Inhaled beclomethasone in the treatment of early COVID-19: a double-blind, placebo-controlled, randomised, hospital-based trial in Sri Lanka.

OBJECTIVES: To study if early initiation of inhaled beclomethasone 1200 mcg in patients with asymptomatic, mild or moderate COVID-19 reduces disease progression to severe COVID-19. DESIGN: Double-blinded, parallel-groups, randomised, placebo-controlled trial. SETTING: A hospital-based study in Sri Lanka. PARTICIPANTS: Adults with asymptomatic, mild or moderate COVID-19, presenting within the first 7 days of symptom onset or laboratory diagnosis of COVID-19, admitted to a COVID-19 intermediate treatment centre in Sri Lanka between July and November 2021. INTERVENTIONS: All participants received inhaled beclomethasone 600 mcg or placebo two times per day, for 10 days from onset of symptoms/COVID-19 test becoming positive if asymptomatic or until reaching primary endpoint, whichever is earlier. PRIMARY OUTCOME MEASURE: Progression of asymptomatic, mild or moderate COVID-19 to severe COVID-19. SECONDARY OUTCOME MEASURES: The number of days with a temperature of 38°C or more and the time to self-reported clinical recovery. RESULTS: A total of 385 participants were randomised to receive beclomethasone(n=193) or placebo(n=192) stratified by age (≤60 or >60 years) and sex. One participant from each arm withdrew from the study. All participants were included in final analysis. Primary outcome occurred in 24 participants in the beclomethasone group and 26 participants in the placebo group (RR 0.90 ; p=0.763). The median time for self-reported clinical recovery in all participants was 5 days (95% CI 3 to 7) in the beclomethasone group and 5 days (95% CI 3 to 8) in the placebo group (p=0.5). The median time for self-reported clinical recovery in patients with moderate COVID-19 was 5 days (95% CI 3 to 7) in the beclomethasone group and 6 days (95% CI 4 to 9) in the placebo group (p=0.05). There were no adverse events. CONCLUSIONS: Early initiation of inhaled beclomethasone in patients with asymptomatic, mild or moderate COVID-19 did not reduce disease progression to severe COVID-19. TRIAL REGISTRATION NUMBER: Sri Lanka Clinical Trials Registry; SLCTR/2021/017.

Can single-inhaler Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium therapy postpone or save biologics for severe asthma?

Inhaled corticosteroids, along with beta2-agonists and anti-muscarinics, represent the cornerstone of asthma treatment. Although the advent of monoclonal antibodies has dramatically changed severe asthma management, there are still patients ineligible or with poor response to biologics. Moreover, high costs associated with monoclonal antibodies prescription are still an open issue, leading clinicians to carefully assess cost-benefit ratio before their administration. From this perspective, the use of single-inhaler Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium in patients with severe asthma could not only improve their clinical and functional performance, but also postpone biologic prescription, with positive repercussions on healthcare costs.

The rising cost of rhinologic medications.

BACKGROUND: The high prescription drug cost in the United States may negatively affect patient prognosis and treatment compliance. OBJECTIVE: To fill the knowledge gap and inform clinicians regarding rhinology medications price changes by evaluating trends in price changes of highly used nasal sprays and allergy medications. METHODS: The 2014-2020 Medicaid National Average Drug Acquisition Cost database was queried for drug pricing information for the following classes of medications: intranasal corticosteroids, oral antihistamines, antileukotrienes, intranasal antihistamines, and intranasal anticholinergics. Individual medications were identified by Food and Drug Administration-assigned National Drug Codes. Per unit, drug prices were analyzed for average annual prices, average annual percentage price changes, and inflation-adjusted annual and composite percentage price changes. RESULTS: Beclometasone (Beconase AQ, 56.7%, QNASL, 77.5%), flunisolide (Nasalide, -14.6%), budesonide (Rhinocort Aqua, -1.2%), fluticasone (Flonase, -6.8%, Xhance, 11.7%), mometasone (Nasonex, 38.2%), ciclesonide (Omnaris, 73.8%), combination azelastine and fluticasone (Dymista, 27.3%), loratadine (Claritin, -20.5%), montelukast (Singulair, 14.5%), azelastine (Astepro, 21.9%), olopatadine (Patanase, 27.3%), and ipratropium bromide (Atrovent, 56.6%) had an overall change in inflation-adjusted per unit cost between 2014 and 2020 (% change). Of 14 drugs evaluated, 10 had an increase in inflation-adjusted prices, for an average increase of 42.06% ± 22.27%; 4 of 14 drugs had a decrease in inflation-adjusted prices, for an average decrease of 10.78% ± 7.36%. CONCLUSION: The rising cost of highly used medications contributes to increased patient acquisition costs and may pose barriers of drug adherence to particularly vulnerable populations.

Beclometasone inhaler-induced recovery of refractory peri-ileostomy skin complications.

Peristomal skin complications (PSCs) are relatively common in ostomy patients, particularly in those with ileostomies. Non-healing irritation presents a clinical challenge and leads to pain and impaired quality of life for patients. METHODS: The cases of four ileostomy patients experiencing severe, challenging PSCs refractory to appliance changes, conventional dressings and barrier creams are discussed. FINDINGS: The cases of one male and one female patient with an end ileostomy post-subtotal colectomy for ulcerative colitis, one female with a defunctioning ileostomy post-anterior resection for sigmoid carcinoma and one male with an end ileostomy with a complex Crohn's surgical history are described. Two puffs of a 250 mcg metered dose beclometasone inhaler were applied to the affected skin once or twice daily. Treatment ranged from 6 to 21 days. Complete resolution was seen in all cases. CONCLUSION: Topical use of a beclometasone inhaler was effective for severe peri-ileostomy PSC secondary to four different aetiologies. Further studies are warranted to determine the effectiveness of this treatment in a larger patient cohort.

Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use.

Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were evaluated due to the increasing use of inhaled cannabis both recreationally and medically. The mechanism of DDI was conducted in an in vitro time-dependent inhibition assay, and further interpreted utilizing a proposed model. In HLuS9, BDP was efficiently metabolized almost completely to 17-BMP, which was then converted to BOH at a much lower rate. CES1 was found as a minor contributor accounting for only 1.4% of BDP metabolism in HLuS9, while arylacetamide deacetylase might be the main enzyme involved. Both THC and CBD inhibited the HLuS9 mediated BDP hydrolysis in a reversible manner, with reported IC50 values estimated as 8.98 and 36.8 µM, respectively. Our proposed model suggested a moderately decreased 17-BMP exposure in lung by concomitant THC from a cannabis cigarette, while the effects from orally administered CBD was expected to be of no clinical relevance.

Assessment of extrafine beclomethasone/formoterol for the treatment of chronic obstructive pulmonary disease: A non-interventional study in a Bulgarian population.

BACKGROUND: The beneficial effects of application of a fixed dose beclomethasone dipropionate (BDP) and formoterol fumarate (F) for the treatment of severe chronic obstructive disease (COPD) has been amply proven in well controlled clinical trials. Whether this also holds for real-world conditions and in such a heterogeneous patient population as is encountered in Bulgaria remained to be investigated. METHODS: In an observational, non-interventional study, 441 Bulgarian patients with severe COPD who were enrolled at 36 sites across the country received extrafine BDP/FF-combination therapy using the NEXThaler® DPI or the Foster® pMDI over a period of 16 weeks. At visits at the beginning, after 4 weeks and at the end of the study, alterations in lung function parameters FEV1 and FVC, disease symptoms, changes in CAT score, and patient distribution in GOLD 2017 categories A through D were assessed. RESULTS: A large share of the Bulgarian patients with severe COPD suffered from serious comorbidities, received additional medication, and about 2/3 were former or current smokers. Extrafine BDP/FF caused an increase in mean FEV1, FVC, a decrease of health impact as assessed by the CAT score, and a considerable shift of the share of category C and D patients towards A and B. In addition, the percentage of patients that were free of symptoms impacting everyday life such as fatigue and shortness of breath at rest increased throughout the study. A comparison of both application devices indicated that the NEXThaler® was superior in terms of lung functional aspects, as these parameters displayed a constant improvement over the observation period, whereas they plateaued at week 4 when using the pMDI. CONCLUSIONS: The therapeutic benefits of extrafine BDP/FF known from clinical trials could also be observed in a real-world setting, even in such a heterogenous patient population as the Bulgarian. The NEXThaler® appeared to be highly efficient in this setting, opening a new choice for the lung specialist and the patient to select the one device considered most suitable and practical.

Characterisation of patients with chronic obstructive pulmonary disease initiating single-device inhaled corticosteroids/long-acting ß2-agonist dual therapy in a primary care setting in England.

INTRODUCTION: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-device dual therapies in England remain unclear. This study describes the characteristics of patients with COPD before initiating treatment with a single-device inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) in primary care in England. METHODS: This is a retrospective, descriptive study of linked primary and secondary healthcare data (Clinical Practice Research Datalink Aurum, Hospital Episode Statistics). Patients with COPD were indexed on first prescription of fixed-dose, single-device ICS/LABA (June 2015-December 2018). Demographics, clinical characteristics, prescribed treatments, healthcare resource use (HCRU) and direct healthcare costs were assessed over 12 months pre-index. Incident users (indexed on first ever prescription) could be non-triple users (no concomitant long-acting muscarinic antagonist at index); a subset were initial maintenance therapy (IMT) users (no history of pre-index maintenance therapy). RESULTS: Overall, 13 451 incident users (non-triple users: 7448, 55.4%; IMT users: 5162, 38.4%) were indexed on beclomethasone dipropionate/formoterol (6122, 45.5%), budesonide/formoterol (2703, 20.1%) or Other ICS/LABA combinations (4626, 34.4%). Overall, 20.8% of incident users had comorbid asthma and 42.6% had ≥1 moderate-to-severe acute exacerbation of COPD pre-index. Baseline characteristics were similar across indexed therapies. At 3 months pre-index, 45.3% and 35.4% of non-triple and IMT users were receiving maintenance treatment. HCRU and direct healthcare costs were similar across indexed treatments. Prescribing patterns varied regionally. CONCLUSION: Patient characteristics, prior treatments, prior COPD-related HCRU and direct healthcare costs were similar across single-device ICS/LABAs in primary care in England. A high proportion of patients were not receiving any respiratory medication pre-index, indicating that prescribing in primary care in England is more closely aligned with national guidelines than global treatment strategies. Comorbid asthma may have influenced prescribing decisions. Less than half of users had preindex exacerbations, suggesting that ICS/LABA is not being prescribed principally based on exacerbation history.

Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis.

INTRODUCTION: Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. METHODS: We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. RESULTS: Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. CONCLUSIONS: Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Eficacia y seguridad del calcipotriol y el dipropionato de betametasona en pacientes adultos con psoriasis vulgar en placas moderada o severa, no respondedores a la terapia tópica y sistémica convencional, y no tributarios a terapia biológica / Efficacy and safety of calcipotriol and betamethasone dipropionate in adult patients with moderate or severe plaque psoriasis vulgaris, unresponsive to conventional topical and systemic therapy, and not amenable to biological therapy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen que expone la evaluación de la eficacia y seguridad del calcipotriol y dipropionato de betametasona (DB) en pacientes adultos con psoriasis vulgar en placas moderada o severa, no respondedores a la terapia tópica y sistémica convencional, y no tributarios a terapia biológica. Así, la médico dermatóloga, Dra. Lorraine Lía Málaga Medina del Servicio de Dermatología del Hospital Nacional Carlos Seguin Escobedo, siguiendo la Directiva N.° 003-IETSI-ESSALUD-2016, envió al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de uso por fuera del petitorio farmacológico de EsSalud el producto farmacéutico calcipotriol en combinación con el (DB), para el tratamiento de los pacientes adultos con psoriasis vulgar en placas moderada o severa, no respondedores a la terapia tópica y sistémica convencional, y no tributarios a terapia biológica. ASPECTOS GENERALES: La psoriasis vulgar en placas es una enfermedad crónica de la piel que se presenta como placas eritematosas y escamosas que aparecen, mayoritariamente, en el cuero cabelludo, el tronco, los glúteos, y los miembros inferiores y superiores (de Rie et al., 2004). Esta enfermedad es considerada como un problema de salud pública por su alta prevalencia, alto riesgo de morbilidad y porque deteriora la calidad de vida y salud mental en los pacientes que la padecen (Boehncke & Schón, 2015). La psoriasis afecta del 1 % al 3 % de la población mundial; y la psoriasis vulgar en placas representa hasta el 90 % de todas las manifestaciones de la psoriasis (Augustin et al., 2010). Además, la presencia de esta enfermedad se asocia a mayor riesgo de sufrir artritis psoriásica, enfermedades cardiovasculares, diabetes mellitus, obesidad, enfermedad del hígado graso no alcohólico y enfermedades inflamatorias del intestino (Gisondi et al., 2020). Asimismo, el 75 % de estos pacientes percibe un deterioro en su calidad de vida y cerca del 10 % ha tenido ideación suicida (Bhosle et al., 2006). METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad del CAL-DB, en comparación con mejor terapia de soporte, en pacientes adultos con psoriasis vulgar en placas moderada o severa no respondedores a la terapia tópica y sistémica convencional y no tributarios a terapia biológica. La búsqueda se realizó en las bases de datos bibliográfica de PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo el National Institute for Health and Care Excellence (NICE), la Agency for Healthcare Research and Quality's (AHRQ), la Scottish I ntercollegiate Guidelines Network (SIGN), la New Zealand Guidelines Group (NZGG), la National Health and Medical Research Council (NHMRC), el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Institute for Quality and Efficiency in Health Care (IQWIG), el Scottish Medicines Consortium (SMC), la Comissáo Nacional de I ncorpornáo de Tecnologías no Sistema Único de Saúde (CONITEC), el Instituto de Evaluación Tecnológica en Salud (IETS) y el Instituto de Efectividad Clínica y Sanitaria (IECS). Finalmente, se realizó una búsqueda adicional en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o aún no publicados. RESULTADOS: Tras ampliar los criterios de selección de documentos, se incluyó una GPC publicada por el NICE (2012) que realiza recomendaciones sobre la evaluación y el tratamiento de pacientes con psoriasis vulgar de severidad moderada o severa. Además, se incluyeron dos ETS publicadas por la CONITEC (2012), y la HAS (2019) que tuvieron como objetivo evaluar la evidencia disponible acerca de la eficacia y seguridad del uso del Cal-DB en pacientes adultos con psoriasis vulgar en placas e incluyeron, en su cuerpo de evidencia, ECA donde participaron pacientes con psoriasis vulgar de severidad moderada a severa. También, se incluyó el estudio pivotal citado en la ficha técnica del Daivobet ® aprobada por DIGEMID (2018), el cual es un ECA de fase II que comparó la eficacia y seguridad del uso del CAL-DB versus el calcipotriol en monoterapia, el DB en monoterapia y placebo, en pacientes con psoriasis vulgar de cualquier severidad de enfermedad (Fleming et al., 2010). Por último, se incluyó un estudio observacional que comparó el uso de la fototerapia y el CAL-DB en pacientes con severidad de enfermedad de moderada a severa (Polanska et al., 2019). ONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso combinado del calcipotriol y el dipropionato de betametasona en pacientes adultos con psoriasis vulgar moderada o severa, no respondedores a la terapia tópica y sistémica convencional y no tributarios a terapia biológica, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud.

Can the response to a single dose of beclomethasone dipropionate predict the outcome of long-term treatment in childhood exercise-induced bronchoconstriction?

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a frequent and highly specific symptom of childhood asthma. Inhaled corticosteroids (ICS) are the mainstay of controller therapy for EIB and asthma; however, a proportion of asthmatic children and adolescents is less responsive to ICS. We hypothesized that a single dose response to ICS could function as a predictor for individual long-term efficacy of ICS. OBJECTIVE: To assess the predictive value of the bronchoprotective effect of a single-dose beclomethasone dipropionate (BDP) against EIB for the bronchoprotective effect of 4 weeks of treatment, using an exercise challenge test (ECT). METHODS: Thirty-two steroid-naïve children and adolescents aged 6 to 18 years with EIB were included in this prospective cohort study. They performed an ECT at baseline, after a single-dose BDP (200µg) and after 4 weeks of BDP treatment (100 µg twice daily) to assess EIB severity. RESULTS: The response to a single-dose BDP on exercise-induced fall in FEV1 showed a significant correlation with the response on exercise-induced fall in FEV1 after 4 weeks of BDP treatment (r = .38, p = .004). A reduction in post-exercise fall in FEV1 of more than 8% after a single-dose BDP could predict BDP efficacy against EIB after 4 weeks of treatment with a positive predictive value of 100% (CI: 86.1-100%) and a negative predictive value of 29.4% (CI: 11.7%-53.7%). CONCLUSION: We found that the individual response to a single-dose BDP against EIB has a predictive value for the efficacy of long-term treatment with BDP. This could support clinicians in providing personalized management of EIB in childhood asthma.

Successful treatment of intractable gastrointestinal tract graft-vs-host disease with oral beclomethasone dipropionate in pediatric and young adult patients: Case reports.

RATIONALE: The gastrointestinal (GI) tract is a common target organ of graft-vs-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT) patients, and GI tract GVHD is often resistant to standard treatments such as corticosteroids. Moreover, longterm use of systemic corticosteroids sometimes induces adverse events such as infection. Beclomethasone dipropionate (BDP) is a potent, topically active corticosteroid, which is metabolized to an active derivative in the intestinal mucosa. Oral BDP therapy is reportedly effective against GI tract GVHD in adult HSCT patients, but its efficacy and safety in pediatric patients remain undefined. Here, we report three pediatric and young adult cases who were treated with oral BDP. PATIENT CONCERNS: Three (6-, 7-, and 18-year-old) patients developed stage 2 to 4 lower GI tract GVHD, which was resistant to standard immunosuppressive therapies. DIAGNOSIS: Lower GI tract GVHD in these patients was histopathologically proven by endoscopic biopsy. INTERVENTIONS: Oral administration of enteric-coated capsules of BDP (3-8 mg/day) was started for the treatment of lower GI tract GVHD. OUTCOMES: With the introduction of oral BDP therapy, their GI tract symptoms promptly resolved (abdominal pain, within 3-7 days; diarrhea, within 2-3 weeks). Subsequently, systemic immunosuppressive agents such as corticosteroids and mycophenolate mofetil were successfully tapered off. During oral BDP therapy, although cytomegalovirus antigenemia and Acinetobacter Iwoffii sepsis developed in 2 cases, both were curable with conventional treatments. In a young adult case, concomitant BK virus-associated hemorrhagic cystitis resolved after oral BDP was introduced and systemic immunosuppressive agents were reduced. Transient growth restriction was observed in a pediatric case who was treated with oral BDP for approximately 300days. LESSONS: Our experiences suggest that oral BDP therapy is an effective approach for GI tract GVHD that is resistant to standard immunosuppressive therapies. Of clinical importance, our case suggests the possibility that oral BDP therapy may improve the immunosuppressive condition in GI tract GVHD patients by contributing to the reduction of systemic immunosuppressive medications as a result of prompt improvement of GI tract GVHD symptoms.

Impact of body mass index on omalizumab response in adults with moderate-to-severe allergic asthma.

BACKGROUND: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI). OBJECTIVE: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category. METHODS: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m2 [normal or underweight], n = 397; 25 to <30 kg/m2 [overweight], n = 330; ≥ 30 kg/m2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance. RESULTS: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39]). CONCLUSION: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI. TRIAL REGISTRATION: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available.

Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma.

BACKGROUND: Black and Latinx patients bear a disproportionate burden of asthma. Efforts to reduce the disproportionate morbidity have been mostly unsuccessful, and guideline recommendations have not been based on studies in these populations. METHODS: In this pragmatic, open-label trial, we randomly assigned Black and Latinx adults with moderate-to-severe asthma to use a patient-activated, reliever-triggered inhaled glucocorticoid strategy (beclomethasone dipropionate, 80 µg) plus usual care (intervention) or to continue usual care. Participants had one instructional visit followed by 15 monthly questionnaires. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included monthly asthma control as measured with the Asthma Control Test (ACT; range, 5 [poor] to 25 [complete control]), quality of life as measured with the Asthma Symptom Utility Index (ASUI; range, 0 to 1, with lower scores indicating greater impairment), and participant-reported missed days of work, school, or usual activities. Safety was also assessed. RESULTS: Of 1201 adults (603 Black and 598 Latinx), 600 were assigned to the intervention group and 601 to the usual-care group. The annualized rate of severe asthma exacerbations was 0.69 (95% confidence interval [CI], 0.61 to 0.78) in the intervention group and 0.82 (95% CI, 0.73 to 0.92) in the usual-care group (hazard ratio, 0.85; 95% CI, 0.72 to 0.999; P = 0.048). ACT scores increased by 3.4 points (95% CI, 3.1 to 3.6) in the intervention group and by 2.5 points (95% CI, 2.3 to 2.8) in the usual-care group (difference, 0.9; 95% CI, 0.5 to 1.2); ASUI scores increased by 0.12 points (95% CI, 0.11 to 0.13) and 0.08 points (95% CI, 0.07 to 0.09), respectively (difference, 0.04; 95% CI, 0.02 to 0.05). The annualized rate of missed days was 13.4 in the intervention group and 16.8 in the usual-care group (rate ratio, 0.80; 95% CI, 0.67 to 0.95). Serious adverse events occurred in 12.2% of the participants, with an even distribution between the groups. CONCLUSIONS: Among Black and Latinx adults with moderate-to-severe asthma, provision of an inhaled glucocorticoid and one-time instruction on its use, added to usual care, led to a lower rate of severe asthma exacerbations. (Funded by the Patient-Centered Outcomes Research Institute and others; PREPARE ClinicalTrials.gov number, NCT02995733.).

Systemic corticosteroids could be used as bridge treatment in children with obstructive sleep apnea syndrome waiting for surgery.

PURPOSE: Local and systemic inflammatory markers and pro-inflammatory cytokines are increased in children with obstructive sleep apnea syndrome (OSAS). Therefore, systemic or topical anti-inflammatory agents are used to treat this syndrome. We evaluated the treatment with systemic corticosteroids in children with severe OSAS and adenotonsillar hypertrophy before surgery. METHODS: This was an unblinded open label study. Children with severe OSAS (diagnosed through polysomnography, obstructive apnea-hypopnea index [AHI] > 10 eV/h) were recruited. Exclusion criteria included age < 3 years, history of acute or chronic cardiorespiratory or neuromuscular or metabolic disease; major craniofacial abnormalities; and chromosomal syndromes and epilepsy. Computer-generated random numbers were used for simple randomization of subjects. All children were treated with intranasal beclomethasone spray, and 15 children additionally received oral betamethasone and 0.1 mg/kg per day for 7 days. Sleep clinical record (SCR) and pulsoximetry were performed before and after 7 days in all children. RESULTS: Among 28 children with severe OSAS mean age was 4.5 ± 1.8 years, AHI 20.4 ± 1.8 eV/h). In children treated with intranasal and oral corticosteroids, mean (95.3 ± 1.1 vs 97.0 ± 0.8%, p = 0.0001) and minimum oxygen saturation (78.8 ± 6.3 vs 89.2 ± 4.2, p = 0.001) improved, and the SCR score (12.6 ± 1.2 vs 8.3 ± 1.1, p = 0.0001) was reduced. Children treated only with intranasal beclomethasone spray showed no differences in outcome measures before and after treatments. When we considered the oximetry measures, after corticosteroid treatment, we obtained statistical differences between the 2 groups (p < 0.01). CONCLUSIONS: These results seem to suggest that a short course of oral betamethasone could be useful to treat children with severe OSAS and adenotonsillar hypertrophy waiting for surgery.

Eficácia e segurança de tripla terapia broncodilatadora comparada à dupla terapia em DPOC grave: revisão rápida de evidências / Effectiveness and safety of triple bronchodilator therapy compared to dual therapy in severe COPD: rapid response review of evidence

Tecnologia: Tripla terapia broncodilatadora (vilanterol/ umeclidínio/ fluticasona, formoterol/ glicopirrônio/ beclometasona) e dupla terapia. Indicação: Tratamento de doença pulmonar obstrutiva crônica (DPOC), formas grave e muito grave. Pergunta: Há diferenças de efeito nos principais desfechos de eficácia e segurança entre a tripla terapia broncodilatadora e as duplas terapias no tratamento de pacientes com DPOC, formas grave e muito grave? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foram selecionadas e incluídas 2 revisões sistemáticas. Conclusão: A tripla terapia broncodilatadora era mais eficaz que a dupla terapia para reduzir a taxa anual de exacerbações moderadas a severas, mas não tinha superioridade para obter ganhos clínicos em outros desfechos (volume expiratório forçado no primeiro segundo, qualidade de vida, índice de dispneia, mortalidade geral, mortalidade respiratória), exceto que a tripla terapia era superior à dupla terapia com agonistas beta-2/ antagonistas antimuscarínicos e similar à dupla terapia com agonistas beta-2/ corticoesteróides inalatórios para reduzir mortalidade. A tripla terapia tinha perfil de segurança similar à dupla terapia, com mesmo risco para eventos adversos e eventos adversos graves. A tripla terapia tinha maior risco para pneumonias que a dupla terapia com agonistas beta-2/ antagonistas antimuscarínicos

Technology: Triple bronchodilator therapy (vilanterol/ umeclidinium/ fluticasone, formoterol/ glycopyrronium/ beclomethasone) and dual therapy. Indication: Treatment of chronic obstructive pulmonary disease (COPD), severe and very severe forms. Question: Are there differences in effects of efficacy and safety outcomes between triple bronchodilator therapy and dual therapies in treating patients with severe and very severe forms of COPD? Methods: Rapid review of evidence (overview) from systematic reviews, with a bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (Methodological Quality Assessment of Systematic Reviews). Results: Two systematic reviews were selected and included. Conclusion: Triple bronchodilator therapy was more effective than dual therapy in reducing the annual rate of moderate to severe exacerbations, but had no superiority for clinical gains in other outcomes (forced expiratory volume in first second, quality of life, dyspnea index, general mortality, respiratory mortality), except that, for reducing mortality, triple therapy was superior to dual therapy with beta-2 agonists/ antimuscarinic antimuscarinics and similar to dual therapy with beta 2 agonists/ inhaled corticosteroids. The triple therapy had a similar safety profile to dual therapy, with the same risk for adverse events and serious adverse events. The triple therapy had a higher risk for pneumonia than a dual therapy with beta-2 agonists/ antimuscarinic antagonists

Ethnic Sensitivity Study of the Extrafine, Single-Inhaler, Triple Therapy Beclomethasone Dipropionate, Formoterol Fumarate, and Glycopyrronium Bromide Pressurized Metered Dose Inhaler in Japanese and Caucasian Healthy Individuals: A Randomized, Double-Blind, Single-Dose Crossover Study.

PURPOSE: A number of single-inhaler, fixed-dose, triple combinations are available for the management of chronic obstructive pulmonary disease and/or asthma. One of these is the extrafine formulation beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB). Given that differences in ethnicity can result in differences in systemic exposure, we evaluated the relative pharmacokinetic (PK) profiles of BDP/FF/GB in Japanese vs Caucasian healthy volunteers to assess the need for dose adjustment. METHODS: This randomized, double-blind, single-dose, 4-way crossover study recruited healthy men and women 20 to 55 years of age; for each Japanese person a Caucasian was enrolled who matched in terms of sex, age, and weight. Study treatments included BDP/FF/GB 200/12/25 and 400/12/25 µg (therapeutic), 800/48/100 µg (supratherapeutic), and placebo. PK blood samples were taken up to 24 hours for evaluation of BDP, beclomethasone 17-monopropionate (B17MP, an active metabolite of BDP), and formoterol and up to 48 h for GB. The primary objective was to characterize the PK profiles of BDP, FF, and GB after administration of a single dose of BDP/FF/GB in Caucasian and Japanese healthy volunteers in terms of the AUC0-t and Cmax of B17MP, formoterol, and GB. FINDINGS: Of the 32 recruited participants (16 Japanese and 16 Caucasian ), 30 completed the study. A clear plasma exposure dose-response relationship was found for all 4 molecules. B17MP Cmax geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC0-t ratios ranged from 1.16 to 1.22; thus, the findings were comparable between the ethnicities. Formoterol exposure was higher in Japanese than Caucasian participants (Cmax, 1.22-1.53; AUC0-t, 1.23-1.40). The GB Cmax with BDP/FF/GB 400/12/25 µg (1.09) and AUC0-t values for all three doses (0.98-1.17) were comparable in the 2 populations, but Cmax with 200/12/25 and 800/48/100 µg were higher in Japanese participants (1.32 and 1.42, respectively). Pharmacodynamic (cortisol, potassium, glucose, blood pressure, heart rate, and QT interval with the Fridericia correction) and safety profile results were similar in the 2 ethnicities, with most patients not experiencing any adverse events. IMPLICATIONS: Exposure to BDP/FF/GB pressurized metered dose inhaler at therapeutic and supratherapeutic doses was associated with higher plasma levels in Japanese versus Caucasian healthy volunteers. These PK differences did not translate into meaningful differences in the safety or pharmacodynamic parameters assessed in this study and were consistent with the results of other long-term (52-week) published studies. Dose adjustments in Japanese people are not deemed necessary. CLINICALTRIALS. GOV IDENTIFIER: NCT03859414.