Efficacy and Safety of Tx360® Transnasal Sphenopalatine Ganglion Block in the Treatment of Chronic Migraine

This is a phase III, multi-center, randomized, double-blind, placebo-controlled, prospective, clinical trial examining the outcomes of subjects with chronic migraine headache who are treated with 0.3cc of 0.5% bupivacaine bilaterally vs 0.3cc of sterile water bilaterally, each delivered to the mucosal surface of the SPG through each nare with the Tx360® device.

Subjects must have a current history of ICHD-III beta migraine with > 14 headache days per month (with 8 or more being migraine) in the 3 months prior to the screening visit. Subjects will be required to have a stable history of doses of migraine prophylactic medication for at least 30 days prior to the start of the 28-day screening/baseline phase and for the duration of the study. At Visit 1, the subject will sign the informed consent indicating they are willing to participate in the study. Initially, subjects who meet the study criteria will participate in a 28-day screening/baseline phase. During the 28-day screening/baseline phase, all subjects will be monitored through the use of electronic Daily Headache Diary (DHD) to ensure they continue to meet all inclusion criteria, and none of the exclusion criteria.

If baseline criteria have been met at the end of the 28-day screening/baseline phase, the subject will return to the clinic for Visit 2 to be randomized into one of the two treatment groups and begin the 4-week treatment phase of the study. Subjects who meet all inclusion criteria, and none of the exclusion criteria, will be assigned to a treatment group based on a computerized randomization number produced by a computer software system. One hundred and eighty subjects will be randomized 1:1 to receive 0.3cc of 0.5% bupivacaine bilaterally or 0.3cc of sterile water bilaterally. One member of the staff will allocate study medication, based on the randomization plan, in a blinded fashion to subject, coordinator, and investigator. At Visit 2, the subject will receive the first treatment.

The subject will return to the clinic three times per week for treatments, totaling 12 treatments.

At visit 13, subjects will receive the last treatment and will be transitioned into the post-treatment phase of the study.

The subject will be followed for an additional 3 months during the post-treatment phase for a total of 20 weeks participation in the study. During this post-treatment phase, the subject will maintain the DHD at an 80% participation rate and two monthly phone visits will take place 1 and 2 months post treatment respectively.

The subject will complete the study at Visit 14 to the clinic for final follow-up.

Inclusion criteria

• Subjects may be included that meet the following criteria:

• willing to participate and sign informed consent
• ability to understand informed consent and study procedures, including able to use the electronic Daily Headache Diary
• in general good health based on investigator's judgment
• male or female, age must be between 18 to 65 years of age, inclusive
• chronic migraine meeting the diagnostic criteria listed in the International Classification of Headache Disorders (ICHD-III beta version, 2013), as follows:

• History of frequent headaches suggestive of chronic migraine (at least 15 days per month with 8 or more being migraine) for at least three months prior to screening
• Verification of headache frequency through prospectively collected baseline information during the 28-day screening/baseline phase demonstrating headaches at least 15 days, with at least 8 days per month fulfilling any one of the following

• Qualify as being a migraine
• Relieved by migraine specific acute medications
• onset of migraine before age 50
• able to differentiate migraine from any other headache they may experience (e.g., tension-type headache)
• stable history of migraine at least 3 months prior to screening with headache free periods
• not currently taking a migraine preventive OR has been taking a stable dose of a preventive for at least 60 days prior to screening and agrees to not start, stop, or change medication and/or dosage during the study period

a) subjects on migraine preventative should have stable headache pattern

• subject is either not of childbearing potential, as defined in the methods section, or if they are of childbearing potential they agree either to remain abstinent or use (or have their partner use) an acceptable method of birth control for the duration of the study
• demonstrated compliance with the electronic Daily Headache Diary during the 28-day screening/baseline phase as defined by entry of headache data on a minimum of 22 to 28 days (80% diary compliance) in or completing the study.

Exclusion criteria

Subjects will be excluded that meet the following criteria:

• unable to complete headache records (diary) as required by protocol
• pregnant, actively trying to become pregnant, or breast-feeding
• history of medication overuse (MO) of opioids, or butalbital, as defined by ICHD-III beta criteria in the previous 12 months and/or MO during 28-day screening/baseline phase (Appendix B).
• history of hemiplegic migraine, basilar migraine, cervicogenic headache, occipital neuralgia or post-traumatic headache as defined by ICHD-III beta criteria (Post traumatic headache needs to have developed within 7 days of the following: injury to the head, regaining of consciousness following injury to the head, or discontinuation of medications that impair ability to send or report headache following the injury to the head.
• has failed greater than 2 migraine preventative medications due to lack of efficacy after adequate trial
• received onabotulinumtoxinA for migraine or for any medical or cosmetic reasons requiring injections in the head, face, or neck during the 4 months before screening.
• has a planned military deployment within the 6 months post screening
• has previously received SPG blocks using the Tx360®device
• history of substance abuse and/or dependence within the past 5 years, in the judgment of the Investigator
• unstable neurological condition or a significantly abnormal neurological examination with focal signs or signs of increased intracranial pressure, in the judgment of the investigator
• suffers from a serious illness, or an unstable medical condition, one that could require hospitalization, or could increase the risk of adverse events, in the judgment of the investigator
• any psychiatric condition with psychotic features, and/or any other psychiatric disorder not stable or well controlled, that would interfere in the ability to complete study activities
• malignancy within the past year, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
• nasal septal deformity such as cleft lip and palate, choanal atresia, atrophic rhinitis, rhinitis, or septal perforation
• recent nasal/midface trauma (< 3 months)
• nasal or facial fracture
• recent nasal/sinus surgery (< 3 months)
• bleeding disorder such as Von Willebrand disease or hemophilia
• severe respiratory distress
• neoplasm such as Angiofibroma, sinus tumor, granuloma
• nasal congestion present more than 10 days with fever (temperature ≥ 100.4 F) and nasal mucous is an abnormal color
• skin around and inside the nasal passage that is dry, cracked, oozing, or bleeding
• recurrent nose bleeds
• allergy to bupivacaine
• has a score > 0 on question 9 of PHQ-9 at any visit
• received any investigational agents within 30 days prior to Visit 1
• plans to participate in another clinical study at any time during this study
• have any other conditions that in the judgment of the Investigator would make the subject unsuitable for inclusion, or would interfere with the subject participating