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Hisaka Igarashi,1 Mamoru Shibata,2 Akichika Ozeki,3 Kathleen Ann Day,4 Taka Matsumura3 1Department of Internal Medicine, Fujitsu Clinic, Kawasaki, Japan; 2Department of Neurology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan; 3Eli Lilly Japan K.K., Kobe, Japan; 4Eli Lilly and Company, Indianapolis, IN, USACorrespondence: Taka MatsumuraMedical Science, Medicines Development Unit Japan, Eli Lilly Japan K.K., 4-15-1 Akasaka, Akasaka Garden City 13F, Minato-ku, Tokyo, 107-0052, JapanTel +81 3 5574 9169Fax +81 3 5574 9979Email matsumura_taka@lilly.comPurpose: This study aimed to extensively evaluate the onset and maintenance effect of galcanezumab compared with placebo for the prevention of episodic migraine in Japanese patients.Patients and Methods: This was a post-hoc analysis of a Phase 2, multicenter, randomized, double-blind, placebo-controlled study conducted between December 2016 and January 2019 (ClinicalTrials.gov: NCT02959177). Patients aged between 18 and 65 years with episodic migraine were randomized to receive a monthly injection of galcanezumab (120 mg: N = 115, 240 mg: N = 114) or placebo (N = 230) for 6 months. Outcome measures included onset of effect at weekly and daily intervals—assessed by change from baseline in the number of migraine headache days and the proportion of patients with migraine headache—with galcanezumab versus placebo. To further confirm the onset and maintenance effect, the 50% response rate was also evaluated.Results: The mean change from baseline in weekly migraine headache days was significantly reduced with galcanezumab (– 0.97 days) compared with placebo (– 0.10 days) at week 1 (p ≤ 0.0001), which was maintained at all subsequent weeks up to week 4 (all p ≤ 0.0001 vs placebo). A significantly smaller proportion of galcanezumab-treated patients had migraine headache compared with placebo-treated patients at day 1 after the first injection (13.6% vs 31.4%, respectively; p ≤ 0.0001), which was also maintained at all subsequent days during the first week after the first injection. Furthermore, the 50% response rate was significantly higher with galcanezumab compared with placebo from week 1 through month 6.Conclusion: The onset of the migraine preventive effect of galcanezumab was rapid compared with placebo, starting from day 1 after the first injection in Japanese patients with episodic migraine. The effect was maintained during the first week and first month, and throughout 6 months of monthly injections of galcanezumab. Galcanezumab is a promising preventive treatment in Japanese patients with episodic migraine.Keywords: calcitonin gene-related peptide, galcanezumab, Japan, migraine disorders, onset of effect, maintenance effect

Objective: To evaluate onset of effect of galcanezumab in patients with episodic migraine. Background: Galcanezumab is a monoclonal antibody that binds to calcitonin gene‐related peptide and is indicated for preventive treatment of migraine. Design/Methods: Data on the primary outcome measure were analyzed from 2 previously published double‐blind, Phase 3 studies (EVOLVE‐1 [N = 858] and EVOLVE‐2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240‐mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ≥50% reduction from baseline in number of MHDs. Results: For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P <.001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab‐treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE‐1, 2.71 [2.00, 3.66], and for EVOLVE‐2, 2.88 [2.16, 3.86]; both P <.001) and each subsequent week compared with placebo‐treated patients (P ≤.004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ≥50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE‐1, 54.3% vs 32.4% [P <.001], and for EVOLVE‐2, 59.4% vs 38.0% [P <.001]). Conclusion: Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine. [ABSTRACT FROM AUTHOR]

Winter savory extract (WSE) is composed of volatile and non-volatile fractions (WSV and WSN, respectively). We have reported that winter savory volatiles such as WSV, carvacrol or thymol (primary and second components in WSV, respectively) contributed to changes in body surface temperature and core body temperature (BST and CBT, respectively) in humans. In this study, we examined WSN, whose effects on body temperature are unclear, and the mixture of WSN with winter savory volatiles, which likely have a different mechanism of action compared with WSN. WSN ingestion inhibited the decrease in wrist and finger BST, whereas mixtures increased the affected skin parts. Furthermore, the onset of effects at the periphery after mixture ingestion was faster than that after WSN ingestion. These results suggest that volatiles added to WSN greatly influence not only the balance of heat production and transfer, but also the rapid onset of effects at the periphery. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic obstructive pulmonary disease (COPD) patients are thought to have limited bronchodilator response, determined by changes in forced expiratory volume in 1s (FEV1). In this study, we assessed bronchodilator response in patients with COPD using not only FEV1 but also changes in lung volume expressed as forced vital capacity (FVC) and inspiratory capacity (IC). We also evaluated the speed of onset of bronchodilation. Methods: Data were from 2 randomized, double-blind, placebo-controlled studies (6-months [NCT00206154]; 12-months [NCT00206167]) in patients with moderate to very severe COPD. Treatments: twice daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9μg, budesonide/formoterol pMDI 160/9μg, formoterol dry powder inhaler (DPI) 9μg, placebo. Results: The percentage of patients with FEV1 improvement (≥12% and ≥200mL; American Thoracic Society [ATS] criterion) was 34–39% post-albuterol (screening). On day of randomization (DOR), a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min: FEV1 (57–59%). Similar results were seen for IC (50–61%) and FVC (57–67%) using the same improvement criteria. The time to ≥15% FEV1 improvement on DOR was 5.0, 4.8, and 7.3min for budesonide/formoterol 320/9, budesonide/formoterol 160/9, and formoterol, respectively. Time to ≥15% FEV1 improvement was better maintained with budesonide/formoterol than formoterol at treatment end (6 and 12 months). Conclusions: Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment. Budesonide/formoterol pMDI also has a rapid (within 5min) onset of bronchodilation that is maintained over time compared with formoterol alone. [ABSTRACT FROM AUTHOR]

Objective. Budesonide/formoterol inhalation aerosol (Symbicort® AstraZeneca, Wilmington, Delaware) is an inhaled corticosteroid (ICS) and long-acting β2-adrenergic agonist (LABA) combination administered twice daily via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) approved in the United States for the long-term maintenance treatment of persistent asthma in patients ≥12 years of age whose asthma cannot be controlled by an ICS alone. The objective was to review efficacy, safety, and pharmacogenetic data on budesonide/formoterol pMDI in the treatment of persistent asthma. Methods. The authors searched PubMed and respiratory meeting databases to identify asthma studies of budesonide/formoterol pMDI. Studies involving traditional and patient-reported outcomes, safety, tolerability, or pharmacogenetics were included. Results. In two 12-week pivotal trials in adolescents and adults, treatment with budesonide/formoterol pMDI 160/4.5 μg × 2 inhalations (320/9 μg) twice daily for moderate to severe persistent asthma or 80/4.5 μg × 2 inhalations (160/9 μg) twice daily for mild to moderate persistent asthma, demonstrated greater efficacy and similar tolerability compared with placebo and the same nominal dose of its monocomponents. Comparisons with formoterol dry powder inhaler (DPI) for predose forced expiratory volume in one second (FEV1) and with budesonide pMDI for 12-hour mean postdose FEV1 demonstrated the anti-inflammatory and bronchodilatory contributions of budesonide and formoterol, respectively. Evaluations of patient-reported outcomes, including asthma-specific quality of life and treatment satisfaction, further supported the clinical benefits of budesonide/formoterol pMDI. In a 52-week tolerability study of patients aged ≥12 years, budesonide/formoterol pMDI was delivered at up to double the maximum dose (640/18 μg twice daily) and demonstrated a safety profile similar to that of budesonide (640 μg twice daily), with no unexpected pattern of abnormalities. Additional studies reported that budesonide/formoterol pMDI 320/9 μg twice daily and fluticasone propionate/salmeterol DPI 250/50 μg twice daily have similar efficacy and tolerability, with significantly more patients achieving ≥15% improvement in FEV1 within 15 minutes with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI. Moreover, inheritance of the Gly16Arg polymorphism of the β2-adrenergic receptor does not appear to affect clinical outcomes with budesonide/formoterol pMDI. Conclusion. Budesonide/formoterol pMDI administered twice daily is effective and generally well tolerated in patients whose asthma is not well controlled on ICS alone. [ABSTRACT FROM AUTHOR]

Background. Feeling a maintenance therapy work right away may provide positive reinforcement and may offer one way to improve adherence in patients with asthma. Precise measurement is required to accurately compare the presence of this effect across clinical trial treatment groups. Methods. Two randomized, controlled studies tested whether timing of assessment (daily vs weekly, study 1; and predose vs postdose, study 2) influenced patients' reports of whether they can feel a medication working right away (perception), and their satisfaction with this perception (satisfaction). These 2-week US-based multicenter double-blind, parallel-group studies included patients ≥18 years of age with mild to moderate persistent asthma. In each, patients were randomized to one of two drugs with different onset profiles: budesonide/formoterol pressurized metered-dose inhaler (pMDI) 80/4.5 μg × 2 inhalations (160/9 μg) twice daily or budesonide pMDI 80 μg × 2 inhalations (160 μg) twice daily. Patients were further randomized to complete previously validated perception and satisfaction questions in a cross-over fashion, either daily and weekly ( N = 123) or predose and postdose ( N = 134). Patient surveys also assessed perceptions of the onset of effect of medication and their value of these perceptions. Results. No significant differences were observed in patients' reports of perception, either daily versus weekly or predose versus postdose. A statistically significant difference in satisfaction was found in study 1 only, favoring weekly recall ( p < 0.05), with sensitivity analysis showing no difference by treatment group ( p = 0.162). Across both studies, most patients (87%) who perceived their inhaler working right away (136 of 157 patients) identified positive airway sensations. Most patients reported that feeling their medication work right away is reassuring and would help them manage their asthma. Conclusion. Assessment timing has no effect on patient response to the perception of feeling a medication working right away. Differences found in satisfaction levels reported with weekly versus daily recall were consistent across treatment groups, indicating that no bias was introduced in favor of either treatment group. Patients characterized the perception of feeling a maintenance therapy working right away as easier breathing and reported this perception as beneficial to patient self-care. [ABSTRACT FROM AUTHOR]

The Onset-of-Effect Questionnaire (OEQ) is a self-administered instrument used to assess patient perception of how quickly asthma maintenance medications begin to work. This study was designed to quantify the relative importance that patients using combination inhaled corticosteroid and long-acting beta2-agonist (ICS/LABA) maintenance medication place on the onset-of-effect outcomes. Patients aged ≥18 years with a self-reported diagnosis of asthma, currently using combination ICS/LABA maintenance medication, completed an Internet-based SC conjoint survey instrument that included 10 choice trade-off tasks. In four choice tasks, patients were asked to choose between two hypothetical medications. In six choice tasks, patients were asked to choose among two hypothetical medications and their current medication. Each choice alternative was defined by response levels of the five OEQ statements and out-of-pocket cost. We used random-parameters logit methods to estimate the relative importance of outcomes assessed by the OEQ. Five hundred nine patients completed the study. Satisfied was the most important OEQ outcome and physical sensations were the least important. When offered a choice, 80% (95% CI, 75-85%) of patients preferred a maintenance medication for which they are satisfied with how quickly they feel it begins to work and 62% (95% CI: 57-67%) of patients preferred a maintenance medication that they feel begins to work right away. Combination maintenance medications with rapid onset of effect, especially those that impact a patients' ability to feel the medication work right away and patient satisfaction with how quickly the medication works, may increase the use of and adherence to maintenance medications. [ABSTRACT FROM AUTHOR]

Background and objectives: Data on the onset of action of COPD medications are lacking. This study compared the onset of bronchodilation following different inhaled therapies in patients with moderate-to-severe COPD and reversible airway obstruction. Methods: In this double-blind, double-dummy, crossover study, 90 patients (aged ≥40 years; FEV1 30–70% predicted) were randomized to a single dose (two inhalations) of budesonide/formoterol 160/4.5 μg, salmeterol/fluticasone 25/250 μg, salbutamol 100 μg or placebo (via pressurized metered-dose inhalers) on four visits. The primary end-point was change in FEV1 5 min after drug inhalation; secondary end-points included inspiratory capacity (IC) and perception of onset of effect. Results: Budesonide/formoterol significantly improved FEV1 at 5 min compared with placebo ( P < 0.0001) and salmeterol/fluticasone ( P = 0.0001). Significant differences were first observed at 3 min. Onset of effect was similar with budesonide/formoterol and salbutamol. Improvements in FEV1 following active treatments were superior to placebo after 180 min (all P < 0.0001); both combinations were better than salbutamol at maintaining FEV1 improvements ( P ≤ 0.0001) at 180 min. Active treatments improved IC at 15 and 185 min compared with placebo ( P < 0.0001). Maximal IC was greater with budesonide/formoterol than salmeterol/fluticasone ( P = 0.0184) at 65 min. Patients reported a positive response to the perceptions of the onset of effect question shortly after receiving active treatments (median time to onset 5 min for active treatments vs 20 min for placebo), with no significant difference between active treatments. Conclusion: Budesonide/formoterol has an onset of bronchodilatory effect in patients with COPD and reversible airway obstruction that is faster than salmeterol/fluticasone and similar to salbutamol. [ABSTRACT FROM AUTHOR]

The onset of effect of acrivastine, a new H-antagonist, has been assessed using antagonism of histamine-induced bronchoconstriction in sensitive volunteers. Acrivastine administered 30, 45, 60 or 90 min before challenge produced a right-shift of the histamine dose-response curve of at least 8-fold indicating that a clinically desired degree of H-antagonism was present within 30 min of ingestion of the recommended therapeutic dose. [ABSTRACT FROM AUTHOR]

In the United States, budesonide/formoterol pressurized metered-dose inhaler (pMDI) is approved for treatment of asthma in patients aged ≥12 years whose asthma is not adequately controlled with an inhaled corticosteroid (ICS) or whose disease severity clearly warrants treatment with an ICS and a long-acting β(2)-adrenergic agonist. This article reviews studies of budesonide/formoterol pMDI in patients with persistent asthma, with a particular focus on patient-reported outcomes (eg, perceived onset of effect, patient satisfaction with treatment, health-related quality of life [HRQL], global assessments, sleep quality and quantity), as these measures reflect patient perceptions of asthma control and disease burden. A search of PubMed and respiratory meetings was performed to identify relevant studies. In two pivotal budesonide/formoterol pMDI studies in adolescents and adults, greater efficacy and similar tolerability were shown with budesonide/formoterol pMDI 160/9 μg and 320/9 μg twice daily versus its monocomponents or placebo. In those studies, improvements in HRQL, patient satisfaction, global assessments of asthma control, and quality of sleep also favored budesonide/formoterol pMDI compared with one or both of its monocomponents or placebo. Budesonide/formoterol pMDI has a rapid onset of effect (within 15 minutes) that patients can feel, an attribute that may have benefits for treatment adherence. In summary, budesonide/formoterol pMDI is effective and well tolerated and has additional therapeutic benefits that may be important from the patient's perspective.

Symptom control in patients with moderate to severe persistent asthma is essential to reduce the significant morbidity associated with the disease. Poor adherence to controller medications has been identified as a major contributing factor to the high level of uncontrolled asthma. This review examines patient perspectives on, and preferences for, controller medications (inhaled corticosteroid and long-acting β(2)-agonist combinations [ICS/LABA]), and how this may affect adherence to therapy. Fluticasone/salmeterol and budesonide/formoterol, the currently available ICS/LABA combination products, have similar efficacy and tolerability based on a recent meta-analysis of asthma trials. Adherence is higher with the combination ICS/LABAs than when the components are administered separately. Investigations into patient preferences for desirable attributes of asthma medications indicate that an effective reliever with a fast onset and long duration of action is preferred and may lead to improved adherence. This rapid onset of effect was perceived and highly valued in patient surveys, and was associated with greater patient satisfaction. Thus, future research should be directed at therapy that offers both anti-inflammatory activity and a rapid onset of bronchodilator effect. To further improve patient adherence and treatment outcome, the effect of these characteristics as well as other factors on adherence should also be investigated.