RESUMO
BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination can potentially reduce the rate of respiratory infections in vulnerable populations. This study evaluates the safety and efficacy of VPM1002 (a genetically modified BCG) as prophylaxis against severe respiratory tract infections including coronavirus disease 2019 (COVID-19) in an elderly population. METHODS: In this phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial, healthy elderly volunteers (N = 2064) were enrolled, randomized (1:1) to receive either VPM1002 or placebo, and followed up remotely for 240 days. The primary outcome was the mean number of days with severe respiratory infections at hospital and/or at home. Secondary endpoints included the incidence of self-reported fever, number of hospital and intensive care unit (ICU) admissions, and number of adverse events. RESULTS: A total of 31 participants in the VPM1002 group reported at least 1 day with severe respiratory disease and a mean number of days with severe respiratory disease of 9.39 ± 9.28 while in the placebo group; 38 participants reported a mean of 14.29 ± 16.25 days with severe respiratory disease. The incidence of self-reported fever was lower in the VPM1002 group (odds ratio, 0.46 [95% confidence interval, .28-.74]; P = .001), and consistent trends to fewer hospitalization and ICU admissions due to COVID-19 were observed after VPM1002 vaccination. Local reactions typical for BCG were observed in the VPM1002-vaccinated group, which were mostly of mild intensity. CONCLUSIONS: Vaccination with VPM1002 is well tolerated and seems to have a prophylactic effect against severe respiratory disease in the elderly. CLINICAL TRIALS REGISTRATION: NCT04435379.
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Vacina BCG , COVID-19 , Idoso , Humanos , Vacina BCG/imunologia , Vacina BCG/normas , COVID-19/prevenção & controle , Método Duplo-Cego , Hospitalização/estatística & dados numéricos , SARS-CoV-2 , Doenças Respiratórias/prevenção & controle , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Masculino , Feminino , Fatores de Tempo , Gravidade do PacienteRESUMO
PURPOSE: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, support in clinical trials by students of human medicine and related disciplines has become of even greater importance than in pre-pandemic times. Documentation in clinical trials adheres to the principles of Good Clinical Practice (GCP), and healthcare professionals involved in the conduct of clinical trials-including students-are obliged to perform documentation in accordance with GCP principles. Unprecedented challenges have arisen with regard to the appropriate training of students as training courses in presence had largely to be suspended due to social-distancing regulations during the heyday of the COVID-19 pandemic. Therefore, novel training formats and self-study training materials for students working in clinical trials are urgently warranted. METHODS: To overcome this shortcoming and to define a common quality standard, an interdisciplinary, multiprofessional (physicians, study nurses, medical students), and binational (Germany, The Netherlands) expert panel convened and devised the Students' guide to documentation in clinical trials. RESULTS: Following a brief description of the different roles in clinical trials (e.g., sponsor, (principal) investigator, monitor) and an introduction into the principles of GCP, the documentation of adverse events, concomitant medication, medical history, and quality control are comprehensively discussed. The Guide concludes with a trilingual medical dictionary (English, German, Dutch) and with recommendations of pertinent literature for further reading. CONCLUSION: Serving both as textbook for self-training and as (quick-) reference work for the daily routine, the Guide has specifically been designed to complement, but not to replace practical training courses for students. While primarily addressed at students of human medicine and related disciplines, the Guide can also be of high relevance and utility to other healthcare professionals involved in the conduct of clinical trials.
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COVID-19 , Estudantes de Medicina , Ensaios Clínicos como Assunto , Documentação , Alemanha , Humanos , PandemiasRESUMO
INTRODUCTION: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol. This exploratory study aimed to determine the effect of Lu AG06466 versus placebo on tics and other symptoms in patients with TS. METHODS: In this phase 1b cross-over study, 20 adult patients with TS on standard-of-care medications were randomized to a single fasted dose of Lu AG06466 (40 mg) or placebo in period 1, followed by the other treatment in period 2. The effects on tics, premonitory urges, and psychiatric comorbidities were evaluated using a variety of scaled approaches at different time points before and after treatment. RESULTS: All scales showed an overall trend of tic reduction, with two out of three tic scales (including the Total Tic Score of the Yale Global Tic Severity Score) showing a significant effect of a single dose of Lu AG06466 versus placebo at various timepoints. Treatment with Lu AG06466 resulted in a significant reduction in premonitory urges versus placebo. Single doses of Lu AG06466 were generally well-tolerated, and the most common adverse events were headache, somnolence, and fatigue. CONCLUSION: In this exploratory trial, a single dose of Lu AG06466 showed statistically significant positive effects on key measures of TS symptoms.
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Transtornos de Tique , Tiques , Síndrome de Tourette , Adulto , Estudos Cross-Over , Endocanabinoides/uso terapêutico , Humanos , Monoacilglicerol Lipases/uso terapêutico , Índice de Gravidade de Doença , Tiques/tratamento farmacológico , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/psicologiaRESUMO
BACKGROUND: Modulation of the endocannabinoid system via monoacylglycerol lipase inhibition with Lu AG06466 (formerly known as ABX-1431) has previously been shown to reduce tics in patients with Tourette syndrome. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of Lu AG06466 in reducing tics, premonitory urges, and comorbidities in patients with Tourette syndrome. METHODS: This was a 12-week, multicenter, randomized, placebo-controlled, double-blind clinical trial of Lu AG06466 given at two dose levels in 49 adults with Tourette syndrome. RESULTS: Both treatment groups showed improvement on the Total Tic Score of the Yale Global Tic Severity Scale; the mean (95% CI) treatment difference at week 8 of 3.0 (0.1, 5.9) (P = 0.043) favored placebo. No significant differences were seen for other endpoints assessing changes in tic severity, premonitory urges, quality of life, and common psychiatric comorbidities. Treatment with Lu-AG06466 was generally safe. CONCLUSIONS: There was no evidence that Lu AG06466 has efficacy in suppressing tics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Monoacilglicerol Lipases/antagonistas & inibidores , Piperazinas/uso terapêutico , Pirrolidinas/uso terapêutico , Tiques , Síndrome de Tourette , Adulto , Humanos , Qualidade de Vida , Índice de Gravidade de Doença , Síndrome de Tourette/tratamento farmacológicoRESUMO
BACKGROUND: The immune response to seasonal influenza vaccines decreases with advancing age. Therefore, an adjuvanted inactivated trivalent influenza vaccine (Fluad®) exists for elderly individuals. Fluad® is more immunogenic and efficacious than conventional influenza vaccines. However, the immune response varies and may still result in high frequencies of poor responders. Therefore, we aimed to a) examine the prevalence of a weak response to Fluad® and b) identify potential risk factors. METHODS: A prospective population-based study among individuals 65-80 years old was conducted in 2015/2016 in Hannover, Germany (n = 200). Hemagglutination-inhibition titers 21 days after vaccination with Fluad® served as indicator of vaccine responsiveness. RESULTS: The percentage of vaccinees with an inadequate vaccine response varied depending on the influenza strain: it was lowest for H3N2 (13.5%; 95% CI, 9.4-18.9%), intermediate for B strain (37.0%; 30.6-43.9%), and highest for H1N1 (49.0%; 42.2-55.9%). The risk of a weak response to the influenza A H1N1 strain was independently associated with self-reported diabetes (AOR, 4.64; 95% CI, 1.16-18.54), a history of herpes zoster (2.27; 1.01-5.10) and, to a much lesser extent, increasing age (change per year, 1.08; 0.99-1.16). In addition, herpes zoster was the only risk factor for a weak response to the H3N2 antigen (AOR, 3.12; 1.18-8.23). We found no significant association between sex, Body Mass Index, cancer, hypertension, heart attack and CMV seropositivity and a weak response to these two influenza A antigens. Despite its occurence in over one third of vaccinees, none of the variables examined proved to be risk factors for a weak response to the B antigen. CONCLUSIONS: A considerable proportion of elderly individuals displayed a weak vaccine response to this adjuvanted seasonal influenza vaccine and further efforts are thus needed to improve immune responses to influenza vaccination among the elderly. Diabetes and herpes zoster were identified as potentially modifiable risk factors for a poor vaccine response against influenza A antigens, but the results also reveal the need for broader investigations to identify risk factors for inadequate responses to influenza B antigens. TRIAL REGISTRATION: No. NCT02362919 (ClinicalTrials.gov, date of registration: 09.02.2015).
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Diabetes Mellitus/imunologia , Herpes Zoster/imunologia , Imunidade Humoral , Vacinas contra Influenza/imunologia , Adjuvantes Imunológicos/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/imunologia , Feminino , Alemanha , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/farmacologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Masculino , Estudos Prospectivos , Estações do Ano , AutorrelatoRESUMO
OBJECTIVE: To determine if inclusion/exclusion (I/E) criteria of clinical trial protocols can be represented as structured queries and executed using a secure federated research platform (InSite) on hospital electronic health records (EHR) systems, to estimate the number of potentially eligible patients. METHODS: Twenty-three clinical trial protocols completed during 2011-2017 across diverse disease areas were analyzed to construct queries that were executed with InSite using EHR records from 24 European hospitals containing records of >14 million patients. The number of patients matching I/E criteria of each protocol was estimated. RESULTS: All protocols could be formalized to some extent into a medical coding system (e.g. ICD-10CM, ATC, LOINC, SNOMED) and mapped to local hospital coding systems. The median number of I/E criteria of protocols tested was 29 (range: 14-47). A median of 55% (range 38-89%) of I/E criteria in each protocol could be transformed into a computable format. The median number of eligible patients identified was 26 per hospital site (range: 1-134). CONCLUSION: Clinical trial I/E eligibility criteria can be structured computationally and executed as queries on EHR systems to estimate the patient recruitment pool at each site. The results further suggest that an increase in structured coded information in EHRs would increase the number of I/E criteria that could be evaluated. Additional work is needed on broader deployment of federated platforms such as InSite.
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Protocolos de Ensaio Clínico como Assunto , Registros Eletrônicos de Saúde , Europa (Continente) , Hospitais , Humanos , Seleção de PacientesRESUMO
Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. TRIAL REGISTRATION: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Diarreia/induzido quimicamente , Feminino , Humanos , Hipopotassemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Polimorfismo de Nucleotídeo Único , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismoRESUMO
Increased adverse health effects in older subjects due to exposure to ambient air pollutants may be related to the inflammatory response induced by these contaminants. The aim of this study was to assess airway and systemic inflammatory responses in older healthy subjects to a controlled experimental exposure with spark-generated elemental carbon black ultrafine particles (cbUFPs) and ozone (O3). Twenty healthy subjects, age 52-75 years, were exposed on three occasions separated by at least 8 weeks. The exposures to filtered air (FA), to cbUFP (50 µg/m3), or to cbUFP in combination with 250 ppb ozone (cbUFP + O3) for 3 h with intermittent exercise were performed double blind, and in random order. Sputum and blood samples were collected 3.5 h after each exposure. Exposure to cbUFP + O3 significantly increased plasma club cell protein 16 (CC16), the number of sputum cells, the number and percent of sputum neutrophils, and sputum interleukin 6 and matrix metalloproteinase 9. Exposure to cbUFP alone exerted no marked effect, except for an elevation in sputum neutrophils in a subgroup of 13 subjects that displayed less than 65% sputum neutrophils after FA exposure. None of the inflammatory markers was correlated with age, and serum cardiovascular risk markers were not markedly affected by cbUFP or cbUFP + O3. Exposure to cbUFP+O3 induced a significant airway and systemic inflammatory response in older healthy volunteer subjects. The effects induced by cbUFP alone suggest that the inflammation was predominantly mediated by O3, although one cannot rule out that the interaction of cbUFP and O3 played a role.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Ozônio/efeitos adversos , Sistema Respiratório/efeitos dos fármacos , Fuligem/efeitos adversos , Sistema Nervoso Simpático/efeitos dos fármacos , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Alemanha , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Sistema Respiratório/imunologia , Sistema Nervoso Simpático/fisiologiaRESUMO
BACKGROUND: Participation in epidemiological studies has strongly declined in recent years. We examined the reasons for (non)participation in population-based health studies among participants and nonparticipants of a prospective study on influenza vaccination among the elderly. METHODS: Males and females between 65 and 80 years of age (N = 5582) were randomly selected from the residents' registration office in Hannover, Germany, and were invited to participate in a study featuring vaccination with a seasonal adjuvanted influenza vaccine (Fluad™, Novartis) including five follow-up visits (day 0, 1/3, 7, 21, 70 with respect to vaccination). A 24-item nonresponder questionnaire, including 10 items on reasons for participating in a hypothetical health study, was mailed to 1500 randomly selected nonparticipants. The same 10 items were included in the end-of-study questionnaire administered to the participants in the vaccination study (n = 200). Logistic regression analysis with backward elimination was used to identify the reasons most strongly associated with nonparticipation. RESULTS: Five hundred thirty-one (35%) nonparticipants and 200 participants (100%) returned the respective questionnaires. Nonparticipation was associated with a lower interest in obtaining personal health information (OR = 3.32) and a preference for less invasive (OR = 3.01) and less time-demanding (OR = 2.19) studies. Responses to other items, e.g. regarding altruistic motives, monetary compensation, general interest of the study, or study approval through ethics committee and data security authority, did not differ between participants and nonparticipants. CONCLUSIONS: Participation rates in health studies among elderly individuals could potentially be improved by reducing interventions and time demand, for instance by implementing methods of self-sampling and remote data collection. TRIAL REGISTRATION: No. 1100359 (ClinicalTrials.gov, date of registration: 09.02.2015).
Assuntos
Inquéritos Epidemiológicos , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Cooperação do Paciente/psicologia , Recusa de Participação/psicologia , Vacinação/estatística & dados numéricos , Idoso , Feminino , Alemanha , Humanos , Masculino , Motivação , Estudos ProspectivosRESUMO
OBJECTIVE: Cognitive control as well as stress reactivity is assumed to depend on prefrontal dopamine and decline with age. Because Ginkgo biloba extract EGb761 increases prefrontal dopamine in animals, we assessed its effects on cognitive functions related to prefrontal dopamine. METHODS: Effects of 240-mg EGb761 daily on task-set-switching, response-inhibition, delayed response, prospective-memory, task-related fMRI-BOLD-signals and the Trier Social Stress-Test were explored in a randomized, placebo-controlled, double-blind pilot-trial in 61 elderly volunteers with subjective memory impairment. RESULTS: Baseline-FMRI-data showed BOLD-responses in regions commonly activated by the specific tasks. Task-switch-costs decreased with EGb761 compared to placebo (ANOVA-interaction: Group × Time × Switch-Costs p = 0.018, multiple tests uncorrected), indicating improved cognitive flexibility. Go-NoGo-task reaction-times corrected for error-rates indicated a trend for improved response inhibition. No treatment effects were found for the delayed response and prospective-memory tasks and fMRI-data. A non-significant trend indicated a potentially accelerated endocrine stress-recovery. EGb761 was safe and well tolerated. CONCLUSION: We observed indications for improved cognitive flexibility without changes in brain activation, suggesting increased processing efficiency with EGb761. Together with a trend for improved response inhibition results are compatible with mild enhancement of prefrontal dopamine. These conclusions on potential beneficial effect of EGb761 on prefrontal dopaminergic functions should be confirmed by direct measurements. © 2016 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.
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Cognição/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Idoso , Envelhecimento , Dopamina/metabolismo , Método Duplo-Cego , Feminino , Ginkgo biloba , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Extratos Vegetais/efeitos adversos , Córtex Pré-Frontal/metabolismo , Tempo de Reação/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológicoRESUMO
Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations. The possibility of ADAD--not previously suspected in two of our patients--should always be considered in neurodegenerative conditions albeit they might neither exhibit the typical clinical picture of Alzheimer's disease nor early onset dementia, which is regarded the primary clinical sign of hereditary neurodegeneration.
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Doença de Alzheimer/genética , Mutação , Presenilina-1/genética , Adulto , Idade de Início , Idoso , Doença de Alzheimer/fisiopatologia , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
PURPOSE: To evaluate the outcomes of patients participating in a program of integrated care for osteoporosis in terms of medication supply, fracture incidence and expenses. METHODS: Outcomes were assessed from secondary data provided by the AOK PLUS health insurance for 2455 participants of the program and the same number of matched controls who were also diagnosed with osteoporosis but did not participate in the program. Supply with Calcium and Vitamin D, antiresorptive agents and analgesics was assessed by defined daily doses. Osteoporotic fractures were identified by hospitalization data. Costs for fracture treatment, medication supply and additional expenses of the program were also included in the dataset. RESULTS: Patients enrolled in the program of integrated care received significantly more medication to treat osteoporosis than controls. There was no significant reduction in fracture incidence among participants of integrated care, but a reduced need of analgesics was noted. Additional costs for patients enrolled in the program were caused by a higher number of drug prescriptions, higher costs for stationary treatment and additional expenses for program related care and diagnostics. CONCLUSIONS: The program of integrated care was not found to be effective in reducing recurrent fractures. Cost effectiveness defined as a reduced rate of fractures in integrated care patients could not be shown by the assessed outcome measures. This missing reduction in fracture incidence may be explained by a non-sufficient improvement - compared to a placebo-controlled clinical trial - in medication supply and non-comparability of our real-world patient population with highly controlled clinical trial participants.
Assuntos
Prestação Integrada de Cuidados de Saúde , Fraturas por Osteoporose/prevenção & controle , Prevenção Secundária , Analgésicos/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Cálcio/administração & dosagem , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Análise Custo-Benefício , Prestação Integrada de Cuidados de Saúde/economia , Suplementos Nutricionais , Custos de Medicamentos , Pesquisa sobre Serviços de Saúde , Custos Hospitalares , Hospitalização , Humanos , Incidência , Estimativa de Kaplan-Meier , Modelos Logísticos , Fraturas por Osteoporose/economia , Fraturas por Osteoporose/epidemiologia , Avaliação de Programas e Projetos de Saúde , Prevenção Secundária/economia , Prevenção Secundária/métodos , Resultado do Tratamento , Estados Unidos/epidemiologia , Vitaminas/administração & dosagemRESUMO
Human challenge studies (HCS) are controlled clinical trials in which participants are deliberately infected with a pathogen. Such trials are being developed for an increasing number of diseases. Partly as a result of the coronavirus disease 2019 (COVID-19) pandemic, there has been a recent ethical debate about the reasons for and against HCS in general, or rather, about the requirements that individual HCS must fulfill to be ethically acceptable. A systematic review was conducted to categorize and summarize such requirements and the reasons given for them. Ethics literature was searched in PubMed, Google Scholar, BELIT, and PhilPapers; eligibility criteria were articles published in a scientific/scholarly journal (original research, reviews, editorials, opinion pieces, and conference/meeting reports). Of 1,322 records identified, 161 publications were included, with 183 requirements (with associated reasons) in 10 thematic categories extracted via qualitative content analysis. In synthesizing and interpreting the requirements and their reasons, three issues emerge as particularly sensitive in the case of HCS: the meaning of the right to withdraw from research procedures, communication of researchers with the public and various stakeholders, and the conditions of informed consent. However, four other issues, not specific to HCS, stand out as the most controversial: the acceptable level of risk to participants, payment of participants, protection of vulnerable groups, and standards for international collaborations. Controversies in these areas indicate that further debate is warranted, possibly leading to more specific instructions in ethics guidance documents.
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COVID-19 , Consentimento Livre e Esclarecido , Humanos , Projetos de PesquisaRESUMO
BACKGROUND: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis. METHODS: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete. FINDINGS: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab). INTERPRETATION: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising. FUNDING: This study was supported by funding from Hoffman-La Roche.
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COVID-19 , Hemofilia A , Masculino , Adulto , Humanos , Feminino , Idoso , Hemofilia A/tratamento farmacológico , Fator VIII/uso terapêutico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Hemorragia/tratamento farmacológicoRESUMO
PURPOSE: Regulatory authorities including the Food and Drug Administration and the European Medicines Agency are encouraging to conduct clinical trials using routinely collected data. The aim of the TransFAIR experimental comparison was to evaluate, within real-life conditions, the ability of the Electronic Health Records to Electronic Data Capture (EHR2EDC) module to accurately transfer from EHRs to EDC systems patients' data of clinical studies in various therapeutic areas. METHODS: A prospective study including six clinical trials from three different sponsors running in three hospitals across Europe has been conducted. The same data from the six studies were collected using both traditional manual data entry and the EHR2EDC module. The outcome variable was the percentage of data accurately transferred using the EHR2EDC technology. This percentage was calculated considering all collected data and the data in four domains: demographics (DM), vital signs (VS), laboratories (LB) and concomitant medications (CM). RESULTS: Overall, 6143 data points (39.6% of the data in the scope of the TransFAIR study and 16.9% when considering all data) were accurately transferred using the platform. LB data represented 65.4% of the data transferred; VS data, 30.8%; DM data, 0.7% and CM data, 3.1%. CONCLUSIONS: The objective of accurately transferring at least 15% of the manually entered trial datapoints using the EHR2EDC module was achieved. Collaboration and codesign by hospitals, industry, technology company, supported by the Institute of Innovation through Health Data was a success factor in accomplishing these results. Further work should focus on the harmonisation of data standards and improved interoperability to extend the scope of transferable EHR data.
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Registros Eletrônicos de Saúde , Tecnologia , Estados Unidos , Humanos , Estudos Prospectivos , Coleta de Dados , Europa (Continente)RESUMO
PURPOSE: The purpose of this study was to investigate the adequacy of hypertension management in hypertensive elderly living in long-term-care facilities compared with home-living elderly. METHODS: This retrospective, cross-sectional, pharmacoepidemiological study compared data from a community-dwelling population (CD) and from four nursing homes (NH) in Dresden, Germany. Individuals aged ≥ 65 with the diagnosis of arterial hypertension were included. Demographical, medical, and drug prescription data as well as blood pressure (BP) values were analyzed and compared descriptively after matching the populations by age and gender. RESULTS: Each population comprised 209 patients (mean age 80.4 years [± 6], 70.3% women). NH showed a higher number of diseases [7 (5-9) vs. 5 (3-7); p < 0.001]. BP (<140/90 mmHg) was better controlled in NH (61.0% vs. 48.1%; p = 0.015). The median number of BP-lowering drugs was three (2-4; CD) and two (1-3; NH) (range: 0-9). Most frequently used antihypertensives were diuretics and beta-blockers. Among renin-angiotensin system (RAS) blockers, angiotensin-receptor blockers (ARBs) were preferred in CD and angiotensin-converting enzyme (ACE) inhibitors in NH. Drug treatment for secondary prevention of myocardial infarction or stroke [acetylsalicylic acid (ASA) 100, RAS-blocker, beta-blocker, statin] was low among both groups (CD 21.3%; NH 1.6%; p = 0.01). NH received more inappropriate drugs, especially tranquillizers (31.2% vs. 21.0%; p < 0.05) [according to the PRISCUS (Latin for "old and venerable") list for potentially inappropriate medications in the elderly (PIM)]. CONCLUSIONS: NH residents showed better BP control than CD elderly while receiving less antihypertensive drugs. The prescription of antihypertensives was assumed to be more cost effective in NH. Nevertheless, inappropriate drug use is still high (NH > CD), and there is an extended need for professional medication assessment in both groups of elderly.
Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Comorbidade , Estudos Transversais , Diuréticos/uso terapêutico , Quimioterapia Combinada , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Feminino , Alemanha/epidemiologia , Transtornos do Metabolismo de Glucose/tratamento farmacológico , Transtornos do Metabolismo de Glucose/epidemiologia , Instituição de Longa Permanência para Idosos , Humanos , Prescrição Inadequada , Masculino , Casas de Saúde , Prevalência , Estudos RetrospectivosRESUMO
The separation of colloidal nanocrystals from their original synthesis medium is an essential process step towards their application, however, the costs on a preparative scale are still a constraint. A new combination of approaches for the purification of hydrophobic Quantum Dots is presented, resulting in an efficient scalable process in regard to time and solvent consumption, using common laboratory equipment and low-cost materials. The procedure is based on a combination of solvent-induced adhesion and solid phase extraction. The platform allows the transition from manual handling towards automation, yielding an overall purification performance similar to one conventional batch precipitation/centrifugation step, which was investigated by thermogravimetry and gas chromatography. The distinct miscibility gaps between surfactants used as nanoparticle capping agents, original and extraction medium are clarified by their phase diagrams, which confirmed the outcome of the flow chemistry process. Furthermore, the solubility behavior of the Quantum Dots is put into context with the Hansen solubility parameters framework to reasonably decide upon appropriate solvent types.
RESUMO
Seasonal influenza outbreaks, especially in high-risk groups such as the elderly, represent an important public health problem. Prevailing inadequate efficacy of seasonal vaccines is a crucial bottleneck. Understanding the immunological and molecular mechanisms underpinning differential influenza vaccine responsiveness is essential to improve vaccination strategies. Here we show comprehensive characterization of the immune response of randomly selected elderly participants (≥ 65 years), immunized with the adjuvanted influenza vaccine Fluad. In-depth analyses by serology, multi-parametric flow cytometry, multiplex and transcriptome analysis, coupled to bioinformatics and mathematical modelling, reveal distinguishing immunological and molecular features between responders and non-responders defined by vaccine-induced seroconversion. Non-responders are specifically characterized by multiple suppressive immune mechanisms. The generated comprehensive high dimensional dataset enables the identification of putative mechanisms and nodes responsible for vaccine non-responsiveness independently of confounding age-related effects, with the potential to facilitate development of tailored vaccination strategies for the elderly.
Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Idoso , Anticorpos Antivirais , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/farmacologia , VacinaçãoRESUMO
BACKGROUND: We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV2 spike (S) protein encapsulated in lipid nanoparticles (LNP). METHODS: This is an interim analysis of a dosage escalation phase 1 study in healthy 18-60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV2 Sprotein and receptor binding domain (RBD), and SARS-CoV2 neutralizing titers (MN50). RESULTS: In 245 volunteers who received 2 CVnCoV vaccinations (2⯵g, nâ¯= 47, 4⯵g, nâ¯= 48, 6⯵g, nâ¯= 46, 8⯵g, nâ¯= 44, 12⯵g, nâ¯= 28) or placebo (nâ¯= 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to Sprotein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to Sprotein or RBD, and 83% (19/23) seroconverted for MN50 in the 12⯵g group. Responses to 12⯵g were comparable to those observed in convalescent sera from known COVID-19 patients. CONCLUSION: In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12⯵g dosages elicited levels of immune responses that overlapped those observed in convalescent sera.
Assuntos
COVID-19 , Nanopartículas , Vacinas , Adolescente , Adulto , Anticorpos Antivirais , COVID-19/terapia , Vacinas contra COVID-19 , Método Duplo-Cego , Humanos , Imunização Passiva , Imunogenicidade da Vacina , Lipídeos , Pessoa de Meia-Idade , RNA Mensageiro , SARS-CoV-2 , Adulto Jovem , Soroterapia para COVID-19RESUMO
There are many angles to consider in drug treatment of obese patients. On the one hand, some specific weight loss drugs are available, on the other, several drugs are associated with unintentional weight changes. When treating an obese patient for any given disease, several physiological changes may influence the pharmacokinetic properties of the drugs required. Thus, increased body weight may influence the efficacy and safety of some drug treatments. Even more complicated is the situation after weight reduction surgery. Due to the various changes to the gastrointestinal tract induced by the different surgical techniques used, and the dynamic changes in body composition thereafter, drug dosing has to be constantly reconsidered. Whereas all of these issues are of clinical importance, none of them have been investigated in the necessary depth and broadness to ensure safe and efficacious drug treatment of the massively obese patient. Individual considerations have to be based on comorbidities, concomitant medication, and on specific drug properties, for example, lipophilicity, volume of distribution, and metabolism. In this article we summarize the data available on different aspects of drug treatment in the obese patient with the hope of improving patient care.