NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis.

BACKGROUND: Chronic rhinosinusitis is common and sometimes complicated by nasal polyps (NPs). Corticosteroid nasal sprays are often unsatisfactory because they are ineffective at delivering medication to high/deep sites of inflammation. OBJECTIVE: We sought to assess whether an exhalation delivery system with fluticasone (EDS-FLU) capable of high/deep drug deposition improves outcomes. METHODS: Patients (n = 323) 18 years and older with moderate-to-severe congestion and NPs were randomized to twice-daily EDS-FLU (93, 186, or 372 µg) or exhalation delivery system (EDS)-placebo for 24 weeks (16 double-blind plus 8 open-label when all received 372 µg). Coprimary end points were change in nasal congestion/obstruction at 4 weeks and summed bilateral polyp grade at 16 weeks. Secondary end points included symptoms, polyp elimination, and functioning. RESULTS: EDS-FLU was superior on both coprimary end points (P < .001 vs EDS-placebo, all doses). Mean polyp grade improved continuously through week 24 (P < .009, all comparisons), with polyps eliminated on at least 1 side in approximately 25% of patients at week 24 versus 8.7% with EDS-placebo (P ≤ .014, all comparisons). Sino-Nasal Outcomes Test scores also improved significantly versus those in patients receiving EDS-placebo (-21.1 to -21.4 vs -11.7 at week 16, P < .05 all doses). At the end of the double-blind period, EDS-FLU (all doses) significantly improved all 4 defining disease symptoms. In most patients (68%), those receiving EDS-FLU reported "much" or "very much" improvement. The number of patients eligible for surgery decreased by 62%-67%. The safety profile was similar to that reported in prior trials evaluating conventional corticosteroid nasal sprays in comparable populations. CONCLUSION: EDS-FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with chronic rhinosinusitis with NPs.

A cross-sectional, population-based survey of U.S. adults with symptoms of chronic rhinosinusitis.

Background: Chronic rhinosinusitis (CRS) is believed to create a substantial population-level disease burden in the United States due to its high prevalence and significant disease morbidity, but many studies of CRS epidemiology are based on administrative or historical record sources rather than primary population sources. Objective: To characterize CRS symptoms, burden, and patient characteristics by using a primary U.S. population-based representative sample. Methods: A demographically and geographically representative sample of 10,336 U.S. adults recruited from a general panel of 4.3 million were obtained by using three-stage randomization. Data collected included a range of respondent-reported CRS symptoms, symptom impact and severity, symptom duration, and treatment. Results: Approximately 11.5% of the respondents (n = 1189) reported defining symptom and duration criteria for CRS. A previous diagnosis of nasal polyps was reported by ∼10% of this population. The remaining respondents reported severe (7.3%) or moderate (3.1%) symptom severity. The most frequently reported defining symptoms were nasal congestion and/or obstruction (94-97%) and drainage (89-92%). CRS participants reported a high average degree of symptom burden (e.g., on a 0-10 scale, 8.2 for CRS with nasal polyps, 8.4 for CRS without nasal polyps with severe symptoms, and 6.4 for CRS without nasal polyps with moderate symptoms). The participants with CRS reported high health-care use for CRS, adverse effects of CRS symptoms on multiple areas of daily life, and high dissatisfaction with currently available treatments. Conclusion: More than 10% of the general U.S. adult population have CRS symptoms. Most report severe symptoms, lack of satisfaction with current treatment options, and a substantial adverse impact on daily functioning.

Saliva oxytocin measures do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men.

Oxytocin plays an important role in social behavior. Thus, there has been significant research interest for the role of the oxytocin system in several psychiatric disorders, and the potential of intranasal oxytocin administration to treat social dysfunction. Measurement of oxytocin concentrations in saliva are sometimes used to approximate peripheral levels of oxytocin; however, the validity of this approach is unclear. In this study, saliva and plasma oxytocin was assessed after two doses of Exhalation Delivery System delivered intranasal oxytocin (8 IU and 24 IU), intravenous oxytocin (1 IU) and placebo in a double-dummy, within-subjects design with men. We found that intranasal oxytocin (8 IU and 24 IU) administration increased saliva oxytocin concentrations in comparison to saliva oxytocin concentration levels after intravenous and placebo administration. Additionally, we found that saliva oxytocin concentrations were not significantly associated with plasma oxytocin concentrations after either intranasal or intravenous oxytocin administration. Altogether, we suggest that saliva oxytocin concentrations do not accurately index peripheral oxytocin after intranasal or intravenous oxytocin administration, at least in men. The data indicates that elevated oxytocin saliva levels after nasal delivery primarily reflect exogenous administered oxytocin that is cleared from the nasal cavity to the oropharynx, and is therefore a weak surrogate for peripheral blood measurements.

Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered® Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan.

OBJECTIVE: To further characterize the clinical utility of AVP-825 based on additional prespecified outcomes and post hoc analyses of COMPASS, a Phase 3 comparative efficacy trial of AVP-825 vs 100 mg oral sumatriptan (NCT01667679). AVP-825 was approved in January 2016 by the US Food and Drug Administration under the name ONZETRA® Xsail® (sumatriptan nasal powder) for the acute treatment of migraine with or without aura in adults. BACKGROUND: AVP-825 is a delivery system that uses a patient's own breath to deliver low-dose sumatriptan powder to the upper posterior regions of the nasal cavity beyond the narrow nasal valve, areas lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. The recommended dose of AVP-825 is 22 mg sumatriptan powder administered as one 11 mg nosepiece in each nostril, which delivers approximately 15-16 mg of sumatriptan intranasally. The COMPASS trial compared AVP-825 22-100 mg oral sumatriptan across multiple migraine attacks for efficacy, safety, and tolerability endpoints. DESIGN/METHODS: COMPASS was a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study with two 12-week double-blind periods. Patients with 2-8 migraine attacks/month were randomized 1:1 to AVP-825 (22 mg) plus oral placebo or an identical placebo delivery system plus 100 mg oral sumatriptan for the first period, and then patients switched treatments for the second period. Patients treated up to 5 qualifying migraines per period within 1 h of onset, even if the intensity of the attack was mild. Results from the primary endpoint (SPID-30, defined as the sum of pain intensity differences from dosing to 30 minutes), key secondary efficacy endpoints and safety assessments have been reported in the primary publication (Tepper et al., 2015). This article reports additional prespecified outcomes, including the SPID-30 for attacks treated when baseline severity was mild vs moderate/severe, measures of sustained response and consistency of effect in patients who experienced multiple migraine attacks, and the results of post hoc analyses performed to assess total migraine freedom (defined as no pain and no migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia), time to pain freedom, time to meaningful pain relief, and local (occurring at the site of administration in the nose) vs systemic treatment-emergent adverse events (TEAEs). RESULTS: A total of 185 patients completed both treatment periods, yielding 1,531 migraine attacks which were treated and assessed (765 AVP-825, 766 oral sumatriptan). Treatment with AVP-825 provided greater reduction in migraine pain intensity which was statistically significant vs oral sumatriptan in the first 30 minutes postdose regardless of whether attacks were treated when pain was mild (least squares mean SPID-30 = 3.90 vs 0.24, P = .0013) or moderate/severe (least squares mean SPID-30 = 13.83 vs 10.07, P = .0002). At every time point from 15 to 90 minutes postdose, the proportion of attacks achieving total migraine freedom was greater and statistically significant after treatment with AVP-825 vs 100 mg oral sumatriptan. AVP-825 treatment resulted in greater odds of achieving pain freedom (odds ratio, OR = 1.29, P < .01) and meaningful pain relief (OR = 1.32, P < .0001), which were also statistically significant compared with oral sumatriptan. In addition, a greater proportion of attacks treated with AVP-825 vs oral sumatriptan was associated with sustained pain freedom, achieving statistical significance when assessed from 1 h postdose through 24 hours postdose (33.3% vs 27.9%; P < .05) and through 48 hours postdose (32.7% vs 27.4%; P < .05). For patients who treated multiple migraine attacks in both treatment periods, a greater proportion had consistent pain relief and pain freedom following treatment with AVP-825 compared to oral sumatriptan across multiple attacks, a difference that achieved statistical significance at 30 minutes postdose. Local TEAEs of abnormal taste and nasal discomfort were more common following AVP-825 treatment. Of the patients experiencing either of these TEAEs, about 90% described the intensity as mild, and only one discontinued treatment because of either of these two TEAEs. CONCLUSIONS: These results from the COMPASS study further demonstrate that treatment with AVP-825 provides earlier onset and more consistent across-episode improvement of pain and migraine-associated symptoms compared with oral sumatriptan, highlighting the clinical advantages of this newly approved intranasal delivery system for low-dose sumatriptan powder.

Reliability of basal plasma vasopressin concentrations in healthy male adults.

OBJECTIVE: The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) play important and interrelated roles in modulating mammalian social behaviour. While the OT system has received considerable research attention for its potential to treat psychiatric symptoms, comparatively little is known about the role of the AVP system in human social behaviour. To better understand the intraindividual stability of basal AVP, the present study assessed the reproducibility of basal plasma AVP concentrations. METHODS: Basal plasma AVP was assessed at four sampling points separated by 8 days, on average, in 16 healthy adult males. RESULTS: Only one out of six comparisons revealed strong evidence for reproducibility of basal AVP concentrations (visit 2 vs. visit 4: r=0.8, p0.1). The concordance correlation coefficient [0.15, 95% CI (-0.55, 0.73)] also revealed poor overall reproducibility. CONCLUSION: Poor reliability of basal AVP concentrations suggests future work covarying AVP with trait markers should proceed with careful consideration of intraindividual fluctuations.

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).

OBJECTIVE: 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. BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative randomized clinical trial across multiple attacks.

OBJECTIVE: The 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. BACKGROUND: In 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. METHODS: This 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. RESULTS: A 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. CONCLUSIONS: AVP-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.

Efficacy of EDS-FLU for Chronic Rhinosinusitis: Two Randomized Controlled Trials (ReOpen1 and ReOpen2).

BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays. OBJECTIVE: Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps). METHODS: Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24. RESULTS: ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -1.58 and -1.60 versus -0.62 (P < .001, P < .001); ReOpen2 (N = 223), -1.54 and -1.74 versus -0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -5.58 and -6.20 versus -1.60 (P = .045, P = .018), and in ReOpen2, -7.00 and -5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids. CONCLUSIONS: EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.

Breath powered nasal delivery: a new route to rapid headache relief.

The nose offers an attractive noninvasive alternative for drug delivery. Nasal anatomy, with a large mucosal surface area and high vascularity, allows for rapid systemic absorption and other potential benefits. However, the complex nasal geometry, including the narrow anterior valve, poses a serious challenge to efficient drug delivery. This barrier, plus the inherent limitations of traditional nasal delivery mechanisms, has precluded achievement of the full potential of nasal delivery. Breath Powered bi-directional delivery, a simple but novel nasal delivery mechanism, overcomes these barriers. This innovative mechanism has now been applied to the delivery of sumatriptan. Multiple studies of drug deposition, including comparisons of traditional nasal sprays to Breath Powered delivery, demonstrate significantly improved deposition to superior and posterior intranasal target sites beyond the nasal valve. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposition of sumatriptan translates into improved absorption and pharmacokinetics. Importantly, the absorption profile is shifted toward a more pronounced early peak, representing nasal absorption, with a reduced late peak, representing predominantly gastrointestinal (GI) absorption. The flattening and "spreading out" of the GI peak appears more pronounced in migraine sufferers than healthy volunteers, likely reflecting impaired GI absorption described in migraineurs. In replicated clinical trials, Breath Powered delivery of low-dose sumatriptan was well accepted and well tolerated by patients, and onset of pain relief was faster than generally reported in previous trials with noninjectable triptans. Interestingly, Breath Powered delivery also allows for the potential of headache-targeted medications to be better delivered to the trigeminal nerve and the sphenopalatine ganglion, potentially improving treatment of various types of headache. In brief, Breath Powered bi-directional intranasal delivery offers a new and more efficient mechanism for nasal drug delivery, providing an attractive option for improved treatment of headaches by enabling or enhancing the benefits of current and future headache therapies.

Improved pharmacokinetics of sumatriptan with Breath Powered™ nasal delivery of sumatriptan powder.

OBJECTIVES: The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22-mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20-mg sumatriptan liquid nasal spray, a 100-mg oral tablet, and a 6-mg subcutaneous injection. BACKGROUND: A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels. METHODS: An open-label, cross-over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. Following randomization, fasted subjects received a single dose of each of the 4 treatments separated by a 7-day washout. Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis. RESULTS: Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8±0.9 mg (mean±standard deviation) of sumatriptan powder in each nostril (total dose 16 mg). Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16-mg sumatriptan powder and 20-mg liquid nasal spray (area under the curve [AUC]0-∞ 64.9 ng*hour/mL vs 61.1 ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8 ng/mL vs 16.4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0-30 minutes 5.8 ng*hour/mL vs 3.6 ng*hour/mL). The magnitude of difference is larger on a per-milligram basis. The absorption profile following standard nasal spray demonstrated bimodal peaks, consistent with lower early followed by higher later absorptions. In contrast, the profile following Breath Powered delivery showed higher early and lower late absorptions. Relative to the 100-mg oral tablet (Cmax 70.2 ng/mL, AUC0-∞, 308.8 ng*hour/mL) and 6-mg injection (Cmax 111.6 ng/mL, AUC0-∞ 128.2 ng*hour/mL), the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower. CONCLUSIONS: Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection.

Efficacy of the exhalation delivery system with fluticasone in patients with chronic rhinosinusitis with nasal polyps whose symptoms recur after sinus surgery.

BACKGROUND: Sinus surgery removes inflamed tissue, restores airflow, and improves delivery of medication into surgically opened spaces. The exhalation delivery system with fluticasone (EDS-FLU; XHANCE® ) uses a novel delivery system to create closed-palate, positive-pressure, bidirectional mechanics that significantly alter the deposition of the topically acting anti-inflammatory medication. We ask whether EDS-FLU efficacy differs for patients with recurrent symptoms after sinus surgery versus patients without surgery. OBJECTIVE: We aimed to compare EDS-FLU treatment responses in patients with recurrent symptoms after endoscopic sinus surgery (ESS) and patients who have never had sinus surgery. METHODS: Data were pooled from two large, controlled trials (NAVIGATE I and II) for exploratory analyses. Chronic rhinosinusitis symptoms, polyp grade, and quality-of-life measures were compared between patients with prior ESS and those without prior ESS. RESULTS: Patients with prior ESS (exhalation delivery system-placebo [n = 53], EDS-FLU 186 µg [n = 52], and EDS-FLU 372 µg [n = 49]) and unoperated patients (exhalation delivery system-placebo [n = 108], EDS-FLU 186 µg [n = 108], and EDS-FLU 372 µg [n = 111]) treated with EDS-FLU reported similar and substantial benefits as measured by multiple symptom and quality-of-life/functioning outcomes (congestion score, 22-Item Sinonasal Outcomes Test [SNOT-22], Rhinosinusitis Disability Index [RSDI], Patient Global Impression of Change) and by nasal polyp grade. In previously operated patients, unlike surgery-naive patients, multiple outcomes (SNOT-22, RSDI, polyp grade) consistently showed numerically but not statistically greater responses to the higher dose. CONCLUSIONS: Patients with recurrent symptoms after sinus surgery who were treated with EDS-FLU demonstrated significant symptom and quality-of-life improvement. Unlike unoperated patients, patients with prior ESS had a numerically but not statistically greater response to the higher dose of EDS-FLU (two sprays per nostril twice a day).

Hypothetical case replacement can be used to quantify the robustness of trial results.

OBJECTIVES: We apply a general case replacement framework for quantifying the robustness of causal inferences to characterize the uncertainty of findings from clinical trials. STUDY DESIGN AND SETTING: We express the robustness of inferences as the amount of data that must be replaced to change the conclusion and relate this to the fragility of trial results used for dichotomous outcomes. We illustrate our approach in the context of an RCT of hydroxychloroquine on pneumonia in COVID-19 patients and a cumulative meta-analysis of the effect of antihypertensive treatments on stroke. RESULTS: We developed the Robustness of an Inference to Replacement (RIR), which quantifies how many treatment cases with positive outcomes would have to be replaced with hypothetical patients who did not receive a treatment to change an inference. The RIR addresses known limitations of the Fragility Index by accounting for the observed rates of outcomes. It can be used for varying thresholds for inference, including clinical importance. CONCLUSION: Because the RIR expresses uncertainty in terms of patient experiences, it is more relatable to stakeholders than P-values alone. It helps identify when results are statistically significant, but conclusions are not robust, while considering the rareness of events in the underlying data.

Role of nasal casts for in vitro evaluation of nasal drug delivery and quantitative evaluation of various nasal casts.

Background: Nasal casts may characterize intranasal drug deposition. Methodology: The Koken cast, described as 'anatomically correct', and the Optinose cast, derived from MRI of a healthy male during velum closure, were dimensionally compared and assessed for deposition assessment suitability. Results: Smallest vertical cross-sectional areas (valve region) for Koken and Optinose right/left: 2.55/2.75 and 1.18/1.18 cm2, respectively, versus a 'normative' mean (range) of 0.85 cm2 (0.2-1.6 cm2). Intranasal volumes differed (computed tomography/water fill): Koken, 35.8/38.6 cm3 and Optinose, 24.1/25.0 cm3, versus a 'normative' mean (range) of 26.4 cm3 (20.9-31.1 cm3). Conclusion: Koken cast dimensions are larger than the normal range and the Optinose cast. The validity of casts for regulatory drug deposition studies is suspect.

A Randomized Comparison of the Pharmacokinetics and Bioavailability of Fluticasone Propionate Delivered via Xhance Exhalation Delivery System Versus Flonase Nasal Spray and Flovent HFA Inhalational Aerosol.

PURPOSE: The exhalation delivery system with fluticasone propionate (Xhance®) has been shown to deliver drug substantially more broadly in the nasal cavity (particularly into superior/posterior regions), with less off-target loss of drug to drip-out and swallowing, than conventional nasal sprays. This open-label study evaluated the systemic bioavailability of Xhance® by comparing the pharmacokinetic (PK) properties of a single dose of fluticasone from 3 products administering the drug using 3 different devices: Xhance®, Flonase® (fluticasone propionate inhalational nasal spray), and Flovent® HFA (fluticasone propionate inhalational aerosol). METHODS: This open-label study was conducted in 2 parts. Study part 1 compared systemic exposure with a single dose of Xhance® 186 or 372 µg versus Flonase® 400 µg (3-way, 3-treatment, 3-sequence, randomized crossover in healthy subjects; n = 90). A separate study, part 2, under the same umbrella protocol, compared systemic exposure with Xhance® 372 µg versus Flovent® HFA 440 µg (2-way, 2-treatment, 2-sequence, randomized crossover in patients with mild to moderate asthma; n = 30). FINDINGS: With Xhance® 186 µg, the geometric least squares mean (LSM) Cmax was higher than with Flonase® 400 µg (16.02 vs 11.66 pg/mL, respectively; geometric mean ratio [GMR], 137.42%) and the geometric LSM AUC0-∞ values were similar (97.30 vs 99.61 pg · h/mL; GMR, 97.78%). With Xhance® 372 µg, the geometric LSM Cmax and AUC0-∞ were higher than with Flonase® 400 µg (Cmax, 23.50 vs 11.66 pg/mL [GMR, 201.53%]; AUC0-∞, 146.61 vs 99.61 pg · h/mL [GMR, 147.19%]). In part 2, the geometric LSM Cmax and AUC0-∞ values were lower with Xhance® 372 µg than with Flovent® HFA 440 µg (Cmax, 25.28 vs 40.02 pg/mL [GMR, 63.18%]; AUC0-∞, 205.78 vs 415.16 pg · h/mL [GMR, 49.57%]). IMPLICATIONS: Similar intranasal doses of Xhance® (372 µg) and Flonase® (400 µg) are clearly not bioequivalent. Systemic exposure is very low with all products. Systemic exposure is higher with Xhance® than with Flonase® and substantially lower than with Flovent® HFA 440 µg and, based on dose normalization, Flovent® HFA 220 µg. ClincalTrials.gov identifier: NCT02266927.

NAVIGATE I: Randomized, Placebo-Controlled, Double-Blind Trial of the Exhalation Delivery System With Fluticasone for Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Chronic rhinosinusitis is a common, high-morbidity chronic inflammatory disease, and patients often experience suboptimal outcomes with current medical treatment. The exhalation delivery system with fluticasone (EDS-FLU) may improve care by increasing superior/posterior intranasal corticosteroid deposition. OBJECTIVE: To evaluate the efficacy and safety of EDS-FLU versus EDS-placebo in patients with nasal polyps (NP). Coprimary end points were change in nasal congestion and polyp grade. Key secondary end points were Sino-Nasal Outcome Test-22 (SNOT-22) and Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R). Other prespecified end points included all 4 cardinal symptoms of NP, 36-Item Short Form Health Survey (SF-36), Patient Global Impression of Change (PGIC), Rhinosinusitis Disability Index (RSDI), and key indicators for surgical intervention. DESIGN: Randomized, double-blind, EDS-placebo-controlled, multicenter study. METHODS: Three hundred twenty-three subjects with NP and moderate-severe congestion/obstruction, most with history of corticosteroid use (94.4%) and/or prior surgery (60.4%), were randomized to EDS-FLU 93 µg, 186 µg, or 372 µg or EDS-placebo twice daily (BID) for 24 weeks (16 double-blind + 8 single-arm extension with EDS-FLU 372 µg BID). RESULTS: All EDS-FLU doses produced significant improvement in both coprimary end points ( P < .05) and in SNOT-22 total score ( P ≤ .005). EDS-FLU significantly improved all 4 cardinal symptoms of NP ( P < .05), including congestion/obstruction, facial pain/pressure, rhinorrhea/post-nasal drip, and hyposmia/anosmia. Approximately 80% of subjects reported improvement with EDS-FLU, with 65% reporting "much" or "very much" improvement by week 16. Adverse events were generally local in nature and similar to other intranasal steroids studied for similar durations in similar populations, with the most common being epistaxis. CONCLUSIONS: In patients with chronic rhinosinusitis with NP (CRSwNP) who were symptomatic despite high rates of prior intranasal steroid use and/or surgery, EDS-FLU produced statistically significant and clinically meaningful improvements compared to EDS-placebo in multiple subjective and objective outcomes (symptoms, SNOT-22, RSDI, SF-36, PGIC, and NP grade), including all 4 cardinal symptoms of CRSwNP.

Low-dose intranasal oxytocin delivered with Breath Powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study.

Little is known about how intranasally administered oxytocin reaches the brain and modulates social behavior and cognition. Pupil dilation is a sensitive index of attentional allocation and effort, and inter-individual variability in pupil diameter during performance of social-cognitive tasks may provide a better assessment of pharmacological effects on the brain than behavioral measures. Here, we leverage the close relationship between pupil and neural activity to inform our understanding of nose-to-brain oxytocin routes and possible dose-response relationships. To this end, we assessed pupil diameter data from a previously reported functional magnetic resonance imaging (fMRI) study under four treatment conditions-including two different doses of intranasal oxytocin using a novel Breath Powered nasal device, intravenous (IV) oxytocin, and placebo-and investigated the association with amygdala activation in response to emotional stimuli. The study used a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. A significant main effect of treatment condition on pupil diameter was observed. Posthoc tests revealed reduced pupil diameter after 8IU intranasal oxytocin compared to placebo, but no significant difference between 8IU intranasal oxytocin and either 24IU intranasal oxytocin or IV oxytocin treatment conditions. Analysis also showed a significant relationship between pupil diameter and right amygdala activation after 8IU intranasal oxytocin. Although there was no significant difference between 8IU intranasal oxytocin and IV oxytocin on right amygdala activity and pupil diameter, the significant difference between 8IU intranasal oxytocin and placebo is consistent with the hypothesis that oxytocin can travel to the brain via a nose-to-brain route.

Antipsychotics, glycemic disorders, and life-threatening diabetic events: a Bayesian data-mining analysis of the FDA adverse event reporting system (1968-2004).

BACKGROUND: This analysis compared diabetes-related adverse events associated with use of different antipsychotic agents. A disproportionality analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) was performed. METHODS: Data from the FDA postmarketing AERS database (1968 through first quarter 2004) were evaluated. Drugs studied included aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone. Fourteen Medical Dictionary for Regulatory Activities (MedDRA) Primary Terms (MPTs) were chosen to identify diabetes-related adverse events; 3 groupings into higher-level descriptive categories were also studied. Three methods of measuring drug-event associations were used: proportional reporting ratio, the empirical Bayes data-mining algorithm known as the Multi-Item Gamma Poisson Shrinker, and logistic regression (LR) analysis. Quantitative measures of association strength, with corresponding confidence intervals, between drugs and specified adverse events were computed and graphed. Some of the LR analyses were repeated separately for reports from patients under and over 45 years of age. Differences in association strength were declared statistically significant if the corresponding 90% confidence intervals did not overlap. RESULTS: Association with various glycemic events differed for different drugs. On average, the rankings of association strength agreed with the following ordering: low association, ziprasidone, aripiprazole, haloperidol, and risperidone; medium association, quetiapine; and strong association, clozapine and olanzapine. The median rank correlation between the above ordering and the 17 sets of LR coefficients (1 set for each glycemic event) was 93%. Many of the disproportionality measures were significantly different across drugs, and ratios of disproportionality factors of 5 or more were frequently observed. CONCLUSIONS: There are consistent and substantial differences between atypical antipsychotic drugs in the disproportionality reporting ratios relating to glycemic effects, especially life-threatening events, in the AERS database. The relative associational rankings of drugs are similar in reports from younger and older patients. These results agree with several other reports in the literature, do not support a "class effect" hypothesis, and provide a strong rationale for further studies to clarify the issue.

Risperidone for treatment-refractory major depressive disorder: a randomized trial.

BACKGROUND: Major depressive disorder has high prevalence, morbidity, and mortality. Inadequate results with antidepressants have prompts addition of a nonstandard treatment (augmentation therapy). OBJECTIVE: To assess whether augmentation therapy with risperidone reduces symptoms and increases response to antidepressant therapy and remission of depression in adults. DESIGN: Multicenter, double-blind, placebo-controlled, randomized trial conducted from 19 October 2004 to 17 November 2005. SETTING: 75 primary care and psychiatric centers. PATIENTS: 274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy. INTERVENTION: After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly assigned to receive risperidone, 1 mg/d, or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/d in some cases. MEASUREMENTS: Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various clinician- and patient-rated assessments. RESULTS: Of the intention-to-treat population (268 patients), 81% (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (+/-SE) HRSD-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 +/- 0.54 vs. 16.2 +/- 0.53; difference, -2.8 +/- 0.72 [95% CI, -4.2 to -1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events. LIMITATIONS: Patients were receiving many different antidepressants, and the duration of augmentation therapy was limited. CONCLUSION: Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures. ClinicalTrials.gov registration number: NCT00095134.