RESUMEN
BACKGROUND: Transparency and reproducibility are expected to be normative practices in clinical trials used for decision-making on marketing authorisations for new medicines. This registered report introduces a cross-sectional study aiming to assess inferential reproducibility for main trials assessed by the European Medicines Agency. METHODS: Two researchers independently identified all studies on new medicines, biosimilars and orphan medicines given approval by the European Commission between January 2017 and December 2019, categorised as 'main studies' in the European Public Assessment Reports (EPARs). Sixty-two of these studies were randomly sampled. One researcher retrieved the individual patient data (IPD) for these studies and prepared a dossier for each study, containing the IPD, the protocol and information on the conduct of the study. A second researcher who had no access to study reports used the dossier to run an independent re-analysis of each trial. All results of these re-analyses were reported in terms of each study's conclusions, p-values, effect sizes and changes from the initial protocol. A team of two researchers not involved in the re-analysis compared results of the re-analyses with published results of the trial. RESULTS: Two hundred ninety-two main studies in 173 EPARs were identified. Among the 62 studies randomly sampled, we received IPD for 10 trials. The median number of days between data request and data receipt was 253 [interquartile range 182-469]. For these ten trials, we identified 23 distinct primary outcomes for which the conclusions were reproduced in all re-analyses. Therefore, 10/62 trials (16% [95% confidence interval 8% to 28%]) were reproduced, as the 52 studies without available data were considered non-reproducible. There was no change from the original study protocol regarding the primary outcome in any of these ten studies. Spin was observed in the report of one study. CONCLUSIONS: Despite their results supporting decisions that affect millions of people's health across the European Union, most main studies used in EPARs lack transparency and their results are not reproducible for external researchers. Re-analyses of the few trials with available data showed very good inferential reproducibility. TRIAL REGISTRATION: https://osf.io/mcw3t/.
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Biosimilares Farmacéuticos , Aprobación de Drogas , Estudios Transversales , Humanos , Difusión de la Información , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).
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Antiinflamatorios/uso terapéutico , Fludrocortisona/uso terapéutico , Hidrocortisona/uso terapéutico , Choque Séptico/tratamiento farmacológico , Anciano , Antiinflamatorios/efectos adversos , Causas de Muerte , Terapia Combinada , Método Doble Ciego , Quimioterapia Combinada , Femenino , Fludrocortisona/efectos adversos , Humanos , Hidrocortisona/efectos adversos , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Recurrencia , Terapia de Reemplazo Renal , Respiración Artificial , Choque Séptico/complicaciones , Choque Séptico/mortalidad , Choque Séptico/terapia , Puntuación Fisiológica Simplificada Aguda , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
AIMS: Monitoring risk-based approaches in clinical trials are encouraged by regulatory guidance. However, the impact of a targeted source data verification (SDV) on data-management (DM) workload and on final data quality needs to be addressed. METHODS: MONITORING was a prospective study aiming at comparing full SDV (100% of data verified for all patients) and targeted SDV (only key data verified for all patients) followed by the same DM program (detecting missing data and checking consistency) on final data quality, global workload and staffing costs. RESULTS: In all, 137 008 data including 18 124 key data were collected for 126 patients from 6 clinical trials. Compared to the final database obtained using the full SDV monitoring process, the final database obtained using the targeted SDV monitoring process had a residual error rate of 1.47% (95% confidence interval, 1.41-1.53%) on overall data and 0.78% (95% confidence interval, 0.65-0.91%) on key data. There were nearly 4 times more queries per study with targeted SDV than with full SDV (mean ± standard deviation: 132 ± 101 vs 34 ± 26; P = .03). For a handling time of 15 minutes per query, the global workload of the targeted SDV monitoring strategy remained below that of the full SDV monitoring strategy. From 25 minutes per query it was above, increasing progressively to represent a 50% increase for 45 minutes per query. CONCLUSION: Targeted SDV monitoring is accompanied by increased workload for DM, which allows to obtain a small proportion of remaining errors on key data (<1%), but may substantially increase trial costs.
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Exactitud de los Datos , Recolección de Datos/normas , Manejo de Datos/normas , Bases de Datos Factuales/normas , Registros Electrónicos de Salud/normas , Control de Formularios y Registros/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Carga de Trabajo/normas , Análisis Costo-Beneficio , Control de Formularios y Registros/economía , Control de Formularios y Registros/normas , Humanos , Estudios ProspectivosRESUMEN
Background: Failure to achieve sustained virological response (SVR) with hepatitis C virus (HCV) direct-acting antiviral (DAA)-based regimens is commonly associated with emergence of resistance-associated substitutions (RASs). Retreatment of patients who failed prior DAAs remains challenging. The aim of this prospective and randomized study was to evaluate the efficacy (primary endpoint: SVR 12 weeks after end of treatment [SVR12]) and safety of sofosbuvir + grazoprevir/elbasvir + ribavirin for 16 or 24 weeks in patients who had failed to achieve SVR on previous NS5A- or NS3-based therapy and with evidence of RASs at failure. Methods: Patients were chronically infected with HCV genotype 1 or 4. Most of them had advanced fibrosis or compensated cirrhosis (liver stiffness 5.8-48.8 kPa). Results: All patients achieved HCV RNA below the lower limit of quantification (either target detected [unquantifiable] or target not detected) during treatment. SVR12 was achieved by 25 of 26 patients. The only patient who did not reach SVR was a patient who died, but HCV RNA was negative at this time (5 weeks after stopping treatment). No patient discontinued treatment because of adverse events or virological failure. Globally, treatment was well tolerated. Conclusions: Our findings support the concept of retreating with sofosbuvir + grazoprevir/elbasvir + ribavirin, for 16 weeks, genotype 1 or 4 DAA-experienced patients with proven NS5A or NS3 RASs. Clinical Trials Registration: NCT02647632.
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Antivirales/uso terapéutico , Benzofuranos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/uso terapéutico , Quinoxalinas/uso terapéutico , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Anciano , Amidas , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral , Retratamiento/estadística & datos numéricos , Sulfonamidas , Respuesta Virológica Sostenida , Insuficiencia del TratamientoRESUMEN
An evaluation of the significance of specified dyserythropoietic features in suspected myelodysplastic syndrome (MDS) and acute myeloid leukaemia with erythroid dysplasia was made by means of evaluation of 100 electronic images of bone marrow erythroblasts from each of 20 subjects: 11 with a myeloid neoplasm, six with another condition that could cause erythroid dysplasia and three healthy controls. The evaluation was carried out independently by seven experienced haematologists/haematopathologists who were blinded to the diagnosis. The majority of the dyserythropoietic features listed in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues were validated, although karyorrhexis was found to be infrequent and lacking in specificity; multinuclearity and megaloblastosis were more often observed but also lacked specificity. Good majority agreement on the identification of dysplastic features was obtained. Despite this, it was demonstrated that a reliable diagnosis of MDS can often not be made on the basis of erythroid morphology alone. Interpretation of dyserythropoiesis must be carried out with full knowledge of other clinicopathological features and with a constant awareness of the other conditions that can be confused with MDS. An iron stain is essential, as cases with ring sideroblasts may otherwise not be recognised as having MDS.
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Eritropoyesis , Neoplasias Hematológicas , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Femenino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Masculino , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patologíaRESUMEN
Dysmetabolic iron overload syndrome (DIOS) is a common cause of hyperferritinemia, accounting for a mild increase of iron stores in insulin-resistant subjects. Iron removal could improve insulin sensitivity. We performed a prospective, randomized, controlled trial (NCT01015525) in nondiabetic DIOS patients with hepatic iron >50 µmol/g at magnetic resonance imaging to compare the metabolic and hepatic outcomes of 1-year maintenance of serum ferritin levels <50 µg/L by bloodletting associated with lifestyle and diet advice (LFDA) to those of LFDA only. Patients were randomly assigned (1:1) with stratification by center (n = 8) and hyperglycemia (>5.6 mmol/L). Sample size was calculated to provide 90% power and a difference in fasting glycemia of 0.25 mmol/L. Analysis was done in an intention-to-treat population. In 2010-2014, 146 patients were randomly assigned to receive venesections with LFDA and 128 to LFDA only. At the end of the study, comparison of iron-depleted patients and controls showed ferritin levels 71 ± 48 µg/L after removal of 4.9 ± 1.6 L of blood versus 733 ± 277 µg/L (P < 0.0001), glycemia 5.44 ± 0.7 versus 5.49 ± 0.7 mmol/L (P = 0.57), body weight +0.5 ± 4.3% versus -0.6 ± 3.3% (P = 0.03), homeostasis model of assessment of insulin resistance 3.39 versus 2.40 (P = 0.002), alanine aminotransaminase 33 ± 22 versus 37 ± 21 IU/L (P = 0.10), aspartate aminotransaminase 27 ± 13 versus 27 ± 10 IU/L (P = 0.81), gamma-glutamyl transferase 54 ± 138 versus 49 ± 35 IU/L (P = 0.72), Fatty Liver Index 58.9 ± 24.6 versus 61.2 ± 22.9 (P = 0.37), and Fibrosis-4 score 1.5 ± 0.6 versus 1.30 ± 0.6 (P = 0.51). Fatigue occurred in 25.3% of venesected patients versus 2.3% of controls (P < 0.0001). In the subgroup of patients who lost weight, glycemia, homeostasis model of assessment of insulin resistance, serum ferritin, lipid profile, and liver function tests improved irrespective of bloodletting. CONCLUSION: In DIOS patients, iron depletion by bloodletting does not improve metabolic and hepatic features, is associated with weight gain, and is not as well tolerated as expected; sustained modification of diet and lifestyle habits remains the first therapeutic intervention in DIOS. (Hepatology 2017;65:465-474).
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Ferritinas/sangre , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/terapia , Flebotomía/métodos , Adulto , Anciano , Análisis de Varianza , Análisis Químico de la Sangre , Distribución de Chi-Cuadrado , Femenino , Estudios de Seguimiento , Humanos , Resistencia a la Insulina/fisiología , Sobrecarga de Hierro/sangre , Estilo de Vida , Pruebas de Función Hepática , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Aumento de Peso/fisiologíaRESUMEN
Beyond the application of legal requirements, clinical trials must have a permanent approach of quality control. The clinical investigation centers (CICs) are academic structures of clinical research certified by the French National institute of health and medical research (Inserm) and whose functioning relies on recommendations of good practice. It is important to accompany this standardization of practices by the implementation of a quality management system. This article presents the process that enabled the CIC of Rennes to become certified ISO 9001 by French standards association (Afnor) certification in May, 2016. The application of the fundamental principles of the standard ISO 9001 in the domain of clinical research is approached. The problem of the perimeter for the certification and the related process mapping are exposed. The activities of methodology, management and analysis of clinical studies were chosen for the initial certification of the CIC of Rennes. The perspectives for the extension of the perimeter of certification are also approached at the end of article.
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Academias e Institutos/normas , Investigación Biomédica/normas , Certificación , Garantía de la Calidad de Atención de Salud/normas , Investigación Biomédica/métodos , Investigación Biomédica/organización & administración , Certificación/métodos , Certificación/normas , Ensayos Clínicos como Asunto/normas , Francia , Humanos , Control de Calidad , Estándares de Referencia , Proyectos de Investigación/normas , Sociedades Médicas/normasAsunto(s)
Fludrocortisona , Glucocorticoides , Antiinflamatorios , Humanos , Hidrocortisona , Choque SépticoRESUMEN
BACKGROUND: Scarce data exist on the efficacy and safety of the PEGylated-interferon/ribavirin/boceprevir regimen in HIV/HCV-coinfected patients who failed to respond to PEGylated-interferon/ribavirin treatment. OBJECTIVES: To evaluate the efficacy and safety of this drug regimen and the impact of the addition of boceprevir(BOC) on atazanavir (ATV) or raltegravir (RAL) pharmacokinetic parameters in a subgroup of patients. METHODS: In this single-arm phase 2 trial, HIV-1/HCV-genotype-1-coinfected patients received PEGylated-interferonα2b (1.5 µg/kg/week)+ ribavirin (800-1400 mg/day) alone until W4 and with BOC(800 mgTID) until W48. Based on virologic response at W8, the three drugs were stopped or PEGylated-interferon/ribavirin was continued alone until W72. The primary endpoint was SVR at W24 off-therapy (SVR24). RESULTS: 64 patients were included. SVR24 was achieved in 53% of patients (CI90%: 43-63%) and in 90% of previous relapsers. In univariate analysis, SVR24 was associated with response to previous HCV treatment, HCV-1b subtype, HCV-RNA decline, ribavirin-Ctrough at W4, and HCV-RNA at W8 but not to fibrosis score, IL28B genotype, or boceprevir-Ctrough at W8. In multivariate analysis, SVR24 remained associated with response to previous HCV treatment [non-responders versus null responders: OR=5.0(1.3-20.0); relapsers vs. null responders: OR=28.8(4.9-169.5)]. HCV treatment was discontinued for adverse events in 17% of patients. A 51% decrease in ATV/r-AUC0-8 h (p<0.01) and a 57% increase in RAL-AUC0-8 h (p<0.01) were observed, although atazanavir/r or raltegravir did not affect BOC-AUC0-8 h significantly. The ATV mean Cthrough fell from 763.8 ng/mL (CI 95%: 230.3-1297.3) without BOC to 507.7 ng/mL (CI 95%: 164-851.4) with BOC. CONCLUSIONS: Boceprevir-based regimen demonstrated a high SVR24 rate in treatment-experienced HIV-HCV genotype-1-coinfected relapsers.
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Antivirales/administración & dosificación , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Prolina/análogos & derivados , Ribavirina/administración & dosificación , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Coinfección/virología , Quimioterapia Combinada/efectos adversos , Femenino , Genotipo , Infecciones por VIH/virología , VIH-1/fisiología , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Interferón-alfa/efectos adversos , Interferón-alfa/farmacocinética , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacocinética , Prolina/administración & dosificación , Prolina/efectos adversos , Prolina/farmacocinética , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Ribavirina/efectos adversos , Ribavirina/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVE: Our aim was to assess the usefulness of cranberry extract in multiple sclerosis (MS) patients suffering from urinary disorders. METHODS: In total, 171 adult MS outpatients with urinary disorders presenting at eight centers were randomized (stratification according to center and use of clean intermittent self-catheterization) to cranberry versus placebo in a 1-year, prospective, double-blind study that was analyzed using a sequential method on an intent-to-treat basis. An independent monitoring board analyzed the results of the analyses each time 40 patients were assessed on the main endpoint. Cranberry extract (36 mg proanthocyanidins per day) or a matching placebo was taken by participants twice daily for 1 year. The primary endpoint was the time to first symptomatic urinary tract infection (UTI), subject to validation by a validation committee. RESULTS: The second sequential analyses allowed us to accept the null hypothesis (no difference between cranberry and placebo). There was no difference in time to first symptomatic UTI distribution across 1 year, with an estimated hazard ratio of 0.99, 95% CI [0.61, 1.60] (p = 0.97). Secondary endpoints and tolerance did not differ between groups. CONCLUSION: Taking cranberry extract versus placebo twice a day did not prevent UTI occurrence in MS patients with urinary disorders. Trial Registration NCT00280592.
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Antiinfecciosos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Proantocianidinas/uso terapéutico , Infecciones Urinarias/prevención & control , Vaccinium macrocarpon , Adulto , Antiinfecciosos/efectos adversos , Método Doble Ciego , Femenino , Francia , Frutas , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico , Fitoterapia , Extractos Vegetales/efectos adversos , Plantas Medicinales , Proantocianidinas/efectos adversos , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/microbiologíaRESUMEN
RATIONALE: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. OBJECTIVES: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. METHODS: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 µg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. MEASUREMENTS AND MAIN RESULTS: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. CONCLUSIONS: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).
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Antiinfecciosos/uso terapéutico , Proteína C/uso terapéutico , Choque Séptico/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada/métodos , Femenino , Fludrocortisona/uso terapéutico , Humanos , Hidrocortisona/uso terapéutico , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Retirada de Medicamento por Seguridad , Resultado del TratamientoRESUMEN
BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.
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Infecciones Comunitarias Adquiridas , Quimioterapia Combinada , Fludrocortisona , Hidrocortisona , Neumonía , Choque Séptico , Humanos , Hidrocortisona/uso terapéutico , Hidrocortisona/administración & dosificación , Choque Séptico/tratamiento farmacológico , Choque Séptico/mortalidad , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/mortalidad , Infecciones Comunitarias Adquiridas/complicaciones , Masculino , Femenino , Fludrocortisona/uso terapéutico , Fludrocortisona/administración & dosificación , Anciano , Persona de Mediana Edad , Neumonía/tratamiento farmacológico , Neumonía/mortalidad , Método Doble Ciego , Antiinflamatorios/uso terapéutico , Antiinflamatorios/administración & dosificación , Resultado del Tratamiento , Proteína C/uso terapéutico , Proteína C/administración & dosificaciónRESUMEN
The purpose of this prospective, nine-center, non-randomized study was to assess the efficacy and safety of Celsior preservation fluid in liver transplantation using unselected donors. As data comparing allograft outcomes following liver transplantation using Celsior and University of Wisconsin (UW) preservation fluids are limited, we also compared our cohort with matched controls selected from the European Liver Transplant Registry (ELTR) who received total liver grafts preserved with UW solution during the same period. One hundred and forty patients who received livers preserved with Celsior were included. The primary endpoint, graft loss at one-yr post-transplantation, was observed in 24 patients (17.1%) which was not significantly different from the 20.0% pre-defined threshold rate (95% confidence interval [CI] 10.9, 23.4; p=0.398). Predictive factors for graft loss on univariate analysis were moderate-to-severe steatosis on the donor graft (5/22 patients with graft loss vs. 8/107 patients without, p=0.046) and duration of warm ischemia (1.4±1.1 h in patients with graft loss vs. 0.9±0.5 h in patients without, p=0.034). Hepatic artery thrombosis and stenosis occurred in seven (5.0%) and six (4.3%) patients, respectively. The comparison of our patients to 420 ELTR controls showed that one-yr graft survival rates (Celsior: 82.9%, 95% CI 75.8, 88.2; UW: 78.6%, 95% CI 74.4, 82.2) and Kaplan-Meier one-yr graft survival distributions (p=0.285) were similar. Within the cold ischemia time achieved in our study, liver preservation with Celsior appeared efficient and safe. Comparison with ELTR patients suggested that liver allograft survival was similar using Celsior or UW solution for preservation of unselected donor grafts.
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Trasplante de Hígado , Soluciones Preservantes de Órganos , Adenosina , Adulto , Alopurinol , Disacáridos , Electrólitos , Femenino , Glutamatos , Glutatión , Supervivencia de Injerto , Histidina , Humanos , Insulina , Trasplante de Hígado/efectos adversos , Masculino , Manitol , Persona de Mediana Edad , Disfunción Primaria del Injerto/diagnóstico , RafinosaRESUMEN
BACKGROUND: Patients with lower extremity peripheral artery disease (PAD) frequently experience claudication, a clinical symptom indicative of reduced walking capacity. Recommended care consists of exercise rehabilitation combined with optimal medical treatment and surgery. The effects of a single oral dose of sildenafil, a phosphodiesterase type-5 inhibitor, on patients with claudication are discussed. The aim of this study was to test the efficacy of a single 100â¯mg dose of sildenafil compared to placebo in terms of maximal walking time (MWT) in patients with claudication. METHODS: The ARTERIOFIL study is a crossover, double-blind, prospective, randomized, single-center study conducted at Angers University Hospital in France. MWT (primary endpoint) was assessed using a treadmill test (10% incline; 3.2â¯km/h). Secondary endpoints (pain-free walking time (PFWT), transcutaneous oximetry during exercise and redox cycle parameters and safety) were also studied. RESULTS: Fourteen patients were included of whom two were ultimately excluded. In the 12 remaining patients, the MWT was significantly improved during the sildenafil period compared with the placebo period (300â¯s [95% CI 172â¯s-428â¯s] vs 402â¯s [95% CI 274â¯s-529â¯s] pâ¯<â¯0.01). Sildenafil had no significant effect on pain-free walking time or skin tissue oxygenation during exercise. According to redox cycle parameters, sildenafil significantly reduced blood glucose and pyruvate levels and the 3-hydroxybutyrate/acetoacetate ratio, while there was no significant effect on lactate, 3-hydroxybutyrate, acetoacetate and free fatty acid levels. Symptomatic transient hypotension was observed in two women. CONCLUSIONS: The ARTERIOFIL study has shown that a single 100â¯mg oral dose of sildenafil had a significant effect on increase in MWT but had no significant effects on PFWT and oxygenation parameters in patients with claudication. A double-blind, prospective, randomized, multicenter study (VIRTUOSE©) is ongoing to evaluate the chronic effect of six month-long sildenafil treatment on MWT in PAD patients with claudication. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at clinicaltrials.gov, registration. number: NCT02832570, (https://clinicaltrials.gov/ct2/show/NCT02832570).
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Tolerancia al Ejercicio/efectos de los fármacos , Claudicación Intermitente/tratamiento farmacológico , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Caminata , Anciano , Biomarcadores/sangre , Estudios Cruzados , Método Doble Ciego , Femenino , Francia , Humanos , Claudicación Intermitente/sangre , Claudicación Intermitente/diagnóstico , Claudicación Intermitente/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/fisiopatología , Inhibidores de Fosfodiesterasa 5/efectos adversos , Estudios Prospectivos , Recuperación de la Función , Citrato de Sildenafil/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Prueba de PasoRESUMEN
BACKGROUND: International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock. METHODS: This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278. FINDINGS: There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0.31; relative risk 0.86, 95% CI 0.65-1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0.69), at hospital discharge (84 [52%] vs 82 [49%], p=0.51), and by day 90 (84 [52%] vs 85 [50%], p=0.73), time to haemodynamic success (log-rank p=0.67), time to vasopressor withdrawal (log-rank p=0.09), and time course of SOFA score. Rates of serious adverse events were also similar. INTERPRETATION: There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.
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Agonistas Adrenérgicos/uso terapéutico , Dobutamina/administración & dosificación , Epinefrina/uso terapéutico , Norepinefrina/administración & dosificación , Choque Séptico/tratamiento farmacológico , Vasoconstrictores/uso terapéutico , Agonistas Adrenérgicos/efectos adversos , Anciano , Dobutamina/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Epinefrina/efectos adversos , Femenino , Mortalidad Hospitalaria , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Norepinefrina/efectos adversos , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Vasoconstrictores/efectos adversosRESUMEN
BACKGROUND: A few direct antiviral agents have been studied in difficult-to-treat patients infected by hepatitis C virus (HCV) genotype 4 (GT4). The efficacy of daclatasvir (DCV), asunaprevir (ASV), pegylated interferon and ribavirin (Peg-IFN/RBV) association was investigated in these patients. PATIENTS AND METHODS: This open-label, single-arm, phase 2 study was conducted in HCV GT4 patients who were null or partial responders to Peg-IFN/RBV. Patients received 24 weeks of DCV (60 mg, once daily), ASV (100 mg, twice daily) and Peg-IFN/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 [sustained virologic response (SVR)12]. RESULTS: Sixty patients were included; 45 (75%) were previous null responders and 27 (45%) had cirrhosis. The most frequent subtypes were GT4a (48%) and GT4d (27%) with 25% of the patients being infected with other subtypes such as 4c, 4r, 4f, 4k, 4j and 4q. The global SVR12 was 95% (90% confidence interval: 90.4-99.6) and 96.3% (90% confidence interval: 87.5-99.5) in cirrhotic patients. All patients achieving SVR12 also achieved SVR24. Previous Peg-IFN/RBV response, IL28b genotype, cirrhosis status or GT4 subtypes did not influence SVR12 rates. Serious adverse events occurred in 13% of the patients, four being cirrhotic and four noncirrhotic. Three (5%) patients stopped HCV therapy prematurely: one because of virologic breakthrough and two because of serious adverse events. Grade 3/4 laboratory abnormalities included leukopenia (33%), neutropenia (27%), thrombocytopenia (4%) and transaminases increase (2%). CONCLUSION: Association of DCV plus ASV and peg-IFN/RBV for 24 weeks demonstrated a high rate of SVR12 in HCV GT4-infected prior nonresponders, independently of the cirrhotic status or the GT4 subtype. The safety profile was acceptable, even in cirrhotic patients.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/uso terapéutico , Adulto , Antivirales/efectos adversos , Carbamatos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Imidazoles/efectos adversos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Isoquinolinas/efectos adversos , Isoquinolinas/uso terapéutico , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pirrolidinas , ARN Viral/sangre , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Ribavirina/efectos adversos , Ribavirina/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Respuesta Virológica Sostenida , Insuficiencia del Tratamiento , Resultado del Tratamiento , Valina/análogos & derivados , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV-HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC). METHODS: Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctrough on anaemia was also studied. RESULTS: Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0-W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctrough was associated with Hb decrease both at W4 and W8 and an RBV Ctrough cutoff value of 2 µg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough (P=0.012). ITPA deficiency, W4 RBV Ctrough and gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response. CONCLUSIONS: ITPA deficiency and RBV Ctrough are still predictive of RBV-induced anaemia in HIV-HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.
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Anemia/diagnóstico , Anemia/etiología , Coinfección , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/genética , Errores Innatos del Metabolismo/complicaciones , Pirofosfatasas/deficiencia , Ribavirina/farmacocinética , Alelos , Antivirales/farmacocinética , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pirofosfatasas/genética , Ribavirina/uso terapéutico , Factores de Riesgo , Inosina TrifosfatasaRESUMEN
BACKGROUND: We aimed at assessing the benefit-to-risk ratio of activated protein C (drotrecogin-alfa activated, DAA) and corticosteroids, given alone or in combination, in patients with septic shock. METHODS: We implemented an investigator-led, publicly funded, multicenter, randomized according to a 2 × 2 factorial design, placebo-controlled, double-blind trial in four parallel groups in which adults with persistent septic shock and no contraindication to DAA were assigned to either DAA alone (24 mg/kg/h for 96 h), or hydrocortisone (50 mg intravenous bolus q6 for 7 days) and fludrocortisone (50 µg once daily through the nasogastric tube for 7 days) alone, or their respective combinations, or their respective placebos. Primary endpoint was 90-day mortality rate. Follow-up duration was 6 months. Statistical analysis was planned to be performed in intent-to-treat once after all participants completed 180-day follow-up and according to the 2 × 2 factorial design. RESULTS: The first patient was recruited in September 2008. The trial was suspended on October 25, 2011, owing to the withdrawal from the market of DAA. At this time, 411 patients had been enrolled. On May 17, 2012, the continuation of the trial on two parallel groups was approved by all legal authorities with the aim of investigating the benefit-to-risk ratio of corticosteroids. On June 30, 2014, the trial was suspended again by the study sponsor upon request of the independent data and safety monitoring board. Recruitment restarted on October 7, 2014, after any safety concern was ruled out. Finally, the trial was completed on June 23, 2015, with the recruitment of 1241 patients. CONCLUSIONS: This report details the design, statistical plan and conduct of a randomized controlled trial of hydrocortisone and fludrocortisone in septic shock. Trial registration The trial was registered at ClinicalTrials.gov under NCT00625209.
RESUMEN
Evaluation of megakaryocyte morphology is difficult but can be essential for the diagnosis of myelodysplastic syndromes (MDS) and other myeloid neoplasms. We agreed upon descriptions and provided images of megakaryoblasts and of normal and dysplastic megakaryocytes, which were used as a basis for assessing the concordance of expert morphologists in their recognition. We showed a high rate of concordance for the recognition of micromegakaryocytes and confirmed their strong association with hematologic neoplasia, including MDS. Concordance was also found to be good for the recognition of multinucleated megakaryocytes, which showed a significant association with MDS. However cytoplasmic abnormalities were found not to be useful in MDS recognition. The occurrence of appreciable numbers of nonlobulated and hypolobulated megakaryocytes in individuals without a myeloid neoplasm was confirmed. We demonstrated that subjects without a myeloid neoplasm can have some megakaryocytes that are assessed as 'dysplastic' or 'possibly dysplastic' and that to avoid over diagnosis of dysplasia, 'possibly dysplastic' forms should be excluded from the count of dysplastic cells. Our results demonstrate that the nature as well as the presence of megakaryocyte dysplasia is important in the diagnosis of MDS; although evaluation of 30 megakaryocytes is strongly recommended, it may be possible to recognize diagnostically important dysplasia when fewer megakaryocytes are present but highly diagnostic forms are seen.
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Megacariocitos/patología , Síndromes Mielodisplásicos/diagnóstico , Control de Calidad , Forma de la Célula , Tamaño de la Célula , Neoplasias Hematológicas/patología , Humanos , Células Progenitoras de Megacariocitos , Trastornos Mieloproliferativos/diagnósticoRESUMEN
OBJECTIVES: Ribavirin (RBV) induced anemia may be influenced by host genetic factors affecting RBV transport solute carrier (SLC) or metabolism inosine triphosphatase (ITPA), as already reported. We investigated the influence of single nucleotide polymorphisms (SNPs) on SLC genes on anemia, RBV trough concentration (Ctrough) and response in HIV-hepatitis C virus coinfected patients receiving triple therapy with boceprevir or telaprevir. METHODS: Patients from the ANRS HC26/HC27 studies were genotyped for SLC28A3 SNPs (rs10868138 and rs56350726) and SL29A1 SNPs (rs760370). Hemoglobin (Hb) decline was collected at baseline day 0 (D0), week 4 (W4) and week 8 (W8), and RBV Ctrough was measured at W4 and W8 by HPLC. A multivariate analysis including SLC SNPs, estimated glomerular filtration rate (eGFR), ITPA deficiency and RBV Ctrough was performed to determine predictive factors of anemia and response. RESULTS: SLC genotyping was performed in 130 patients. Neither SLC28A3 nor SLC29A1 SNPs were associated with Hb decline both at W4 and W8. No association was found between SLC polymorphisms and RBV Ctrough. Independent predictive factors of Hb decline at W4 were D0 Hb, ITPA deficiency and W4 RBV Ctrough in the multivariate analysis (Pâ<â0.05). Only D0 Hb, W4 RBV Ctrough and eGFRD0-W8 were predictive of anemia at W8 (Pâ<â0.05). Response was not influenced by SLC SNPs. CONCLUSION: eGFR, but not SLC polymorphisms, influences anemia in HIV-hepatitis C virus coinfected patients receiving boceprevir-based or telaprevir-based therapy. RBV is still a cornerstone of hepatitis C treatment, thus renal function and RBV Ctrough should be monitored in patients receiving RBV regimen combined with first-generation direct-acting antiviral agent.