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1.
JAMA ; 325(15): 1513-1523, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877274

RESUMO

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.


Assuntos
Anemia Falciforme/tratamento farmacológico , Dor/tratamento farmacológico , Poloxâmero/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/complicações , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Placebos/efeitos adversos , Placebos/uso terapêutico , Poloxâmero/efeitos adversos , Vasodilatadores/efeitos adversos , Adulto Jovem
2.
Medicine (Baltimore) ; 100(16): e25437, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879675

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of morbidity and mortality in clinical practice. This study aims to determine the ranolazine for prevention and treatment of atrial fibrillation. METHOD: This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols. Chinese electronic Database (CBM, Wanfang, and CNKI) and international electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) will be searched for all relevant published articles. We will apply no language or the year of publication restrictions. Study selection, data collection, and assessment of study bias will be conducted independently by a pair of independent reviewers. The Cochrane risk of bias (ROB) tool will be used for the risk of bias assessment. The quality of evidence will be evaluated by Grading of Recommendations Assessment Development and Evaluation (GRADE) system. The statistical analysis of this meta-analysis will be calculated by Review manager version 5.3. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: This review will evaluate the value of ranolazine interventions for patients with AF, and provide meaningful conclusions or high-level evidence for clinical practice and further research. TRIAL REGISTRATION: This study protocol was registered in open Science framework (OSF), (Registration DOI: 10.17605/OSF.IO/T6W9Q).


Assuntos
Antiarrítmicos/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Ranolazina/administração & dosagem , Prevenção Secundária/métodos , Bloqueadores dos Canais de Sódio/administração & dosagem , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/mortalidade , Fibrilação Atrial/prevenção & controle , Humanos , Metanálise como Assunto , Placebos/administração & dosagem , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Medição de Risco , Bloqueadores dos Canais de Sódio/efeitos adversos , Resultado do Tratamento
3.
Medicine (Baltimore) ; 100(13): e25383, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787645

RESUMO

INTRODUCTION: Diastolic heart failure (DHF) is an important pathological type of heart failure, that involves multiple organ dysfunction and multiple complications. The prevalence of DHF is high, and effective treatments are lacking. Chinese herbs are an alternative therapy for DHF. Shen'ge formula (SGF) is a classical formula from which patients can benefit, but convincing evidence of its efficacy is lacking. Therefore, we designed this randomized controlled trial protocol. METHODS/DESIGN: This randomized, double-blind, placebo-controlled clinical trial will evaluate the efficacy and safety of SGF in the treatment of DHF. A total of 130 patients with DHF will be enrolled in the trial and treated with SGF granules or placebo for 12 weeks and followed up for 12 weeks. The primary outcome measurement will be to changes in plasma N-terminal brain natriuretic peptide precursor before versus after treatment, while the second primary outcome measurement will be changes in heart function before versus after treatment and the 12-week follow-up period. It will also include echocardiography, a cardiopulmonary exercise test, cardiac function grading, traditional Chinese medicine syndrome score, and the Minnesota Heart Failure Quality of Life Scale. Adverse events will be evaluated throughout the trial. DISCUSSION: The results of this trial will demonstrate whether SGF could alleviate symptoms, improve cardiac function, reduce readmission rates, and improve quality of life of patients with DHF. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000036533, registered on August 24, 2020.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Insuficiência Cardíaca Diastólica/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Medicamentos de Ervas Chinesas/efeitos adversos , Ecocardiografia , Teste de Esforço , Feminino , Seguimentos , Insuficiência Cardíaca Diastólica/sangue , Insuficiência Cardíaca Diastólica/complicações , Insuficiência Cardíaca Diastólica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Placebos/administração & dosagem , Placebos/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
4.
Trials ; 22(1): 95, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33499921

RESUMO

BACKGROUND: Epidemiological studies have shown that young women often suffer from primary dysmenorrhea (PD) which is a common cause that affects their routine work and quality of life. Chinese herbal medicine has been widely used for PD in China. A systematic review found that Xuefu Zhuyu (XFZY) has a promising effect on PD management, yet there is a dearth of high-quality evidence in support of this claim. We want to conduct a randomized controlled trial to evaluate the efficacy and safety of XFZY for PD patients. METHODS: This is a protocol for a multicenter, randomized, placebo-controlled trial. A total of 248 participants with PD will be recruited at 6 centers and randomized into two groups-a herbal treatment group and a placebo group. The participants will receive either XFZY or placebo, three times per day, for 3 menstrual cycles, with a 12-week follow-up. The primary outcome will be the mean change in pain intensity as measured by VAS, while the change in menstrual pain duration, the change in peak pain intensity as measured by VAS, the Cox Menstrual Symptom Scale (CMSS), quality of life EQ-5D-5L, cumulative painkiller consumption, and health economics will be included as secondary outcomes. Adverse events will also be reported. DISCUSSION: This protocol describes a multicenter, double-blind, randomized, placebo-controlled trial that investigates the efficacy and safety of XFZY for primary dysmenorrhea. Validated evaluation tools will assess dysmenorrhea severity. We believe that this research will provide important evidence regarding the use of XFZY to treat dysmenorrhea. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900026819 . Registered on 23 October 2019.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Dismenorreia/tratamento farmacológico , Adolescente , Adulto , Analgésicos/administração & dosagem , China , Ensaios Clínicos Fase IV como Assunto , Método Duplo-Cego , Esquema de Medicação , Medicamentos de Ervas Chinesas/efeitos adversos , Dismenorreia/complicações , Dismenorreia/diagnóstico , Dismenorreia/psicologia , Feminino , Humanos , Estudos Multicêntricos como Assunto , Medição da Dor/estatística & dados numéricos , Placebos/administração & dosagem , Placebos/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
Lancet Respir Med ; 9(4): 360-372, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493448

RESUMO

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.


Assuntos
Cuidados Críticos/métodos , Heparina/administração & dosagem , Respiração Artificial/efeitos adversos , /epidemiologia , Atividades Cotidianas , Administração por Inalação , Adulto , Idoso , Austrália/epidemiologia , Método Duplo-Cego , Feminino , Hemoptise/induzido quimicamente , Hemoptise/epidemiologia , Heparina/efeitos adversos , Mortalidade Hospitalar , Humanos , Hipóxia/induzido quimicamente , Hipóxia/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Placebos/administração & dosagem , Placebos/efeitos adversos , /etiologia , Autorrelato/estatística & dados numéricos , Índice de Gravidade de Doença , Sobreviventes/estatística & dados numéricos , Fatores de Tempo , Resultado do Tratamento
6.
Trials ; 22(1): 2, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397432

RESUMO

OBJECTIVE: General: To assess the virucidal efficacy of povidone iodine (PVP-I) on COVID-19 virus located in the nasopharynx Specific: i. To evaluate the efficacy of povidone iodine (PVP-I) to removeCOVID-19 virus located in the nasopharynx ii. To assess the adverse events of PVP-I TRIAL DESIGN: This is a single-center, open-label randomized clinical trial with a 7-arm parallel-group design. PARTICIPANTS: The study will be conducted at Dhaka Medical College Hospital, Dhaka, Bangladesh. INCLUSION CRITERIA: All RT-PCR-confirmed COVID-19 cases aged between 15-90 years with symptoms for the past 4 days will be screened. Those who give informed consent, are willing to participate, and accept being randomized to any assigned group will also be considered for final inclusion. EXCLUSION CRITERIA: Patients with known sensitivity to PVP-I aqueous antiseptic solution or any of its listed excipients or previously diagnosed thyroid disease or who had a history of chronic renal failure: stage ≥3 by estimated glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) or had acute renal failure (KDIGO ≥stage 2: creatinine ≥2 times from the baseline) or patients who required invasive or noninvasive ventilation or planned within the next 6 hours were considered for exclusion. Moreover, lactating or pregnant women will also be restricted to include here. INTERVENTION AND COMPARATOR: This RCT consist of seven arms: Arm-1 (intervention group): will receive povidone iodine (PVP-I) nasal irrigation (NI) at a concentration of 0.4% Arm-2 (intervention group): will receive PVP-I nasal irrigation at a concentration of 0.5% Arm-3 (intervention group): will receive PVP-I nasal irrigation at a concentration of 0.6%. Arm-4 (intervention group): will receive PVP-I nasal spray (NS) at a concentration of 0.5%. Arm-5 (intervention group): will receive PVP-I nasal spray at a concentration of 0.6%. Arm-6 (placebo comparator group): will receive distilled water through NI Arm-7 (Placebo comparator group): will receive distilled water through NS The intervention arms will be compared to the placebo comparator arms. Other supportive and routine care will be the same in both groups. MAIN OUTCOMES: The primary outcome is the proportion of cases that remain COVID-19 positive following the intervention. It will be assessed from 1 minutes to 15 minutes after the intervention. Any occurrence of adverse effects following the intervention will be documented as a secondary outcome. RANDOMIZATION: The assignment to the study (intervention) or control (comparator) group will be allocated in equal numbers through randomization using random number generation in Microsoft Excel by a statistician who is not involved in the trial. The allocation scheme will be made by an independent statistician using a sealed envelope. The participants will be allocated immediately after the eligibility assessment and consenting procedures. BLINDING (MASKING): This is an open-label clinical trial, and no blinding or masking will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 189 confirmed cases of COVID-19 will be randomized into seven groups. In each arm, a total of 27 participants will be recruited. TRIAL STATUS: The current trial protocol is Version 1.5 from September 10, 2020. Recruitment began September 30, 2020 and is anticipated to be completed, including data analysis by February 28, 2021. TRIAL REGISTRATION: The trial protocol has been registered in the ClinicalTrials.gov on September 16, 2020. NCT Identifier number: NCT04549376 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Nasofaringe/virologia , Povidona-Iodo/administração & dosagem , /efeitos dos fármacos , Administração Intranasal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bangladesh , /virologia , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lavagem Nasal , Sprays Nasais , Nasofaringe/efeitos dos fármacos , Placebos/administração & dosagem , Placebos/efeitos adversos , Povidona-Iodo/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
7.
Medicine (Baltimore) ; 99(45): e23014, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157947

RESUMO

BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal disease. Acupuncture, including electroacupuncture (EA) is widely used as a complementary and alternative treatment for patients with FD. This study aimed to explore the effectiveness of EA for the treatment of FD. METHODS: We searched Embase, PubMed, and the Cochrane Central Register of Controlled Trials (Cochrane Library) for randomized controlled trials of FD treated by EA from inception to February 3, 2020. Two reviewers will independently screen studies for data extraction and assess the quality and risk of bias. The Cochrane Collaboration's risk of bias tool, RevMan 5.3 software were used for meta-analysis. Data were pooled to calculate relative risk and 95% confidence intervals (CIs) of substantial improvement after treatment for dichotomous data and mean differences (SMDs) and 95% CIs for continuous data. RESULTS: Seven randomized clinical trials included 853 patients. This meta-analysis investigated the effectiveness of EA alone in the treatment of FD relative to sham-EA or pharmacologic medication (PM). The results showed that EA could significantly improve clinical symptoms. Compared with sham-EA, EA was more effective in reducing symptom scores (SMD -3.44, 95% CI -4.21 to -2.67) and increasing normal slow waves of electrogastrogram (SMD 0.93, 95% CI -0.30 to1.55). When EA was combined with PM, there was no significant difference in reducing symptom scores (SMD -0.18, 95% CI -0.51 to 0.16), increasing the effective rate of clinical symptoms (risk ratio 1.04, 95% CI 0.96 to 1.13), enhancing the level of plasma motilin (SMD 0.93, 95% CI -0.30 to1.55), and reducing gastric half-emptying time (SMD 0.02, 95% CI -0.16 to 0.20). The results also showed that there were very few adverse events reported. CONCLUSION: This meta-analysis suggests that EA is better than the placebo (sham-EA) in treating FD, and the therapeutic effect of EA on FD is equivalent to that of PM on FD. Compared with PM, EA for FD is safer and has fewer adverse reactions. Despite limitations due to the quality and number of the included studies, EA might be used as an effective and safe treatment for FD.


Assuntos
Dispepsia/fisiopatologia , Dispepsia/terapia , Eletroacupuntura/métodos , Terapia por Acupuntura/métodos , Estudos de Casos e Controles , Eletroacupuntura/efeitos adversos , Humanos , Motilina/sangue , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
8.
Cochrane Database Syst Rev ; 7: CD006634, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32678465

RESUMO

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, in which the pathogenesis is believed to be partly influenced by the gut microbiome. Probiotics can be used to manipulate the microbiome and have therefore been considered as a potential therapy for CD. There is some evidence that probiotics benefit other gastrointestinal conditions, such as irritable bowel syndrome and ulcerative colitis, but their efficacy in CD is unclear. This is the first update of a Cochrane Review previously published in 2008. OBJECTIVES: To assess the efficacy and safety of probiotics for the induction of remission in CD. SEARCH METHODS: The following electronic databases were searched: MEDLINE (from inception to 6 July 2020), Embase (from inception to 6 July 2020), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane IBD Review Group Specialised Trials Register, World Health Organization (WHO) International Clinical Trials Registry, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared probiotics with placebo or any other non-probiotic intervention for the induction of remission in CD were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the methodological quality of included studies. The primary outcome was clinical remission. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes. MAIN RESULTS: There were two studies that met criteria for inclusion. One study from Germany had 11 adult participants with mild-to-moderate CD, who were treated with a one-week course of corticosteroids and antibiotics (ciprofloxacin 500 mg twice daily and metronidazole 250 mg three times a day), followed by randomised assignment to Lactobacillus rhamnosus strain GG (two billion colony-forming units per day) or corn starch placebo. The other study from the United Kingdom (UK) had 35 adult participants with active CD (CDAI score of 150 to 450) randomised to receive a synbiotic treatment (comprised of freeze-dried Bifidobacterium longum and a commercial product) or placebo. The overall risk of bias was low in one study, whereas the other study had unclear risk of bias in relation to random sequence generation, allocation concealment, and blinding. There was no evidence of a difference between the use of probiotics and placebo for the induction of remission in CD (RR 1.06; 95% CI 0.65 to 1.71; 2 studies, 46 participants) after six months. There was no difference in adverse events between probiotics and placebo (RR 2.55; 95% CI 0.11 to 58.60; 2 studies, 46 participants). The evidence for both outcomes was of very low certainty due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: The available evidence is very uncertain about the efficacy or safety of probiotics, when compared with placebo, for induction of remission in Crohn's disease. There is a lack of well-designed RCTs in this area and further research is needed.


Assuntos
Doença de Crohn/terapia , Probióticos/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Bifidobacterium longum , Ciprofloxacino/uso terapêutico , Doença de Crohn/microbiologia , Microbioma Gastrointestinal , Humanos , Lactobacillus rhamnosus , Metronidazol/uso terapêutico , Placebos/efeitos adversos , Probióticos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão
9.
BMJ ; 370: m1668, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32690477

RESUMO

Despite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights "predictive coding" and "bayesian brain" as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.


Assuntos
Dor Crônica/tratamento farmacológico , Relações Médico-Paciente/ética , Placebos/efeitos adversos , Padrões de Prática Médica/ética , Teorema de Bayes , Dor Crônica/psicologia , Decepção , Método Duplo-Cego , Ética Médica , Humanos , Efeito Placebo , Placebos/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos
12.
Lancet ; 395(10234): 1444-1451, 2020 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-32234534

RESUMO

BACKGROUND: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. METHODS: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. FINDINGS: From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months. INTERPRETATION: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. FUNDING: Medtronic.


Assuntos
Hipertensão/cirurgia , Rim/inervação , Rim/cirurgia , Adulto , Anti-Hipertensivos/normas , Austrália/epidemiologia , Áustria/epidemiologia , Teorema de Bayes , Pressão Sanguínea/fisiologia , Canadá/epidemiologia , Feminino , Alemanha/epidemiologia , Grécia/epidemiologia , Humanos , Hipertensão/diagnóstico , Hipertensão/etnologia , Irlanda/epidemiologia , Japão/epidemiologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Placebos/efeitos adversos , Estudos Prospectivos , Simpatectomia/métodos , Resultado do Tratamento , Reino Unido/epidemiologia , Estados Unidos/epidemiologia
13.
Trials ; 21(1): 161, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046750

RESUMO

BACKGROUND: Impulsivity and compulsivity are related to emotional and social maladjustment and often underlie psychiatric disorders. Recently, alterations in microbiota composition have been shown to have implications for brain development and social behavior via the microbiota-gut-brain axis. However, the exact mechanisms are not fully identified. Recent evidence suggests the modulatory effect of synbiotics on gut microbiota and the contribution of these agents in ameliorating symptoms of many psychiatric diseases. To date, no randomized controlled trial has been performed to establish the feasibility and efficacy of this intervention targeting the reduction of impulsivity and compulsivity. We hypothesize that supplementation with synbiotics may be an effective treatment in adults with high levels of impulsivity and/or compulsivity. METHODS/DESIGN: This is a prospective, multicenter, double-blind, randomized controlled trial with two arms: treatment with a synbiotic formula versus placebo treatment. The primary outcome is the response rate at the end of the placebo-controlled phase (response defined as a Clinical Global Impression-Improvement Scale score of 1 or 2 = very much improved or much improved, plus a reduction in the Affective Reactivity Index total score of at least 30% compared with baseline). A total of 180 participants with highly impulsive behavior and a diagnosis of attention deficit/hyperactivity disorder (ADHD) and/or borderline personality disorder, aged 18-65 years old, will be screened at three study centers. Secondary outcome measures, including changes in general psychopathology, ADHD symptoms, neurocognitive function, somatic parameters, physical activity, nutritional intake, and health-related quality of life, will be explored at assessments before, during, and at the end of the intervention. The effect of the intervention on genetics, microbiota, and several blood biomarkers will also be assessed. Gastrointestinal symptoms and somatic complaints will additionally be explored at 1-week follow-up. DISCUSSION: This is the first randomized controlled trial to determine the effects of supplementation with synbiotics on reducing impulsive and compulsive behavior. This clinical trial can contribute to explaining the mechanisms involved in the crosstalk between the intestinal microbiome and the brain. If effects can be established by reducing impulsive and compulsive behavior, new cost-effective treatments might become available to these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03495375. Registered on 26 February 2018.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/dietoterapia , Microbioma Gastrointestinal/fisiologia , Comportamento Impulsivo/fisiologia , Probióticos/administração & dosagem , Adolescente , Adulto , Idoso , Transtorno do Deficit de Atenção com Hiperatividade/microbiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Placebos/administração & dosagem , Placebos/efeitos adversos , Probióticos/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
14.
Trials ; 21(1): 14, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907006

RESUMO

BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015.


Assuntos
Suplementos Nutricionais , Neuroproteção/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Adulto , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Neuroproteção/fisiologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Transtornos Psicóticos/sangue , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Vitamina D/efeitos adversos , Vitamina D/sangue , Vitamina D/fisiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/psicologia , Adulto Jovem
15.
Trials ; 21(1): 12, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907056

RESUMO

BACKGROUND: Worldwide, hypertension is an important public health challenge because of its high prevalence and the concomitant risks of cardiovascular disease. It induces half of the coronary heart disease and approximately two-thirds of the cerebrovascular disease burden. Vascular endothelial dysfunction has important roles in the pathophysiology of essential hypertension. Types I and II hypertension can be treated with sang-qi granules (SQG), a Chinese herbal formula. Several experimental studies on animals have shown that SQG can lower blood pressure and myocardial fibrosis by suppressing inflammatory responses. However, no standard clinical trial has confirmed this. Whether SQG can improve endothelial cell function is unknown. METHODS/DESIGN: In this randomized double-blind double-simulation controlled trial, 300 patients with stage I or II hypertension will be recruited and randomly allocated in a 1:1:1 ratio to group A (treatment with SQG and placebo instead of Losartan), group B (treatment with Losartan and placebo instead of SQG), and group C (treatment with SQG and Losartan). In this study, 10 g of SQG (or its placebo) will be administrated twice a day and 50 mg of Losartan (or its placebo) will be administrated once in the morning. The primary endpoint is the drug efficiency for each of the three groups. The secondary endpoints are the change in average systolic and diastolic blood pressure during the day and the night, the change in the rate at which blood pressure drops at night, assessment of target organ damage (heart rate variability, ankle-brachial pressure index, and pulse wave velocity), assessment of any improvement in symptoms (Hypertension Symptom Scale, syndrome integral scale in traditional Chinese medicine, Pittsburgh Sleep Quality Index Scale, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and the 36-Item Short Form Health Survey), blood lipids, serum indicators of vascular function (changes in serum levels of ET-1, TXA2, NO, and PGI2), and safety indicators. DISCUSSION: This study aims to provide clinical evidence on the efficacy and safety of SQG in the treatment of hypertension. Moreover, the possible mechanism by which SQG may lower blood pressure will be explored by observing the protective effect of SQG on vascular endothelial function, as well as its effect on related clinical symptoms, risk factors, and the target organs of hypertension. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR1800016427. Registered on 1 June 2018.


Assuntos
Anti-Hipertensivos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial , China , Método Duplo-Cego , Esquema de Medicação , Medicamentos de Ervas Chinesas/efeitos adversos , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Losartan/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
16.
Gastroenterology ; 158(6): 1554-1573.e12, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31926171

RESUMO

BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/mortalidade , Azetidinas/efeitos adversos , Herpes Zoster/induzido quimicamente , Herpes Zoster/imunologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Incidência , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/mortalidade , Inibidores de Janus Quinases/administração & dosagem , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Janus Quinases/metabolismo , Piperidinas/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/imunologia , Psoríase/mortalidade , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/mortalidade , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversos
17.
Gastroenterology ; 158(3): 550-561, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31711921

RESUMO

BACKGROUND & AIMS: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS: In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. RESULTS: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.


Assuntos
Acetatos/administração & dosagem , Bloqueio Atrioventricular/epidemiologia , Colite Ulcerativa/tratamento farmacológico , Hemorragia Gastrointestinal/prevenção & controle , Indóis/administração & dosagem , Acetatos/efeitos adversos , Adulto , Doenças Assintomáticas/epidemiologia , Bloqueio Atrioventricular/induzido quimicamente , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Colonoscopia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Indóis/efeitos adversos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/métodos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Estudo de Prova de Conceito , Reto , Índice de Gravidade de Doença , Receptores de Esfingosina-1-Fosfato/imunologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Resultado do Tratamento
18.
Gastroenterology ; 158(5): 1334-1345.e5, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31812510

RESUMO

BACKGROUND & AIMS: Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. METHODS: Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. RESULTS: We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (-0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. CONCLUSIONS: In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices. ClinicalTrials.gov number: NCT02462967.


Assuntos
Galectina 3/antagonistas & inibidores , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pectinas/administração & dosagem , Idoso , Biópsia , Método Duplo-Cego , Esquema de Medicação , Feminino , Galectina 3/metabolismo , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/etiologia , Hipertensão Portal/patologia , Infusões Intravenosas , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Pectinas/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Pressão na Veia Porta/efeitos dos fármacos , Índice de Gravidade de Doença , Resultado do Tratamento
19.
J Am Acad Dermatol ; 82(4): 936-945, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31809827

RESUMO

BACKGROUND: Long-term maintenance treatment is required for patients with psoriasis. OBJECTIVES: To evaluate the efficacy and safety of guselkumab in patients with moderate to severe psoriasis through 3 years of treatment. METHODS: In 2 ongoing, phase 3 trials of guselkumab (VOYAGE 1 and VOYAGE 2), the proportions of patients achieving at least 90% and 100% improvement in the Psoriasis Area and Severity Index (PASI 90 and PASI 100, respectively) and Investigator's Global Assessment (IGA) scores of 0/1 and 0 were summarized for the guselkumab group (including placebo-to-guselkumab crossover). Patients who met treatment failure rules were considered nonresponders. Safety outcomes (rates/100 patient-years [PY]) were evaluated based on data pooled across studies through week 156. RESULTS: Three-year response rates for the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively, were 82.8% and 77.2% for PASI 90, 50.8% and 48.8% for PASI 100, 82.1% and 83.0% for IGA score of 0/1, and 53.1% and 52.9% for IGA score of 0. Safety event rates across studies occurred through week 156 as follows: serious adverse events, 5.68/100 PY; serious infections, 1.15/100 PY; nonmelanoma skin cancers, 0.28/100 PY; malignancies other than nonmelanoma skin cancer, 0.47/100 PY; and major adverse cardiovascular events, 0.28/100 PY. Week 156 and week 100 rates were consistent. LIMITATIONS: There was no comparator arm beyond 1 year. CONCLUSIONS: Guselkumab shows durable efficacy and a consistent safety profile in patients with moderate to severe psoriasis treated for up to 3 years.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
20.
Gastroenterology ; 158(1): 111-122.e10, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593702

RESUMO

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Transtornos de Deglutição/tratamento farmacológico , Esofagite Eosinofílica/tratamento farmacológico , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/imunologia , Método Duplo-Cego , Esofagite Eosinofílica/complicações , Esofagite Eosinofílica/imunologia , Mucosa Esofágica/diagnóstico por imagem , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/imunologia , Esofagoscopia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-4/imunologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
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