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1.
Sci Rep ; 12(1): 1839, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115574

RESUMO

Mortality remains high after emergency open surgery for a ruptured abdominal aortic aneurysm (RAAA). The aim of the present study was to assess, if intravenous (IV) Interferon (IFN) beta-1a improve survival after surgery by up-regulating Cluster of differentiation (CD73). This is a multi-center phase II double-blind, 2:1 randomized, parallel group comparison of the efficacy and safety of IV IFN beta-1a vs. placebo for the prevention of death after open surgery for an infra-renal RAAA. All study patients presented a confirmed infra-renal RAAA, survived the primary emergency surgery and were treated with IFN beta-1a (10 µg) or matching placebo for 6 days after surgery. Major exclusion criteria included fatal hemorrhagic shock, chronic renal replacement therapy, diagnosed liver cirrhosis, severe congestive heart failure, advanced malignant disease, primary attempt of endovascular aortic repair (EVAR), and per-operative suprarenal clamping over 30 min. Main outcome measure was all-cause mortality at day 30 (D30) from initial emergency aortic reconstruction. The study was pre-maturely stopped due to a reported drug-drug interaction and was left under-powered. Out of 40 randomized patients 38 were included in the outcome analyses (27 IFN beta-1a and 11 placebo). There was no statistically significant difference between treatment groups at baseline except more open-abdomen and intestinal ischemia was present in the IFN beta-1a arm. D30 all-cause mortality was 22.2% (6/27) in the IFN beta-1a arm and 18.2% (2/11) in the placebo arm (OR 1.30; 95% CI 0.21-8.19). The most common adverse event relating to the IFN beta-1a was pyrexia (20.7% in the IFN beta-1a arm vs. 9.1% in the placebo arm). Patients with high level of serum CD73 associated with survival (P = 0.001) whereas the use of glucocorticoids and the presence of IFN beta-1a neutralizing antibodies associated with a poor CD73 response and survival. The initial aim of the trial, if postoperative INF beta-1a treatment results on better RAAA survival, could not be demonstrated. Nonetheless the anticipated target mechanism up-regulation of CD73 was associated with 100% survival. According to present results the INF beta-1a induced up-regulation of serum CD73 was blocked with both use of glucocorticoids and serum IFN beta-1a neutralizing antibodies. The study was pre-maturely stopped due to interim analysis after a study concerning the use if IV IFN beta-1a in ARDS suggested that the concomitant use of glucocorticoids and IFN beta-1a block the CD73 induction. Trial registration: ClinicalTrials.gov NCT03119701. Registered 19/04/2017 (retrospectively registered).


Assuntos
5'-Nucleotidase/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Aneurisma da Aorta Abdominal/terapia , Ruptura Aórtica/terapia , Interferon beta-1a/uso terapêutico , Procedimentos Cirúrgicos Vasculares , Adjuvantes Imunológicos/efeitos adversos , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/mortalidade , Ruptura Aórtica/diagnóstico , Ruptura Aórtica/imunologia , Ruptura Aórtica/mortalidade , Método Duplo-Cego , Interações Medicamentosas , Término Precoce de Ensaios Clínicos , Emergências , Feminino , Finlândia , Proteínas Ligadas por GPI/metabolismo , Glucocorticoides/efeitos adversos , Humanos , Interferon beta-1a/efeitos adversos , Interferon beta-1a/imunologia , Masculino , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/mortalidade
2.
Clin Pharmacol Ther ; 111(2): 391-403, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33998672

RESUMO

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor, after first administration to healthy male and female participants. Participants (n = 116) were recruited into this phase I, double-blind, randomized, placebo-controlled, single ascending dose and multiple ascending dose (10-day) study. The primary outcome was the safety and tolerability of BIA 10-2474. Secondary outcomes were pharmacokinetics of BIA 10-2474 and pharmacodynamics, considering plasma concentrations of anandamide and three other fatty acid amides (FAAs) and leukocyte FAAH activity. Single oral doses of 0.25-100 mg and repeated oral doses of 2.5-50 mg were evaluated. BIA 10-2474 was well tolerated up to 100 mg as a single dose and up to 20 mg once daily for 10 days. In the cohort receiving repeated administrations of 50 mg, there were central nervous system adverse events in five of six participants, one with fatal outcome, which led to early termination of the study. BIA 10-2474 showed a linear relationship between dose and area under plasma concentration-time curve (AUC) across the entire dose range and reached steady state within 5-6 days of administration, with an accumulation ratio, based on AUC0-24h , of <2 on Day 10. BIA 10-2474 was rapidly absorbed with a mean terminal elimination half-life of 8-10 hours (Day 10). BIA 10-2474 caused reversible, dose-related increases in plasma FAAs. In conclusion, we propose that these data, as well as the additional data generated since the clinical trial was stopped, do not provide a complete mechanistic explanation for the tragic fatality.


Assuntos
Amidoidrolases/antagonistas & inibidores , Sistema Nervoso Central/efeitos dos fármacos , Óxidos N-Cíclicos/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Piridinas/efeitos adversos , Administração Oral , Sistema Nervoso Central/fisiopatologia , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/farmacocinética , Método Duplo-Cego , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Término Precoce de Ensaios Clínicos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , França , Voluntários Saudáveis , Humanos , Masculino , Segurança do Paciente , Piridinas/administração & dosagem , Piridinas/farmacocinética , Medição de Risco , Fatores de Risco
3.
J Am Coll Cardiol ; 78(19): 1875-1885, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34736563

RESUMO

BACKGROUND: There is limited evidence that fractional flow reserve (FFR) is effective in guiding therapeutic strategy in multivessel coronary artery disease (CAD) beyond prespecified percutaneous coronary intervention or coronary graft surgery candidates. OBJECTIVES: The FUTURE (FUnctional Testing Underlying coronary REvascularization) trial aimed to evaluate whether a treatment strategy based on FFR was superior to a traditional strategy without FFR in the treatment of multivessel CAD. METHODS: The FUTURE trial is a prospective, randomized, open-label superiority trial. Multivessel CAD candidates were randomly assigned (1:1) to treatment strategy based on FFR in all stenotic (≥50%) coronary arteries or to a traditional strategy without FFR. In the FFR group, revascularization (percutaneous coronary intervention or surgery) was indicated for FFR ≤0.80 lesions. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events at 1 year. RESULTS: The trial was stopped prematurely by the data safety and monitoring board after a safety analysis and 927 patients were enrolled. At 1-year follow-up, by intention to treat, there were no significant differences in major adverse cardiac or cerebrovascular events rates between groups (14.6% in the FFR group vs 14.4% in the control group; hazard ratio: 0.97; 95% confidence interval: 0.69-1.36; P = 0.85). The difference in all-cause mortality was nonsignificant, 3.7% in the FFR group versus 1.5% in the control group (hazard ratio: 2.34; 95% confidence interval: 0.97-5.18; P = 0.06), and this was confirmed with a 24 months' extended follow-up. FFR significantly reduced the proportion of revascularized patients, with more patients referred to exclusively medical treatment (P = 0.02). CONCLUSIONS: In patients with multivessel CAD, we did not find evidence that an FFR-guided treatment strategy reduced the risk of ischemic cardiovascular events or death at 1-year follow-up. (Functional Testing Underlying Coronary Revascularisation; NCT01881555).


Assuntos
Ponte de Artéria Coronária , Doença da Artéria Coronariana , Estenose Coronária , Vasos Coronários , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Intervenção Coronária Percutânea , Complicações Pós-Operatórias/mortalidade , Idoso , Angiografia Coronária/métodos , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/cirurgia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/etiologia , Estenose Coronária/cirurgia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Efeitos Adversos de Longa Duração/mortalidade , Masculino , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Valor Preditivo dos Testes , Medição de Risco/métodos , Índice de Gravidade de Doença
4.
JAMA ; 326(17): 1703-1712, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34633405

RESUMO

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.


Assuntos
Aspirina/uso terapêutico , COVID-19/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Trombose/prevenção & controle , Adulto , Aspirina/efeitos adversos , COVID-19/complicações , Relação Dose-Resposta a Droga , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos
6.
JAMA ; 326(11): 1013-1023, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34463700

RESUMO

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.


Assuntos
Dióxido de Carbono/sangue , Circulação Extracorpórea , Respiração Artificial/métodos , Insuficiência Respiratória/terapia , Idoso , Término Precoce de Ensaios Clínicos , Circulação Extracorpórea/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/mortalidade , Volume de Ventilação Pulmonar
7.
CMAJ Open ; 9(2): E693-E702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34145052

RESUMO

BACKGROUND: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death. METHODS: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data. RESULTS: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety. INTERPRETATION: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04329611.


Assuntos
Assistência Ambulatorial , COVID-19 , Hospitalização/estatística & dados numéricos , Hidroxicloroquina , Respiração Artificial/estatística & dados numéricos , Assistência Ambulatorial/métodos , Assistência Ambulatorial/estatística & dados numéricos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Vida Independente/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Mortalidade , Avaliação de Resultados em Cuidados de Saúde , Serviços Preventivos de Saúde/métodos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
8.
J Clin Psychopharmacol ; 41(4): 381-388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34181361

RESUMO

PURPOSE/BACKGROUND: No study to date has compared lithium and lamotrigine as maintenance mood stabilizers for bipolar II disorder. The aim of this study was to evaluate and compare these two medications in terms of their maintenance efficacy and side effect profile, thus evaluating their comparative cost/benefit profile. METHODS/PROCEDURES: Forty-four subjects with a newly diagnosed bipolar II disorder were randomly assigned to receive either lithium or lamotrigine treatment in a 20-week single-blinded study. Subjects received either slow-release lithium progressively up-titrated to achieve a serum level of 0.8 mEq/L, or lamotrigine increased progressively to a maintenance dose of 200 mg/d. Our primary outcome measure examined daily data on hypomanic and depressive symptoms. Secondary measures evaluated hypomanic and depressive symptom severity, global functioning, and global improvement in hypomanic and depressive symptoms. FINDINGS/RESULTS: We terminated the trial principally because of severe ongoing side effects experienced by many of those receiving lithium, and with additional concerns about initial severe side effects (including psychosis) experienced by several assigned to lamotrigine. Analyses of study completer data for 28 participants suggested comparable efficacy of both medications; however, lamotrigine had a distinctly lower rate of severe side effects across the study. We calculated that if study trends on outcome measures were valid, then an extremely large sample would be required to demonstrate superiority of either drug, thus making it unlikely that any such adequately powered study will be mounted in the future. IMPLICATIONS/CONCLUSIONS: The small sample size limits any definitive conclusions, but our data suggest that lithium and lamotrigine are likely to have equal efficacy as mood stabilizers for those with a bipolar II condition but that, as maintenance treatments, lithium has more distinctive side effects.


Assuntos
Transtorno Bipolar , Depressão , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Lamotrigina , Compostos de Lítio , Mania , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antimaníacos/administração & dosagem , Antimaníacos/efeitos adversos , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Depressão/diagnóstico , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Lamotrigina/administração & dosagem , Lamotrigina/efeitos adversos , Compostos de Lítio/administração & dosagem , Compostos de Lítio/efeitos adversos , Compostos de Lítio/sangue , Masculino , Mania/diagnóstico , Mania/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Escalas de Graduação Psiquiátrica , Método Simples-Cego
9.
J Cereb Blood Flow Metab ; 41(11): 2805-2819, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34018825

RESUMO

Clinical positron emission tomography (PET) research is costly and entails exposing participants to radioactivity. Researchers should therefore aim to include just the number of subjects needed to fulfill the purpose of the study. In this tutorial we show how to apply sequential Bayes Factor testing in order to stop the recruitment of subjects in a clinical PET study as soon as enough data have been collected to make a conclusion. By using simulations, we demonstrate that it is possible to stop a study early, while keeping the number of erroneous conclusions low. We then apply sequential Bayes Factor testing to a real PET data set and show that it is possible to obtain support in favor of an effect while simultaneously reducing the sample size with 30%. Using this procedure allows researchers to reduce expense and radioactivity exposure for a range of effect sizes relevant for PET research.


Assuntos
Simulação por Computador/estatística & dados numéricos , Tomografia por Emissão de Pósitrons/efeitos adversos , Tomografia por Emissão de Pósitrons/economia , Exposição à Radiação/prevenção & controle , Adulto , Teorema de Bayes , Estudos de Casos e Controles , Término Precoce de Ensaios Clínicos/ética , Término Precoce de Ensaios Clínicos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Exposição à Radiação/efeitos adversos , Projetos de Pesquisa , Tamanho da Amostra
11.
Respiration ; 100(8): 804-810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33965944

RESUMO

BACKGROUND: Bronchoscopic lung volume reduction using endobronchial coils is a new treatment for patients with severe emphysema. To date, the benefits have been modest and have been suggested to be much larger in patients with severe hyperinflation and nonmulti-comorbidity. OBJECTIVE: We aimed to evaluate the efficacy and safety of endobronchial coil treatment in a randomized multicenter clinical trial using optimized patient selection. METHOD: Patients with severe emphysema on HRCT scan with severe hyperinflation (residual volume [RV] ≥200% predicted and RV/total lung capacity [TLC] >55%) were randomized to coil treatment or control. Primary outcome measures were differences in the forced expiratory volume in 1 s (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score at 6 months. RESULTS: Due to premature study termination, a total of 120 patients (age 63 ± 7 years, FEV1 29 ± 7% predicted, RV 251 ± 41% predicted, RV/TLC 67 ± 6%, and SGRQ 58 ± 13 points), instead of 210 patients, were randomized. At study termination, 91 patients (57 coil and 34 control) had 6-month results available. Analyses showed significantly greater improvements in favor of the coil group. The increase in FEV1 was greater in the coil group than that in the control group by + 10.3 [+4.7 to +16.0] % and in SGRQ by -10.6 [-15.9 to -5.4] points. At study termination, there were 5 (6.8%) deaths in the coil cohort reported. CONCLUSION: Despite early study termination, coil treatment compared to control results in a significant improvement in the lung function and quality of life benefits for up to 6 months in patients with emphysema and severe hyperinflation. These improvements were of clinical importance but were associated with a higher likelihood of serious adverse events.


Assuntos
Broncoscopia , Enfisema/terapia , Pneumonectomia/instrumentação , Adulto , Idoso , Idoso de 80 Anos ou mais , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonectomia/métodos , Estudos Prospectivos , Próteses e Implantes , Índice de Gravidade de Doença
13.
Stat Med ; 40(14): 3215-3226, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-33844323

RESUMO

Phase I cancer clinical trials have been proposed novel designs such as algorithm-based, model-based, and model-assisted designs. Model-based and model-assisted designs have a higher identification rate of maximum tolerated dose (MTD) than algorithm-based designs, but are limited by the fact that the sample size is fixed. Hence, it would be very attractive to estimate the MTD with sufficient accuracy and complete the trial early. O'Quigley proposed the early completion of a trial with the continual reassessment method among model-based designs when the MTD is estimated with sufficient accuracy. However, the proposed early completion method based on the binary outcome trees has a problem that the calculation cost is high when the number of remaining patients is large. Among model-assisted designs, the Bayesian optimal interval (BOIN) design provides the simplest approach for dose adjustment. We propose the novel early completion method for the clinical trials with the BOIN design when the MTD is estimated with sufficient accuracy. This completion method can be easily calculated. In addition, the method does not require many more patients treated for the determination of early completion. We confirm that the BOIN design applying the early completion method has almost the same MTD identification rate compared to the BOIN design through simulations conducted based on over 30 000 scenarios.


Assuntos
Término Precoce de Ensaios Clínicos , Modelos Estatísticos , Neoplasias , Teorema de Bayes , Ensaios Clínicos Fase I como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Neoplasias/terapia
14.
Clin Transl Oncol ; 23(8): 1666-1677, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33876416

RESUMO

BACKGROUND: Sequential treatment of Panitumumab (Pb) plus Paclitaxel (Px) as induction treatment (IT) followed by concurrent bioradiotherapy (Bio-RT) with Pb may be an alternative for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in patients ineligible for high-dose cisplatin therapy. METHODS: Phase II, single-arm, multicentre study, with two-stage design, in patients ≥ 18 years with stage III-IVa-b LA-SCCHN unfit for platinum. Patients received Px + Pb (9 weeks) as IT followed by Bio-RT + Pb. Primary endpoint: overall response rate (ORR) after IT, defined as: more than 70% of patients achieving complete response (CR) or partial response (PR) to IT. Secondary end-points: progression-free survival, organ preservation rate, safety profile. RESULTS: Study ended prematurely (51 patients) due to slow recruitment. ORR: 66.7% (95% CI: 53.7-79.6), 8 (15.7%) CR and 26 (51.0%) PR. 39 patients (76%) completed radiotherapy (RT). Pb and/or Px-related adverse events (AEs) grade 3-4: 56.9% during IT and 63.4% during the concomitant phase, of which most common were skin toxicity (33.3%). Five deaths occurred during treatment, two of them (3.9%) were Pb and/or Px-related. CONCLUSIONS: Although underpowered, ORR was higher than the pre-specified boundary for considering the treatment active. Although Px + Pb as IT provides some benefit, the safety profile is worse than expected. To consider Pb + Px as IT as an alternative for platinum-unsuitable LA-SCCHN, further research/investigation would be needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Paclitaxel/uso terapêutico , Panitumumabe/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Causas de Morte , Término Precoce de Ensaios Clínicos , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Quimioterapia de Indução/métodos , Masculino , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão , Paclitaxel/efeitos adversos , Panitumumabe/efeitos adversos , Intervalo Livre de Progressão , Espanha , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
17.
Lancet Respir Med ; 9(5): 476-486, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798455

RESUMO

BACKGROUND: Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. FINDINGS: Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. INTERPRETATION: In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. FUNDING: German Center for Lung Research, Roche Pharma.


Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Piridonas/farmacologia , Testes de Função Respiratória/métodos , Anti-Inflamatórios não Esteroides/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Análise de Intenção de Tratamento , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/fisiopatologia , Avaliação de Sintomas/estatística & dados numéricos
18.
Cancer Med ; 10(7): 2332-2340, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33666378

RESUMO

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients. METHODS: A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm). RESULTS: Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47). CONCLUSION: Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Curcumina/farmacocinética , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Término Precoce de Ensaios Clínicos , Humanos , Masculino , Futilidade Médica , Adesão à Medicação , Pessoa de Meia-Idade , Placebos/uso terapêutico , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Qualidade de Vida
19.
Calcif Tissue Int ; 109(1): 1-11, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33712920

RESUMO

Periods of absence from supervised group exercise while maintaining physical activity might be a frequent pattern in adults' exercise habits. The aim of the present study was to determine detraining effects on musculoskeletal outcomes after a 3-month detraining period in early post-menopausal, osteopenic women. Due to the COVID-19 pandemic, we terminated the 18-month randomized controlled ACTLIFE exercise intervention immediately after the 13-month follow-up assessment. This put an abrupt stop to the high-intensity aerobic and resistance group exercise sessions undertaken three times per week by the exercise group (EG: n = 27) and the gentle exercise program performed once per week for the attention control group (CG: n = 27); but both groups were permitted to conduct individual outdoor activity for the 3-month lock-down period. Study endpoints were lean body mass (LBM), bone mineral density (BMD) at the lumbar spine (LS), maximum hip-/leg extension strength and power. Detraining-induced reductions of LBM, hip/leg strength and power (but not BMD-LS) were significantly greater (p < 0.001 to p = 0.044) compared with the CG. Significant exercise effects, i.e. differences between EG and CG, present after 13 months of exercise, were lost after 3 months of detraining for LBM (p = 0.157) and BMD-LS (p = 0.065), but not for strength (p < 0.001) and power (p < 0.001). Of note, self-reported individual outdoor activities and exercise increased by about 40% in both groups during the lock-down period. Three months' absence from a supervised group exercise protocol resulted in considerable detraining effects for musculoskeletal parameters. Thus, exercise programs for adults should be continuous rather than intermittent.Trial registration number: ClinicalTrials.gov: NCT04420806, 06.05.2020.


Assuntos
Densidade Óssea , Exercício Físico , Sistema Musculoesquelético , Osteoporose Pós-Menopausa , Adulto , Término Precoce de Ensaios Clínicos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pós-Menopausa
20.
JAMA ; 325(9): 833-842, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33651090

RESUMO

Importance: Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. Objective: To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. Design, Setting, and Participants: This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). Interventions: All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. Main Outcome and Measures: The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. Results: Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. Conclusions and Relevance: Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. Trial Registration: ClinicalTrials.gov Identifier: NCT02101853.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Leucemia de Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Quimioterapia de Consolidação/efeitos adversos , Intervalo Livre de Doença , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Adulto Jovem
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