Use of the Tx360 Nasal Applicator in the Treatment of Chronic Migraine (Tx360)

Use of the Tx360 Nasal Applicator for Transnasal Sphenopalatine Ganglion Block in the Treatment of Chronic Migraine: A Double-blind Placebo-controlled Study

Migraine imposes a substantial burden on patients in terms of diminished daily functioning, quality of life, and financial loss. Pain severity and duration correlates with reduced measures of daily functioning, and overall health status. The sphenopalatine ganglion (SPG) has been implicated in a variety of cephalalgias. This has been well represented in the literature dating back over a century. Access to this structure can be gained via a small area of mucosa just posterior and superior to the tail of the middle turbinate on the lateral nasal wall. At this aspect, there is no bony boundary to the SPG. Blocking the SPG using local anesthetics relieves pain. Unfortunately, many current interventions are cumbersome, invasive, and expensive. The purpose of this study is to evaluate the efficacy of the Tx360™, a new nasal applicator device, in the treatment of head and face pain and to examine the economic implications. The Tx360™ is a single use device designed to deliver a topical local anesthetic to the specific area of mucosa associated with the SPG. A total of 42 study participants will be accepted into this double-blind placebo-controlled study. 28 will receive SPG blocks using a 0.3 mL of a 0.5% solution of Marcaine delivered by the Tx360™ while 14 will receive a placebo of saline substituted for the Marcaine. Both patient sets will also be given a piece of lemon hard candy as a taste distractor. Participants must have a chronic migraine history with over 15 symptomatic days per month over the past three months. The treatment plan consists of six weeks of treatment, two times per week. Short and longer term assessments will be retrieved and analyzed as detailed in the Study Design.

42 study participants will be included in this double-blind placebo-controlled study. Following enrollment of 42 subjects and completion of the 6-week Treatment Period by all active subjects, an analysis of the treatment effect will be performed for a reassessment of sample size and, if deemed appropriate, the study will continue with enrollment of additional subjects to ensure a more statistically robust interpretation of the data. The results of the statistical analysis will be blinded from Investigators and coordinators. The procedure will be delivered to all subjects who agree to participate, meet inclusion criteria, and sign informed consent. At Visit 1 following Informed Consent, a physical exam and vital signs will be completed. A medical, headache, and medication history (to include age, sex, height and weight, and duration and location of headache pain, as well as history of ER visits) will be collected on all subjects. Eligible subjects will be provided with a Baseline Headache Diary and instructed to treat migraines for the following month in their usual manner with their usual treatment. The daily Diary will document headache, acute treatment and response, and migraine associated symptoms (nausea, vomiting, light sensitivity, or sound sensitivity) to establish a Baseline number of headache days and severity. Visit 2 will be scheduled for 1 month following Visit 1. Following Visit 1, Visits 2-13 (treatment visits) will be scheduled to occur twice weekly (during the regular Monday - Friday work week) at least 2 days apart. Treatments should not occur on consecutive days. At Visit 2, the Baseline Headache Diary will be reviewed and those subjects continuing to meet eligibility will be dispensed a 6-week Treatment Period Diary and complete Before Procedure questions to include the Pain Intensity Numeric Rating Scale (NRS), the Modified Pain Characteristic Questionnaire, and a baseline Headache Impact Test-6 (HIT-6), have vital signs completed, and the medical, headache, and medication history updated. Subjects will be randomized 2:1 to Group A or Group B. Group A will receive treatment with 0.3 mL of 0.5% Marcaine delivered bilaterally with the Tx360™ device to the mucosa associated with the SPG. Group B will receive saline substituted for Marcaine delivered bilaterally with the Tx360TM device to the mucosa associated with the SPG. To maintain the blinding of the treatment groups, neither the Investigator nor research personnel who are involved in evaluating the subject should prepare the study medication. An independent research staff person with no involvement in the study conduct will place study medication (either Marcaine for a subject randomized to Group A or Placebo/saline for a subject randomized to Group B) in a 1cc Luer Lok tip syringe and assemble the syringe and Tx360TM catheter as instructed in training. A label with the subject Drug Number will be placed on the device at that time. The research staff person administering the study medication will verify that the Drug Number assignment is correct. Both Groups will be given a piece of lemon hard candy as a taste distractor. At each treatment visit (Visits 2-13), in addition to Before Procedure questions, subjects will complete 15-minute and 30-minute After Procedure questionnaires to include the NRS and, at 30 minutes, the Patient's Global Impression of Change (PGIC). Subjects will take home a questionnaire to include the NRS, PGIC, satisfaction question, and the Modified Pain Characteristic Questionnaire to be completed at 24 hours following treatment and be instructed to return the 24-hour After Procedure questionnaire to the clinic at the next visit. At Visits 2-15 vital signs will be completed, medications will be updated, and Non-Serious Adverse Events will be collected after the first treatment. Serious Adverse Events will be collected once the informed consent has been signed and throughout the study. At Visits 5, 8, and 11, the Treatment Period Headache Diary will be collected, reviewed, and re-dispensed. At Visit 13, the 1-Month Post-Treatment Period Diary will be dispensed. The subject will return to the clinic at Visit 14 between 24 and 96 hours following the final treatment at Visit 13 to return the 24-hour After Procedure Questionnaire and complete the 1-Month Treatment Period HIT-6. The Treatment Period Diary will be collected. At Visit 15, 1 month following the final treatment, each subject will return to the clinic and complete a 1-Month Follow Up HIT-6 and the 1-Month Follow Up Questionnaire. The 1-Month Post-Treatment Period Diary will be collected. At 6 months following the final treatment, each subject will be phoned to complete the 6-Month Follow Up Questionnaire to include the NRS, PGIC, satisfaction question, the Modified Pain Characteristic Questionnaire, and a 6-Month Follow Up HIT-6. Treatment Medication Subjects randomized to Group A will be administered 0.3 mL of 0.5% Marcaine delivered bilaterally with the Tx360™ device to the mucosa associated with the SPG. Twelve treatments will be administered over a period of 6 weeks. Subjects randomized to Group B will be administered saline substituted for Marcaine delivered bilaterally with the Tx360TM device to the mucosa associated with the SPG for treatment of chronic migraine. Twelve treatments will be administered over a period of 6 weeks. Rescue Medication Subjects will be allowed to rescue with medication mutually agreed upon by subject and Investigator at the time of screening.

Group A will receive treatment with 0.3 mL of 0.5% Marcaine delivered bilaterally with the Tx360™ device to the mucosa associated with the Sphenopalatine Ganglion (SPG)

Group B will receive saline placebo delivered bilaterally with the Tx360TM device to the mucosa associated with the SPG.

Marcaine used as a topical local anesthetic to block the SPG by delivering Marcaine directly to the specific area of mucosa associated with the SPG.

Compare Numeric Rating Scale (NRS) scores Before Procedure,15-Minute Post Treatment, 30-Minutes Post Treatment, 24-Hour Post Treatment for all 12 treatments (Marcaine vs. Saline). NRS is a likert scale ranging from 0-10 with 0 being no pain and 10 being worst possible pain. For each individual time point, all 12 treatments were averaged for that time point and a single value was used for comparison between the two groups.

Compare percentage change in Numeric Rating Scale (NRS) score from Before Procedure to 15-Minutes, Before Procedure to 30-Minutes, Before Procedure to 24-Hours After Procedure for all 12 treatments (Mean of all 12 treatments for each timepoint, comparing Group A to Group B). NRS is a likert scale ranging from 0-10 with 0 being no pain and 10 being worst possible pain.

15 Minutes Post Treatment, 30 minutes Post Treatment and 24 hours Post Treatment, assessed up to 6 weeks

Compare 24-Hour After Procedure Patient's Global Impression of Change (PGIC) score for 12 treatments (Mean of all 12 treatments for each timepoint, comparing Group A to Group B). PGIC is a likert scale ranging from 1 to 7 with 1 being very much improved and 7 being very much worse.

Compare Modified Pain Characteristic Questionnaire scores Before Procedure vs. 24-Hour After Procedure, Before Procedure vs. 1-Month Follow Up, and Before Procedure vs. 6-Month Follow Up (Mean of all 12 treatments for each timepoint, comparing Group A to Group B). The modified pain characteristic questionnaire is a series of 11 questions on a likert scale ranging from 0 to 10 with 0 being no pain or does not interfere and 10 being worst pain or completely interferes. Percentage questions range from 0 to 100.

Compare change in the number of migraine headache days per month reported in Baseline Period Diary vs. Treatment Period Diary vs. Post-Treatment Period Diary.

Number of acute medications used during Treatment period (6 weeks) and Follow-Up (4 weeks) (Group A vs. Group B).

Total Headache Impact Test (HIT-6) scores Pre-Treatment at Visit 2 vs. Post-Treatment (following final treatment), and at 1-Month Post-Treatment (Group A vs. Group B). HIT-6 is a series of 6 likert scale questions ranging from 1 to 5 with 1 being never and 5 being always. The HIT-6 answer options are weighted as follows: Never (1) = 6 points each, Rarely (2) = 9 points each, Sometimes (3) = 10 points each, Very often (4) = 11 points each, Always (5) = 13 points each. The total score for the HIT-6 ranges from 36 (subject answers all 6 questions as "Never") to 78 subject answers all 6 questions as "Always"), with higher total scores indicating more impact than lower scores, i.e., headaches cause greater impact on the subject's life.

Satisfaction scores Visit 2 vs. following treatment (Treatment 12) and at 1-Month Post-Treatment (Group A vs. Group B). Satisfaction scores are a likert scale ranging from 1 to 5 with 1 being complete dissatisfaction and 5 being complete satisfaction.

Inclusion Criteria: Is male or female, in otherwise good health, 18 to 80 years of age. Has history of chronic migraine (with or without aura) according to the criteria proposed by the Headache Classification Committee of the International Headache Society for at least 3 months prior to enrollment. Has onset of migraine before age 50. Is able to differentiate migraine from any other headache they may experience (e.g., tension-type headache). Is not currently taking a migraine preventive or has been taking preventive for at least 30 days prior to screening and agrees to not start, stop, or change medication and/or dosage during the study period. If female of childbearing potential, agrees to use, for the duration of the study, a medically acceptable form of contraception as determined by the Investigator. Complete abstinence from intercourse from 2 weeks prior to administration of study drug throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the study drug; or, Surgically sterile (hysterectomy or tubal ligation or otherwise incapable of pregnancy); or, Sterilization of male partner; or, Intrauterine device with published data showing lowest expected failure rate is less than 1% per year; or, Double barrier method (i.e., 2 physical barriers OR 1 physical barrier plus spermicide) for a least 1 month prior to Visit 1 and throughout study; or, Hormonal contraceptives for at least 3 months prior to Visit 1 and throughout study. Has pain presentation in frontal, temporal, ophthalmic, maxillary, mandibular, facial, or intraoral location. Exclusion Criteria: Is male or female, in otherwise good health, 18 to 80 years of age. Has history of chronic migraine (with or without aura) according to the criteria proposed by the Headache Classification Committee of the International Headache Society for at least 3 months prior to enrollment. Has onset of migraine before age 50. Is able to differentiate migraine from any other headache they may experience (e.g., tension-type headache). Is not currently taking a migraine preventive or has been taking preventive for at least 30 days prior to screening and agrees to not start, stop, or change medication and/or dosage during the study period. If female of childbearing potential, agrees to use, for the duration of the study, a medically acceptable form of contraception as determined by the Investigator. Complete abstinence from intercourse from 2 weeks prior to administration of study drug throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the study drug; or, Surgically sterile (hysterectomy or tubal ligation or otherwise incapable of pregnancy); or, Sterilization of male partner; or, Intrauterine device with published data showing lowest expected failure rate is less than 1% per year; or, Double barrier method (i.e., 2 physical barriers OR 1 physical barrier plus spermicide) for a least 1 month prior to Visit 1 and throughout study; or, Hormonal contraceptives for at least 3 months prior to Visit 1 and throughout study. Has pain presentation in frontal, temporal, ophthalmic, maxillary, mandibular, facial, or intraoral location.

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