Transnasal Evaporative Cooling Device for Migraine: A Prospective, Randomized, Double-blind, Multicenter Trial

Transnasal Evaporative Cooling Device for Migraine: A Prospective, Randomized, Double-blind, Multicenter Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Transnasal Evaporative Cooling Device for Migraine: A Prospective, Randomized, Double-blind, Multicenter Trial Larry Charleston, Amaal Starling, Nauman Tariq This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6108236/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: There is a need for effective and affordable nondrug therapies for the acute treatment of migraine. Transnasal neuromodulation via evaporative cooling may modulate the sphenopalatine ganglion, which is implicated in migraine. The study aimed to evaluate the safety, tolerability, and optimal dose of this method for acute migraine treatment. Methods: A prospective, randomized, double-blind, multicenter study was conducted at 3 US sites. Subjects received 15 minutes of in-clinic treatment during a migraine attack. Twenty-four subjects were randomized into three groups: 24 liters per minute (LPM), 18 LPM, and 6 LPM. Pain and Most Bothersome Symptom (MBS) were recorded at baseline 2 and 24 hours post treatment. The primary endpoint was pain relief (PR) at 2 hours. Secondaryendpoints included tolerability, MBS relief and pain freedom (PF) at 2 hours and 24 hours Results: Eighty-seven adults with episodic migraine with or without aura were enrolled. PR at 2 hours without rescue medication (woRM) was reported by 89% (8/9) of the participants who received 6LPM. PR at 2 hwoRM was reported to be 56% (5/9) and 50% (3/6) in the 18LPM and 24LPM groups, respectively. PF at 2 hours woRM was reported by 44% (4/9) of participants in the 6LPM group, and no participants in the 18LPM or 24LPM group reported PF at 2 hours. MBS relief at 2 hwas 78% (7/9), 67% (6/9) and 50% (3/6) in the 16, 18 & 24LPM groups, respectively. No adverse events occurred in the 6LPM group,and none were serious or severe in any group. Moderate discomfort was reported by 11% (1/9) of the participants in the 6LPM group. In contrast, 33% (3/9) and 83% ofthe 18LPM and 24LPM groups reported moderate or severe discomfort, respectively. Zero, one, and two subjects discontinued the 15-minute session in the 6LPM, 18LPM, and 24LPM groups, respectively. The study was terminated early because of slow subject accrual. Conclusions: Lower flow rates during transnasal cooling were both effective and tolerable for acute migraine treatment. The study became a dose-ranging trial, with lower flow rates,showing greater efficacy. A future at-home study is planned. Trial Registration: ClinicalTrials.gov Identifier: NCT04936061; Registration date: June 15, 2021. The full study protocol can be accessed at https://clinicaltrials.gov/study/NCT04936061. acute treatment clinical trial migraine neuromodulation headache sphenopalatine ganglion pain relief pain freedom Figures Figure 1 Figure 2 Figure 3 BACKGROUND Migraine is a severely disabling neurologic condition and is the sixth most disabling disorder worldwide, affecting more than a billion people. Migraine attacks are recurrent episodes of headache associated with sensory sensitivities (light and sound) and nausea and/or vomiting. Migraine can cause a significant reduction in quality of life and a loss of productivity. The global economic burden of migraine is staggering at approximately $ 20 billion in the U.S. and $ 56 billion worldwide per year. Migraine affects significantly more women than men and is the leading cause of disability in people under the age of fifty. 1 The first-line acute treatment options for migraine attacks are medications such as triptans and NSAIDs, which can be associated with adverse effects, are contraindicated in those with cardiovascular issues, and may put patients at risk for medication-overuse headache. A large study of U.S. adults with migraine reported that of those who had ever used oral triptans, more than half discontinued taking them. 2 The most common reasons for oral triptan discontinuation are perceived lack of efficacy (38.4%) and side effects (22.8%). 2 Sixty percent of patients using prescription acute treatment medications still report having moderate-to-severe headache-related disability. 3 Noninvasive neuromodulation therapies that target migraine pathophysiology are gaining traction owing to their tolerability, safety profile, and relative effectiveness. Current first-line acute therapies for migraine are suboptimal, expensive, and ineffective. There is an enormous unmet need for an effective and affordable nondrug acute therapy for migraine attacks to significantly improve quality of life and substantially reduce the cost burden to our healthcare system and society. Ineffective acute treatment for migraine can lead to an increase in attack frequency and disease severity. 4 The prevalence of migraine in the U.S. is increasing, with 15% of the population living with episodic migraine or chronic migraine, which is defined as 15 or more headache days per month with at least 8 days with migraine features. Migraine is one of the most common reasons for emergency room visits. Despite treatment recommendations, opioids are still overprescribed for patients with migraine. This is especially the case in emergency departments (EDs), where one study reported that opioids are prescribed at more than 50% of ED visits for migraine. 5 This phenomenon is likely a contributor to the opioid epidemic. The use of opioids in this population carries a high risk of ‘medication-overuse-headache’ when used more than 10 times/month and can quickly lead to opioid dependency. 6 Chronic migraine is the most severe form of migraine associated with high levels of disability, disease burden, healthcare utilization, and economic impact. 7 The pathophysiology of migraine is complex. There is evidence that the headache phase of migraine involves the activation of nociceptors in the trigeminal ganglion. 8 The sphenopalatine ganglion (SPG), a large ganglion behind the superior nasal turbinate, is closely associated with the trigeminal system. 9 Several studies have shown that intranasal SPG nerve block with lidocaine provides relief from migraine attacks. 10 , 11 , 12 This study was based on several premises. First, Singal et al. reported no statistically significant difference in the mean change in pain scores between the oxygen- and room air-treated arms, although both study arms achieved substantial relief of symptoms. 13 A pilot study conducted by Vanderpol and colleagues using transnasal evaporative cooling resulted in significant relief from headache and other migraine symptoms. 14 Transnasal evaporative cooling for migraine may help attenuate trigemino-vascular system activation via the sphenopalatine ganglion. 15 Moreover, temperature changes may be transmitted from the mucosa of the nasal sinuses to the dura mater (the meningeal covering) of the brain via venous blood, which may aid in vasoconstriction of the blood vessels supplying the b5rain, reduce the release of inflammatory mediators, and attenuate overall inflammation/local edema. 14 The goal of this study was to evaluate the safety, tolerability, and optimal dose of a transnasal cooling device for the acute treatment of migraine. We hypothesized that a transnasal evaporative cooling device for migraine (CoolStat Transnasal Thermal Regulating Device) would reduce pain and symptom relief during a migraine attack. Transnasal evaporative cooling is a novel method of acute drug-free migraine treatment that uses only clean, dry air. The CoolStat Transnasal Neuromodulation Device produces a flow of dry filtered air at ambient temperature to induce evaporative cooling energy exchange in the turbinates and upper airway. This area is implicated in migraine disease in several ways, including the involvement of the sphenopalatine ganglion and trigeminal nerve endings. While the mechanism of action for evaporative cooling on migraine relief is not yet well defined, feasibility testing with a prototype device showed significant pain relief in those with migraine compared to sham, 16 as did a subsequent tolerability study with the CoolStat device. METHODS Standard Protocol Approvals, Registrations, and Patient Consents This study was conducted at 3 sites in the United States (Atrium Health Wake Forest Baptist Neurosciences Institute in Charlotte, NC; Michigan State University College of Human Medicine in East Lansing, MI; and Mayo Clinic in Scottsdale, AZ). The study protocol and informed consent form were reviewed and approved by the Advarra Institutional Review Board (Pro00054590) on June 30, 2021. This study was conducted under IDE #G210131. Written informed consent was obtained from all participants before they underwent any study procedures. The first patient was enrolled in October 2021, and the last patient completed the study in August 2022. The study is registered with ClinicalTrials.gov (NCT04936061). All study participants provided written informed consent prior to initiating any study procedures. Study Design and Participants Participants with migraine with or without aura participated in this prospective, randomized, double-blind, multicenter trial. Participants were eligible to participate if they were 18–80 years old, met the International Classification of Headache Disorders (ICHD 3-beta) criteria for episodic migraine with 2–8 migraine headache days per month and less than 15 headache days per month, had a diagnosis of episodic migraine for at least one year, and were on stable migraine preventive medications in the 6 weeks prior to enrollment. The inclusion and exclusion criteria are listed in Table 1 . Table 1 Inclusion and exclusion criteria Inclusion Criteria 1. Meets the International Classification of Headache Disorders (ICHD-3) diagnostic criteria for migraine with or without aura, with the exception of ''complicated migraine'' (i.e., hemiplegic migraine, ophthalmoplegic migraine, migrainous infarction). 2. Patient is between 18 and 80 years of age. 3. Patient experiences 2 to 8 migraine attacks per month. 4. Patient is in good reported general health, with no fever (< 38.3C/101F). 5. Patient has had diagnosis of migraine with or without aura over at least 1 year. 6. Migraine onset before 50 years of age. 7. Migraine prophylaxis medication unchanged for 6 weeks prior to study enrollment. 8. Able to attend treatment session within 6 hours of migraine onset, with 48 hours of pain freedom prior to onset of migraine attack. 9. Migraine pain severity of Grade 2 or Grade 3 on day of treatment. 10. Provision of signed and dated informed consent form. 11. Stated willingness to comply with all study procedures and availability for the duration of the study. Exclusion Criteria 1. Patient has difficulty distinguishing his or her migraine attacks from tension-type headaches 2. Patient has uncontrolled hypertension. 3. Patient has a fever (≥ 38.3C/101F). 4. Patient has used opioid medication or barbiturates in the past month. 5. Patient has Medication Overuse Headache (MOH), New Daily Persistent Headache (NDPH) or Chronic Tension Type Headache (CTTH). 6. Patient has 15 or more headache days per month. 7. Patient has used acute treatment(s) for migraine in the 48 hours preceding treatment, i.e., over-the-counter (OTC) medications, prescription medications, or medical device). 8. Patient has received Botox treatment, supraorbital or occipital nerve blocks in the last 4 weeks. 9. Intolerance to intranasal neurostimulation or sensory processing disorder that makes the treatment not applicable. 10. Recurrent epistaxis or chronic rhinosinusitis. 11. Recent facial trauma, sinus or intranasal surgery within the last 4 months. 12. Known or suspected pregnancy. 13. Unable to fully understand the consent process and provide informed consent due to either language barriers or mental capacity. Transnasal Neuromodulation Device The CoolStat Transnasal Neuromodulation Device produces a flow of dry filtered air at ambient temperature to induce evaporative cooling energy exchange in the turbinates and upper airway. The air flow is delivered from the CoolStat to the subject via an air hose and hand-held nebulizer. The air flow is delivered into one nostril and flows freely out of the other nostril and the mouth. This process locally extracts energy from this area and cools the adjacent tissue in the nasopharynx. The CoolStat also delivers a continuous mist of saline to the subject to keep the turbinates moist and comfortable and to further promote evaporative cooling. The CoolStat Transnasal Thermal Regulating Device [hereafter CoolStat] is noninvasive and uses no chemicals or cooling agents. 17 , and the process air and saline do not contact sterile body tissue, blood or other fluids. CoolStat is not used to support or assist with life support, patient breathing or respiratory functions. The CoolStat device weighs less than 15 lbs and can be mounted on an IV pole or sit on a bed or table near the patient (Fig. 1 ). The primary functional component inside the device is a blower, which is used to generate a flow of air. Local ambient room air is pulled into the device and is pumped across a desiccant material that extracts all moisture from the incoming air. The dry air then passes through a flexible air tube with redundant in-line air filters and is delivered to the patient via a hand-held nebulizer (Fig. 1 ). The dry air flow goes into the patient’s nostril and exits through the other nostril and the mouth, inducing evaporative cooling energy exchange in the turbinates and upper airway. 17 This energy exchange results in a local cooling effect. In this study, both the CoolStat devices and treatment administration protocols were standardized across sites and investigators. Randomization, masking, and blinding Subjects who met all the study eligibility criteria and returned to the headache clinic with a qualifying migraine attack were randomly assigned to one of the three doses. The randomization was blocked by site. The random allocation sequence was developed by an independent biostatistician and programmed into the iMedNet Electronic Data Capture (EDC) randomization tool. The subjects were only randomized and treated one time to eliminate within-subject bias. For up to sixty days after enrolling in the study, subjects returned to the headache clinic with a qualifying migraine attack for randomization and a single treatment. If a subject did not return to the clinic to treat a migraine attack within 60 days following their screening and enrollment visit, they had the opportunity to reconsent for another 60-day enrollment period. If they declined to reconsent, they were withdrawn from the study. The CoolStat devices were operated in blind mode for this study, in which the different doses were coded to a set of nine numbers. The hardware composition and function of the active and sham devices were identical. The randomization tool within the iMedNet (EDC) allocated each subject a coded flow number. In addition, the foil packaging containing the desiccant cartridges was marked with a set of three letters. The iMedNet randomization tool also allocated each subject to the appropriate desiccant cartridge lot via these letters per their randomization assignment. A research nurse or designee ran the randomization task in the EDC to assign participants to interventions. To assess blinding, participants were asked at the end of the study of their presumed group assignment (active or sham). The subjects, investigators, and outcome assessors were blinded to group assignment until the entire study was finished. Study procedures After enrollment, the participants were instructed to return to the headache clinic within 60 days during a qualifying migraine attack for a single treatment session. A qualifying migraine attack met the following criteria: (1) moderate or severe pain severity, (2) onset of head pain within 6 hours of treatment, and (3) no rescue medication taken within the 48 hours before treatment. If the subject met all the qualifying migraine attack criteria upon arriving at the headache clinic, they were then randomized to a treatment group and received the one-time 15-minute study intervention. The three treatment groups were 18 LPM (active treatment group 1), 24 LPM (active treatment group 2) and 6 LPM (sham group). A depiction of the study design can be found in Fig. 2 . Participants were instructed to avoid taking rescue medications within 2 hours post treatment. Pain scores (none, mild, moderate, or severe) were recorded at baseline and at 0, 2, and 24 hours post treatment. Migraine-associated symptoms, including nausea, photophobia, and phonophobia, were recorded at the time of treatment. The participants reported the absence and presence of all associated symptoms (including their MBS) on the same scale (none, mild, moderate, or severe) at baseline and 0, 2, and 24 hours post treatment. At 2 and 24 hours, the participants reported if, when and what type of rescue medication was used. The study staff recorded all reported adverse event (AE) dates, natures, treatments (if any), and progress in a provided AE collection form. The subjects were instructed to notify the investigator immediately of any serious AEs experienced during the study. Outcome Measures The primary outcome measures were (1) pain relief at 2 hours post treatment with CoolStat for one qualifying migraine attack, defined as a reduction in a moderate or severe migraine headache at baseline to a mild or no headache; (2) safety, defined as the incidence of adverse events; and (3) tolerability, defined as the percentage of subjects who failed to complete the full treatment session. The secondary outcome measures included pain relief at 0 h and at 24 h post treatment (defined as a reduction in a moderate or severe migraine pain at baseline to a mild or no pain on a 4-point Visual Rating Scale (VRS)); pain freedom (defined as a score of 0, none, on a 4-point VRS scale) at 0 h, 2 h, and 24 h posttreatment; MBS relief (defined as reduction in symptom score from severe or moderate to mild or none, or from mild to none; based on a 4-point VRS scale) and MBS freedom (defined as a score of 0, none, on a 4-point VRS scale) at 0 h, 2 h, and 24 h post treatment; and the use of rescue medication between 2 and 24 h post treatment. Statistical methods For this study’s sample size calculation, we estimated the effect size from a preliminary randomized, single-blinded study (subjects were blinded) that was conducted using an alpha prototype of our cooling device. 16 In that study, 56% of the subjects in the dry air treatment group reported freedom from headache pain at two hours post treatment, whereas 8% of the subjects in the sham group reported freedom from headache pain. Our analysis using this effect size as a basis for calculation indicated that a minimum sample size of 17 subjects in each group would be required to achieve at least 80% power to detect a significant difference at the 5% level of significance. A conservative approach was taken considering the large effect size from the initial study and planned for 25 subjects per group to account for error in estimates based on the preliminary results, for a total sample size of 75 subjects. Only the first 75 subjects who returned to the headache clinic with a qualifying migraine attack within 60 days were randomized to a treatment group. Accounting for a 25% withdrawal rate, 100 participants were initially planned to be enrolled. However, a much higher rate of subject withdrawal was discovered after six months of enrollment, with nearly 80% of the subjects withdrawn due to consent expiration. As a result, the protocol was amended to allow for up to 300 consented participants. The intention-to-treat (ITT) population included all the participants who underwent randomization and was used for the primary endpoint analysis and safety analysis. Pain relief at 2 hours post treatment without the use of rescue medication (woRM), coded as a binary variable, was the primary endpoint in this study. The primary statistical analysis was based on a mixed logistic regression model. The mixed logistic model included a random effect model to account for the positive association between repeated measurements in the same patient. The model also included fixed effects for treatment and time, both of which are treated as continuous variables, meaning that we are assuming trends (linear regression on the logit scale). The values for the treatment variable were the actual doses in liters per minute (6, 18, 24), and those for time were the integers 0–3. Statistical analysis was conducted using Stata release 17 (StataCorp LLC, College Station, TX, USA). RESULTS Participant Recruitment Between August 26, 2021, and July 31, 2022, 6671 people applied to participate in the study via a web-based recruitment campaign. A total of 3228 of those applicants passed the initial screening quiz, and 1544 of those who passed the initial screening quiz provided contact information for study staff to reach out to them. Among those, 181 applicants provided their migraine-specific health records for eligibility screening by the Principal Investigators. Eighty-seven of those who were screened were enrolled (provided informed consent), and 24 were randomized to a treatment group (see Fig. 3 and Table 2 for patient characteristics). Among the 63 nonrandomized patients, 59 failed to return to the headache clinic with a qualifying migraine attack within 60 days, 3 experienced post consent screening failure, and 1 withdrew from the study. Among the 59 patients who failed to return to the headache clinic with a qualifying migraine within 60 days, the most common reasons given were (1) not having migraine attacks during headache clinic business hours, (2) not being able to visit the headache clinic during limited clinic hours (Monday through Friday between 8 am and 3 pm), or (3) the COVID-19 pandemic made subjects wary of coming into the headache clinic for an in-person research visit. Given the large number of subjects initially screened, the study was terminated early, and the data from the 24 randomized subjects were analyzed. The demographic and clinical characteristics are shown in Table 2 . The age differences were minimal; all the subjects were female, and the majority were white. Because the numbers are small, a single subject can make a considerable difference in an analysis, so even larger differences cannot be considered reliable. Table 2 Demographic and clinical characteristics of the participants in the ITT analysis. Variable 6 LPM (n = 9) 18 LPM (n = 9) 24 LPM (n = 6) Age, y (SD) 50.3 (9.7) 51.4 (13.2) 37.8 (12.3) Female, % (n) 100 (9) 100 (9) 100 (6) White, % (n) 77.8 (7) 88.9 (8) 83.3 (5) Migraine with aura, % (n) Yes 55.6 (5) 33.3 (3) 66.7 (4) Sometimes 11.1 (1) 22.2 (2) 0.0 (0) No 33.3 (3) 44.4 (4) 33.3 (2) MBS, % (n) None 0.0 (0) 11.1 (1) 0.0 (0) Nausea 44.4 (4) 11.1 (1) 16.7 (1) Photophobia 44.4 (4) 66.7 (6) 66.7 (4) Phonophobia 11.1 (1) 11.1 (1) 16.7 (1) Baseline pain severity Moderate (Grade 2) 88.9 (8) 88.9 (8) 100 (6) Severe (Grade 3) 11.1 (1) 11.1 (1) 0.0 (0) Enrollment location Atrium Health 44.4 (4) 55.6 (5) 66.7 (4) Michigan State 33.3 (3) 22.2 (2) 16.7 (1) Mayo Clinic 22.2 (2) 22.2 (2) 16.7 (1) SD = standard deviation; MBS = most bothersome symptom Efficacy Outcomes This study was designed as a randomized, sham-controlled trial with three treatments, 6LPM (sham), 18 LPM and 24 LPM, with the latter having greater activity. Unfortunately, only 24 subjects could be enrolled during the first year, and it was decided to terminate the study early because of insufficient accrual. In addition, the 6 LPM flow that was intended to serve as a sham treatment was found to deliver active therapy. This ultimately became a dose-ranging study. According to the study’s Medical Advisory Board, upon their interim review of the data, a clear dose response was identified in that higher flow rates were less effective and less tolerable than lower flow rates were. Pain relief at 2 hours post treatment without the use of rescue medication (woRM) was the primary endpoint in this study. Pain relief at 2 hours woRM was reported by 89% (8/9) of the participants who received 6 LPM flow. Pain freedom woRM at 2 hours was reported by 44% (4/9) of participants who received a 6LPM flow. Pain relief at 2 hours woRM was reported by 56% (5/9) and 50% (3/6) of the 18LPM and 24LPM groups, respectively. No participants in the 18LPM or 24LPM groups reported pain freedom at 2 hours. MBS relief woRM was reported at 2 h by 78% (7/9) in the 6LPM group. MBS relief at 2 h woRM was reported by 67% (6/9) and 50% (3/6) of the 18LPM and 24LPM groups, respectively. Table 3 shows the pain and MBS outcomes at 2 hours post treatment. Pain and MBS relief at 24 hours post treatment without the use of rescue medication (woRM) was the secondary endpoint in this study. Pain relief at 24 hours woRM was reported by 67% (6/9) of the participants who received 6 LPM flows. Pain freedom woRM at 24 hours was reported by 11% (1/9) of participants who received a 6LPM flow. Pain relief at 24 hours woRM was reported by 22% (2/9) and 33% (2/6) of the 18LPM and 24LPM groups, respectively. Eleven percent (1/9) of the subjects in the 18LPM group and 17% (1/6) of the subjects in the 24LPM group reported pain freedom at 24 hours woRM. MBS freedom woRM was reported at 24 hours by 56% (5/9) in the 6LPM group. MBS relief at 24 hours woRM was reported by 11% (1/9) of the participants, with no subjects in the 18Lpm group reporting MBS freedom at 24 hours woRM. Thirty-three percent (2/6) of the 24LPM groups reported MBS freedom at 24 hours woRM. Table 3 shows the pain and MBS outcomes at 24 hours post treatment. Tolerability Tolerability was assessed via the following outcomes: (1) inability to complete the full 15-minute treatment session, (2) treatment discomfort score of moderate or severe, and (3) use of rescue medication before the 2-hour post treatment primary outcome assessment (Table 3 ). As the flow rates increased, the treatments were rated as less tolerable for all three variables, with the 6 LPM flow being the most tolerable to patients. Table 3 Study outcomes. 6LPM 18LPM 24LPM n 9 9 6 Pain data Pain relief 2 hours without rescue medication (woRM) 88.9% (8) 56% (5) 50% (3) Pain relief 24 hours (woRM) 66.7% (6) 22% (2) 33.3% (2) Pain freedom 2 hours (woRM) 44.4% (4) 0% (0) 0% (0) Pain freedom 24 hours (woRM) 11.1% (1) 11.1% (1) 16.7% (1) Most Bothersome Symptom (MBS) data MBS relief 2 hours (woRM) 77.7% (7) 66.7% (6) 50% (3) MBS relief 24 hours (woRM) 55.6% (5) 11.1% (1) 33.3% (2) MBS freedom 2 hours (woRM) 55.6% (5) 33.3% (3) 33.3% (2) MBS freedom 24 hours (woRM) 55.6% (5) 0% (0) 33.3% (2) Tolerability data Stopped treatment early 0% (0) 11.1% (1) 33.3% (2) Moderate or severe discomfort during treatment 11.1% (1) 33.3% (3) 83.3% (5) Rescue medication taken within 2 hours post treatment 11.1% (1) 11.1% (1) 33.3% (2) Safety Safety analyses were performed on all 24 participants. The percentage of participants who experienced at least one adverse event was 25% (6/24). Eight device-related adverse events were reported during 24 treatments (33%), four in the 24 LPM group, four in the 18 LPM group, and none in the 6 LPM sham group. Device-related adverse events included burning sensations/discomfort in the nostril, nasal congestion, dizziness, increased head pain, and increased nausea (Table 4 ). Five of the adverse events were mild, resolved within 24 hours and did not require medical treatment. Two of the adverse events resulted in early termination of the CoolStat treatment session. One of the adverse events was moderate and resulted in the subject taking rescue medication. This adverse event resolved within 24 hours. There were no device-related serious adverse events or unanticipated adverse device effects, and none of the participants withdrew from the study because of adverse events. Table 4 Incidence of adverse events and device-related adverse events in the ITT population 6 LPM (n = 9) 18 LPM (n = 9) 24 LPM (n = 6) Patients reporting at least one adverse event, % (n) 0.0 (0) 33.3 (3) 50.0 (3) Device-related adverse events incidence Burning sensation 0.0 (0) 11.1 (1) 33.3 (2) Nasal congestion 0.0 (0) 11.1 (1) 0.0 (0) Dizziness 0.0 (0) 0.0 (0) 16.7 (1) Increased head pain 0.0 (0) 11.1 (1) 0.0 (1) Increased nausea 0.0 (0) 11.1 (1) 0.0 (0) Blinding The investigators, outcome assessors, and participants were blinded to their treatment assignment. Upon treatment completion, the participants were asked about their presumed group assignment (18LPM or 24LPM active, with the sham being 6LPM). A total of 66.7% (4/6) of patients in the 24 LPM group and 44.4% (4/9) of patients in the 18 LPM group thought they received active treatment. A total of 77.8% (7/9) of patients in the 6 LPM “sham” group thought they received active treatment. We acknowledge that this blinding assessment has limitations because the sham was found to be active. In addition to the primary endpoint analysis, this blinding assessment supported the conclusion that the sham delivered active therapy. DISCUSSION Here, we present our results, which compare 3 different doses of intranasal dehumidified air therapy for migraine attacks. Although we anticipated that 6LPM would be a sham dose, our results suggest that this dose yielded more positive results than the 18 and 24LPM arm doses. Thus, the 6LPM dose is unlikely to represent a true sham. As a result, this study was a dosing study, which may be due to the novelty of the target and method of treating migraine disease. The positive signal and feasibility of our results suggest that the CoolStat device may be an effective nonmedicinal, noninvasive alternative acute treatment option for migraine attacks. However, our sample size was small, and the study was terminated prematurely because of the slow recruitment of subjects. Our primary outcome of pain relief at 2 hours in the 6LPM group was 89%. Across all three study arms, the weighted average of pain relief without rescue medication at 2 hours was 71%, which is comparable to that of other FDA-cleared acute migraine devices, such as remote electronic neuromodulation device at 67%, 18 transcutaneous trigeminal nerve stimulator device at 55%, 19 and combined occipital trigeminal neurostimulation device at 60%. 20 Each of these studies enrolled participants with episodic migraine and used pain relief at 2 hours post treatment as the primary endpoint. Across these studies, there was some variability in the treatment setting and time to treatment initiation after migraine onset. Participants in the transcutaneous trigeminal nerve stimulator device study were treated during a clinic visit and were required to have a minimum duration of 3 hours prior to treatment. The remote electronic neuromodulation device and combined occipital trigeminal neurostimulation device were used by study participants in their homes, and treatment was initiated within 1 hour of symptom onset. The major limitation of our study was its very small sample size and lack of a true sham arm, as our a priori “sham arm” was not sham. Another limitation of our study is that all of the treated subjects were female. Owing to the small sample size, the sex distribution was skewed, as migraine is three times more common in females than in males. While there was an extremely high level of interest based on online recruitment campaign metrics, the in-clinic, centralized design of this trial had several drawbacks related to the migraine population. Participants with migraine are much less likely to travel to a headache clinic within the first few hours of a migraine attack. In addition, by the time patients arrive at the clinic, their migraine attacks are more likely to be refractory to treatment. Abortive therapies initiated within the first hour of headache onset have greater chances of pain relief and a lower risk of recurrence than nonearly users do. 21 , 22 The increased length of time after onset of the migraine attack and the requirement for travel to a clinic posed challenges to trial execution and partially contributed to the early termination of this study owing to an insufficient subject accrual rate. This study was conducted during the Sars-cov-2 (COVID-19) pandemic, which may have resulted in the avoidance of in-clinic treatment visits. Recruiting patients with episodic migraine disease from comprehensive headache centers present with challenges. Some of these challenges may be due to referral patterns. Many patients are referrals and second opinions from primary clinics; therefore, the baseline frequency of headache days per month is much higher, 23 , 24 making them ineligible for our study. Thus, the recruitment of patients with episodic headache disease may be improved with collaboration from other medical practices (e.g., primary care providers, obstetrics, and gynecology practices). general neurology, etc.) as well as from community engagement. A more patient-friendly (e.g., in-home) device and paradigm may be ideal for future studies. A larger at-home pilot study with an updated sham and refined dosing is underway. CONCLUSIONS Our results suggest that transnasal cooling at lower flow rates may be effective and tolerable for treating acute migraine attacks. Future research with larger and more diverse populations as well as control groups is needed to validate these findings. Since all three doses in this study delivered therapy, this cannot be considered a sham-controlled trial. Nevertheless, tolerability and outcome data obtained from this study are useful for dose-ranging analysis. Logistical challenges that require subjects experiencing a migraine headache attack to travel to a clinic for in-person randomization and study device treatment exist. An at-home study with an updated sham and refined dosing is underway. Declarations Ethics Approval and Consent to Participate The study protocol and informed consent form were reviewed and approved by the Advarra Institutional Review Board (Pro00054590) on June 30, 2021. This study was conducted in accordance with the Declaration of Helsinki under IDE #G210131. Written informed consent was obtained from all participants before they underwent any study procedures. Consent for Publication Not applicable. Compliance with CONSORT Guidelines We confirm that our manuscript adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting randomized controlled trials. All relevant items of the CONSORT checklist have been followed, and necessary information has been included to ensure transparency and reproducibility of the trial methodology and results. Data Availability Data supporting the findings in the present study are reported in the article and in the supplementary materials. The data collected and analyzed for the current study are available from the corresponding author on reasonable request. Competing Interests LCIV has received personal compensation for serving as a consultant for AbbVie, Accolade, Amgen, Amneal, Aurene, Biohaven, Haleon, LinPharma, Lundbeck, Pfizer, and Satsuma. He is on the advisory panel for Mi-Helper Inc. (stock options), and received grant/research support from the Disparities in Headache Advisory Council and Amgen. He has received CME honoraria from American Headache Society, American Academy of Neurology, BrainWeekend, Migraine360 CME Program, NeurologyWeek, Continuing Education Health Interactive, and the Primary Care Education Consortium. He receives a salary as an adjunct faculty from Thomas Jefferson University. He is a non-compensated associate editor for Headache : The Journal of Head and Face Pain, serves as a non-compensated Board of Directors as Treasurer/Secretary for the Clinical Neurological Society of America, and serves a Board of Director of the American Headache Society as Chair of the American Headache Society’s Equity Diversity and Inclusion Advisory Council (non-voting). AS has received personal compensation from AbbVie (consulting), Allergan (consulting), Amneal (consulting), Axsome Therapeutics (consulting), eNeura (advisory board), Everyday Health (consulting), Lundbeck (consulting), Med-IQ (consulting), Medscape (consulting), Miller Medical (consulting), Pfizer (consulting), Salvia (consulting), Satsuma (consulting), and WebMD (consulting). NT reports no disclosures. Funding This study was funded by CoolTech, LLC, and the National Institute of Neurological Disorders and Stroke (NINDS). Authors’ Contributions Charleston Health Neurology & Head Pain Consultants, Pinckney MI Larry Charleston IV Division of Headache, Department of Neurology, Mayo Clinic Scottsdale Amaal Starling Headache Center, Atrium Health Wake Forest Baptist Neuroscience Institute Nauman Tariq Contributions: LC, AS, and NT had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All Authors recruited patients, and drafted and critically reviewed the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript. Corresponding Author: Larry Charleston IV, [email protected] Acknowledgements Independent biostatistician Christopher Cox conducted the statistical analysis for this manuscript. References Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50 s: will health politicians now take notice? J Headache Pain. 2018;19(1):17. Published 2018 Feb 21. doi:10.1186/s10194-018-0846-2 Lipton RB, Munjal S, Buse DC, Alam A, Fanning KM, Reed ML, Schwedt TJ, Dodick DW. Unmet Acute Treatment Needs From the 2017 Migraine in America Symptoms and Treatment Study. Headache. 2019 Sep;59(8):1310-1323. doi: 10.1111/head.13588. Epub 2019 Aug 13. PMID: 31410844; PMCID: PMC6771753. Buse DC, Nahas SJ, Stewart WBF, Armand CE, Reed ML, Fanning KM, Manack Adams A, Lipton RB. Optimized Acute Treatment of Migraine Is Associated With Greater Productivity in People With Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. J Occup Environ Med. 2023 Apr 1;65(4):e261-e268. doi: 10.1097/JOM.0000000000002801. Epub 2023 Jan 25. PMID: 36701797; PMCID: PMC10090340. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 2015 Feb 17;84(7):688-95. doi: 10.1212/WNL.0000000000001256. Epub 2015 Jan 21. Minen, M.T., Tanev, K. and Friedman, B.W. (2014), Evaluation and Treatment of Migraine in the Emergency Department: A Review. Headache: The Journal of Head and Face Pain, 54: 1131-1145. Bigal, M.E., Serrano, D., Buse, D., Scher, A., Stewart, W.F. and Lipton, R.B. (2008), Acute Migraine Medications and Evolution From Episodic to Chronic Migraine: A Longitudinal Population‐Based Study. Headache: The Journal of Head and Face Pain, 48: 1157-1168. Amiri P, Kazeminasab S, Nejadghaderi SA, Mohammadinasab R, Pourfathi H, Araj-Khodaei M, Sullman MJM, Kolahi AA, Safiri S. Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities. Front Neurol. 2022 Feb 23;12:800605. doi: 10.3389/fneur.2021.800605. PMID: 35281991; PMCID: PMC8904749. Puledda F, Messina R, Goadsby PJ (2017) An update on migraine: current understanding and future directions. J Neurol 264:2031–2039. Robbins MS, Robertson C, Kaplan E, et al. The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache. Headache 2016;56:240-58 Maizels M, Geiger AM: Intranasal lidocaine for migraine: a randomized trial and open-label follow-up. Headache 1999;39:543–551. Kudrow L, Kudrow DB, and Sandweiss JH. Rapid and Sustained Relief of Migraine Attacks With Intranasal Lidocaine: Preliminary Findings. Headache: The Journal of Head and Face Pain, vol. 35, no. 2, pp. 79–82, 1995. Binfalah M, Alghawi E, Shosha E, Alhilly A, Bakhiet M. Sphenopalatine Ganglion Block for the Treatment of Acute Migraine Headache. Pain Res Treat. 2018;2018:2516953. Published 2018 May 7. doi:10.1155/2018/2516953 Singhal, A. B., Maas, M. B., Goldstein, J. N., et al. High-flow oxygen therapy for treatment of acute migraine: A randomized crossover trial. Cephalalgia 2017; 37(8), 730-736 Vanderpol, J., Bishop, B., Matharu, M. et al. Therapeutic effect of intranasal evaporative cooling in patients with migraine: a pilot study. J Headache Pain 16, 5 (2015). Noseda, R., & Burstein, R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. PAIN® 2013; 154, S44-S53 Shah R, Assis F, Narasimhan B, et al. Trans-nasal high-flow dehumidified air in acute migraine headaches: A randomized controlled trial. Cephalalgia. February 2021. Transnasal Induction of Normothermia in NCCU Fever Patients. Clinicaltrials.gov identifier: NCT03360656. Updated June 18, 2023. Accessed March 20, 2025. https://clinicaltrials.gov/study/NCT03360656 Yarnitsky D, Dodick DW, Grosberg BM, Burstein R, Ironi A, Harris D, Lin T, Silberstein SD. Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache. 2019 Sep;59(8):1240-1252. doi: 10.1111/head.13551. Epub 2019 May 9. PMID: 31074005; PMCID: PMC6767146. Chou DE, Shnayderman Yugrakh M, Winegarner D, Rowe V, Kuruvilla D, Schoenen J. Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial. Cephalalgia. 2019 Jan;39(1):3-14. doi: 10.1177/0333102418811573. Epub 2018 Nov 17. PMID: 30449151; PMCID: PMC6348457. Tepper SJ, Grosberg B, Daniel O, Kuruvilla DE, Vainstein G, Deutsch L, Sharon R. Migraine treatment with external concurrent occipital and trigeminal neurostimulation-A randomized controlled trial. Headache. 2022 Sep;62(8):989-1001. doi: 10.1111/head.14350. Epub 2022 Jun 24. PMID: 35748757. Goadsby PJ, Zanchin G, Geraud G, de Klippel N, Diaz-Insa S, Gobel H, Cunha L, Ivanoff N, Falques M, Fortea J. Early vs. nonearly intervention in acute migraine-'Act when Mild (AwM)'. A double-blind, placebo-controlled trial of almotriptan. Cephalalgia. 2008 Apr;28(4):383-91. doi: 10.1111/j.1468-2982.2008.01546.x. Epub 2008 Feb 20. Erratum in: Cephalalgia. 2008 Jun;28(6):679. PMID: 18294251. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician. 2011 Feb 1;83(3):271-80. Erratum in: Am Fam Physician. 2011 Oct 1;84(7):738. PMID: 21302868. Peres MFP, Swerts DB, de Oliveira AB, Silva-Neto RP. Migraine patients' journey until a tertiary headache center: an observational study. J Headache Pain. 2019 Aug 15;20(1):88. doi: 10.1186/s10194-019-1039-3. PMID: 31416424; PMCID: PMC6734236. Ziegeler C, Brauns G, Jürgens TP, May A. Shortcomings and missed potentials in the management of migraine patients - experiences from a specialized tertiary care center. J Headache Pain. 2019 Aug 1;20(1):86. doi: 10.1186/s10194-019-1034-8. PMID: 31370788; PMCID: PMC6734431. Additional Declarations Competing interest reported. LC serves on the advisory board for Mi-Helper, Inc. (an affiliate of CoolTech, LLC). AS and NT declare no further conflicts of interest. Supplementary Files CONSORT2010Checklist.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6108236","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":437114478,"identity":"196c4f59-3d25-4310-ad84-369e9fe9cfe2","order_by":0,"name":"Larry Charleston","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACPgbGBhjb8AGQ4OEjpIUNSYuxAUgLG2EtCGAmgS6CXQv74TbpgorD+fxih7dVfs2xk2FjYH746AY+LTyJbdIzzhy2nDk7rey27LZkoMPYjI1z8GmRYGw25m07bGBwO8fstuQ2ZqAWHjZpwlr+QbQUS26rJ0pL42PeBogWxo/bDhOhhSex8THPsXQDydlpxdKM247zsDET8As/+/EHh3lqrA34pZM3fvy5rdqen7354WN8WlAAMw+YJFY5CDD+IEX1KBgFo2AUjBgAAMO/PdXRC0TOAAAAAElFTkSuQmCC","orcid":"","institution":"Charleston Health Neurology \u0026 Head Pain Consultants","correspondingAuthor":true,"prefix":"","firstName":"Larry","middleName":"","lastName":"Charleston","suffix":""},{"id":437114479,"identity":"de6a04f6-617b-4b49-9cac-1cbca53a0173","order_by":1,"name":"Amaal Starling","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Amaal","middleName":"","lastName":"Starling","suffix":""},{"id":437114480,"identity":"81406508-5e3a-479a-a758-7aa442a52a96","order_by":2,"name":"Nauman Tariq","email":"","orcid":"","institution":"Atrium Health Wake Forest Baptist Neuroscience Institute","correspondingAuthor":false,"prefix":"","firstName":"Nauman","middleName":"","lastName":"Tariq","suffix":""}],"badges":[],"createdAt":"2025-02-25 21:23:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6108236/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6108236/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79907818,"identity":"d1c1eff4-b9b6-4762-9f21-c753bf558825","added_by":"auto","created_at":"2025-04-04 11:14:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":198390,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCoolStat Device and handheld nasal interface\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6108236/v1/e9de8d3da605f7b73debf1cb.png"},{"id":79907799,"identity":"a4935d93-aba1-4876-8ec1-d8302868686b","added_by":"auto","created_at":"2025-04-04 11:14:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72109,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design flowchart\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6108236/v1/bf0ef9ec269b0fe64a53ee99.png"},{"id":79907801,"identity":"0df5a68a-19c0-4182-83d9-f87e9c16a7c9","added_by":"auto","created_at":"2025-04-04 11:14:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":44496,"visible":true,"origin":"","legend":"\u003cp\u003eRecruitment, \u003cstrong\u003ee\u003c/strong\u003enrollment, and randomization of participants.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6108236/v1/5ffceb6b882152b2e17aa66e.png"},{"id":95186991,"identity":"9d849671-284d-4ba0-be21-108ba0e39c88","added_by":"auto","created_at":"2025-11-05 09:23:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1188999,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6108236/v1/f38194f2-717a-47b7-b799-7ccda7bc145c.pdf"},{"id":79907803,"identity":"9bd55ec9-cfd3-4cf7-9064-93c9eb701ae2","added_by":"auto","created_at":"2025-04-04 11:14:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1553676,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6108236/v1/73b312279eb315cef363f3df.pdf"}],"financialInterests":"Competing interest reported. LC serves on the advisory board for Mi-Helper, Inc. (an affiliate of CoolTech, LLC). AS and NT declare no further conflicts of interest.","formattedTitle":"\u003cp\u003eTransnasal Evaporative Cooling Device for Migraine: A Prospective, Randomized, Double-blind, Multicenter Trial\u003c/p\u003e","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eMigraine is a severely disabling neurologic condition and is the sixth most disabling disorder worldwide, affecting more than a billion people. Migraine attacks are recurrent episodes of headache associated with sensory sensitivities (light and sound) and nausea and/or vomiting. Migraine can cause a significant reduction in quality of life and a loss of productivity. The global economic burden of migraine is staggering at approximately \u003cspan\u003e$\u003c/span\u003e20\u0026nbsp;billion in the U.S. and \u003cspan\u003e$\u003c/span\u003e56\u0026nbsp;billion worldwide per year.\u003c/p\u003e \u003cp\u003eMigraine affects significantly more women than men and is the leading cause of disability in people under the age of fifty.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The first-line acute treatment options for migraine attacks are medications such as triptans and NSAIDs, which can be associated with adverse effects, are contraindicated in those with cardiovascular issues, and may put patients at risk for medication-overuse headache. A large study of U.S. adults with migraine reported that of those who had ever used oral triptans, more than half discontinued taking them.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The most common reasons for oral triptan discontinuation are perceived lack of efficacy (38.4%) and side effects (22.8%).\u003csup\u003e2\u003c/sup\u003e Sixty percent of patients using prescription acute treatment medications still report having moderate-to-severe headache-related disability.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Noninvasive neuromodulation therapies that target migraine pathophysiology are gaining traction owing to their tolerability, safety profile, and relative effectiveness.\u003c/p\u003e \u003cp\u003eCurrent first-line acute therapies for migraine are suboptimal, expensive, and ineffective. There is an enormous unmet need for an effective and affordable nondrug acute therapy for migraine attacks to significantly improve quality of life and substantially reduce the cost burden to our healthcare system and society. Ineffective acute treatment for migraine can lead to an increase in attack frequency and disease severity.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe prevalence of migraine in the U.S. is increasing, with 15% of the population living with episodic migraine or chronic migraine, which is defined as 15 or more headache days per month with at least 8 days with migraine features. Migraine is one of the most common reasons for emergency room visits. Despite treatment recommendations, opioids are still overprescribed for patients with migraine. This is especially the case in emergency departments (EDs), where one study reported that opioids are prescribed at more than 50% of ED visits for migraine.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This phenomenon is likely a contributor to the opioid epidemic. The use of opioids in this population carries a high risk of \u0026lsquo;medication-overuse-headache\u0026rsquo; when used more than 10 times/month and can quickly lead to opioid dependency.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Chronic migraine is the most severe form of migraine associated with high levels of disability, disease burden, healthcare utilization, and economic impact.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe pathophysiology of migraine is complex. There is evidence that the headache phase of migraine involves the activation of nociceptors in the trigeminal ganglion.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The sphenopalatine ganglion (SPG), a large ganglion behind the superior nasal turbinate, is closely associated with the trigeminal system.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Several studies have shown that intranasal SPG nerve block with lidocaine provides relief from migraine attacks.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study was based on several premises. First, Singal et al. reported no statistically significant difference in the mean change in pain scores between the oxygen- and room air-treated arms, although both study arms achieved substantial relief of symptoms.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e A pilot study conducted by Vanderpol and colleagues using transnasal evaporative cooling resulted in significant relief from headache and other migraine symptoms.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Transnasal evaporative cooling for migraine may help attenuate trigemino-vascular system activation via the sphenopalatine ganglion.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Moreover, temperature changes may be transmitted from the mucosa of the nasal sinuses to the dura mater (the meningeal covering) of the brain via venous blood, which may aid in vasoconstriction of the blood vessels supplying the b5rain, reduce the release of inflammatory mediators, and attenuate overall inflammation/local edema.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe goal of this study was to evaluate the safety, tolerability, and optimal dose of a transnasal cooling device for the acute treatment of migraine. We hypothesized that a transnasal evaporative cooling device for migraine (CoolStat Transnasal Thermal Regulating Device) would reduce pain and symptom relief during a migraine attack. Transnasal evaporative cooling is a novel method of acute drug-free migraine treatment that uses only clean, dry air. The CoolStat Transnasal Neuromodulation Device produces a flow of dry filtered air at ambient temperature to induce evaporative cooling energy exchange in the turbinates and upper airway. This area is implicated in migraine disease in several ways, including the involvement of the sphenopalatine ganglion and trigeminal nerve endings. While the mechanism of action for evaporative cooling on migraine relief is not yet well defined, feasibility testing with a prototype device showed significant pain relief in those with migraine compared to sham,\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e as did a subsequent tolerability study with the CoolStat device.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStandard Protocol Approvals, Registrations, and Patient Consents\u003c/h2\u003e \u003cp\u003eThis study was conducted at 3 sites in the United States (Atrium Health Wake Forest Baptist Neurosciences Institute in Charlotte, NC; Michigan State University College of Human Medicine in East Lansing, MI; and Mayo Clinic in Scottsdale, AZ). The study protocol and informed consent form were reviewed and approved by the Advarra Institutional Review Board (Pro00054590) on June 30, 2021. This study was conducted under IDE #G210131. Written informed consent was obtained from all participants before they underwent any study procedures. The first patient was enrolled in October 2021, and the last patient completed the study in August 2022. The study is registered with ClinicalTrials.gov (NCT04936061). All study participants provided written informed consent prior to initiating any study procedures.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design and Participants\u003c/h3\u003e\n\u003cp\u003eParticipants with migraine with or without aura participated in this prospective, randomized, double-blind, multicenter trial. Participants were eligible to participate if they were 18\u0026ndash;80 years old, met the International Classification of Headache Disorders (ICHD 3-beta) criteria for episodic migraine with 2\u0026ndash;8 migraine headache days per month and less than 15 headache days per month, had a diagnosis of episodic migraine for at least one year, and were on stable migraine preventive medications in the 6 weeks prior to enrollment. The inclusion and exclusion criteria are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInclusion and exclusion criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInclusion Criteria\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Meets the International Classification of Headache Disorders (ICHD-3) diagnostic criteria for migraine with or without aura, with the exception of ''complicated migraine'' (i.e., hemiplegic migraine, ophthalmoplegic migraine, migrainous infarction).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Patient is between 18 and 80 years of age.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Patient experiences 2 to 8 migraine attacks per month.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Patient is in good reported general health, with no fever (\u0026lt;\u0026thinsp;38.3C/101F).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. Patient has had diagnosis of migraine with or without aura over at least 1 year.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6. Migraine onset before 50 years of age.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7. Migraine prophylaxis medication unchanged for 6 weeks prior to study enrollment.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8. Able to attend treatment session within 6 hours of migraine onset, with 48 hours of pain freedom prior to onset of migraine attack.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9. Migraine pain severity of Grade 2 or Grade 3 on day of treatment.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10. Provision of signed and dated informed consent form.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11. Stated willingness to comply with all study procedures and availability for the duration of the study.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExclusion Criteria\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Patient has difficulty distinguishing his or her migraine attacks from tension-type headaches\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Patient has uncontrolled hypertension.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Patient has a fever (\u0026ge;\u0026thinsp;38.3C/101F).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Patient has used opioid medication or barbiturates in the past month.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. Patient has Medication Overuse Headache (MOH), New Daily Persistent Headache (NDPH) or Chronic Tension Type Headache (CTTH).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6. Patient has 15 or more headache days per month.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7. Patient has used acute treatment(s) for migraine in the 48 hours preceding treatment, i.e., over-the-counter (OTC) medications, prescription medications, or medical device).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8. Patient has received Botox treatment, supraorbital or occipital nerve blocks in the last 4 weeks.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9. Intolerance to intranasal neurostimulation or sensory processing disorder that makes the treatment not applicable.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10. Recurrent epistaxis or chronic rhinosinusitis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11. Recent facial trauma, sinus or intranasal surgery within the last 4 months.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12. Known or suspected pregnancy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13. Unable to fully understand the consent process and provide informed consent due to either language barriers or mental capacity.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eTransnasal Neuromodulation Device\u003c/h3\u003e\n\u003cp\u003eThe CoolStat Transnasal Neuromodulation Device produces a flow of dry filtered air at ambient temperature to induce evaporative cooling energy exchange in the turbinates and upper airway. The air flow is delivered from the CoolStat to the subject via an air hose and hand-held nebulizer. The air flow is delivered into one nostril and flows freely out of the other nostril and the mouth. This process locally extracts energy from this area and cools the adjacent tissue in the nasopharynx. The CoolStat also delivers a continuous mist of saline to the subject to keep the turbinates moist and comfortable and to further promote evaporative cooling.\u003c/p\u003e \u003cp\u003eThe CoolStat Transnasal Thermal Regulating Device [hereafter CoolStat] is noninvasive and uses no chemicals or cooling agents.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, and the process air and saline do not contact sterile body tissue, blood or other fluids. CoolStat is not used to support or assist with life support, patient breathing or respiratory functions.\u003c/p\u003e \u003cp\u003eThe CoolStat device weighs less than 15 lbs and can be mounted on an IV pole or sit on a bed or table near the patient (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The primary functional component inside the device is a blower, which is used to generate a flow of air. Local ambient room air is pulled into the device and is pumped across a desiccant material that extracts all moisture from the incoming air. The dry air then passes through a flexible air tube with redundant in-line air filters and is delivered to the patient via a hand-held nebulizer (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The dry air flow goes into the patient\u0026rsquo;s nostril and exits through the other nostril and the mouth, inducing evaporative cooling energy exchange in the turbinates and upper airway.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e This energy exchange results in a local cooling effect.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn this study, both the CoolStat devices and treatment administration protocols were standardized across sites and investigators.\u003c/p\u003e\n\u003ch3\u003eRandomization, masking, and blinding\u003c/h3\u003e\n\u003cp\u003eSubjects who met all the study eligibility criteria and returned to the headache clinic with a qualifying migraine attack were randomly assigned to one of the three doses. The randomization was blocked by site. The random allocation sequence was developed by an independent biostatistician and programmed into the iMedNet Electronic Data Capture (EDC) randomization tool. The subjects were only randomized and treated one time to eliminate within-subject bias. For up to sixty days after enrolling in the study, subjects returned to the headache clinic with a qualifying migraine attack for randomization and a single treatment. If a subject did not return to the clinic to treat a migraine attack within 60 days following their screening and enrollment visit, they had the opportunity to reconsent for another 60-day enrollment period. If they declined to reconsent, they were withdrawn from the study.\u003c/p\u003e \u003cp\u003eThe CoolStat devices were operated in blind mode for this study, in which the different doses were coded to a set of nine numbers. The hardware composition and function of the active and sham devices were identical. The randomization tool within the iMedNet (EDC) allocated each subject a coded flow number. In addition, the foil packaging containing the desiccant cartridges was marked with a set of three letters. The iMedNet randomization tool also allocated each subject to the appropriate desiccant cartridge lot via these letters per their randomization assignment. A research nurse or designee ran the randomization task in the EDC to assign participants to interventions.\u003c/p\u003e \u003cp\u003eTo assess blinding, participants were asked at the end of the study of their presumed group assignment (active or sham). The subjects, investigators, and outcome assessors were blinded to group assignment until the entire study was finished.\u003c/p\u003e\n\u003ch3\u003eStudy procedures\u003c/h3\u003e\n\u003cp\u003eAfter enrollment, the participants were instructed to return to the headache clinic within 60 days during a qualifying migraine attack for a single treatment session. A qualifying migraine attack met the following criteria: (1) moderate or severe pain severity, (2) onset of head pain within 6 hours of treatment, and (3) no rescue medication taken within the 48 hours before treatment. If the subject met all the qualifying migraine attack criteria upon arriving at the headache clinic, they were then randomized to a treatment group and received the one-time 15-minute study intervention. The three treatment groups were 18 LPM (active treatment group 1), 24 LPM (active treatment group 2) and 6 LPM (sham group). A depiction of the study design can be found in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eParticipants were instructed to avoid taking rescue medications within 2 hours post treatment. Pain scores (none, mild, moderate, or severe) were recorded at baseline and at 0, 2, and 24 hours post treatment. Migraine-associated symptoms, including nausea, photophobia, and phonophobia, were recorded at the time of treatment. The participants reported the absence and presence of all associated symptoms (including their MBS) on the same scale (none, mild, moderate, or severe) at baseline and 0, 2, and 24 hours post treatment. At 2 and 24 hours, the participants reported if, when and what type of rescue medication was used.\u003c/p\u003e \u003cp\u003eThe study staff recorded all reported adverse event (AE) dates, natures, treatments (if any), and progress in a provided AE collection form. The subjects were instructed to notify the investigator immediately of any serious AEs experienced during the study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures\u003c/h2\u003e \u003cp\u003eThe primary outcome measures were (1) pain relief at 2 hours post treatment with CoolStat for one qualifying migraine attack, defined as a reduction in a moderate or severe migraine headache at baseline to a mild or no headache; (2) safety, defined as the incidence of adverse events; and (3) tolerability, defined as the percentage of subjects who failed to complete the full treatment session.\u003c/p\u003e \u003cp\u003eThe secondary outcome measures included pain relief at 0 h and at 24 h post treatment (defined as a reduction in a moderate or severe migraine pain at baseline to a mild or no pain on a 4-point Visual Rating Scale (VRS)); pain freedom (defined as a score of 0, none, on a 4-point VRS scale) at 0 h, 2 h, and 24 h posttreatment; MBS relief (defined as reduction in symptom score from severe or moderate to mild or none, or from mild to none; based on a 4-point VRS scale) and MBS freedom (defined as a score of 0, none, on a 4-point VRS scale) at 0 h, 2 h, and 24 h post treatment; and the use of rescue medication between 2 and 24 h post treatment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical methods\u003c/h3\u003e\n\u003cp\u003eFor this study\u0026rsquo;s sample size calculation, we estimated the effect size from a preliminary randomized, single-blinded study (subjects were blinded) that was conducted using an alpha prototype of our cooling device.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In that study, 56% of the subjects in the dry air treatment group reported freedom from headache pain at two hours post treatment, whereas 8% of the subjects in the sham group reported freedom from headache pain.\u003c/p\u003e \u003cp\u003eOur analysis using this effect size as a basis for calculation indicated that a minimum sample size of 17 subjects in each group would be required to achieve at least 80% power to detect a significant difference at the 5% level of significance. A conservative approach was taken considering the large effect size from the initial study and planned for 25 subjects per group to account for error in estimates based on the preliminary results, for a total sample size of 75 subjects.\u003c/p\u003e \u003cp\u003eOnly the first 75 subjects who returned to the headache clinic with a qualifying migraine attack within 60 days were randomized to a treatment group. Accounting for a 25% withdrawal rate, 100 participants were initially planned to be enrolled. However, a much higher rate of subject withdrawal was discovered after six months of enrollment, with nearly 80% of the subjects withdrawn due to consent expiration. As a result, the protocol was amended to allow for up to 300 consented participants.\u003c/p\u003e \u003cp\u003eThe intention-to-treat (ITT) population included all the participants who underwent randomization and was used for the primary endpoint analysis and safety analysis.\u003c/p\u003e \u003cp\u003ePain relief at 2 hours post treatment without the use of rescue medication (woRM), coded as a binary variable, was the primary endpoint in this study. The primary statistical analysis was based on a mixed logistic regression model. The mixed logistic model included a random effect model to account for the positive association between repeated measurements in the same patient. The model also included fixed effects for treatment and time, both of which are treated as continuous variables, meaning that we are assuming trends (linear regression on the logit scale). The values for the treatment variable were the actual doses in liters per minute (6, 18, 24), and those for time were the integers 0\u0026ndash;3. Statistical analysis was conducted using Stata release 17 (StataCorp LLC, College Station, TX, USA).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eParticipant Recruitment\u003c/h2\u003e \u003cp\u003eBetween August 26, 2021, and July 31, 2022, 6671 people applied to participate in the study via a web-based recruitment campaign. A total of 3228 of those applicants passed the initial screening quiz, and 1544 of those who passed the initial screening quiz provided contact information for study staff to reach out to them. Among those, 181 applicants provided their migraine-specific health records for eligibility screening by the Principal Investigators. Eighty-seven of those who were screened were enrolled (provided informed consent), and 24 were randomized to a treatment group (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e for patient characteristics). Among the 63 nonrandomized patients, 59 failed to return to the headache clinic with a qualifying migraine attack within 60 days, 3 experienced post consent screening failure, and 1 withdrew from the study. Among the 59 patients who failed to return to the headache clinic with a qualifying migraine within 60 days, the most common reasons given were (1) not having migraine attacks during headache clinic business hours, (2) not being able to visit the headache clinic during limited clinic hours (Monday through Friday between 8 am and 3 pm), or (3) the COVID-19 pandemic made subjects wary of coming into the headache clinic for an in-person research visit. Given the large number of subjects initially screened, the study was terminated early, and the data from the 24 randomized subjects were analyzed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe demographic and clinical characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The age differences were minimal; all the subjects were female, and the majority were white. Because the numbers are small, a single subject can make a considerable difference in an analysis, so even larger differences cannot be considered reliable.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of the participants in the ITT analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 LPM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 LPM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 LPM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.3 (9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.4 (13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.8 (12.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77.8 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.9 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.3 (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMigraine with aura, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.6 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.7 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSometimes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.4 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMBS, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.4 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.7 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhotophobia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.4 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.7 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.7 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhonophobia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.7 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline pain severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate (Grade 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88.9 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.9 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere (Grade 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnrollment location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrium Health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.4 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.6 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.7 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMichigan State\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.7 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMayo Clinic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.7 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSD\u0026thinsp;=\u0026thinsp;standard deviation; MBS\u0026thinsp;=\u0026thinsp;most bothersome symptom\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003eEfficacy Outcomes\u003c/h2\u003e \u003cp\u003eThis study was designed as a randomized, sham-controlled trial with three treatments, 6LPM (sham), 18 LPM and 24 LPM, with the latter having greater activity. Unfortunately, only 24 subjects could be enrolled during the first year, and it was decided to terminate the study early because of insufficient accrual. In addition, the 6 LPM flow that was intended to serve as a sham treatment was found to deliver active therapy. This ultimately became a dose-ranging study. According to the study\u0026rsquo;s Medical Advisory Board, upon their interim review of the data, a clear dose response was identified in that higher flow rates were less effective and less tolerable than lower flow rates were.\u003c/p\u003e \u003cp\u003ePain relief at 2 hours post treatment without the use of rescue medication (woRM) was the primary endpoint in this study. Pain relief at 2 hours woRM was reported by 89% (8/9) of the participants who received 6 LPM flow. Pain freedom woRM at 2 hours was reported by 44% (4/9) of participants who received a 6LPM flow. Pain relief at 2 hours woRM was reported by 56% (5/9) and 50% (3/6) of the 18LPM and 24LPM groups, respectively. No participants in the 18LPM or 24LPM groups reported pain freedom at 2 hours. MBS relief woRM was reported at 2 h by 78% (7/9) in the 6LPM group. MBS relief at 2 h woRM was reported by 67% (6/9) and 50% (3/6) of the 18LPM and 24LPM groups, respectively. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the pain and MBS outcomes at 2 hours post treatment.\u003c/p\u003e \u003cp\u003ePain and MBS relief at 24 hours post treatment without the use of rescue medication (woRM) was the secondary endpoint in this study. Pain relief at 24 hours woRM was reported by 67% (6/9) of the participants who received 6 LPM flows. Pain freedom woRM at 24 hours was reported by 11% (1/9) of participants who received a 6LPM flow. Pain relief at 24 hours woRM was reported by 22% (2/9) and 33% (2/6) of the 18LPM and 24LPM groups, respectively. Eleven percent (1/9) of the subjects in the 18LPM group and 17% (1/6) of the subjects in the 24LPM group reported pain freedom at 24 hours woRM. MBS freedom woRM was reported at 24 hours by 56% (5/9) in the 6LPM group. MBS relief at 24 hours woRM was reported by 11% (1/9) of the participants, with no subjects in the 18Lpm group reporting MBS freedom at 24 hours woRM. Thirty-three percent (2/6) of the 24LPM groups reported MBS freedom at 24 hours woRM. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the pain and MBS outcomes at 24 hours post treatment.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTolerability\u003c/h2\u003e \u003cp\u003eTolerability was assessed via the following outcomes: (1) inability to complete the full 15-minute treatment session, (2) treatment discomfort score of moderate or severe, and (3) use of rescue medication before the 2-hour post treatment primary outcome assessment (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). As the flow rates increased, the treatments were rated as less tolerable for all three variables, with the 6 LPM flow being the most tolerable to patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6LPM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18LPM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24LPM\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePain data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain relief 2 hours without rescue medication (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88.9% (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56% (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50% (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain relief 24 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.7% (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22% (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain freedom 2 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.4% (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain freedom 24 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.7% (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMost Bothersome Symptom (MBS) data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMBS relief 2 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77.7% (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.7% (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50% (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMBS relief 24 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.6% (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMBS freedom 2 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.6% (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3% (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMBS freedom 24 hours (woRM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.6% (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTolerability data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStopped treatment early\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate or severe discomfort during treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3% (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.3% (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRescue medication taken within 2 hours post treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.3% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eSafety analyses were performed on all 24 participants. The percentage of participants who experienced at least one adverse event was 25% (6/24). Eight device-related adverse events were reported during 24 treatments (33%), four in the 24 LPM group, four in the 18 LPM group, and none in the 6 LPM sham group. Device-related adverse events included burning sensations/discomfort in the nostril, nasal congestion, dizziness, increased head pain, and increased nausea (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Five of the adverse events were mild, resolved within 24 hours and did not require medical treatment. Two of the adverse events resulted in early termination of the CoolStat treatment session. One of the adverse events was moderate and resulted in the subject taking rescue medication. This adverse event resolved within 24 hours. There were no device-related serious adverse events or unanticipated adverse device effects, and none of the participants withdrew from the study because of adverse events.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence of adverse events and device-related adverse events in the ITT population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 LPM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 LPM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 LPM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients reporting at least one adverse event, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33.3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e50.0 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDevice-related adverse events incidence\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBurning sensation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33.3 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNasal congestion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.7 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased head pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased nausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eThe investigators, outcome assessors, and participants were blinded to their treatment assignment. Upon treatment completion, the participants were asked about their presumed group assignment (18LPM or 24LPM active, with the sham being 6LPM). A total of 66.7% (4/6) of patients in the 24 LPM group and 44.4% (4/9) of patients in the 18 LPM group thought they received active treatment. A total of 77.8% (7/9) of patients in the 6 LPM \u0026ldquo;sham\u0026rdquo; group thought they received active treatment. We acknowledge that this blinding assessment has limitations because the sham was found to be active. In addition to the primary endpoint analysis, this blinding assessment supported the conclusion that the sham delivered active therapy.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eHere, we present our results, which compare 3 different doses of intranasal dehumidified air therapy for migraine attacks. Although we anticipated that 6LPM would be a sham dose, our results suggest that this dose yielded more positive results than the 18 and 24LPM arm doses. Thus, the 6LPM dose is unlikely to represent a true sham. As a result, this study was a dosing study, which may be due to the novelty of the target and method of treating migraine disease. The positive signal and feasibility of our results suggest that the CoolStat device may be an effective nonmedicinal, noninvasive alternative acute treatment option for migraine attacks. However, our sample size was small, and the study was terminated prematurely because of the slow recruitment of subjects.\u003c/p\u003e \u003cp\u003eOur primary outcome of pain relief at 2 hours in the 6LPM group was 89%. Across all three study arms, the weighted average of pain relief without rescue medication at 2 hours was 71%, which is comparable to that of other FDA-cleared acute migraine devices, such as remote electronic neuromodulation device at 67%,\u003csup\u003e18\u003c/sup\u003e transcutaneous trigeminal nerve stimulator device at 55%,\u003csup\u003e19\u003c/sup\u003e and combined occipital trigeminal neurostimulation device at 60%.\u003csup\u003e20\u003c/sup\u003e Each of these studies enrolled participants with episodic migraine and used pain relief at 2 hours post treatment as the primary endpoint. Across these studies, there was some variability in the treatment setting and time to treatment initiation after migraine onset. Participants in the transcutaneous trigeminal nerve stimulator device study were treated during a clinic visit and were required to have a minimum duration of 3 hours prior to treatment. The remote electronic neuromodulation device and combined occipital trigeminal neurostimulation device were used by study participants in their homes, and treatment was initiated within 1 hour of symptom onset. The major limitation of our study was its very small sample size and lack of a true sham arm, as our a priori \u0026ldquo;sham arm\u0026rdquo; was not sham. Another limitation of our study is that all of the treated subjects were female. Owing to the small sample size, the sex distribution was skewed, as migraine is three times more common in females than in males.\u003c/p\u003e \u003cp\u003eWhile there was an extremely high level of interest based on online recruitment campaign metrics, the in-clinic, centralized design of this trial had several drawbacks related to the migraine population. Participants with migraine are much less likely to travel to a headache clinic within the first few hours of a migraine attack. In addition, by the time patients arrive at the clinic, their migraine attacks are more likely to be refractory to treatment. Abortive therapies initiated within the first hour of headache onset have greater chances of pain relief and a lower risk of recurrence than nonearly users do. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The increased length of time after onset of the migraine attack and the requirement for travel to a clinic posed challenges to trial execution and partially contributed to the early termination of this study owing to an insufficient subject accrual rate. This study was conducted during the Sars-cov-2 (COVID-19) pandemic, which may have resulted in the avoidance of in-clinic treatment visits.\u003c/p\u003e \u003cp\u003eRecruiting patients with episodic migraine disease from comprehensive headache centers present with challenges. Some of these challenges may be due to referral patterns. Many patients are referrals and second opinions from primary clinics; therefore, the baseline frequency of headache days per month is much higher,\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e making them ineligible for our study. Thus, the recruitment of patients with episodic headache disease may be improved with collaboration from other medical practices (e.g., primary care providers, obstetrics, and gynecology practices). general neurology, etc.) as well as from community engagement.\u003c/p\u003e \u003cp\u003eA more patient-friendly (e.g., in-home) device and paradigm may be ideal for future studies. A larger at-home pilot study with an updated sham and refined dosing is underway.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eOur results suggest that transnasal cooling at lower flow rates may be effective and tolerable for treating acute migraine attacks. Future research with larger and more diverse populations as well as control groups is needed to validate these findings. Since all three doses in this study delivered therapy, this cannot be considered a sham-controlled trial. Nevertheless, tolerability and outcome data obtained from this study are useful for dose-ranging analysis. Logistical challenges that require subjects experiencing a migraine headache attack to travel to a clinic for in-person randomization and study device treatment exist. An at-home study with an updated sham and refined dosing is underway.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol and informed consent form were reviewed and approved by the Advarra Institutional Review Board (Pro00054590) on June 30, 2021. This study was conducted in accordance with the Declaration of Helsinki under IDE #G210131. Written informed consent was obtained from all participants before they underwent any study procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with CONSORT Guidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe confirm that our manuscript adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting randomized controlled trials. All relevant items of the CONSORT checklist have been followed, and necessary information has been included to ensure transparency and reproducibility of the trial methodology and results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting the findings in the present study are reported in the article and in the supplementary materials. The data collected and analyzed for the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLCIV\u0026nbsp;has received personal compensation for serving as a consultant for AbbVie, Accolade, Amgen, Amneal, Aurene, Biohaven, Haleon, LinPharma, Lundbeck, Pfizer, and Satsuma. He is on the advisory panel for Mi-Helper Inc. (stock options), and received grant/research support from the Disparities in Headache Advisory Council and Amgen. He has received CME honoraria from American Headache Society, American Academy of Neurology, BrainWeekend, Migraine360 CME Program, NeurologyWeek, Continuing Education Health Interactive, and the Primary Care Education Consortium. He receives a salary as an adjunct faculty from Thomas Jefferson University. He is a non-compensated associate editor for \u003cem\u003eHeadache\u003c/em\u003e: The Journal of Head and Face Pain, serves as a non-compensated Board of Directors as Treasurer/Secretary for the Clinical Neurological Society of America, and serves a Board of Director of the American Headache Society as Chair of the American Headache Society\u0026rsquo;s Equity Diversity and Inclusion Advisory Council (non-voting).\u003c/p\u003e\n\u003cp\u003eAS has received personal compensation from AbbVie (consulting), Allergan (consulting), Amneal (consulting), Axsome Therapeutics (consulting), eNeura (advisory board), Everyday Health (consulting), Lundbeck (consulting), Med-IQ (consulting), Medscape (consulting), Miller Medical (consulting), Pfizer (consulting), Salvia (consulting), Satsuma (consulting), and WebMD (consulting).\u003c/p\u003e\n\u003cp\u003eNT reports no disclosures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by CoolTech, LLC, and the National Institute of Neurological Disorders and Stroke (NINDS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCharleston Health Neurology \u0026amp; Head Pain Consultants, Pinckney MI\u003c/p\u003e\n\u003cp\u003eLarry Charleston IV\u003c/p\u003e\n\u003cp\u003eDivision of Headache, Department of Neurology, Mayo Clinic Scottsdale\u003c/p\u003e\n\u003cp\u003eAmaal Starling\u003c/p\u003e\n\u003cp\u003eHeadache Center, Atrium Health Wake Forest Baptist Neuroscience Institute\u003c/p\u003e\n\u003cp\u003eNauman Tariq\u003c/p\u003e\n\u003cp\u003eContributions:\u003c/p\u003e\n\u003cp\u003eLC, AS, and NT had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All Authors recruited patients, and drafted and critically reviewed the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Larry Charleston IV, [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndependent biostatistician Christopher Cox conducted the statistical analysis for this manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSteiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50 s: will health politicians now take notice? J Headache Pain. 2018;19(1):17. Published 2018 Feb 21. doi:10.1186/s10194-018-0846-2\u003c/li\u003e\n\u003cli\u003eLipton RB, Munjal S, Buse DC, Alam A, Fanning KM, Reed ML, Schwedt TJ, Dodick DW. Unmet Acute Treatment Needs From the 2017 Migraine in America Symptoms and Treatment Study. Headache. 2019 Sep;59(8):1310-1323. doi: 10.1111/head.13588. Epub 2019 Aug 13. PMID: 31410844; PMCID: PMC6771753.\u003c/li\u003e\n\u003cli\u003eBuse DC, Nahas SJ, Stewart WBF, Armand CE, Reed ML, Fanning KM, Manack Adams A, Lipton RB. Optimized Acute Treatment of Migraine Is Associated With Greater Productivity in People With Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. J Occup Environ Med. 2023 Apr 1;65(4):e261-e268. doi: 10.1097/JOM.0000000000002801. Epub 2023 Jan 25. PMID: 36701797; PMCID: PMC10090340.\u003c/li\u003e\n\u003cli\u003eLipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 2015 Feb 17;84(7):688-95. doi: 10.1212/WNL.0000000000001256. Epub 2015 Jan 21.\u003c/li\u003e\n\u003cli\u003eMinen, M.T., Tanev, K. and Friedman, B.W. (2014), Evaluation and Treatment of Migraine in the Emergency Department: A Review. Headache: The Journal of Head and Face Pain, 54: 1131-1145.\u003c/li\u003e\n\u003cli\u003eBigal, M.E., Serrano, D., Buse, D., Scher, A., Stewart, W.F. and Lipton, R.B. (2008), Acute Migraine Medications and Evolution From Episodic to Chronic Migraine: A Longitudinal Population‐Based Study. Headache: The Journal of Head and Face Pain, 48: 1157-1168.\u003c/li\u003e\n\u003cli\u003eAmiri P, Kazeminasab S, Nejadghaderi SA, Mohammadinasab R, Pourfathi H, Araj-Khodaei M, Sullman MJM, Kolahi AA, Safiri S. Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities. Front Neurol. 2022 Feb 23;12:800605. doi: 10.3389/fneur.2021.800605. PMID: 35281991; PMCID: PMC8904749.\u003c/li\u003e\n\u003cli\u003ePuledda F, Messina R, Goadsby PJ (2017) An update on migraine: current understanding and future directions. J Neurol 264:2031\u0026ndash;2039.\u003c/li\u003e\n\u003cli\u003eRobbins MS, Robertson C, Kaplan E, et al. The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache. Headache 2016;56:240-58\u003c/li\u003e\n\u003cli\u003eMaizels M, Geiger AM: Intranasal lidocaine for migraine: a randomized trial and open-label follow-up. Headache 1999;39:543\u0026ndash;551.\u003c/li\u003e\n\u003cli\u003eKudrow L, Kudrow DB, and Sandweiss JH. Rapid and Sustained Relief of Migraine Attacks With Intranasal Lidocaine: Preliminary Findings. Headache: The Journal of Head and Face Pain, vol. 35, no. 2, pp. 79\u0026ndash;82, 1995.\u003c/li\u003e\n\u003cli\u003eBinfalah M, Alghawi E, Shosha E, Alhilly A, Bakhiet M. Sphenopalatine Ganglion Block for the Treatment of Acute Migraine Headache. Pain Res Treat. 2018;2018:2516953. Published 2018 May 7. doi:10.1155/2018/2516953\u003c/li\u003e\n\u003cli\u003eSinghal, A. B., Maas, M. B., Goldstein, J. N., et al. High-flow oxygen therapy for treatment of acute migraine: A randomized crossover trial. Cephalalgia 2017; 37(8), 730-736\u003c/li\u003e\n\u003cli\u003eVanderpol, J., Bishop, B., Matharu, M. et al. Therapeutic effect of intranasal evaporative cooling in patients with migraine: a pilot study. J Headache Pain 16, 5 (2015).\u003c/li\u003e\n\u003cli\u003eNoseda, R., \u0026amp; Burstein, R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. PAIN\u0026reg; 2013; 154, S44-S53\u003c/li\u003e\n\u003cli\u003eShah R, Assis F, Narasimhan B, et al. Trans-nasal high-flow dehumidified air in acute migraine headaches: A randomized controlled trial. Cephalalgia. February 2021.\u003c/li\u003e\n\u003cli\u003eTransnasal Induction of Normothermia in NCCU Fever Patients. Clinicaltrials.gov identifier: NCT03360656. Updated June 18, 2023. Accessed March 20, 2025. https://clinicaltrials.gov/study/NCT03360656\u003c/li\u003e\n\u003cli\u003eYarnitsky D, Dodick DW, Grosberg BM, Burstein R, Ironi A, Harris D, Lin T, Silberstein SD. Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache. 2019 Sep;59(8):1240-1252. doi: 10.1111/head.13551. Epub 2019 May 9. PMID: 31074005; PMCID: PMC6767146.\u003c/li\u003e\n\u003cli\u003eChou DE, Shnayderman Yugrakh M, Winegarner D, Rowe V, Kuruvilla D, Schoenen J. Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial. Cephalalgia. 2019 Jan;39(1):3-14. doi: 10.1177/0333102418811573. Epub 2018 Nov 17. PMID: 30449151; PMCID: PMC6348457.\u003c/li\u003e\n\u003cli\u003eTepper SJ, Grosberg B, Daniel O, Kuruvilla DE, Vainstein G, Deutsch L, Sharon R. Migraine treatment with external concurrent occipital and trigeminal neurostimulation-A randomized controlled trial. Headache. 2022 Sep;62(8):989-1001. doi: 10.1111/head.14350. Epub 2022 Jun 24. PMID: 35748757.\u003c/li\u003e\n\u003cli\u003eGoadsby PJ, Zanchin G, Geraud G, de Klippel N, Diaz-Insa S, Gobel H, Cunha L, Ivanoff N, Falques M, Fortea J. Early vs. nonearly intervention in acute migraine-\u0026apos;Act when Mild (AwM)\u0026apos;. A double-blind, placebo-controlled trial of almotriptan. Cephalalgia. 2008 Apr;28(4):383-91. doi: 10.1111/j.1468-2982.2008.01546.x. Epub 2008 Feb 20. Erratum in: Cephalalgia. 2008 Jun;28(6):679. PMID: 18294251.\u003c/li\u003e\n\u003cli\u003eGilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician. 2011 Feb 1;83(3):271-80. Erratum in: Am Fam Physician. 2011 Oct 1;84(7):738. PMID: 21302868.\u003c/li\u003e\n\u003cli\u003ePeres MFP, Swerts DB, de Oliveira AB, Silva-Neto RP. Migraine patients\u0026apos; journey until a tertiary headache center: an observational study. J Headache Pain. 2019 Aug 15;20(1):88. doi: 10.1186/s10194-019-1039-3. PMID: 31416424; PMCID: PMC6734236.\u003c/li\u003e\n\u003cli\u003eZiegeler C, Brauns G, J\u0026uuml;rgens TP, May A. Shortcomings and missed potentials in the management of migraine patients - experiences from a specialized tertiary care center. J Headache Pain. 2019 Aug 1;20(1):86. doi: 10.1186/s10194-019-1034-8. PMID: 31370788; PMCID: PMC6734431.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute treatment, clinical trial, migraine, neuromodulation, headache, sphenopalatine ganglion, pain relief, pain freedom","lastPublishedDoi":"10.21203/rs.3.rs-6108236/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6108236/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThere is a need for effective and affordable nondrug therapies for the acute treatment of migraine.\u003cstrong\u003e \u003c/strong\u003eTransnasal neuromodulation via evaporative cooling may modulate the sphenopalatine ganglion, which is implicated in migraine. The study aimed to evaluate the safety, tolerability, and optimal dose of this method for acute migraine treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA prospective, randomized, double-blind, multicenter study was conducted at 3 US sites. \u0026nbsp;Subjects received 15 minutes of in-clinic treatment during a migraine attack. Twenty-four subjects were randomized into three groups: 24 liters per minute (LPM), 18 LPM, and 6 LPM. Pain and Most Bothersome Symptom (MBS) were recorded at baseline 2 and 24 hours post treatment. The primary endpoint was pain relief (PR) at 2 hours. Secondaryendpoints included tolerability, MBS relief and pain freedom (PF) at 2 hours and 24 hours\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eEighty-seven adults with episodic migraine with or without aura were enrolled. PR at 2 hours without rescue medication (woRM) was reported by 89% (8/9) of the participants who received 6LPM. PR at 2 hwoRM was reported to be 56% (5/9) and 50% (3/6) in the 18LPM and 24LPM groups, respectively. PF at 2 hours woRM was reported by 44% (4/9) of participants in the 6LPM group, and no participants in the 18LPM or 24LPM group reported PF at 2 hours. MBS relief at 2 hwas 78% (7/9), 67% (6/9) and 50% (3/6) in the 16, 18 \u0026amp; 24LPM groups, respectively. No adverse events occurred in the 6LPM group,and none were serious or severe in any group.\u003c/p\u003e\n\u003cp\u003eModerate discomfort was reported by 11% (1/9) of the participants in the 6LPM group. In contrast, 33% (3/9) and 83% ofthe 18LPM and 24LPM groups reported moderate or severe discomfort, respectively. Zero, one, and two subjects discontinued the 15-minute session in the 6LPM, 18LPM, and 24LPM groups, respectively. The study was terminated early because of slow subject accrual.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eLower flow rates during transnasal cooling were both effective and tolerable for acute migraine treatment. The study became a dose-ranging trial, with lower flow rates,showing greater efficacy. A future at-home study is planned.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eClinicalTrials.gov Identifier: NCT04936061; Registration date: June 15, 2021. The full study protocol can be accessed at https://clinicaltrials.gov/study/NCT04936061.\u003c/p\u003e","manuscriptTitle":"Transnasal Evaporative Cooling Device for Migraine: A Prospective, Randomized, Double-blind, Multicenter Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-04 11:14:47","doi":"10.21203/rs.3.rs-6108236/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"797d501a-b022-4b0d-a9cc-b5269cbf38df","owner":[],"postedDate":"April 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-05T09:23:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-04 11:14:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6108236","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6108236","identity":"rs-6108236","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}