylprednisolone administration include teratogenic effect on unborn 
fetuses. Risks will be mitigated by pre-treatment urine pregnancy test to screen for pregnancy in 
patients of child-bearing age.  
Risks associated with bilateral versus unilateral injection are present, including from 
catheterization and dose toxicity. Intra-arterial navigation to obtain access to the contralateral 
middle meningeal artery present similar risks associated with intravascular access, as described 
above. Although risk of contralateral access is present, this phase 1 protocol uses a bilateral 
injection approach, as unilateral treatment has only been shown to be effective in patients with 
migraine-related symptoms that are exclusively localized to one side.1 Although risk of toxicity 
from dose quantity is present, the dosages outlined in this study are well below the threshold for 
toxicity per the Prescribing Information. Moreover, a prior case report using lidocaine 
hydrochloride/methylprednisolone sodium succinate administered intra-arterially into the middle 
meningeal artery bilaterally for the indication of migraine and headache, using the dosing 
approach described in Section 6.1.5/Amendment #2, demonstrated no safety concerns in two 
patients.16 In a separate dose-escalation study in four patients, intra-arterial lidocaine was 
administered in 2mg/mL increments until 50 mg per middle meningeal artery (100mg lidocaine 
total), and there were no adverse effects reported.17 Based on prior clinical experience in the same 
or greater dosing amount with the same route of administration for the same indication, the risk 
for toxicity is expected to be minimal.  
Benefits to subjects for the research include potential resolution of intractable migraine 
symptoms following treatment. Potential benefit also includes presenting an alternative, 
minimally invasive pharmacologic approach to intractable migraine to substitute chronic, 
frequent treatment with oral medications. 
3.4.1. Drug-Related Risks 
 
No specific lidocaine-related risks are anticipated for the investigational dosing amount 
and route. The following are potential complications for lidocaine use per Section 5 
(WARNINGS AND PRECAUTIONS) for the Prescription Drug Labeling of NDA 006488. 
Patients are contraindicated from use if they have a known history of hypersensitivity to lidocaine 
 
16 Qureshi AI, Pfeiffer K, Babar S, Huang W, Lobanova I, Ishfaq MF, et al. Intra-arterial injection of lidocaine into middle meningeal 
artery to treat intractable headaches and severe migraine. J Neuroimaging. 2021;31(6):1126-34. 
17 Qureshi AI, Qureshi MH, Khan AA, Suri MF. Effect of intra-arterial injection of lidocaine and methyl-prednisolone into middle 
meningeal artery on intractable headaches. J Vasc Interv Neurol. 2014;7(5):69-72. 

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and local anesthetics of the amide type. Lidocaine administration has been associated with cases 
of methemoglobinemia. Drugs within the anesthetic agent pharmacologic class may trigger 
familial malignant hyperthermia. Small doses injected percutaneously into the head and neck area 
for retrobulbar, dental, and stellate ganglion blocks, have been reported to rarely cause confusion, 
convulsions, respiratory depression and/or arrest, cardiovascular stimulation and/or depression, 
and thus, require close cardiopulmonary monitoring during medication administration.  
No specific methylprednisolone-related risks are anticipated for the investigational 
dosing amount and route. The following are potential complications for methylprednisolone use 
per Section 5 (WARNINGS AND PRECAUTIONS) for the Prescription Drug Labeling of NDA 
011856. Complications with methylprednisolone treatment are dependent on dosage size, 
duration, and route of administration. Methylprednisolone has been associated with rare serious 
neurological adverse events, including spinal cord infarction, paraplegia, quadriplegia, cortical 
blindness, and stroke, with epidural administration. There have been rare reports of anaphylactoid 
reactions. Large doses of corticosteroids have been associated with elevated blood pressure and 
increased potassium and calcium excretion. After recent myocardial infarction, there has been a 
suggested association between drugs within the corticosteroid pharmacologic class and left 
ventricular free wall rupture. Chronic methylprednisolone use is associated with hypothalamic-
pituitary adrenal axis suppression, Cushing’s syndrome, and hypoglycemia. High doses of cyclic, 
pulsed methylprednisolone administration are associated with toxic acute hepatitis. Corticosteroid 
use is associated with increased susceptibility to infections, including fungal infections.  
Other risks of participation include very rare adverse events related to route of 
administration, including allergic response to agents, vessel injury, access site hematoma, and 
infection. 
 
4. 
STUDY OBJECTIVES 
4.1. 
Primary Objective 
Primary outcome is safety of the lidocaine and methylprednisolone co-administration 
intra-arterially into the middle meningeal arteries. The endpoints that will be analyzed to examine 
this outcome include: incidence of all adverse events; incidence of adverse events attributed to the 
study drug; and incidence of any serious adverse events.  
4.2. 
Secondary Objectives 
Efficacy is a secondary outcome that will be examined. The endpoints for evaluation 
include difference in MIDAS, 4-point verbal pain scale, and 11-point numeric pain scale scores 
prior to drug administration and 1 week, 6 weeks, and 3 months after drug administration.  
 
5. 
STUDY DESIGN 
5.1. 
General Approach for Evaluation of Treatment 
 
This study will be a non-randomized, open-label phase 1 clinical trial. Participants above 
the age of 18 years who have an established diagnosis of intractable migraine (defined as failure 
of four other pharmacologic agents) and are active patients at our institution (i.e., have an 
appointment with a neurologic care provider during the enrollment period) will be offered 
enrollment. Either intolerance or side effects requiring early discontinuation or adequate trial at 
therapeutic dose without relief constitutes failure of therapy. 
 
A neurological provider will perform a baseline assessment of enrolled patient’s medical 
history and symptom scale scores, including MIDAS, 4-point verbal pain scale, and 11-point 

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numeric pain scales (Appendix G). An experienced neurointerventional co-investigator will inject 
20 mg methylprednisolone and 40 mg lidocaine into the middle meningeal artery bilaterally. Each 
patient will receive a total of two doses of the 40mg lidocaine/20mg methylprednisolone co-
administration of drugs (i.e., one dose administered within the left middle meningeal artery, and 
the other dose in the right middle meningeal artery). Immediate post-operative clinical evaluation, 
and evaluation at subsequent follow-up appointments with a neurological provider will involve 
assessment of neurological functional status, symptom scores, and occurrence of any associated 
adverse event at 1 week, 6 weeks, and 3 months. To evaluate the primary safety outcome, data 
will be analyzed to yield the prevalence of any adverse event, treatment-related adverse events, 
and serious and/or fatal adverse events. Data comparing pairwise differences in pre- and post-
drug changes in symptom scores at 1-week, 6-week, and 3-month follow-up clinical encounters 
will be analyzed to assess secondary efficacy outcome.  
5.2. 
Description of First Year Trial(s) 
This study will be a non-randomized, open-label phase 1 clinical trial. Qualifying patients 
as described in Section 4.3 will be offered the option to be enrolled within the clinical trial, 
including explanation of study-related components and a pre-specified 3-month clinical follow-up 
duration. 
5.3. 
Number of Subjects to be Evaluated 
Up to 10 patients will be evaluated. Sample size was determined off of norms for phase 1 
trials, as there lacks sufficient data to conduct a power analysis. Patients who are lost to follow-up 
and/or withdraw early from the study will not be replaced.  
 
5.4. 
Duration of Trial and Subject Involvement 
The duration of the clinical investigation will be 1 year, with patient involvement lasting 
approximately 4 months from enrollment to completion of clinical trial-related follow-up.  
 
5.5. 
Administrative Organization 
Participating Units: Cooper University Health Care is the only study site participating in this 
study. The clinical laboratory core within Cooper University Health Care will be utilized per 
protocol. Data management and coordination will be within a validated database within Cooper 
University Health Care maintained by the study team subject to approval by the Cooper 
University Institutional Review Board.  
 
Principal Investigator: Dr. Daniel A. Tonetti, MD, Assistant Professor of Neurosurgical 
Surgery at Cooper University Health Care. Dr. Tonetti is a highly qualified open and 
endovascular neurosurgery who will lead this trial, given his prior experience in leading and 
coordinating early-stage clinical trials. His contributions to the field of Cerebrovascular 
Neurosurgery and Endovascular Neurosurgery are notable, as evidenced by his experience with 
over 100 peer-reviewed publications, numerous abstracts, and international/national 
presentations. Within the Cooper Neurological Institute, a prominent institution with a specialized 
South Jersey Headache clinic, Dr. Tonetti works alongside a team of skilled neurologists and 
advanced practices providers who actively treat patients suffering from intractable migraine 
headaches. 
 
 
 

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Additional Personnel: The following sub-investigators comprise of the core study team. 
 
Dr. Hamza A. Shaikh, MD, Scientific Advisor, is an Assistant Professor of Neurological 
Surgery and Radiology at Cooper University Health Care. He has been actively working as a 
Neurointerventional Radiologist and senior Neuroradiologist at Cooper University Health Care, 
and has founded and developed the Neurointerventional program to its current standing. He has 
extensive expertise in neurointerventional approaches to intracranial pathology. He will be 
responsible for overseeing development, coordination, and completion of the project aims. He 
will serve as an advisor and mentor for the principal investigator. Dr. Shaikh and Dr. Tonetti will 
work closely together to implement the research program as a team, along with their senior 
colleagues.  
 
Dr. Ajith J. Thomas, MD, Sub-Investigator, is a Professor of Neurological Surgery and 
Chairman/Chief for the Department of Neurosurgery at Cooper University Health Care. He is a 
neurointerventional physician that will participate in clinical care including enrolling candidates, 
performing investigational procedures, and providing follow-up care for enrolled patients.  
 
Dr. Tudor G. Jovin, MD, Sub-Investigator, is a Professor of Neurology and Neurological 
Surgery and Chairman/Chief of Neurology at Cooper University Health Care. He is a 
neurointerventional physician that will participate in clinical care including enrolling candidates, 
performing investigational procedures, and providing follow-up care for enrolled patients.  
 
Dr. Larisa Syrow, MD, Sub-Investigator, is an Associate Professor of Clinical Neurology at 
Cooper University Health Care. She is a headache specialist who will be participating in the 
enrollment process and follow-up care for patients.  
 
Dr. Jane Khalife, MD, MS, Sub-Investigator, is an Attending Neurologist at Cooper University 
Health Care. She is a neurointerventional physician that will participate in clinical care including 
enrolling candidates, performing investigational procedures, and providing follow-up care for 
enrolled patients.  
 
Dr. Pratit D. Patel, MD, Sub-Investigator, is an Assistant Professor of Neurology at Cooper 
University Health Care. He is a neurointerventional physician that will participate in clinical care 
including enrolling candidates, performing investigational procedures, and providing follow-up 
care for enrolled patients.  
 
Manisha C. Koneru, MS, Graduate Research Assistant, has education and training in statistical 
methods and clinical trial design. She will be assisting in report generation, data collection, and 
statistical analyses.  
 
Lindsay Colman, MS, Clinical Coordinator, will assist with administrative responsibilities, 
including maintaining records of enrollees, generating compliance reports for oversight 
committees, and continued compliance with regulatory requirements.  
 
6. 
SUBJECT SELECTION 
6.1. 
Inclusion Criteria 
 
1. 
Male or female ≥18 years of age.  

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2. 
Documentation of a diagnosis of intractable migraine without aura, including failure of at 
least four classes of preventative drugs. Either intolerance or side effects requiring early 
discontinuation or adequate trial at therapeutic dose without relief constitutes failure of 
therapy. 
3. 
Written informed consent obtained from subject and ability for subject to comply with the 
requirements of the study. 
6.2. 
Exclusion Criteria 
1. 
Pregnant, breastfeeding, or unwilling to practice contraception during participation in the 
study. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal 
ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, 
patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used 
with a spermicide, or (4) an intrauterine device (IUD). 
2. 
Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
3. 
Patients with concomitant intracranial pathology (e.g., intracranial malignancy).  
4. 
Blood glucose level on screening complete metabolic blood panel > 400 mg/dL.  
5. 
Patients with known hypersensitivity and/or contraindication to either lidocaine 
hydrochloride or methylprednisolone sodium succinate, including: 
• 
Patients with known history of hypersensitivity to local anesthetics of the amide type.  
• 
Patients with systemic fungal infections. 
• 
Patients with known or suspected hypersensitivity to cow’s milk or its components or 
other dairy products (SOLU-MEDROL® 40mg presentation includes lactose 
monohydrate, and may contain trace amounts of milk ingredients).  
6. 
Patients taking chronic medications that, when co-administered with lidocaine and other 
local anesthetics, are at increased risk of developing methemoglobinemia: nitrates/nitrites, 
local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, 
acetaminophen, metoclopramide, quinine, sulfasalazine.  
7. 
Patients taking chronic medications that, when co-administered with methylprednisolone, are 
at increased risk for hypokalemia, altered drug levels, convulsions, or altered clearance: 
amphotericin B, diuretics, aminoglutethimide, macrolide antibiotics, anticholinesterases, 
antitubercular drugs, cholestyramine, cyclosporine, digitalis glycosides, estrogens (including 
oral contraceptives), hepatic enzyme inducers/inhibitors, and ketoconazole.  
8. 
Patients have known contraindications for angiography. Patients with contrast allergy will be 
premedicated with diphenhydramine and steroids.  
9. 
Patient has known active systemic infection or sepsis.  
10. Patient has contraindication to anesthetic agents used for conscious sedation/monitored 
anesthesia care (MAC).  
11. Concurrent participation in another research protocol for investigation of an experimental 
therapy.  
12. Known or suspected inability to adhere to study protocol or protocol requirements, as per the 
discretion of the Investigator or treating provider.  

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6.3. 
Recruitment 
Patients meeting inclusion/exclusion criteria and have an existing clinical encounter with 
a Cooper University Health Care neurological provider during the enrollment period will be 
offered enrollment. Recruitment will include explanation of the study using standardized 
language by a subinvestigator and written information about the study using simple language. The 
patient will have an opportunity to deny enrollment, proceed with providing consent, or opt for a 
follow-up phone outreach by a subinvestigator within 1-2 weeks. The purpose of the follow-up 
phone outreach is to provide a standardized approach for when the patient expresses that they 
need more time to make a decision regarding participation, and thus are deferring making a 
decision to consent or decline. The 2-week period will provide the opportunity for the patient to 
review the informed consent document and discuss their participation with other supportive 
individuals (i.e., family members, friends, primary care provider, etc.). This also provides the 
patient with an opportunity to deliberate any questions they may have. The follow-up phone 
outreach with physician study personnel is to a) address any questions that have arisen during the 
deliberation process and b) ascertain whether the patient has decided to consent to participate or 
not. No further advertising will be performed.  
6.4. 
Screening 
Upon enrollment, the neurological provider will be asked to verify past medical history 
(i.e., tobacco use, obesity status, past traumatic brain injury, diabetes mellitus, hypertension, 
hyperlipidemia) and current medications during the clinical encounter. Patients would undergo a 
pre-treatment serum metabolic blood panel to document baseline serum glucose levels, which is a 
routine biomarker to assess prior to administering glucocorticoid medications. Specific for 
research purposes only, patients would also be asked to score baseline MIDAS, 4-point verbal 
rating scale, and 11-point numeric pain scores (Appendix G). Patients will be instructed to keep a 
Study Diary, and will be instructed to record migraine episodes and any adverse events with date 
of onset, duration, and description for four weeks before and three months after treatment. 
Patients with baseline serum glucose of above 400 mg/dL will fail screening procedures 
and not be included within the study due to elevated risk of acute exacerbation of steroid 
hyperglycemia during methylprednisolone administration.  
 
7. 
STUDY TREATMENT, PROCEDURES, AND GUIDELINES 
7.1. 
Study Intervention 
After baseline screening assessment, patients will be scheduled within one month for 
investigational drug administration. Xylocaine®-MPF will be prepared for administration of 40 
mg of active lidocaine hydrochloride per dose as described in Section 3.1.4. A total of two doses 
(40 mg lidocaine hydrochloride per dose; 80 mg total) of lidocaine hydrochloride will be prepared 
for the injection of each dose into each middle meningeal artery (left and right). SOLU-
MEDROL® will be prepared for administration of 20 mg of active methylprednisolone sodium 
succinate as described in Section 3.1.4. A total of two doses (20 mg methylprednisolone sodium 
succinate per dose; 40 mg total) of methylprednisolone sodium succinate will be prepared for the 
injection of each dose into each middle meningeal artery (left and right). No placebo agents will 
be used during the study. Agents will not be blinded. Agents will be prepared and stored per 
instructions contained within Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) of 
the Prescribing Information and manufactures’ guidelines contained within the packaging insert.  
The treatment will be administered in the Acute Stroke and NeuroInterventional Suite at 
Cooper University Health Care. The care team will include an experienced neurointerventional 
physician with extensive experience in proper catheter placement and technical specifications 

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necessary for the procedure below, certified and licensed angiography technicians, a dedicated 
anesthesiology care team, pharmacy team, and nursing team comprised of neurocritical care 
certified nurses (including post-procedural recovery and observation). Within the immediate 
treatment area, availability to resuscitative equipment and continuous vital sign monitoring, 
including rapid cycling continuous blood pressure monitoring (with measurements at least every 
5 minutes), continuous pulse oximetry, respiratory rate, continuous heart rate monitor, and 
electrocardiographic monitoring, will be ensured. For safety, patients may be sedated using 
institutional monitored anesthesia care (MAC) protocol under the care of a licensed 
anesthesiologist, and thus will not require intubation. Patients will be monitored continuously 
throughout the procedure and for four hours post-operatively in a dedicated post-angiography 
care unit. 
 
The following steps will be performed interprocedurally:  
1. Intra-arterial access will be obtained under ultrasound guidance via femoral or radial 
artery.  
2. Fluoroscopic-guided catheterization and intracranial vascular access to the middle 
meningeal artery will be obtained using devices per neurointerventional provider 
discretion.  
3. Manual infusion of 40 mg lidocaine bolus will occur over 5 minutes.  
4. The provider will wait 2 minutes before administering active medications to assess for 
toxicity or acute adverse reactions. 
5. Manual infusion of 20 mg methylprednisolone bolus will occur over 5 minutes.  
6. The provider will wait at least 5 minutes before administering active medications to the 
contralateral side to assess for toxicity or acute adverse reactions.  
7. The intravascular access will be retracted from intracranial circulation and navigated to 
the contralateral middle meningeal artery.  
8. As described in Steps 3-5, infusion of lidocaine and methylprednisolone will occur.  
9. Intravascular catheters will be retracted and access site will be sealed with appropriate 
closure device.  
 
The following intra-procedural protocol adjustment is allowed: in the event of concern for 
overdose or other toxicity, the protocol permits administering half-strength dosages prior to 
completing administration of full dosage amounts (for example, administering 20 mg of lidocaine 
over the 2-5 min, waiting 2 minutes, and then subsequently administering the remaining 20 mg of 
lidocaine over another 2-5 min interval to result in a complete administration of a full dose). If 
this protocol adjustment is enacted, the Investigator must document this variation from standard 
protocol in procedural documentation.  
Following study drug administration, patient will be monitored for post-procedure recovery 
by a nursing staff member for at least 4 hours. During this time, the patient’s vital signs will be 
monitored, including continuous electrocardiogram, pulse oximetry, cyclic blood pressure 
monitoring (with measurements obtained at least every 15 minutes), respiratory rate, and heart 
rate monitoring. The catheterization access site will be assessed 2 hours following administration 
to ensure adequate closure and absence of access site hematoma.  
7.2. 
Study Assessment and Activities 
Summary of all study-related visits and activities are described in Table 1, including screening 
procedures and study drug administration. 
 
 
 

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Table 1. Schedule of Study Visits  
 
Visit 1 
(Screening) 
Visit 2 
(Administration) 
(Week 0)a 
Visit 3 
(Week 1)b 
Visit 4 
(Week 6)b 
Visit 5 
(Week 12)b 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant 
Medication Review 
X 
X 
X 
X 
X 
Complete 
Neurological Physical 
Exam 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Comprehensive 
Metabolic Blood Panel  
X 
X 
 
 
 
Pregnancy Test (Urine 
or Serum) 
X 
 
 
 
 
MIDAS Score 
(Appendix A) 
X 
X 
X 
X 
X 
4-point Verbal Rating 
Scale (Appendix B) 
X 
X 
X 
X 
X 
11-point Numeric Pain 
Rating Scale 
(Appendix C) 
X 
X 
X 
X 
X 
Subject Diary Review 
X 
X 
X 
X 
X 
Study Drug 
Administration 
 
X 
 
 
 
aApproximately 4 weeks of Visit 1 
b± 2 days 
 
7.2.1. Visit 1 (Screening) 
1. Review the study with the subject and obtain written informed consent and HIPAA 
authorization.  
2. Assign the subject a unique screening number.  
3. Record demographics data.  
4. Record medical history, including history of tobacco use, obesity status, past traumatic 
brain injury, diabetes mellitus, hypertension, hyperlipidemia, migraines), diagnosis date, 
and prior preventative medications trialed for migraine treatment.  
5. Record current, concomitant medications. 
6. Perform a complete neurological physical exam, including visual field assessment, 
fundoscopic exam, cranial nerve exam, peripheral motor and sensory fields, and reflexes.  
7. Perform and record vital signs, including blood pressure monitoring.  
8. Perform clinical laboratory tests (i.e., complete metabolic blood panel and pregnancy test 
as applicable).  
9. Administer migraine-related symptom scores (i.e., MIDAS, 4-point Verbal Rating Scale, 
11-point Numeric Pain Rating Scale).  
10. Initiate Subject Diary, including instructions to record migraine episodes and any adverse 
events with date of onset, duration, and description.  
11. Schedule subject for Visit 2 (study drug administration).  

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7.2.2. Visit 2 (Administration)  
(Week 0 – Approximately 4 weeks after Visit 1). 
1. Record any changes to concomitant medications. 
2. Perform a complete neurological physical exam, including visual field assessment, 
fundoscopic exam, cranial nerve exam, peripheral motor and sensory fields, and reflexes.  
3. Perform and record vital signs, including blood pressure monitoring.  
4. Administer study drug (lidocaine hydrochloride and methylprednisolone serially).  
5. Perform clinical laboratory tests (i.e., complete metabolic blood panel) following study 
drug administration.  
6. Administer migraine-related symptom scores (i.e., MIDAS, 4-point Verbal Rating Scale, 
11-point Numeric Pain Rating Scale).  
7. Review Subject Diary, including details of any migraine episodes.  
8. Schedule subject for Visit 3.  
7.2.3. Visit 3 (Week 1 ± 2 days) 
1. Record any changes to concomitant medications. 
2. Perform a complete neurological physical exam, including visual field assessment, 
fundoscopic exam, cranial nerve exam, peripheral motor and sensory fields, and reflexes.  
3. Perform and record vital signs, including blood pressure monitoring.  
4. Administer migraine-related symptom scores (i.e., MIDAS, 4-point Verbal Rating Scale, 
11-point Numeric Pain Rating Scale).  
5. Review Subject Diary, including any incidence of adverse events.  
6. Schedule subject for Visit 4.  
7.2.4. Visit 4 (Week 6 ± 2 days) 
1. Record any changes to concomitant medications. 
2. Perform a complete neurological physical exam, including visual field assessment, 
fundoscopic exam, cranial nerve exam, peripheral motor and sensory fields, and reflexes.  
3. Perform and record vital signs, including blood pressure monitoring.  
4. Administer migraine-related symptom scores (i.e., MIDAS, 4-point Verbal Rating Scale, 
11-point Numeric Pain Rating Scale).  
5. Review Subject Diary, including any incidence of adverse events.  
6. Schedule subject for Visit 5.  
7.2.5. Visit 5 (Week 12 ± 2 days) 
1. Record any changes to concomitant medications. 
2. Perform a complete neurological physical exam, including visual field assessment, 
fundoscopic exam, cranial nerve exam, peripheral motor and sensory fields, and reflexes.  
3. Perform and record vital signs, including blood pressure monitoring.  
4. Administer migraine-related symptom scores (i.e., MIDAS, 4-point Verbal Rating Scale, 
11-point Numeric Pain Rating Scale).  
5. Review Subject Diary, including any incidence of adverse events.  
8. 
DATA SAFETY MONITORING 
8.1. 
Safety Monitoring Plan 
Data safety monitoring will be undertaken jointly by the Institutional Review Board and 
Investigator, including training all co-investigators to report research-related adverse events to 
Investigator within 12 hours. A safety report to the Institutional Review Board after either 

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reaching half of anticipated enrollment (10 subjects) or eight months following trial start, 
whichever event occurs first, will be prepared.  
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the 
administration of an investigational product, whether or not related to that investigational product. 
An unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Prescribing Information or of greater severity or frequency than expected based on the 
information in the Prescribing Information. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents. Adverse 
events will be recorded in the patient study records. Adverse events will be described by duration 
(start and stop dates and times), severity, outcome, treatment and relation to study drug, or if 
unrelated, the cause. 
 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 will be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant. The modified criteria can be found in the study 
manual. If the experience is not covered in the modified criteria, the guidelines shown in Table 2 
below should be used to grade severity. 
Table 2. AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug will be assessed using the following the guidelines in 
Table 3. 
Table 3. AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 

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Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
 
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
All personnel will document all SAEs that occur (whether or not related to study drug). The 
collection period for all SAEs will begin after study drug administration and end after the final 
study visit have been completed. 
Consistent with federal regulations and in accordance with standard operating procedures and 
policies of the Cooper University Health Care Institutional Review Board (IRB), all potential 
unanticipated problems that are 1) unforeseen and 2) indicate that participants are at increased 
risk of harm will be promptly reported to the Cooper University Health Care IRB. The 
Investigator will report internal and external AEs to the Cooper University Health Care IRB 
within 7 days of discovery that meet above criteria for an unanticipated problem requiring prompt 
reporting to the IRB. SAEs meeting prompt reporting criteria will be reported to the Cooper 
University Health Care IRB within 1 day of discovery by telephone, fax, or email, with a full 
report submitted within 7 days of notification. Full reports will include: a) whether the occurrence 
of the adverse event alters the risk-benefit relationship of study participation, b) whether the 
protocol and/or consent form require modification, and c) whether any additional information 
needs to be given to the subjects who are already enrolled. Per federal regulations, SAEs meeting 
prompt reporting criteria will be reported within 7 calendar days if life-threatening or fatal or 
within 15 calendar days for all other types of qualifying reportable events to the appropriate 
regulatory body (i.e., FDA).  
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. 
CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). The Investigator grants 
permission to appropriate regulatory authorities to conduct on-site monitoring and/or auditing of 
all appropriate study documentation. 

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9. 
STATISTICAL METHODS AND CONSIDERATIONS 
9.1. 
Analysis Plan 
An intention to treat analysis will be performed. Prevalence of any adverse event, 
treatment-related adverse events, and serious and/or fatal adverse events will be calculated. 
Secondary analyses assessing pairwise differences in pre- and post-interventional changes in 
symptom scores will also be performed to identify trends and as the basis for future power 
analyses. Categorical variable data will be summarized as frequencies with Agresti-Coull 
intervals as applicable. Quantitative variable data will be summarized as medians with 
interquartile ranges. Spearman’s rank correlation coefficient, two-sided Student’s t-test, chi-
square tests, and nonparametric equivalences may be conducted at 0.05 significance level.  
9.2. 
Interim Analysis 
One interim analysis is planned for formal evaluation of safety during phase 1. Interim analysis 
will be performed when a total of 10 patients (50%) have completed Study Visit 3 (1 week 
follow-up after study treatment).  
 
10. 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
10.1. Informed Consent 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], 
CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability 
Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form and HIPAA authorization and 
provide the documents to submit to the IRB/IEC. The consent form generated by the Investigator 
must be approved by the IRB/IEC. The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior 
to entering the subject into the trial. Information should be given in both oral and written form 
and subjects must be given ample opportunity to inquire about details of the study. A copy of the 
signed consent form will be given to the subject and the original will be maintained with the 
subject’s records. 
10.2. Investigator and Facilities Data 
 
The Principal Investigator is Dr. Daniel A. Tonetti, MD, Assistant Professor of 
Neurosurgical Surgery at Cooper University Health Care. Please refer to FDA Form 1572 
(Appendix H) for further contact information. Dr. Tonetti is a highly qualified open and 
endovascular neurosurgery who will lead this trial, given his prior experience in leading and 
coordinating early-stage clinical trials. His contributions to the field of Cerebrovascular 
Neurosurgery and Endovascular Neurosurgery are notable, as evidenced by his experience with 
over 100 peer-reviewed publications, numerous abstracts, and international/national 
presentations. Within the Cooper Neurological Institute, a prominent institution with a specialized 
South Jersey Headache clinic, Dr. Tonetti works alongside a team of skilled neurologists and 

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advanced practices providers who actively treat patients suffering from intractable migraine 
headaches.  
Investigation is to be conducted at Cooper University Health Care in Camden, New 
Jersey, USA. Please refer to FDA Form 1572 (Appendix H) for further details on facility data.  
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of 
Clinical Investigators (21 CFR 312). The protocol will be reviewed and approved by: 
 
Name: Cooper University Health Care Institutional Review Board 
Address: 1 Cooper Plaza, Camden, NJ, 08103, USA 
 
Serious adverse experiences regardless of causality will be reported to the institutional 
review board in accordance with the standard operating procedures and policies of the 
institutional review board, and the Investigator will keep the institutional review board informed 
as to the progress of the study. The Investigator will obtain assurance institutional review board 
compliance with regulations. 
Any documents that the institutional review board may need to fulfill its responsibilities 
(such as protocol, protocol amendments, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the institutional review board. The institutional review board’s written unconditional 
approval of the study protocol and the informed consent form will be in the possession of the 
Investigator before the study is initiated. This approval must refer to the study by exact protocol 
title and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written institutional review board approval except when necessary to eliminate immediate 
hazards to the patients or when the change(s) involves only logistical or administrative aspects of 
the study. Such modifications will be submitted to the institutional review board and written 
verification that the modification was submitted and subsequently approved should be obtained. 
The institutional review board must be informed of revisions to other documents originally 
submitted for review; serious and/or unexpected adverse experiences occurring during the study 
in accordance with the standard operating procedures and policies of the institutional review 
board; new information that may affect adversely the safety of the patients of the conduct of the 
study; an annual update and/or request for re-approval; and when the study has been completed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11. 
APPENDICES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11.1. Appendix A: The Migraine Disability Assessment Test (MIDAS) 
 
Over the past ______, please answer the following questions about ALL headaches you 
have had.  
 
___ 1. On how many days in the last _____ did you miss work or school because of your 
headache?  
 
___ 2. How many days in the last _____ was your productivity in work or school reduced 
by half or more because of your headaches? (Exclude days that were counted in question 
#1 where you missed work or school) 
 
___ 3. How many days in the last _____ did you not do household work (such as 
housework, repairs, maintenance, shopping, caring for yourself, children, relatives) 
because of your headaches?  
 
___ 4. How many days in the last _____ was your productivity in household work 
reduced by half or more because of your headaches? (Exclude days that were counted in 
question #1 where you did not do any household work) 
 
___ 5. How many days in the last _____ did you miss family, social, or leisure activities 
because of your headaches?  
 
Add the total number of days from questions 1-5:  
 
MIDAS Grade 
Definition 
MIDAS Score 
I 
Little of No Disability 
0-5 
II 
Mid Disability 
6-10 
III 
Moderate Disability 
11-20 
IV 
Severe Disability 
21+ 
 
 
 
 
 
 
 

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11.2. Appendix B: 4-Point Verbal Pain Scale 
 
Provider, please ask: “How would you describe your pain?” 
 
Score 
Pain Descriptor 
Severity of Pain 
0 
None 
No pain 
1 
Mild 
Pain reported in response to questioning only, 
without any behavioral signs 
2 
Moderate 
Pain reported in response to questioning and 
accompanied by behavioral signs, or pain reported 
spontaneously without questioning 
3 
Severe 
Strong verbal response accompanied by facial 
grimacing, withdrawal of the hand, or tears 
 
Grade is determined based on patient descriptor and provider interpretation based on 
criteria in “Severity of Pain” column 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11.3. Appendix C: 11-Point Numeric Pain Scale 
 
Provider, please ask: “On a scale of 0-10, with 10 being the worst pain imaginable, how 
would you rate your headache-related pain?”  
 
 
 
Score 
Pain 
0 
No Pain 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
Worst Pain Imaginable