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ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial.

ABSTRACT: INTRODUCTION:Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds to and inactivates this immune-suppressive lipid mediator. Human albumin solution (HAS) could thus be repurposed as an immune-restorative drug in these patients.This is a phase III randomised controlled trial (RCT) to verify whether targeting a serum albumin level of ?35?g/L in hospitalised patients with decompensated cirrhosis using repeated intravenous infusions of 20% HAS will reduce incidence of infection, renal dysfunction and mortality for the treatment period (maximum 14 days or discharge if <14 days) compared with standard medical care. METHODS AND ANALYSIS:Albumin To prevenT Infection in chronic liveR failurE stage 2 is a multicentre, open-label, interventional RCT. Patients with decompensated cirrhosis admitted to the hospital with a serum albumin of <30?g/L are eligible, subject to exclusion criteria. Patients randomised to intravenous HAS will have this administered, according to serum albumin levels, for up to 14 days or discharge. The infusion protocol aims to increase serum albumin to near-normal levels.The composite primary endpoint is: new infection, renal dysfunction or mortality within the trial treatment period. Secondary endpoints include mortality at up to 6?months, incidence of other organ failures, cost-effectiveness and quality of life outcomes and time to liver transplant. The trial will recruit 866 patients at more than 30 sites across the UK. ETHICSANDDISSEMINATION:Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001-0001). The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the National Institute for Health Research (ISRCTN 14174793). This manuscript refers to version 6.0 of the protocol. Results will be disseminated through peer-reviewed journals and international conferences. Recruitment of the first participant occurred on 25 January 2016.

SUBMITTER: China L

PROVIDER: S-EPMC6196858 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial.

China Louise L Skene Simon S SS Bennett Kate K Shabir Zainib Z Hamilton Roseanna R Bevan Scott S Chandler Torsten T Maini Alexander A AA Becares Natalia N Gilroy Derek D Forrest Ewan H EH O'Brien Alastair A

BMJ open 20181021 10

<h4>Introduction</h4>Circulating prostaglandin E<sub>2</sub> levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds to and inactivates this immune-suppressive lipid mediator. Human albumin solution (HAS) could thus be repurposed as an immune-restorative drug in these patients.This is a phase III randomised controlled trial (RCT) to verify whether targeting a serum albumin level of ≥35 g/L in hospitalised patients with decompe ...[more]

PMID: 30344180

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Project description:Background & aimsInfections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial.MethodsWe performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels.ResultsThe patients' mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded.ConclusionsIn a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.

Project description:The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure.Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4% albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model.Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median -68 μmol/L, interquartile range [IQR] -107.5 to -33.5, p = 0.001; SPAD: -59 μmol/L, -84.5 to +36.5, p = 0.001). However, bile acids (MARS: -39 μmol/L, -105.6 to -8.3, p < 0.001; SPAD: -9 μmol/L, -36.9 to +11.4, p = 0.131), creatinine (MARS: -24 μmol/L, -46.5 to -8.0, p < 0.001; SPAD: -2 μmol/L, -9.0 to +7.0/L, p = 0.314) and urea (MARS: -0.9 mmol/L, -1.93 to -0.10, p = 0.024; SPAD: -0.1 mmol/L, -1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10%, -0.8 to +20.9%, p < 0.001; SPAD: +7%, -7.5 to +15.5%, p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD.Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation.German Clinical Trials Register ( www.drks.de) DRKS00000371. Registered 8 April 2010.

Project description:IntroductionHand orthoses are often provided to improve performance of activities of daily life (ADL). Yet, the manufacturing process of conventional custom-fabricated hand orthoses is a time-consuming and labour-intensive process. Even though three-dimensional (3D) printing of orthoses is a rapidly growing area that can facilitate the manufacturing process of hand orthoses, evidence on the effectiveness, costs and production time of 3D-printed orthoses in chronic hand conditions is scarce. This study aims to assess (1) the preliminary effectiveness of 3D-printed orthoses compared with conventionally custom-fabricated orthoses in persons with chronic hand conditions, (2) production time and costs of both orthoses and (3) experiences of the participants and orthotists with the manufacturing process of the 3D-printed orthosis.Methods and analysisIn this prospective non-randomised interventional feasibility study, 20 adults with various chronic hand conditions using a conventional thumb, wrist or wrist-thumb orthosis will be provided with a 3D-printed corresponding type of orthosis. Assessments will be done 2 weeks prior to the intervention and at baseline for the conventional orthosis, and at 1 month and 4 months follow-up for the 3D-printed orthosis. The primary outcome is change from baseline in ADL performance (custom short form Dutch-Flemish Patient-Reported Outcomes Measurement Information System-Upper Extremity; ADL domain Michigan Hand Outcomes Questionnaire Dutch language version (MHQ-DLV)) at 4 months follow-up. Secondary outcomes include general hand function (MHQ-DLV), satisfaction with the orthosis (Dutch Client Satisfaction with Device; Dutch version of the Quebec User Evaluation of Satisfaction with Assistive Technology), usability (in-house questionnaire) and quality of life (EuroQoL 5-Dimension 5-Level). Costs and production time of the conventional and 3D-printed orthoses will be prospectively recorded. Experiences regarding the manufacturing process will be obtained from participants and orthotists (in-house questionnaire).Ethics and disseminationThe Medical Ethics Committee of the Amsterdam UMC, Academic Medical Centre, has waived the requirement for ethical review of this study. Results will be disseminated through peer-reviewed journals, scientific conferences, and media aimed at a broad audience including patients.Trial registration numberNCT05320211.

Project description:IntroductionRespiratory distress syndrome is a complication of prematurity and extremely preterm infants born before 28 weeks' gestation often require endotracheal intubation and mechanical ventilation. In this high-risk population, mechanical ventilation is associated with lung injury and contributes to bronchopulmonary dysplasia. Therefore, clinicians attempt to extubate infants as quickly and use non-invasive respiratory support such as nasal continuous positive airway pressure (CPAP) to facilitate the transition. However, approximately 60% of extremely preterm infants experience 'extubation failure' and require reintubation. While CPAP pressures of 5-8 cm H2O are commonly used, the optimal CPAP pressure is unknown, and higher pressures may be beneficial in avoiding extubation failure. Our trial is the Extubation CPAP Level Assessment Trial (ÉCLAT). The aim of this trial is to compare higher CPAP pressures 9-11 cm H2O with a current standard pressures of 6-8 cmH2O on extubation failure in extremely preterm infants.Methods and analysis200 extremely preterm infants will be recruited prior to their first extubation from mechanical ventilation to CPAP. This is a parallel group randomised controlled trial. Infants will be randomised to one of two set CPAP pressures: CPAP 10 cmH2O (intervention) or CPAP 7 cmH2O (control). The primary outcome will be extubation failure (reintubation) within 7 days. Statistical analysis will follow standard methods for randomised trials on an intention to treat basis. For the primary outcome, this will be by intention to treat, adjusted for the prerandomisation strata (GA and centre). We will use the appropriate parametric and non-parametric statistical tests.Ethics and disseminationEthics approval has been granted by the Monash Health Human Research Ethics Committees. Amendments to the trial protocol will be submitted for approval. The findings of this study will be written into a clinical trial report manuscript and disseminated via peer-reviewed journals (on-line or in press) and presented at national and international conferences.Trial registration numberACTRN12618001638224; pre-results.

Dataset Information

ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial.

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ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial.

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