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A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study).

ABSTRACT: To evaluate the efficacy and safety of AVP-825, a drug-device combination of low-dose sumatriptan powder (22?mg loaded dose) delivered intranasally through a targeted Breath Powered device vs an identical device containing lactose powder (placebo device) in the treatment of migraine headache.Early treatment of migraine headaches is associated with improved outcome, but medication absorption after oral delivery may be delayed in migraineurs because of reduced gastric motility. Sumatriptan powder administered with an innovative, closed-palate, Bi-Directional, Breath Powered intranasal delivery mechanism is efficiently absorbed across the nasal mucosa and produces fast absorption into the circulation. Results from a previously conducted placebo-controlled study of AVP-825 showed a high degree of headache relief with an early onset of action (eg, 74% AVP-825 vs 38% placebo device at 1 hour, P<.01).In this double-blind, placebo-controlled, parallel-group study in adults with a history of migraine with or without aura, participants were randomized via computer-generated lists to AVP-825 or placebo device to treat a single migraine headache of moderate or severe intensity. The primary endpoint was headache relief (defined as reduction of headache pain intensity from severe or moderate migraine headache to mild or none) at 2 hours post-dose.Two hundred and thirty patients (116 AVP-825 and 114 placebo device) were randomized, of whom 223 (112 and 111, respectively) experienced a qualifying migraine headache (their next migraine headache that reached moderate or severe intensity). A significantly greater proportion of AVP-825 patients reported headache relief at 2 hours post-dose compared with those using the placebo device (68% vs 45%, P=.002, odds ratio 2.53, 95% confidence interval [1.45, 4.42]). Between-group differences in headache relief were evident as early as 15 minutes, reached statistical significance at 30 minutes post-dose (42% vs 27%, P=.03), and were sustained at 24 hours (44% vs 24%, P=.002) and 48 hours (34% vs 20%, P=.01). Thirty-four percent of patients treated with AVP-825 were pain-free at 2 hours compared with 17% using the placebo device (P=.008). More AVP-825 patients reported meaningful pain relief (patient interpretation) of migraine within 2 hours of treatment vs placebo device (70% vs 45%, P<.001), and fewer required rescue medication (37% vs 52%, P=.02). Total migraine freedom (patients with no headache, nausea, phonophobia, photophobia, or vomiting) reached significance following treatment with AVP-825 at 1 hour (19% vs 9%; P=.04). There were no serious adverse events (AEs), and no systemic AEs occurred in more than one patient. Chest pain or pressure was not reported, and only one patient taking AVP-825 reported mild paresthesia. No other triptan sensations were reported.Targeted delivery of a low-dose of sumatriptan powder via a novel, closed-palate, Breath Powered, intranasal device (AVP-825) provided fast relief of moderate or severe migraine headache in adults that reached statistical significance over placebo by 30 minutes. The treatment was well tolerated with a low incidence of systemic AEs.

SUBMITTER: Cady RK

PROVIDER: S-EPMC4320758 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study).

Cady Roger K RK McAllister Peter J PJ Spierings Egilius L H EL Messina John J Carothers Jennifer J Djupesland Per G PG Mahmoud Ramy A RA

Headache 20141030 1

<h4>Objective</h4>To evaluate the efficacy and safety of AVP-825, a drug-device combination of low-dose sumatriptan powder (22 mg loaded dose) delivered intranasally through a targeted Breath Powered device vs an identical device containing lactose powder (placebo device) in the treatment of migraine headache.<h4>Background</h4>Early treatment of migraine headaches is associated with improved outcome, but medication absorption after oral delivery may be delayed in migraineurs because of reduced ...[more]

PMID: 25355310

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Project description:ObjectiveThe objective of this study was to compare the efficacy, tolerability, and safety of AVP-825, an investigational bi-directional breath-powered intranasal delivery system containing low-dose (22 mg) sumatriptan powder, vs 100 mg oral sumatriptan for acute treatment of migraine in a double-dummy, randomized comparative efficacy clinical trial allowing treatment across multiple migraine attacks.BackgroundIn phases 2 and 3, randomized, placebo-controlled trials, AVP-825 provided early and sustained relief of moderate or severe migraine headache in adults, with a low incidence of triptan-related adverse effects.MethodsThis was a randomized, active-comparator, double-dummy, cross-over, multi-attack study (COMPASS; NCT01667679) with two ≤12-week double-blind periods. Subjects experiencing 2-8 migraines/month in the past year were randomized 1:1 using computer-generated sequences to AVP-825 plus oral placebo tablet or an identical placebo delivery system plus 100 mg oral sumatriptan tablet for the first period; patients switched treatment for the second period in this controlled comparative design. Subjects treated ≤5 qualifying migraines per period within 1 hour of onset, even if pain was mild. The primary end-point was the mean value of the summed pain intensity differences through 30 minutes post-dose (SPID-30) using Headache Severity scores. Secondary outcomes included pain relief, pain freedom, pain reduction, consistency of response across multiple migraines, migraine-associated symptoms, and atypical sensations. Safety was also assessed.ResultsA total of 275 adults were randomized, 174 (63.3%) completed the study (ie, completed the second treatment period), and 185 (67.3%) treated at least one migraine in both periods (1531 migraines assessed). There was significantly greater reduction in migraine pain intensity with AVP-825 vs oral sumatriptan in the first 30 minutes post-dose (least squares mean SPID-30 = 10.80 vs 7.41, adjusted mean difference 3.39 [95% confidence interval 1.76, 5.01]; P < .001). At each time point measured between 15 and 90 minutes, significantly greater rates of pain relief and pain freedom occurred with AVP-825 treatment compared with oral sumatriptan. At 2 hours, rates of pain relief and pain freedom became comparable; rates of sustained pain relief and sustained pain freedom from 2 to 48 hours remained comparable. Nasal discomfort and abnormal taste were more common with AVP-825 vs oral sumatriptan (16% vs 1% and 26% vs 4%, respectively), but ∼90% were mild, leading to only one discontinuation. Atypical sensation rates were significantly lower with AVP-825 than with conventional higher dose 100 mg oral sumatriptan.ConclusionsAVP-825 (containing 22 mg sumatriptan nasal powder) provided statistically significantly greater reduction of migraine pain intensity over the first 30 minutes following treatment, and greater rates of pain relief and pain freedom within 15 minutes, compared with 100 mg oral sumatriptan. Sustained pain relief and pain freedom through 24 and 48 hours was achieved in a similar percentage of attacks for both treatments, despite substantially lower total systemic drug exposure with AVP-825. Treatment was well tolerated, with statistically significantly fewer atypical sensations with AVP-825.

Project description:BackgroundThe commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent.ObjectiveThe objective of this study was to assess the efficacy of acute treatment of migraine with DFN-02, including its effect on migraine-related functional disability and patient satisfaction with treatment.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-02 in adults with episodic migraine. Functional disability and subject satisfaction with treatment were prespecified endpoints, assessed in real-time by subjects, using an electronic diary.ResultsIn total, 107 subjects were randomized. DFN-02 was significantly superior to placebo for the reduction in functional disability score from predose level at 2 h after treatment (- 1.2 vs. - 0.6, p < 0.001). Subjects treated with DFN-02 were also more likely to be satisfied or very satisfied than subjects treated with placebo at 2 h postdose (70.0% vs. 44.2%, p = 0.027). Using the Patient Perception of Migraine Questionnaire-Revised at 24 h postdose, DFN-02 mean scores were significantly superior to placebo for the subscales of efficacy (65.2 vs. 42.5, p = 0.016) and function (68.9 vs. 42.1, p = 0.001), and for total score (71.0 vs. 56.6, p = 0.016); global medication effectiveness (p = 0.027); and overall satisfaction (p = 0.019). Placebo was significantly better than DFN-02 on the tolerability subscale (94.8 vs. 88.5, p = 0.026). At 24 h postdose, subjects reported significantly higher satisfaction with DFN-02 compared with satisfaction reported pre-randomization regarding their usual migraine medication (p = 0.012).ConclusionDFN-02 was superior to placebo for the relief of migraine-related functional disability, and provided greater satisfaction than placebo or subjects' usual acute treatment.Trial registrationClinicalTrials.gov identifier: NCT02856802.

Project description:BACKGROUND:In a previous randomized, double-blind, proof-of-concept study in rapidly escalating migraine, a 3 mg dose of subcutaneous sumatriptan (DFN-11) was associated with fewer and shorter triptan sensations than a 6 mg dose. The primary objective of the study was to assess the efficacy and safety of acute treatment with DFN-11 compared with placebo in episodic migraine. METHODS:This was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-11 in the acute treatment of adults with episodic migraine (study RESTOR). The primary endpoint was the proportion of subjects taking DFN-11 who were pain free at 2 h postdose in the double-blind period compared with placebo. Secondary endpoints included earlier postdose timepoints, assessments of pain relief and subjects' freedom from their most bothersome symptom (MBS) (among nausea, photophobia, and phonophobia). Safety and tolerability were assessed. RESULTS:A total of 392 subjects was screened, 268 (68.4%) were randomized, and 234 (87.3% of those randomized) completed the double-blind treatment period. The proportion of subjects who were pain free at 2 h postdose was significantly greater in the DFN-11 group than in the placebo group (51.0% vs 30.8%, P??=??0.0023). Compared with placebo, significantly higher proportions of subjects treated with DFN-11 were also pain free at 30, 60, and 90 min postdose (P?????0.0195). DFN-11 was significantly superior to placebo for pain relief at 60 min, 90 min, and 2 h postdose (P???0.0179). At 2 h postdose, DFN-11 was also significantly superior to placebo for freedom from photophobia (P??=??0.0056) and phonophobia (P??=??0.0167). Overall, 33.3% (37/111) who received DFN-11 and 13.4% (16/119) who received placebo experienced at least 1 treatment-emergent adverse event (TEAE), the most common of which were injection site swelling (7.2% vs 0.8%) and pain (7.2% vs 5.9%). Chest discomfort was about half as common in the DFN-11 treatment group as it was in the placebo group (0.9% vs 1.7%). CONCLUSIONS:This study met its primary endpoint, pain freedom at 2 h postdose, with DFN-11 significantly better than placebo, and the incidence of TEAEs and triptan sensations with DFN-11 was low. The 3 mg dose of sumatriptan in DFN-11 appears to be an effective alternative to a 6 mg SC dose of sumatriptan, with good safety and tolerability. ( clinicaltrials.gov : NCT02569853; registered 07 October 2015).

Project description:To compare the efficacy of ketorolac nasal spray (NS) vs. placebo and sumatriptan NS for the acute treatment of migraine.This was a randomized, double-blind, placebo and active-comparator, crossover study. Adult migraineurs were randomized to ketorolac NS 31.5 mg, sumatriptan NS 20 mg, or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack. Patients seeking headache care at a headache center or in response to community advertisement were recruited. Adult participants with episodic migraine who experienced ?2 migraine attacks per month were eligible for the Ketorolac vs. Sumatriptan vs. Placebo Nasal Spray migraine study. Participants were randomized to treatment arms by a research pharmacist, in a 1:1:1 ratio using computer-generated lists. The primary outcome was 2-hour pain relief. Secondary outcomes included 2-hour pain freedom and absence of migraine associated symptoms, and 24-hour sustained pain relief and pain freedom.Of the 72 randomized participants, 54 (75%) treated at least one attack and 49 (68%) completed all three treatments, for a total of 152 treated migraine attacks. Both ketorolac NS (72.5%, P?<?.001) and sumatriptan NS (69.4%, P?=?.001) were more effective than placebo (38.3%) for 2-hour pain relief and 2-hour pain freedom (ketorolac: 43.1%, P?=?.004; sumatriptan: 36.7%, P?=?.046; placebo: 18.4%). Ketorolac NS, but not sumatriptan NS, was more effective than placebo in 2-hour absence of nausea. Both ketorolac NS and sumatriptan NS were more effective than placebo for 24-hour sustained pain relief (ketorolac: 49%, P?<?.001; sumatriptan: 31%, P?=?.01, placebo: 20%). Only ketorolac NS was superior to placebo for 24-hour (ketorolac: 35.3%, P?=?.003; sumatriptan: 22.4%, P?=?.18, placebo: 12.2%) sustained pain freedom. Nasal burning and dysgeusia were the most common adverse effects for active treatments.This study supports that ketorolac NS is superior to placebo and that it is non-inferior to sumatriptan NS for the acute abortive treatment of migraine.

Project description:A 6-mg dose of SC sumatriptan is the most efficacious and fast-acting acute treatment for migraine, but a 3-mg dose of SC sumatriptan may improve tolerability while maintaining efficacy.This randomized, double-blind, crossover study compared the efficacy and tolerability of 3 mg subcutaneous (SC) sumatriptan (DFN-11) with 6 mg SC sumatriptan in 20 adults with rapidly-escalating migraine attacks. Eligible subjects were randomized (1:1) to treat 1 attack with DFN-11 and matching placebo autoinjector consecutively or 2 DFN-11 autoinjectors consecutively and a second attack similarly but with the alternative dose (3 mg or 6 mg).The proportions of subjects who were pain-free at 60 min postdose, the primary endpoint, were similar following treatment with 3 mg SC sumatriptan and 6 mg SC sumatriptan (50% vs 52.6%, P??=??.87). The proportions of subjects experiencing pain relief (P?????.48); reductions in migraine pain intensity (P?????.78); and relief from nausea, photophobia, or phonophobia (P?????.88) with 3 mg SC sumatriptan and 6 mg SC sumatriptan were similar, as were the mean scores for satisfaction with treatment (M??=??2.6 vs M??=??2.4, P??=??.81) and the mean number of rescue medications used (M??=??.11 vs M??=??.26, P??=??.32). The most common adverse events with the 3- and 6-mg doses were triptan sensations - paresthesia, neck pain, flushing, and involuntary muscle contractions of the neck - and the incidence of adverse events with both doses was similar (32 events total: 3 mg, n??=??14 [44%]; 6 mg, n??=??18 [56%], P??=??.60). Triptan sensations affected 4 subjects with the 6-mg dose only, 1 subject with the 3-mg dose only, and 7 subjects with both sumatriptan doses. Chest pain affected 2 subjects (10%) treated with the 6-mg dose and no subjects (0%) treated with the 3-mg dose of DFN-11. There were no serious adverse events.The 3-mg SC dose of sumatriptan in DFN-11 provided relief of migraine pain and associated symptoms comparable to a 6-mg SC dose of sumatriptan. Tolerability was similar with both study medications; DFN-11 treatment was associated with fewer triptan sensations than the 6-mg dose. DFN-11, with its 3-mg dose of sumatriptan, may be a clinically useful alternative to higher-dose autoinjectors.

Project description:ImportanceTriptans, the most efficient acute treatment for migraine attacks, are 5-HT1B/1D receptor agonists, but their precise mechanism of action is not completely understood. The extent to which triptans enter the central nervous system and bind to 5-HT1B receptors in the brain is unknown.ObjectivesTo determine the occupancy of sumatriptan to central 5-HT1B receptors, and to investigate changes in brain serotonin levels during migraine attacks.Design, setting, and participantsThis study of 8 patients in Denmark used a within-participant design and was conducted from April 20, 2015, to December 5, 2016. Participants were otherwise healthy patients with untreated episodic migraine without aura, aged between 18 and 65 years, and recruited from the general community. Data analysis was performed from January 2017 to April 2018.InterventionsAll participants underwent positron emission tomographic scans after injection of [11C]AZ10419369, a specific 5-HT1B receptor radiotracer. All participants were scanned 3 times: (1) during an experimentally induced migraine attack, (2) after a subcutaneous injection of 6-mg subcutaneous sumatriptan, and (3) on a migraine attack-free day. Scans 1 and 2 were conducted on the same study day. Each scan lasted for 90 minutes.Main outcome and measureThe primary outcome was the nondisplaceable binding potential of [11C]AZ10419369 across 7 brain regions involved in pain modulation. The binding potential reflects receptor density, and changes in binding potential reflects displacement of the radiotracer. The occupancy of sumatriptan was estimated from the 2 scans before and after sumatriptan administration.ResultsEight patients with migraine were included in the study; of these participants, 7 (87%) were women. The mean (SD) age of participants on study day 1 was 29.5 (9.2) years and on study day 2 was 30.0 (8.9) years. Sumatriptan was associated with statistically significantly reduced 5-HT1B receptor binding across pain-modulating regions (mean [SD] binding potential, 1.20 [0.20] vs 1.02 [0.22]; P = .001), corresponding to a mean (SD) drug occupancy rate of 16.0% (5.3%). Furthermore, during migraine attacks, as compared with outside of attacks, 5-HT1B receptor binding was statistically significantly associated with reduced in pain-modulating regions (mean [SD] binding potential, 1.36 [0.22] vs 1.20 [0.20]; P = .02).Conclusions and relevanceTreatment with sumatriptan during migraine attacks appeared to be associated with a decrease in 5-HT1B receptor binding, a finding that is most likely associated with the binding of sumatriptan to central 5-HT1B receptors, but the contribution of ongoing cerebral serotonin release to the lower binding cannot be excluded; the migraine attack-associated decrease in binding could indicate that migraine attacks are associated with increases in endogenous serotonin.

Dataset Information

A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study).

Publications

A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study).

Similar Datasets

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