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16 results found

Vergis N, Patel VC, Bogdanowicz K, Czyzewska-Khan J, Keshinro R, Fiorentino F, Day E, Middleton P, Atkinson S, Cross M, Babalis D, Foster N, Quaglia A, Lloyd J, Goldin RD, Rosenberg W, Parker R, Richardson P, Masson S, Whitehouse G, Sieberhagen C, Patch D, Dhanda A, Lord E, Forrest E, Naoumov N, Thursz Met al., 2022, Il-1beta Signal Inhibition in acute alcoholic hepatitis: a multicentre, randomised, double-blind, placebo-controlled phase 2 trial of canakinumab therapy (ISAIAH), Publisher: ELSEVIER, Pages: S34-S35, ISSN: 0168-8278

Conference paper

Vergis N, Patel V, Bogdanowicz K, Czyzewska-Khan J, Fiorentino F, Day E, Cross M, Foster N, Lord E, Goldin R, Forrest E, Thursz Met al., 2021, IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis, Trials, Vol: 22, Pages: 1-16, ISSN: 1745-6215

Background: Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, Canakinumab, in the treatment of AH.Methods: This is multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the United Kingdom. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is reduction in lobular inflammation, comparing histological appearances at baseline with appearances at 28 days. Patients with evidence of ongoing disease activity will receive a second infusion of Canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. Discussion: This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signaling may improve histology and survival for patients with AH. Trial registration: Prospectively registered with EudraCT 2017-003724-79.

Journal article

Patel PB, Brett S, O'Callaghan D, Anjum A, Cross M, Warwick J, Gordon ACet al., 2020, A randomized clinical trial of methylnaltrexone for the treatment of opioid induced constipation & gastrointestinal stasis in intensive care patients; results from the MOTION trial, Intensive Care Medicine, Vol: 46, Pages: 747-755, ISSN: 0342-4642

PurposeConstipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid induced constipationMethodsThe MOTION trial is a multi-centre, double blind, randomised placebo controlled trial to investigate whether methylnaltrexone alleviatesopioid induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 hours) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day,escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficileinfection and finally 28 day, ICU and hospital mortality.ResultsA total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant differencein time to rescue-free laxation between the groups (Hazard ratio 1.42, 95%CI 0.82-2.46, p=0.22). There were no significant differencesin the majority of secondary outcomes, particularly days 1-3. However, during days 4-28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p=0.01) and a greater incidence of diarrhoea in the placebo group (p=0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group

Journal article

Antcliffe DB, Santhakumaran S, Orme RML, Ward JK, Al-Beidh F, ODea K, Perkins GD, Singer M, McAuley DF, Mason AJ, Cross M, Ashby D, Gordon ACet al., 2019, Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial, Intensive Care Medicine, Vol: 45, Pages: 1392-1400, ISSN: 0342-4642

PurposeMyocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects.MethodsTwo cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values.ResultsLevosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers.ConclusionAdding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Journal article

Gordon AC, Santhakumaran S, Al-Beidh F, Orme RML, Perkins GD, Singer M, McAuley DF, Mason AJ, Ward JK, ODea KP, Felton T, Cross M, Best-Lane J, Lexow J, Campbell A, Ashby Det al., 2018, Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT, Efficacy and Mechanism Evaluation, Vol: 5, Pages: 1-124, ISSN: 2050-4365

Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial

Journal article

Poulter NR, Savopoulos C, Anjum A, Apostolopoulou M, Chapman N, Cross M, Falaschetti E, Fotiadis S, James RM, Kanellos I, Szigeti M, Thom S, Sever P, Thompson D, Hatzitolios AIet al., 2018, Randomized crossover trial of the impact of morning or evening dosing of antihypertensive agents on 24-hour ambulatory blood pressure: the HARMONY trial, Hypertension, Vol: 72, Pages: 870-873, ISSN: 0194-911X

Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing. This trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing. Patients aged 18 to 80 years with reasonably controlled hypertension (≤150/≤90 mm Hg) on stable therapy of ≥1 antihypertensive agent were recruited from 2 centers in London and Thessaloniki. Patients were randomized to receive usual therapy either in the morning (6 am–11 am) or evening (6 pm–11 pm) for 12 weeks when participants crossed over to the alternative timing for a further 12 weeks. Clinic blood pressures and a 24-hour recording were taken at baseline, 12, and 24 weeks and routine blood tests were taken at baseline. The study had 80% power to detect 3 mm Hg difference in mean 24-hour systolic blood pressure (α=0.05) by time of dosing. A 2-level hierarchical regression model adjusted for center, period, and sequence was used. Of 103 recruited patients (mean age, 62; 44% female), 95 patients (92%) completed all three 24-hour recordings. Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am–10 pm) and nighttime (10 pm–7 am) blood pressure levels nor on clinic levels. Stratification by age (≤65/≥65 years) or sex did not affect results. In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels.

Journal article

Johnston SL, Szigeti M, Cross M, 2018, Correction: Azithromycin for acute exacerbations of Asthma: The AZALEA randomized clinical trial (JAMA Internal Medicine (2016) 176:11 (1630-1637) DOI: 10.1001/jamainternmed.2016.5664), JAMA Internal Medicine, Vol: 178, Pages: 1003-1003, ISSN: 2168-6106

© 2018 American Medical Association. All rights reserved. IncorrectNumbersofAdverseEventsReported: The Original Investigation titled "Azithromycin for Acute Exacerbations of Asthma: The AZALEAR and omized Clinical Trial,"1published in the November 2016 issue of JAMA Internal Medicine, reported incorrect numbers of adverse events owing to a recently discovered error in the AZALEA clinical trial database. In the last paragraph of the Results section, "a reduced frequency of respiratory, thoracic, and mediastinal (63 of 64 respiratory) adverse events (27 vs 37, respectively)" should read "a reduced frequency of respiratory, thoracic, and mediastinal (61 of 62 respiratory) adverse events (26 vs 36, respectively)." Inthe online-only Supplement, numbers of adverse events were reported incorrectly in eTables 16 through 19. This article and its supplement have been corrected online.

Journal article

Johnston SL, Szigeti M, Cross M, Brightling C, Chaudhuri R, Harrison T, Mansur A, Robison L, Sattar Z, Jackson D, Mallia P, Wong E, Corrigan C, Higgins B, Ind P, Singh D, Thomson NC, Ashby D, Chauhan Aet al., 2016, Azithromycin for acute exacerbations of asthma. The AZALEA randomized clinical trial, JAMA Internal Medicine, Vol: 176, Pages: 1630-1637, ISSN: 2168-6106

Importance Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.Objective To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.Design, Setting, and Participants The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom–based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.Interventions Azithromycin 500 mg daily or matched placebo for 3 days.Main Outcomes and Measures The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of −0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.Results Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference

Journal article

Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RML, Santhakumaran S, Mason AJ, Cross M, Al-Beidh F, Best-Lane J, Brealey D, Nutt CL, McNamee JJ, Reschreiter H, Breen A, Liu KD, Ashby Det al., 2016, Levosimendan for the prevention of acute organ dysfunction in sepsis, New England Journal of Medicine, Vol: 375, Pages: 1638-1648, ISSN: 0028-4793

BACKGROUNDLevosimendan is a calcium-sensitizing drug with inotropic and other propertiesthat may improve outcomes in patients with sepsis.METHODSWe conducted a double-blind, randomized clinical trial to investigate whether levosimendanreduces the severity of organ dysfunction in adults with sepsis. Patientswere randomly assigned to receive a blinded infusion of levosimendan (at a dose of0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placeboin addition to standard care. The primary outcome was the mean daily SequentialOrgan Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scoresfor each of five systems range from 0 to 4, with higher scores indicating more severedysfunction; maximum score, 20). Secondary outcomes included 28-day mortality,time to weaning from mechanical ventilation, and adverse events.RESULTSThe trial recruited 516 patients; 259 were assigned to receive levosimendan and257 to receive placebo. There was no significant difference in the mean (±SD) SOFAscore between the levosimendan group and the placebo group (6.68±3.96 vs.6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29;P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9%in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendangroup were less likely than those in the placebo group to be successfullyweaned from mechanical ventilation over the period of 28 days (hazard ratio,0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group thanin the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolutedifference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04).CONCLUSIONSThe addition of levosimendan to standard treatment in adults with sepsis was notassociated with less severe organ dysfunction or lower mortality. Levosim

Journal article

Poulter NR, Anjum A, Cross M, Falaschetti E, Savopoulos C, Szigeti M, Thom S, Hatzitolios Aet al., 2016, A COMPARISON OF THE IMPACT OF MORNING OR NIGHT DELIVERY OF ANTIHYPERTENSIVE AGENTS ON 24 HOUR AMBULATORY BLOOD PRESSURE MONITORING (ABPM) LEVELS: A RANDOMISED CROSS-OVER TRIAL, [OP.LB01.07] A COMPARISON OF THE IMPACT OF MORNING OR NIGHT DELIVERY OF ANTIHYPERTENSIVE AGENTS ON 24 HOUR AMBULATORY BLOOD PRESSURE MONITORING (ABPM) LEVELS: A RANDOMISED CROSS-OVER TRIAL, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E37-E38, ISSN: 0263-6352

Conference paper

Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ, VANISH Investigatorset al., 2016, Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial, The Journal of the American Medical Association, Vol: 316, Pages: 509-518, ISSN: 0002-9955

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1

Journal article

Patel PB, Brett SJ, O'Callaghan D, Anjum A, Cross M, Warwick J, Gordon ACet al., 2016, Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION), BMJ Open, Vol: 6, ISSN: 2044-6055

Introduction: Gastro-intestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid induced constipation and gastro-intestinal dysmotility.Methods: This is a single centre, multi-site, double blind, randomised placebo controlled trial. Eighty-four patients will be recruited from four Intensive Care Units (ICU) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation, and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.Ethics and Dissemination: The trial protocol, the Patient / legal representative Information Sheets and Consent Forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. Upon completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.

Journal article

Hopkins E, Meyerowitz J, Kelly S, Bower M, Fidler S, Cross M, Cason J, Frater Jet al., 2016, The effect of chemotherapy on the HIV reservoir in patients on suppressive ART with malignancy: an observational study, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 15-15, ISSN: 1464-2662

Conference paper

Poulter N, Anjum A, Cross M, Falaschetti E, Savopoulos C, Szigeti M, Thom S, Hatzitolios Aet al., 2016, A comparison of the impact of morning or night delivery of antihypertensive agents on 24 hour ambulatory blood pressure monitoring (ABPM) levels: a randomised cross-over trial, Pages: 641-641

Conference paper

Poulter N, Anjum A, Cross M, Falaschetti E, Savopoulos C, Kanellos I, Szigeti M, Thom S, Hatzitolios Aet al., 2016, LBOS 01-01A COMPARISON OF THE IMPACT OF MORNING OR NIGHT DELIVERY OF ANTIHYPERTENSIVE AGENTS ON 24 HOUR ABPM LEVELS: A RANDOMISED CROSS-OVER TRIAL (HARMONY).

Conference paper

Johnston SL, Szigeti M, Cross M, Brightling CE, Chaudhuri R, Harrison T, Mansur AH, Robinson L, Sattar Z, Jackson DJ, Mallia P, Wong EHC, Corrigan C, Higgins B, Ind P, Singh D, Thomson NC, Ashby D, Chauhan Aet al., 2016, A Randomised, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy Of Oral Azithromycin (500 Mg Od) As A Supplement To Standard Care For Adult Patients With Acute Exacerbations Of Asthma (the Azalea Trial), Publisher: AMER THORACIC SOC

Conference paper

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