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1.
Trials ; 21(1): 491, 2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32503663

RESUMEN

OBJECTIVES: The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF. TRIAL DESIGN: A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial. PARTICIPANTS: Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/µL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 µg/mL. INTERVENTION AND COMPARATOR: Inhaled sargramostim 125 µg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 µg/m2 body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m µg/m2 body surface area once daily for 5 days. MAIN OUTCOMES: The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group. TRIAL STATUS: SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on March 30th, 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neumonía Viral/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Respiratoria/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase IV como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Pandemias , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Respiración Artificial , Adulto Joven
2.
Bioanalysis ; 11(22): 2049-2060, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31829738

RESUMEN

Aim: To develop and validate a simple method using UPLC-MS/MS for determination of apatinib and its three active metabolites in a Phase IV clinical trial. Materials & methods: All compounds were separated on a Hypersil GOLD™ aQ C18 Polar Endcapped LC column (50 × 2.1 mm, 1.9 µm, Thermo) using 5 mmol/l ammonium acetate with 0.1% formic acid:acetonitrile (20:80, v/v) as the mobile phase after a rapid liquid-liquid extraction. This method was validated over the linear concentration range of 1.00-1000 ng/ml for each compound. Results: The interassay precision and accuracy were less than ±15%. The validated method was successfully applied to determine concentrations of clinical samples in non-small-cell lung cancer patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Ensayos Clínicos Fase IV como Asunto , Neoplasias Pulmonares/metabolismo , Piridinas/metabolismo , Espectrometría de Masas en Tándem/métodos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Límite de Detección , Modelos Lineales , Extracción Líquido-Líquido , Neoplasias Pulmonares/tratamiento farmacológico , Piridinas/aislamiento & purificación , Piridinas/uso terapéutico
3.
Prog Cardiovasc Dis ; 62(4): 342-348, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31442511

RESUMEN

Concerns of elevated cardiovascular disease (CVD) risk with some anti-diabetic medications warranted phase 4 clinical trials to demonstrate CVD safety of newly marketed anti-diabetic drugs. Although initially designed to evaluate safety, some of these CVD outcome trials (CVOTs) have in fact shown CVD benefits. New medication classes, like glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have shown reductions in the risk of major adverse cardiovascular events (MACE) including, myocardial infarction, stroke, CV death, and heart failure (HF). Perhaps more importantly, SGLT2 inhibitors demonstrated reduction in the risk of HF hospitalizations, being the first class of anti-diabetic drugs to do so. Conversely, dipeptidyl peptidase 4 (DPP-4) inhibitors did not significantly affect atherosclerotic CVD end-points and some actually increased the risk of HF hospitalizations. Further, the adverse/beneficial CVD effects of these medications may not be class specific. This review focuses on the main results of these CVOTs while highlighting the heterogeneity of CVD end-points within each class and discusses important mechanistic insights and adverse effect profiles.


Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Péptido 1 Similar al Glucagón/administración & dosificación , Seguridad del Paciente/estadística & datos numéricos , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/efectos de los fármacos , Ensayos Clínicos Fase IV como Asunto , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Estudios de Seguimiento , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Incidencia , Masculino , Persona de Mediana Edad , Medición de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación
4.
BMC Musculoskelet Disord ; 20(1): 357, 2019 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-31387574

RESUMEN

BACKGROUND: Scaphoid fractures are the most common carpal fractures. They often need to be treated by surgery, where the use of a compression screw is the globally accepted gold standard. Surgeons may choose between different implant materials including titanium alloys, which remain in the body or are removed after healing. An alternative are biodegradable magnesium-based implants. Properties of magnesium alloys include high stability, osteoconductivity, potential reduction of infections and few artifacts in magnetic resonance imaging (MRI). The aim of this trial is to demonstrate non-inferiority of magnesium-based compression screws compared with titanium Herbert screws for scaphoid fractures. METHODS: The trial is designed as a multicenter, blinded observer, randomized controlled parallel two-group post market trial. Approximately 190 patients will be randomized (1:1) with stratification by center either to titanium or magnesium-based compression screws. Follow-up is 1 year per patient. Surgical procedures and aftercare will be performed according to the German treatment guideline for scaphoid fractures. The first primary endpoint is the patient-rated wrist evaluation (PRWE) score after 6 months. The second primary endpoint is a composite safety endpoint including bone union until 6 months, no adverse device effect (ADE) during surgery or wound healing and no serious ADE or reoperation within 1 year. The third primary endpoint is the difference in change MRI artifacts over time. Non-inferiority will be investigated for primary endpoints 1 (t-test confidence interval) and 2 (Wilson's score interval) using both the full analysis set (FAS) and the per protocol population at the one-sided 2.5% test-level. Superiority of magnesium over titanium screws will be established using the FAS at the two-sided 5% test-level (Welch test) only if non-inferiority has been established for both primary endpoints. Secondary endpoints include quality of life. DISCUSSION: This study will inform care providers whether biodegradable magnesium-based implants are non-inferior to standard titanium Herbert screws for the treatment of scaphoid fractures in terms of wrist function and safety. Furthermore, superiority of magnesium-based implants may be demonstrated using MRI, which is used as surrogate endpoint for screw degradation. TRIAL REGISTRATION: DRKS, DRKS00013368 . Registered Dec 04, 2017.


Asunto(s)
Implantes Absorbibles/efectos adversos , Tornillos Óseos/efectos adversos , Fijación Interna de Fracturas/instrumentación , Hueso Escafoides/lesiones , Traumatismos de la Muñeca/cirugía , Adolescente , Adulto , Ensayos Clínicos Fase IV como Asunto , Estudios de Equivalencia como Asunto , Fijación Interna de Fracturas/efectos adversos , Humanos , Magnesio/efectos adversos , Imagen por Resonancia Magnética , Masculino , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Reoperación/estadística & datos numéricos , Hueso Escafoides/diagnóstico por imagen , Hueso Escafoides/cirugía , Titanio/efectos adversos , Resultado del Tratamiento , Traumatismos de la Muñeca/diagnóstico por imagen , Traumatismos de la Muñeca/fisiopatología , Articulación de la Muñeca/diagnóstico por imagen , Articulación de la Muñeca/fisiopatología , Adulto Joven
5.
BMC Infect Dis ; 19(1): 484, 2019 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-31146698

RESUMEN

BACKGROUND: Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents. METHODS: A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4+ cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4+ ≤/>200cells/µL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses). RESULTS: The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78-2.59) and NNRTIs (ORs 1.51-1.86), and similar but numerically higher than other INSTIs. CD4+ count increase was significantly greater with DTG than PIs (difference: 23.63-31.47 cells/µL) and efavirenz (difference: 34.54 cells/µL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76-100%) and NNRTIs (probability: 50-100%), and a greater CD4+ count increase versus PIs (probability: 72-100%) and NNRTIs (probability: 60-100%). DTG was more likely to result in patients achieving VS (probability: 94-100%), and a greater CD4+ count increase (probability: 53-100%) versus other core agents, including INSTIs (probability: 94-97% and 53-93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents. CONCLUSION: INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL, who can be difficult to treat.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Adolescente , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/clasificación , Teorema de Bayes , Benzoxazinas/uso terapéutico , Recuento de Linfocito CD4 , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase IV como Asunto/estadística & datos numéricos , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Masculino , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ritonavir/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Adulto Joven
6.
BMC Med ; 17(1): 105, 2019 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-31159786

RESUMEN

BACKGROUND: News stories represent an important source of information. We aimed to evaluate the impact of "spin" (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit. METHODS: We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants' interpretation assessed by one specific question "What do you think is the probability that 'treatment X' would be beneficial to patients?" (scale, 0 [very unlikely] to 10 [very likely]). RESULTS: For each RCT, 300 participants were randomly assigned to assess a news story with spin (n = 150) or without spin (n = 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0-2.3], p < 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0-2.5], p < 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4-3.2], p < 0.001). CONCLUSIONS: Spin in health news stories reporting studies of pharmacologic treatments affects patients'/caregivers' interpretation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094078 , NCT03094104 , NCT03095586.


Asunto(s)
Cuidadores/psicología , Comunicación , Exactitud de los Datos , Quimioterapia/psicología , Pacientes/psicología , Percepción , Adolescente , Adulto , Anciano , Actitud Frente a la Salud , Cuidadores/educación , Ensayos Clínicos Fase I como Asunto/psicología , Ensayos Clínicos Fase II como Asunto/psicología , Ensayos Clínicos Fase III como Asunto/psicología , Ensayos Clínicos Fase IV como Asunto/psicología , Evaluación Preclínica de Medicamentos/psicología , Femenino , Humanos , Internet/normas , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto/normas , Proyectos de Investigación/normas , Medición de Riesgo , Adulto Joven
7.
Drugs ; 79(9): 997-1008, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31119643

RESUMEN

Tiotropium/olodaterol (Stiolto® Respimat®; Spiolto® Respimat®) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter referred to as tiotropium) and the long-acting ß2-adrenergic agonist olodaterol. It is available in several countries, including the USA, Japan, China and those of the EU, where it is indicated for the long-term maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy of tiotropium/olodaterol 5/5 µg/day in patients with COPD was evaluated in phase III or IV trials of 6-52 weeks' duration. Tiotropium/olodaterol improved lung function to a greater extent than each of its individual components or placebo in 12- and 52-week trials. In 6-week trials, tiotropium/olodaterol provided greater lung function benefits over 24 h than the individual components, placebo or twice-daily fluticasone propionate/salmeterol. Tiotropium/olodaterol also demonstrated beneficial effects on health-related quality of life (HR-QoL), dyspnoea, inspiratory capacity, exercise endurance and the need for rescue medication. In an 8-week open-label trial, umeclidinium/vilanterol was superior to tiotropium/olodaterol for the primary endpoint of trough forced expiratory volume in 1 s. The tolerability profile of tiotropium/olodaterol was generally similar to that of the individual components. In conclusion, tiotropium/olodaterol provides a useful option for the maintenance treatment of COPD, with the convenience of once-daily administration via a single inhaler.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Benzoxazinas/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Bromuro de Tiotropio/uso terapéutico , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Benzoxazinas/farmacología , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Fase IV como Asunto , Combinación de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacología , Calidad de Vida , Bromuro de Tiotropio/farmacología , Resultado del Tratamiento
8.
Arthritis Res Ther ; 21(1): 111, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31046809

RESUMEN

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Vigilancia de Productos Comercializados/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Índice de Severidad de la Enfermedad , Espondilitis Anquilosante/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Artritis Psoriásica/diagnóstico , Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Fase IV como Asunto/métodos , Humanos , Vigilancia de Productos Comercializados/tendencias , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Espondilitis Anquilosante/diagnóstico , Factores de Tiempo
9.
Value Health ; 22(3): 340-347, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30832972

RESUMEN

INTRODUCTION: Diary-derived symptom score and rescue medication use endpoints, such as symptom-free days (SFDs) and rescue medication-free days (RFD), are frequently used as clinical trial endpoints. Estimates of meaningful change for SFDs and RFDs have not been generated in pediatric populations. This research aimed to generate evidence supporting estimates of the individual within-patient changes that constitute an important or meaningful change in SFDs, RFDs, and updated estimates on the Childhood Asthma Control Test (C-ACT) in pediatric asthma populations aged 5-11 years. METHODS: Semistructured, qualitative interviews were conducted with children (ages 8-11 years) who had asthma and parents/caregivers of children (4-11 years) with asthma. Before the interview (4-9 days) participants were asked to complete a morning and evening diary. RESULTS: On average, parent/caregiver estimates of the difference in SFDs between a "very bad" and a "little bad" week for their children's asthma were largely concordant with the values reported by their children (differences of 1.8 and 1.4 SFDs, respectively). Both parents/caregivers and children were able to articulate what a meaningful level of change would be on the C-ACT at the item level. This qualitative study generated C-ACT item-level meaningful change estimates in the region of 1-3 category change, which potentially suggests that, if scaled up to represent C-ACT total score, this would lead to change estimates of 7-15 points. CONCLUSIONS: Our findings suggest that both children with asthma and parents/caregivers can quantitatively estimate and to some extent qualitatively articulate meaningful change in SFDs and RFDs.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto/normas , Ensayos Clínicos Fase IV como Asunto/normas , Uso Significativo/normas , Asma/epidemiología , Niño , Preescolar , Femenino , Humanos , Masculino , Uso Significativo/tendencias , Registros Médicos/normas
10.
Trials ; 20(1): 101, 2019 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-30717805

RESUMEN

BACKGROUND: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy. METHODS: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9-10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5-9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect. DISCUSSION: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT03369210 ).


Asunto(s)
Anemia/terapia , Transfusión de Eritrocitos/métodos , Isquemia/prevención & control , Atención Perioperativa/métodos , Procedimientos Quirúrgicos Operativos , Factores de Edad , Anciano , Anciano de 80 o más Años , Anemia/sangre , Anemia/complicaciones , Anemia/mortalidad , Biomarcadores/sangre , Causas de Muerte , Ensayos Clínicos Fase IV como Asunto , Transfusión de Eritrocitos/efectos adversos , Transfusión de Eritrocitos/mortalidad , Femenino , Alemania , Hemoglobinas/metabolismo , Humanos , Isquemia/sangre , Isquemia/diagnóstico , Isquemia/etiología , Masculino , Estudios Multicéntricos como Asunto , Readmisión del Paciente , Atención Perioperativa/efectos adversos , Atención Perioperativa/mortalidad , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Procedimientos Quirúrgicos Operativos/efectos adversos , Procedimientos Quirúrgicos Operativos/mortalidad , Factores de Tiempo , Resultado del Tratamiento
11.
EBioMedicine ; 41: 50-61, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30738832

RESUMEN

BACKGROUND: We and others have shown that dipeptidyl peptidase-IV (DPP4) expression is increased in obesity/atherosclerosis and is positively correlated with atherosclerotic burden. However, the mechanism by which DPP4 expression is regulated in obesity remains unclear. In this study, we investigated the pathways regulating the expression of DPP4 on macrophages. METHODS: Flowsight® Imaging Flow Cytometry was employed for the detection of DPP4 and immunophenotyping. DPP4 enzymatic activity was measured by a DPPIV-Glo™ Protease Assay kit. FINDINGS: Human monocytes expressed a moderate level of membrane-bound DPP4. Obese patients with body mass index (BMI) ≥ 30 had a higher level of monocyte DPP4 expression, in parallel with higher levels of HOMA-IR, blood glucose, triglycerides, and non-HDL cholesterol, compared to those in the non-obese (BMI < 30) patients. Oxidized low-density lipoprotein (oxLDL), but not native LDL, up-regulated DPP4 expression on macrophages with a preferential increase in CD36+ cells. OxLDL mediated DPP4 up-regulation was considerably diminished by Toll-like receptor-4 (TLR4) knockdown and CD36 deficiency. TRIF deficiency, but not MyD88 deficiency, attenuated oxLDL-induced DPP4 increase. INTERPRETATION: Our study suggests a key role for oxLDL and downstream CD36/TLR4/TRIF in regulating DPP4 expression. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism linking post-prandial glucose metabolism to lipoprotein abnormality-potentiated atherosclerosis.


Asunto(s)
Dipeptidil Peptidasa 4/genética , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Obesidad/metabolismo , Regulación hacia Arriba , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Antígenos CD36/metabolismo , Células Cultivadas , Ensayos Clínicos Fase IV como Asunto , Dipeptidil Peptidasa 4/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptor Toll-Like 4/metabolismo
12.
Cancer Immunol Immunother ; 68(2): 163-174, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30315349

RESUMEN

Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.e. EL-4 lymphoma, MC-38 colorectal carcinoma, and 4T1 mammary carcinoma. In vivo treatment with HDC delayed EL-4 and 4T1 tumor growth and reduced the ROS formation by intratumoral MDSCs. HDC treatment of EL-4 bearing mice also reduced the accumulation of intratumoral MDSCs and reduced MDSC-induced suppression of T cells ex vivo. Experiments using GR1-depleted and Nox2 knock out mice supported that the anti-tumor efficacy of HDC required presence of NOX2+ GR1+ cells in vivo. In addition, treatment with HDC enhanced the anti-tumor efficacy of programmed cell death receptor 1 (PD-1) and PD-1 ligand checkpoint blockade in EL-4- and MC-38-bearing mice. Immunomodulatory effects of a HDC-containing regimen on MDSCs were further analyzed in a phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996) where patients with acute myeloid leukemia received HDC in conjunction with low-dose IL-2 (HDC/IL-2) for relapse prevention. Peripheral CD14+HLA-DR-/low MDSCs (M-MDSCs) were reduced during cycles of HDC/IL-2 therapy and a pronounced reduction of M-MDSCs during HDC/IL-2 treatment heralded favorable clinical outcome. We propose that anti-tumor properties of HDC may comprise the targeting of MDSCs.


Asunto(s)
Anticuerpos/farmacología , Histamina/farmacología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Adulto , Animales , Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Ensayos Clínicos Fase IV como Asunto , Supervivencia sin Enfermedad , Sinergismo Farmacológico , Femenino , Histamina/uso terapéutico , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Resultado del Tratamiento
13.
Alzheimers Dement ; 15(3): 388-399, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30339801

RESUMEN

INTRODUCTION: Reimbursement of amyloid-positron emission tomography (PET) is lagging due to the lack of definitive evidence on its clinical utility and cost-effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease-Diagnostic and Patient Management Study (AMYPAD-DPMS) is designed to fill this gap. METHODS: AMYPAD-DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid-PET performed early in the diagnostic workup; ARM2, amyloid-PET performed after 8 months; and ARM3, amyloid-PET performed whenever the physician chooses to do so. ENDPOINTS: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very-high-confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient-related outcomes, and methods for image quantitation. EXPECTED IMPACTS: AMYPAD-DPMS will supply physicians and health care payers with real-world data to plan management decisions.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/economía , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Protocolos de Ensayos Clínicos como Asunto , Ensayos Clínicos Fase IV como Asunto , Disfunción Cognitiva/economía , Disfunción Cognitiva/metabolismo , Análisis Costo-Beneficio , Manejo de la Enfermedad , Humanos , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Tomografía de Emisión de Positrones/economía , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo
14.
Trials ; 19(1): 707, 2018 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-30591073

RESUMEN

BACKGROUND: Despite the high prevalence of insomnia in patients with advanced cancer, there are no randomized controlled trials on pharmacological interventions for insomnia in this group of patients. A variety of pharmacological agents is recommended to manage sleep disturbance for insomnia in the general population, but their efficacy and safety in adults with advanced cancer are not established. Thus, there is a need to evaluate the effectiveness of medications for insomnia in order to improve the evidence in patients with advanced cancer. One of the most used sleep medications at present in patients with cancer is zopiclone. METHODS: This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 100 patients with metastatic cancer who report insomnia will be randomly allocated to zopiclone or placebo. The treatment duration with zopiclone/placebo is 6 consecutive nights. The primary endpoint is patient-reported sleep quality during the final study night (night 6) assessed on a numerical rating scale of 0-10, where 0 = Best sleep and 10 = Worst possible sleep. Secondary endpoints include the mean patient-reported total sleep time and sleep onset latency during the final study night (night 6). DISCUSSION: Results from this study on treatment of insomnia in advanced cancer will contribute to clinical decision-making and improve the treatment of sleep disturbance in this patient cohort. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02807922 . Registered on 21 June 2016.


Asunto(s)
Compuestos de Azabiciclo/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Neoplasias/complicaciones , Piperazinas/administración & dosificación , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Sueño/efectos de los fármacos , Compuestos de Azabiciclo/efectos adversos , Ensayos Clínicos Fase IV como Asunto , Método Doble Ciego , Esquema de Medicación , Humanos , Hipnóticos y Sedantes/efectos adversos , Estudios Multicéntricos como Asunto , Neoplasias/diagnóstico , Noruega , Piperazinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastornos del Inicio y del Mantenimiento del Sueño/diagnóstico , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/fisiopatología , Factores de Tiempo , Resultado del Tratamiento
15.
Trials ; 19(1): 637, 2018 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-30454042

RESUMEN

BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.


Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Antiarrítmicos/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Unidades de Cuidados Intensivos , Morfolinas/uso terapéutico , Choque Séptico/tratamiento farmacológico , Urea/análogos & derivados , Antagonistas Adrenérgicos beta/efectos adversos , Antiarrítmicos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos Fase IV como Asunto , Europa (Continente) , Humanos , Morfolinas/efectos adversos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Choque Séptico/diagnóstico , Choque Séptico/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Urea/efectos adversos , Urea/uso terapéutico , Vasoconstrictores/uso terapéutico
16.
BMJ Open ; 8(10): e020242, 2018 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-30282677

RESUMEN

INTRODUCTION: There is a need for fast-acting, non-injection antiagitation treatments that are well tolerated and can be used outside of healthcare facilities. In phase II/III trials, an inhaled formulation of loxapine (ADASUVE®), a well-established, first-generation antipsychotic agent, provided rapid control of mild to moderate agitation in the hospital setting. The present study was designed to investigate the safety and efficacy of inhaled loxapine when self-administered outside the hospital setting. METHODS AND ANALYSIS: This phase IV, multicentre, single-arm, open-label clinical trial is being conducted in five countries in Europe: Spain, Germany, Norway, Romania and Austria. The aim is to include approximately 500 patients with schizophrenia or bipolar disorder who previously received and responded well to inhaled loxapine in the hospital setting. Eligible patients will be followed up for 6 months from baseline. They will be given a 10 mg dose of inhaled loxapine to self-administer outside the hospital setting to treat an agitation episode, should one occur. Patients will also be given a short-acting beta-agonist bronchodilator for treatment of possible severe respiratory side effects. The primary endpoint is incidence of serious adverse events (AEs) and respiratory AEs of special interest related to use of inhaled loxapine outside the hospital setting. Secondary endpoints include incidence of other AEs, Clinical Global Impression-Improvement scores up to 2 hours after self-administration of inhaled loxapine, time to improvement of agitation, patient satisfaction with treatment, treatment outcomes according to agitation severity and concordance between the patient (or a family member/caregiver) and the physician in scoring of agitation severity and the decision to self-administer inhaled loxapine. ETHICS AND DISSEMINATION: The protocol received ethics committee approval in the participating countries between January and August 2016. The results of this study will be disseminated through one or more scientific papers. TRIAL REGISTRATION NUMBER: EudraCT2015-003331-36; NCT02525991; Pre-results.


Asunto(s)
Antipsicóticos/administración & dosificación , Trastorno Bipolar/complicaciones , Loxapina/administración & dosificación , Agitación Psicomotora/tratamiento farmacológico , Esquizofrenia/complicaciones , Administración por Inhalación , Antipsicóticos/efectos adversos , Ensayos Clínicos Fase IV como Asunto , Europa (Continente) , Humanos , Loxapina/efectos adversos , Estudios Multicéntricos como Asunto , Nebulizadores y Vaporizadores , Autoadministración , Resultado del Tratamiento
17.
Trials ; 19(1): 413, 2018 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-30064517

RESUMEN

BACKGROUND: While it is has been proven that tranexamic acid (TXA) reduces blood loss in primary total hip and knee arthroplasty (THA and TKA), there is little published evidence on the use of TXA beyond 3 h post-operatively. Most blood loss occurs after wound closure and the primary aim of this study is to determine if the use of oral TXA post-operatively for up to 24 h will reduce calculated blood loss at 48 h beyond an intra-operative intravenous bolus alone following primary THA and TKA. To date, most TXA studies have excluded patients with a history of thromboembolic disease. METHODS/DESIGN: This is a phase IV, single-centred, open-label, parallel-group, randomised controlled trial. Participants are randomised to one of three groups: group 1, an intravenous (IV) bolus of TXA peri-operatively plus oral TXA post-operatively for 24 h; group 2, an IV bolus of TXA peri-operatively or group 3, standard care (no TXA). Eligible participants, including those with a history of thromboembolic disease, are allocated to these groups with a 2:2:1 allocation ratio. The primary outcome is the indirectly calculated blood loss 48 h after surgery. Researchers and patients are not blinded to the treatment; however, staff processing blood samples are. Originally 1166 participants were required to complete this study, 583 THA and 583 TKA. However, following an interim analysis after 100 THA and 100 TKA participants had been recruited to the study, the data monitoring ethics committee recommended stopping group 3 (standard care). DISCUSSION: TRAC-24 will help to determine whether an extended TXA dosing regimen can further reduce blood loss following primary THA and TKA. By including patients with a history of thromboembolic disease, this study will add to our understanding of the safety profile of TXA in this clinical situation. TRIAL REGISTRATION: ISRCTN registry, ISRCTN58790500 . Registered on 3 June 2016, EudraCT: 2015-002661-36.


Asunto(s)
Antifibrinolíticos/administración & dosificación , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Pérdida de Sangre Quirúrgica/prevención & control , Cuidados Intraoperatorios , Cuidados Posoperatorios , Hemorragia Posoperatoria/prevención & control , Ácido Tranexámico/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antifibrinolíticos/efectos adversos , Ensayos Clínicos Fase IV como Asunto , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Cuidados Intraoperatorios/efectos adversos , Masculino , Persona de Mediana Edad , Irlanda del Norte , Cuidados Posoperatorios/efectos adversos , Hemorragia Posoperatoria/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Factores de Tiempo , Ácido Tranexámico/efectos adversos , Resultado del Tratamiento , Adulto Joven
18.
Trials ; 19(1): 324, 2018 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-29925421

RESUMEN

BACKGROUND: The efficacy of a combination of a calcium channel blocker (CCB) plus chlorthalidone (diuretic) versus a CCB plus an angiotensin receptor blocker (ARB) in patients not responding to CCB monotherapy has not been evaluated previously. We plan to compare the efficacy and safety of S-amlodipine (CCB) plus chlorthalidone versus S-amlodipine plus telmisartan (ARB) combinations among hypertension patients unresponsive to amlodipine monotherapy. METHODS/DESIGN: This study is a prospective, randomized, double-blind, multicenter, parallel, non-inferiority phase 4 study. Hypertension patients who have been treated with amlodipine (5 mg) or S-amlodipine (2.5 mg) monotherapy for ≥2 weeks and whose mean diastolic blood pressure (DBP) is greater than 90 mmHg will be randomized to either S-amlodipine (2.5 mg) plus chlorthalidone (25 mg) or S-amlodipine (2.5 mg) plus telmisartan (40 mg) therapy. The primary efficacy endpoint is mean sitting DBP change after 12 weeks of treatment. The study objective is to prove the non-inferiority of the former combination (test drug) as compared to the latter one (control) with a non-inferiority margin of 3 mmHg in mean DBP change. The secondary endpoints are 6-week DBP change, 6- and 12-week sitting systolic BP (SBP) change, and the attainment of the target BP (SBP < 140 mmHg or DBP < 90 mmHg). Urine albumin, albumin/creatinine ratio (ACR), pulse wave velocity, central BP, 24-h ambulatory BP monitoring, and body fluid composition analysis will be performed at each hospital's discretion. The sample size was estimated as 170 in total with 1:1 randomization. DISCUSSION: This is the first study comparing the efficacy of a CCB plus chlorthalidone versus a CCB plus an ARB in patients who are not responding to CCB single therapy. The study result will help clinicians to choose between chlorthalidone and telmisartan in CCB-unresponsive patients. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03226340. Registered on 2 December 2015.


Asunto(s)
Amlodipino/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Clortalidona/uso terapéutico , Diuréticos/uso terapéutico , Hipertensión/tratamiento farmacológico , Telmisartán/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Amlodipino/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Antihipertensivos/efectos adversos , Bloqueadores de los Canales de Calcio/efectos adversos , Clortalidona/efectos adversos , Ensayos Clínicos Fase IV como Asunto , Diuréticos/efectos adversos , Método Doble Ciego , Combinación de Medicamentos , Resistencia a Medicamentos , Estudios de Equivalencia como Asunto , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estudios Prospectivos , República de Corea , Telmisartán/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
19.
Trials ; 19(1): 263, 2018 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-29720238

RESUMEN

BACKGROUND: Acute appendicitis is one of the most common indications for emergency surgery. In patients with a complex appendicitis, prolonged antibiotic prophylaxis is recommended after appendectomy. There is no consensus regarding the optimum duration of antibiotics. Guidelines propose 3 to 7 days of treatment, but shorter courses may be as effective in the prevention of infectious complications. At the same time, the global issue of increasing antimicrobial resistance urges for optimization of antibiotic strategies. The aim of this study is to determine whether a short course (48 h) of postoperative antibiotics is non-inferior to current standard practice of 5 days. METHODS: Patients of 8 years and older undergoing appendectomy for acute complex appendicitis - defined as a gangrenous and/or perforated appendicitis or appendicitis in presence of an abscess - are eligible for inclusion. Immunocompromised or pregnant patients are excluded, as well as patients with a contraindication to the study antibiotics. In total, 1066 patients will be randomly allocated in a 1:1 ratio to the experimental treatment arm (48 h of postoperative intravenously administered (IV) antibiotics) or the control arm (5 days of postoperative IV antibiotics). After discharge from the hospital, patients participate in a productivity-cost-questionnaire at 4 weeks and a standardized telephone follow-up at 90 days after appendectomy. The primary outcome is a composite endpoint of infectious complications, including intra-abdominal abscess (IAA) and surgical site infection (SSI), and mortality within 90 days after appendectomy. Secondary outcomes include IAA, SSI, restart of antibiotics, length of hospital stay (LOS), reoperation, percutaneous drainage, readmission rate, and cost-effectiveness. The non-inferiority margin for the difference in the primary endpoint rate is set at 7.5% (one-sided test at ɑ 0.025). Both per-protocol and intention-to-treat analyses will be performed. DISCUSSION: This trial will provide evidence on whether 48 h of postoperative antibiotics is non-inferior to a standard course of 5 days of antibiotics. If non-inferiority is established, longer intravenous administration following appendectomy for complex appendicitis can be abandoned, and guidelines need to be adjusted accordingly. TRIAL REGISTRATION: Dutch Trial Register, NTR6128 . Registered on 20 December 2016.


Asunto(s)
Absceso Abdominal/prevención & control , Antibacterianos/administración & dosificación , Apendicectomía , Apendicitis/cirugía , Infección de la Herida Quirúrgica/prevención & control , Absceso Abdominal/economía , Absceso Abdominal/microbiología , Absceso Abdominal/mortalidad , Administración Intravenosa , Antibacterianos/efectos adversos , Antibacterianos/economía , Apendicectomía/efectos adversos , Apendicectomía/economía , Apendicectomía/mortalidad , Apendicitis/economía , Apendicitis/microbiología , Apendicitis/mortalidad , Ensayos Clínicos Fase IV como Asunto , Análisis Costo-Beneficio , Esquema de Medicación , Costos de los Medicamentos , Estudios de Equivalencia como Asunto , Femenino , Costos de Hospital , Humanos , Tiempo de Internación , Masculino , Estudios Multicéntricos como Asunto , Países Bajos , Estudios Prospectivos , Factores de Riesgo , Infección de la Herida Quirúrgica/economía , Infección de la Herida Quirúrgica/microbiología , Infección de la Herida Quirúrgica/mortalidad , Factores de Tiempo , Resultado del Tratamiento
20.
Trials ; 19(1): 244, 2018 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-29685164

RESUMEN

BACKGROUND: The annual new-case detection rate for leprosy, while generally stable over the last decade, shows that transmission rates have remained stagnant despite the successful worldwide administration of multidrug therapy since the 1980s. As such, novel control strategies are urgently needed. Focusing on managing leprosy patient contacts, the most susceptible to contracting the disease, has been seen as a potential strategy in limiting the spread of leprosy as shown by a number of recent epidemiological studies. Immunoprophylaxis with Bacillus Calmette-Guérin (BCG) has been seen as an effective preventive measure due to its ability to stimulate the development of cellular immunity which is essential in controlling the disease, especially in its multibacillary (MB) forms. The association of immunoprophylaxis with chemoprophylaxis in a single dose of rifampicin has been shown to be a promising preventive strategy, although a variety of studies have found instances of early case detection just a few months after BCG vaccination. METHODS/DESIGN: The present study is a phase IV chemoprophylactic clinical trial consisting of administration of a single dose of rifampicin in MB leprosy patient contacts under care at the Souza Araújo Outpatient Clinic/FIOCRUZ as part of a randomized (2:1), double-blind, placebo-controlled study. It is comprised of two groups: 1) rifampicin + BCG; and 2) placebo + BCG. DISCUSSION: The aim is to evaluate whether the use of chemoprophylaxis with a single dose of rifampicin in MB leprosy patient contacts prior to the BCG vaccine would be able to prevent the onset of leprosy in those cases that may occur just a few months after vaccination. Contact subclinical infections (polymerase chain reaction) and the immunological parameters (anti-PGL-1, anti-LID-1, and IFN-γ) will be evaluated and the results will be compared after 12 months of follow-up. TRIAL REGISTRATION: The Brazilian Registry of Clinical Trials (ReBEC), RBR-69QK5P . Retrospectively registered on 1 June 2017.


Asunto(s)
Vacuna BCG/administración & dosificación , Trazado de Contacto , Leprostáticos/administración & dosificación , Lepra Multibacilar/prevención & control , Rifampin/administración & dosificación , Adolescente , Adulto , Anciano , Vacuna BCG/efectos adversos , Brasil , Niño , Preescolar , Ensayos Clínicos Fase IV como Asunto , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Lactante , Leprostáticos/efectos adversos , Lepra Multibacilar/inmunología , Lepra Multibacilar/microbiología , Lepra Multibacilar/transmisión , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Rifampin/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vacunación , Adulto Joven
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