RESUMO
BACKGROUND: This ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination. METHODS: Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination. RESULTS: Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9-89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2-93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels. CONCLUSIONS: Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.
Assuntos
Vacina contra Herpes Zoster , Herpes Zoster , Adjuvantes Imunológicos , Idoso , Seguimentos , Herpes Zoster/prevenção & controle , Herpesvirus Humano 3 , Humanos , Pessoa de Meia-Idade , Vacinas SintéticasRESUMO
AIMS: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). METHODS AND RESULTS: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. CONCLUSION: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Compostos Benzidrílicos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Volume SistólicoRESUMO
Background: The immunogenicity and safety of an adjuvanted herpes zoster subunit (HZ/su) vaccine when coadministered with a quadrivalent seasonal inactivated influenza vaccine (IIV4) was investigated in a phase 3, open-label, randomized clinical trial in adults aged ≥50 years. Methods: Subjects were randomized 1:1 to receive either HZ/su (varicella zoster virus glycoprotein E; AS01B Adjuvant System) and IIV4 at day 0 followed by a second HZ/su dose at month 2 (coadministration group), or IIV4 at month 0 and HZ/su at months 2 and 4 (control group). The primary objectives were the HZ/su vaccine response rate in the coadministration group and the noninferiority of the antibody responses to HZ/su and IIV4 in the coadministration compared with the control group. Safety information was collected throughout the duration of the study. Results: A total of 413 subjects were vaccinated in the coadministration group and 415 in the control group. The HZ/su vaccine response rate in the coadministration group was 95.8% (95% confidence interval, 93.3%-97.6%) and the anti-glycoprotein E GMCControl/Coadmin ratio was 1.08 (.97-1.20). The primary noninferiority objectives were met. No safety concerns were observed. Conclusions: No interference in the immune responses to either vaccine was observed when the vaccines were coadministered, and no safety concerns were identified. Clinical Trials Registration: NCT01954251.
Assuntos
Adjuvantes Imunológicos/farmacologia , Vacina contra Herpes Zoster/imunologia , Herpes Zoster/imunologia , Herpes Zoster/prevenção & controle , Imunogenicidade da Vacina/imunologia , Vacinas contra Influenza/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacologia , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Vacina contra Herpes Zoster/efeitos adversos , Herpesvirus Humano 3/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Vacinas contra Influenza/administração & dosagem , Influenza Humana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estações do Ano , Vacinação/métodos , Vacinas de Produtos Inativados , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversosRESUMO
While obesity impairs health-related quality of life (HRQOL), lifestyle interventions targeting weight reduction have been effective in improving HRQOL. Therefore, we hypothesised that a meal replacement-based lifestyle intervention, which has been shown to successfully reduce weight, would also improve HRQOL more effectively than a lifestyle intervention alone. In the international, multicenter, randomised-controlled ACOORH-trial (Almased-Concept-against- Overweight-and-Obesity-and-Related-Health-Risk), overweight or obese participants with elevated risk for metabolic syndrome (n = 463) were randomised into two groups. Both groups received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement for 6 months. HRQOL was estimated at baseline, after 3 and 12 months, using the SF-36 questionnaire, and all datasets providing HRQOL data (n = 263) were included in this predefined subanalysis. Stronger improvements in the physical component summary (PCS) were observed in the intervention compared to the control group, peaking after 3 months (estimated treatment difference 2.7 [1.2; 4.2]; p < 0.0001), but also in the long-term. Multiple regression analysis demonstrated that insulin levels and the achieved weight loss were associated with the mental component summary (MCS) after 12 months (p < 0.05). Thus, meal replacement-based lifestyle intervention is not only effective in weight reduction but, concomitantly, in enhancing HRQOL.
Assuntos
Hipoglicemia , Síndrome Metabólica , Exercício Físico , Humanos , Estilo de Vida , Síndrome Metabólica/complicações , Síndrome Metabólica/terapia , Obesidade/complicações , Obesidade/terapia , Sobrepeso/complicações , Sobrepeso/terapia , Qualidade de Vida , Redução de PesoRESUMO
Lifestyle interventions including meal replacement are suitable for prevention and treatment of obesity and type-2-diabetes. Since leptin is involved in weight regulation, we hypothesised that a meal replacement-based lifestyle intervention would reduce leptin levels more effectively than lifestyle intervention alone. In the international, multicentre, randomised-controlled ACOORH-trial (Almased-Concept-against-Overweight-and-Obesity-and-Related- Health-Risk), overweight or obese participants with metabolic syndrome criteria (n = 463) were randomised into two groups and received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement. Data were collected at baseline, after 1, 3, 6, and 12 months. All datasets providing leptin data (n = 427) were included in this predefined subanalysis. Serum leptin levels significantly correlated with sex, body mass index, weight, and fat mass at baseline (p < 0.0001). Stronger leptin reduction has been observed in the intervention compared to the control group with the lowest levels after 1 month of intervention (estimated treatment difference −3.4 µg/L [1.4; 5.4] for females; −2.2 µg/L [1.2; 3.3] for males; p < 0.001 each) and was predictive for stronger reduction of body weight and fat mass (p < 0.001 each) over 12 months. Strongest weight loss was observed after 6 months (−5.9 ± 5.1 kg in females of the intervention group vs. −2.9 ± 4.9 kg in the control group (p < 0.0001); −6.8 ± 5.3 kg vs. −4.1 ± 4.4 kg (p = 0.003) in males) and in those participants with combined leptin and insulin decrease. A meal replacement-based lifestyle intervention effectively reduces leptin which is predictive for long-term weight loss.
Assuntos
Hipoglicemia , Sobrepeso , Índice de Massa Corporal , Dieta Redutora , Feminino , Humanos , Leptina , Masculino , Obesidade , Sobrepeso/terapia , Redução de PesoRESUMO
Lifestyle interventions, including meal replacement, are effective in the prevention and treatment of type-2-diabetes and obesity. Since insulin is the key weight regulator, we hypothesised that the addition of meal replacement to a lifestyle intervention reduces insulin levels more effectively than lifestyle intervention alone. In the international multicentre randomised controlled ACOORH (Almased Concept against Overweight and Obesity and Related Health Risk) trial, overweight or obese persons who meet the criteria for metabolic syndrome (n = 463) were randomised into two groups. Both groups received nutritional advice focusing on carbohydrate restriction and the use of telemonitoring devices. The intervention group substituted all three main meals per day in week 1, two meals per day in weeks 2-4, and one meal per day in weeks 5-26 with a protein-rich, low-glycaemic meal replacement. Data were collected at baseline and after 1, 3, 6 and 12 months. All datasets providing insulin data (n = 446) were included in this predefined subanalysis. Significantly higher reductions in insulin (-3.3 ± 8.7 µU/mL vs. -1.6 ± 9.8 µU/mL), weight (-6.1 ± 5.2 kg vs. -3.2 ± 4.6 kg), and inflammation markers were observed in the intervention group. Insulin reduction correlated with weight reduction and the highest amount of weight loss (-7.6 ± 4.9 kg) was observed in those participants with an insulin decrease > 2 µU/mL. These results underline the potential for meal replacement-based lifestyle interventions in diabetes prevention, and measurement of insulin levels may serve as an indicator for adherence to carbohydrate restriction.
Assuntos
Proteínas Alimentares/farmacologia , Jejum/sangue , Índice Glicêmico , Inflamação/sangue , Insulina/sangue , Refeições , Adulto , Idoso , Biomarcadores , Peso Corporal , Doença Crônica , Feminino , Índice Glicêmico/efeitos dos fármacos , Humanos , Inflamação/patologia , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Adulto JovemRESUMO
Although meal replacement can lead to weight reduction, there is uncertainty whether this dietary approach implemented into a lifestyle programme can improve long-term dietary intake. In this subanalysis of the Almased Concept against Overweight and Obesity and Related Health Risk (ACOORH) study (n = 463), participants with metabolic risk factors were randomly assigned to either a meal replacement-based lifestyle intervention group (INT) or a lifestyle intervention control group (CON). This subanalysis relies only on data of participants (n = 119) who returned correctly completed dietary records at baseline, and after 12 and 52 weeks. Both groups were not matched for nutrient composition at baseline. These data were further stratified by sex and also associated with weight change. INT showed a higher increase in protein intake related to the daily energy intake after 12 weeks (+6.37% [4.69; 8.04] vs. +2.48% [0.73; 4.23], p < 0.001) of intervention compared to CON. Fat and carbohydrate intake related to the daily energy intake were more strongly reduced in the INT compared to CON (both p < 0.01). After sex stratification, particularly INT-women increased their total protein intake after 12 (INT: +12.7 g vs. CON: -5.1 g, p = 0.021) and 52 weeks (INT: +5.7 g vs. CON: -16.4 g, p = 0.002) compared to CON. Protein intake was negatively associated with weight change (r = -0.421; p < 0.001) after 12 weeks. The results indicate that a protein-rich dietary strategy with a meal replacement can improve long-term nutritional intake, and was associated with weight loss.
Assuntos
Peso Corporal , Ingestão de Alimentos , Refeições , Adulto , Ingestão de Energia , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/dietoterapia , Fatores de Risco , Redução de PesoRESUMO
BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.
Assuntos
Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Clorobenzenos/administração & dosagem , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Androstadienos/efeitos adversos , Álcoois Benzílicos/efeitos adversos , Canadá , Clorobenzenos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Europa (Continente) , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Batefenterol is a novel bifunctional muscarinic antagonist ß2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development. PATIENTS AND METHODS: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42. RESULTS: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed. CONCLUSION: Batefenterol 300 µg may represent the optimal dose for Phase III studies.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Carbamatos/administração & dosagem , Inaladores de Pó Seco , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Idoso , Carbamatos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Alemanha , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/efeitos adversos , África do Sul , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Fluticasone furoate/vilanterol (FF/VI) is a novel, once-daily, inhaled corticosteroid/long-acting ß2-agonist combination approved for the treatment of COPD and asthma. We compared the safety and efficacy of FF/VI and tiotropium (TIO) in subjects with moderate-to-severe COPD with greater risk for comorbid cardiovascular disease (CVD). METHODS: This randomized, blinded, double-dummy, parallel-group study compared a once-daily morning dose of FF/VI 100/25 mcg delivered via ELLIPTA™ with TIO 18 mcg via HandiHaler(®) for 12 weeks in subjects with diagnosed COPD, forced expiratory volume in 1 second (FEV1) 30%-70% predicted, and CVD or CVD risk. The primary endpoint was change from baseline in 24-hour weighted mean FEV1 on Day 84. Other efficacy endpoints included time to onset of bronchodilation, trough FEV1, other spirometry measures, rescue medication use, symptoms, quality of life (St George's Respiratory Questionnaire-COPD [SGRQ-C]), and health status (COPD Assessment Tests [CAT]) measures. Safety endpoints included cardiovascular monitoring, cortisol excretion, COPD exacerbations, and adverse events, including prespecified drug effects. RESULTS: Both FF/VI and TIO improved the 24-hour weighted mean FEV1 from baseline after 12 weeks with no significant difference between treatments. Other endpoints favored FF/VI for time to onset of bronchodilation, rescue medication use, dyspnea, SGRQ-C and CAT scores, or favored TIO for change from baseline in forced vital capacity and inspiratory capacity. Pneumonia occurred more frequently in the FF/VI group, and two TIO-treated subjects died following cardiovascular events. Other safety measures were similar between groups, and cardiovascular monitoring did not reveal increased CVD risk. CONCLUSION: Both FF/VI and TIO were efficacious in improving lung function in subjects with COPD and comorbid CVD or CVD risk factors, with minor differences in efficacy and safety profiles.
Assuntos
Androstadienos , Álcoois Benzílicos , Doenças Cardiovasculares/complicações , Clorobenzenos , Volume Expiratório Forçado/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Brometo de Tiotrópio , Administração por Inalação , Adulto , Idoso , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Avaliação de Sintomas/métodos , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/efeitos adversos , Resultado do TratamentoRESUMO
INTRODUCTION: Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24-h activity. FF is in development as a once-daily treatment for asthma as monotherapy and in combination with vilanterol (VI), a long-acting ß2 agonist. Corticosteroids can have systemic effects on hypothalamic-pituitary-adrenal (HPA) axis function, potentially resulting in cortisol suppression. OBJECTIVES: To assess the effect of FF/VI compared with placebo on the HPA axis by evaluating 24-h weighted mean serum cortisol levels in adolescent and adult patients with persistent asthma. METHODS: One hundred eighty-five patients with >12 weeks history of asthma were randomised in a 4:4:4:1 ratio to one of two once-daily FF/VI treatments (100/25 µg or 200/25 µg), placebo or an active control group that received inhaled placebo plus one prednisolone 10 mg capsule daily for the last 7 days of the study. Twenty-four-hour serum and urinary cortisol was measured at baseline and on day 42. RESULTS: Non-inferiority in 24-h weighted mean serum cortisol after 6 weeks of treatment with once-daily FF/VI at either strength was shown. Treatment ratios [95% confidence interval (CI)] to placebo for FF/VI 100/25 µg [0.99 (0.87-1.12)] or FF/VI 200/25 µg [0.97 (0.86-1.10)] indicated non-inferiority of both FF/VI doses to placebo as the lower limit of the 95% CI was greater than the predefined 0.8. Prednisolone substantially reduced 24-h weighted mean serum cortisol [treatment ratio to placebo 0.34 (0.28-0.41)]. FF/VI was well-tolerated, and no safety concerns were identified. CONCLUSIONS: FF/VI was found to be non-inferior to placebo on HPA axis function, with no indication of significant cortisol suppression after 42 days.