Imperial College London

MrNicholasJohnson

Faculty of MedicineSchool of Public Health

Research Fellow
 
 
 
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+44 (0)20 7594 1751nicholas.johnson

 
 
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Stadium HouseWhite City Campus

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Summary

 

Publications

Publication Type
Year
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26 results found

Rockall AG, Li X, Johnson N, Lavdas I, Santhakumaran S, Prevost AT, Punwani S, Goh V, Barwick TD, Bharwani N, Sandhu A, Sidhu H, Plumb A, Burn J, Fagan A, Wengert GJ, Koh D-M, Reczko K, Dou Q, Warwick J, Liu X, Messiou C, Tunariu N, Boavida P, Soneji N, Johnston EW, Kelly-Morland C, De Paepe KN, Sokhi H, Wallitt K, Lakhani A, Russell J, Salib M, Vinnicombe S, Haq A, Aboagye EO, Taylor S, Glocker Bet al., 2023, Development and evaluation of machine learning in whole-body magnetic resonance imaging for detecting metastases in patients with lung or colon cancer: a diagnostic test accuracy study, Investigative Radiology, Vol: 58, Pages: 823-831, ISSN: 0020-9996

OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient spec

Journal article

Patel P, Thomas R, Hamady M, Hague J, Raja J, Tan T, Bloom S, Richards T, Weiss CR, Prechtl CG, Smith C, Sasikaran T, Hesketh R, Bourmpaki E, Johnson NA, Fiorentino F, Ahmed ARet al., 2023, EMBIO trial study protocol: left gastric artery embolisation for weight loss in patients living with obesity with a BMI 35-50 kg/m², BMJ Open, Vol: 13, ISSN: 2044-6055

Introduction Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities.Methods and analysis 76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18–70 with a body mass index 35–50 kg/m2 and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months.Ethics and dissemination This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and

Journal article

Ruban A, Aldubaikhi G, Johnson NA, Glaysher MA, Chhina N, Byrne J, Marchesi J, Teare JP, Goldstone AP, Miras A, Li JVet al., 2023, ENDOBARRIER®, A DUODENAL-JEJUNAL BYPASS LINER DEVICE, ALTERS THE GLOBAL METABOLIC AND THE GUT BACTERIAL PROFILES OF PATIENTS WITH OBESITY AND DIABETES, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S1457-S1457, ISSN: 0016-5085

Conference paper

Kanagaratnam P, McCready J, Tayebjee M, Shepherd E, Sasikaran T, Todd D, Johnson N, Kyriacou A, Hayat S, Hobson NA, Mann I, Balasubramaniam R, Whinnett Z, Earley M, Petkar S, Veasey R, Kirubakaran S, Coyle C, Kim M-Y, Lim PB, O'Neill J, Davies DW, Peters NS, Babalis D, Linton N, Falaschetti E, Tanner M, Shah J, Poulter Net al., 2023, Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial, EP Europace, Vol: 25, Pages: 863-872, ISSN: 1099-5129

Aims:There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF.Methods and results:We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097–0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639–2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test).Conclusion:The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met.Trial registrationClinical Trials Registration: NCT02459574.

Journal article

Whinnett ZI, Shun-Shin MJ, Tanner M, Foley P, Chandrasekaran B, Moore P, Adhya S, Qureshi N, Muthumala A, Lane R, Rinaldi A, Agarwal S, Leyva F, Behar J, Bassi S, Ng A, Scott P, Prasad R, Swinburn J, Tomson J, Sethi A, Shah J, Lim PB, Kyriacou A, Thomas D, Chuen J, Kamdar R, Kanagaratnam P, Mariveles M, Burden L, March K, Howard JP, Arnold A, Vijayaraman P, Stegemann B, Johnson N, Falaschetti E, Francis DP, Cleland JGF, Keene Det al., 2023, Effects of haemodynamically atrio-ventricular optimized His bundle pacing on heart failure symptoms and exercise capacity: the His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) randomized, double-blind, cross-over trial, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 25, Pages: 274-283, ISSN: 1388-9842

Journal article

Farne H, Glanville N, Johnson N, Kebadze T, Aniscenko J, Regis E, Zhu J, Trujillo-Torralbo M-B, Kon OM, Mallia P, Prevost A, Edwards M, Johnston S, Singanayagam A, Jackson Det al., 2022, Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomized controlled trial, Thorax, Vol: 77, Pages: 950-959, ISSN: 0040-6376

Background and aimsThe CRTH2 antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesized that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomized to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 three weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post-infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant- and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0-14 (difference 3.0 (95% CI -29.0 to 17.0), P=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo- but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events, or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

Journal article

Aldhwayan MM, Al-Najim W, Ruban A, Glaysher MA, Johnson B, Chhina N, Dimitriadis GK, Prechtl CG, Johnson NA, Byrne JP, Goldstone AP, Teare JP, Le Roux CW, Miras ADet al., 2022, Does bypass of the proximal small intestine impact food intake, preference, and taste function in humans? An experimental medicine study using the duodenal-jejunal bypass liner, Nutrients, Vol: 14, ISSN: 2072-6643

The duodenal-jejunal bypass liner (Endobarrier) is an endoscopic treatment for obesity and type 2 diabetes mellitus (T2DM). It creates exclusion of the proximal small intestine similar to that after Roux-en-Y Gastric Bypass (RYGB) surgery. The objective of this study was to employ a reductionist approach to determine whether bypass of the proximal intestine is the component conferring the effects of RYGB on food intake and sweet taste preference using the Endobarrier as a research tool. A nested mechanistic study within a large randomised controlled trial compared the impact of lifestyle modification with vs. without Endobarrier insertion in patients with obesity and T2DM. Forty-seven participants were randomised and assessed at several timepoints using direct and indirect assessments of food intake, food preference and taste function. Patients within the Endobarrier group lost numerically more weight compared to the control group. Using food diaries, our results demonstrated similar reductions of food intake in both groups. There were no significant differences in food preference and sensory, appetitive reward, or consummatory reward domain of sweet taste function between groups or changes within groups. In conclusion, the superior weight loss seen in patients with obesity and T2DM who underwent the Endobarrier insertion was not due to a reduction in energy intake or change in food preferences.

Journal article

Lee MJ, Collins S, Babalis D, Johnson N, Falaschetti E, Prevost AT, Ashraf A, Jacob M, Cole T, Hurley L, Pace M, Ogbe A, Khan M, Zacharopoulou P, Brown H, Sutherland E, Box H, Fox J, Deeks S, Horowitz J, Nussenzweig MC, Caskey M, Frater J, Fidler Set al., 2022, The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial, Trials, Vol: 23, ISSN: 1745-6215

Background:Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control.Methods:RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures.Discussion:The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tes

Journal article

Ruban A, Miras A, glaysher M, Goldstone A, Teare Jet al., 2022, Duodenal-jejunal bypass liner for the management of Type 2 diabetes and obesity: a multicenter randomized controlled trial, Annals of Surgery, Vol: 275, Pages: 440-447, ISSN: 0003-4932

Objective: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.Summary Background Data: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.Methods: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.Results: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44–2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8–39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group.Conclusions: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions.Trial Registration: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research

Journal article

Ruban A, Miras AD, Glaysher MA, Goldstone AP, Prechtl CG, Johnson N, Chhina N, Al-Najim W, Aldhwayan M, Klimowska-Nassar N, Smith C, Lord J, Li JV, Flores L, Al-Lababidi M, Dimitriadis GK, Patel M, Moore M, Chahal H, Ahmed AR, Cousins J, Aldubaikhi G, Glover B, Falaschetti E, Ashrafian H, Roux CWL, Darzi A, Byrne JP, Teare JPet al., 2022, Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity, Annals of Surgery, Vol: 275, Pages: 440-447, ISSN: 0003-4932

<jats:sec> <jats:title>Objective:</jats:title> <jats:p>The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.</jats:p> </jats:sec> <jats:sec> <jats:title>Summary Background Data:</jats:title> <jats:p>This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44–2.0; <jats:italic toggle="yes">P</jats:italic> = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8–39; <jats:italic toggle="yes">P</jats:italic> = .007). The DJBL grou

Journal article

Patel B, Mumby S, Johnson N, Falaschetti E, Hansen J, Adcock I, McAuley D, Takata M, Karbing DS, Jabaudon M, Schellengowski P, Rees SEet al., 2022, Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)-trial protocol, Trials, Vol: 23, Pages: 1-18, ISSN: 1745-6215

BackgroundThe acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.MethodsWe will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.DiscussionDespite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strateg

Journal article

Whinnett Z, Tanner M, Chandrasekaran B, Foley P, Moore P, Adhya S, Qureshi N, Muthumala A, Behar J, Lane RE, Rinaldi CA, Agarwal S, Farwell D, Leyva F, Bassi S, Ng GA, Scott P, Prasad R, Swinburn J, Tomson J, Kyriacou A, Thomas DE, Chuen J, Kamdar R, Lim PB, Sethi A, Shah J, Vijayaraman P, Johnson N, Falaschetti E, Mariveles M, Kanagaratnam P, Cleland J, Francis D, Keene Det al., 2021, His-Optimized Pacing in Patients With a Long PR Interval, Narrow QRS and Heart Failure: Results of the Hope-hf Clinical Trial, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E587-E587, ISSN: 0009-7322

Conference paper

Glaysher M, Ward J, Aldhwayan M, Ruban A, Prechtl CG, Fisk HL, Chhina N, Al-Najim W, Smith C, Klimowska-Nassar N, Johnson N, Falaschetti E, Goldstone AP, Miras AD, Byrne JP, Calder PC, Teare Jet al., 2021, The effect of a duodenal-jejunal bypass liner on lipid profile and blood concentrations of long chain polyunsaturated fatty acids, Clinical Nutrition, Vol: 40, Pages: 2343-2354, ISSN: 0261-5614

Background & aimsDuodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs).MethodsSub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18–65 years with type-2 diabetes mellitus and body mass index 30–50 kg/m2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group.ResultsWeight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group.ConclusionOne year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation.

Journal article

Ruban A, Glaysher MA, Miras AD, Goldstone AP, Prechtl CG, Johnson N, Li J, Aldhwayan M, Aldubaikhi G, Glover B, Lord J, Onyimadu O, Falaschetti E, Klimowska-Nassar N, Ashrafian H, Byrne J, Teare JPet al., 2020, A duodenal sleeve bypass device added to intensive medical therapy for obesity with type 2 diabetes: a RCT, Efficacy and Mechanism Evaluation, Vol: 7, Pages: 1-130, ISSN: 2050-4365

BackgroundThe EndoBarrier® (GI Dynamics Inc., Boston, MA, USA) is an endoluminal duodenal–jejunal bypass liner developed for the treatment of patients with obesity and type 2 diabetes mellitus. Meta-analyses of its effects on glycaemia and weight have called for larger randomised controlled trials with longer follow-up.ObjectivesThe primary objective was to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level reduction of ≥ 20%. The secondary objectives were to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level of < 42 mmol/mol, blood pressure of < 135/85 mmHg, and the effectiveness on total body weight loss. Additional secondary outcomes were to investigate the cost-effectiveness and mechanism of action of the effect of a duodenal–jejunal bypass liner on brain reward system responses, insulin sensitivity, eating behaviour and metabonomics.DesignA multicentre, open-label, randomised controlled trial.SettingImperial College Healthcare NHS Trust and University Hospital Southampton NHS Foundation Trust.ParticipantsPatients aged 18–65 years with a body mass index of 30–50 kg/m2 and with inadequately controlled type 2 diabetes mellitus who were on oral glucose-lowering medications.InterventionsParticipants were randomised equally to receive intensive medical therapy alongside a duodenal–jejunal bypass liner device (n = 85) or intensive medical therapy alone for 12 months (n = 85), and were followed up

Journal article

Lyon A, Babalis D, Morley-Smith AC, Hedger M, Suarez Barrientos A, Foldes G, Couch LS, Chowdhury RA, Tzortzis KN, Peters NS, Rog-Zielinska EA, Yang YH, Welch S, Bowles CT, Rahman Haley S, Bell AR, Rice A, Sasikaran T, Johnson NA, Falaschetti E, Parameshwar J, Lewis C, Tsui S, Simon A, Pepper J, Rudy JJ, Zsebo KM, MacLeod KT, Terracciano CM, Hajjar RJ, Banner N, Harding SEet al., 2020, Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device – the SERCA-LVAD TRIAL, Gene Therapy, Vol: 27, Pages: 579-590, ISSN: 0969-7128

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. Enrolled subjects were randomised to receive a single intracoronary infusion of 1x1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort, which may help guide future trial design.

Journal article

Ruban A, Glaysher M, Miras A, Prechtl CG, Goldstone AP, Johnson NA, Aldhwayan M, Chhina N, Al-Najim W, Ashrafian H, Patel M, Byrne J, Teare JPet al., 2020, ONE YEAR OF DUODENAL-JEJUNAL BYPASS LINER THERAPY (ENDOBARRIER®) LEADS TO SIGNIFICANT CHANGES IN LIVER BIOCHEMISTRY ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE, GI Fellows Sessions at Digestive Disease Week / 61st Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract, Publisher: MOSBY-ELSEVIER, Pages: AB225-AB226, ISSN: 0016-5107

Conference paper

Cro S, Forbes G, Johnson NA, Kahan BCet al., 2020, Evidence of unexplained discrepancies between planned and conducted statistical analyses: a review of randomized trials, BMC Medicine, Vol: 18, ISSN: 1741-7015

Evidence of unexplained discrepancies between planned and conducted statistical analyses: a review of randomised trials

Journal article

Ruban A, Liu Z, Glaysher M, Ashrafian H, Miras A, Prechtl C, Goldstone A, Aldhwayan M, Chhina N, Al-Najim W, Johnson N, Patel M, Li J, Byrne J, Teare Jet al., 2020, One year of duodenal-jejunal bypass liner therapy (Endobarrier (R)) leads to perturbations in the metabolic profile of urine, plasma and stool of obese diabetic patients., 11th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S10-S10, ISSN: 0960-8923

Conference paper

Glaysher M, Miras A, Ruban A, Prechtl C, Shojaee-Moradie F, Jackson N, Coppin L, Aldhwayan M, Johnson N, Chhina N, Al-Najim W, Smith C, Klimowska-Nassar N, Goldstone A, Patel M, Le Roux C, Umpleby M, Byrne J, Teare Jet al., 2020, The effect of a duodenal-jejunal bypass liner device (Endobarrier®) on insulin sensitivity, 11th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S25-S26, ISSN: 0960-8923

Conference paper

Glaysher M, Ward J, Aldhwayan M, Ruban A, Prechtl C, Fisk H, Gelauf C, Chhina N, Al-Najim W, Smith C, Klimowska-Nassar N, Johnson N, Goldstone A, Miras A, Patel M, Byrne J, Calder P, Teare Jet al., 2020, The effect of a duodenal-jejunal bypass liner device (Endobarrier®) on lipid profile and blood concentrations of long chain polyunsaturated fatty acids, 11th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S16-S17, ISSN: 0960-8923

Conference paper

Johnson NA, Sasikaran T, 2019, AVATAR-AF: Getting to the heart of data management for analysis (5 simple rules to follow to ensure data integrity), 5th International Clinical Trials Methodology Conference, Publisher: BMC

Conference paper

Kahan B, Forbes G, Ahmad T, Johnson N, Cro Set al., 2019, Statistical transparency in clinical trials: an evaluation of unexplained discrepancies between planned and conducted analyses, Publisher: BMC

Conference paper

Mann I, Sasikaran T, Sandler B, Babalis D, Johnson N, Falaschetti E, Copley A, Tayebjee M, Todd D, Shepherd E, McCready J, Poulter N, Kanagaratnam Pet al., 2019, Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation (AVATAR-AF): design and rationale, American Heart Journal, Vol: 214, Pages: 36-45, ISSN: 0002-8703

Atrial Fibrillation (AF) ablation using the cryoballoon is effective at reducing symptomatic AF episodes. The prevalence of AF is increasing with the aging population and access to such treatment would be enhanced by reducing the resource requirements. Relinquishing electrical mapping of the pulmonary veins (PV) removes the need for PV catheters, electrical recording equipment and staff trained in using this equipment. Moreover, the majority of complications are peri-procedural so overnight hospitalization maybe unnecessary. We tested this streamlined approach to AF ablation against medical therapy using the endpoint of time to all hospital episodes. METHODS: The AVATAR-AF study is a prospective, multicenter, randomized controlled trial testing the primary hypothesis that AF ablation done without PV mapping or overnight hospitalization is more effective than anti-arrhythmic drugs at reducing all hospital episodes related to recurrent atrial arrhythmias. We included a third arm to test a secondary hypothesis that confirming PV entrance block as per consensus guidelines can improve outcomes. Three hundred twenty-one patients with documented paroxysmal AF will be randomized in a 1:1:1 manner to one of three investigation arms: (1) AVATAR protocol cryoballoon ablation without assessment of acute PV isolation or overnight hospitalization; (2) medical therapy with anti-arrhythmic drugs; or (3) conventional cryoballoon ablation with assessment of acute PV isolation. The primary endpoint is defined as the time to all hospital episodes (including outpatient consultation) related to treatment for atrial arrhythmia. CONCLUSION: The AVATAR-AF study will determine whether the resource utilization for AF ablation can be reduced whilst maintaining superiority over medical therapy.

Journal article

Behary P, Tharakan G, Alexiadou K, Johnson N, Wewer Albrechtsen NJ, Kenkre J, Cuenco J, Hope D, Anyiam O, Choudhury S, Alessimii H, Poddar A, Minnion J, Doyle C, Frost G, Le Roux C, Purkayastha S, Moorthy K, Dhillo W, Holst JJ, Ahmed AR, Prevost AT, Bloom SR, Tan TMet al., 2019, Combined GLP-1, oxyntomodulin, and peptide YY improves body weight and glycemia in obesity and prediabetes/type 2 diabetes: a randomized single-blinded placebo controlled study, Diabetes Care, Vol: 42, Pages: 1446-1453, ISSN: 0149-5992

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity. RESEARCH DESIGN AND METHODS: In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (n = 15) or saline (n = 11) infusion for 4 weeks. We also studied 21 patients who had undergone RYGB and 22 patients who followed a very low-calorie diet (VLCD) as unblinded comparators. Outcomes measured were 1) body weight, 2) fructosamine levels, 3) glucose and insulin during a mixed meal test (MMT), 4) energy expenditure (EE), 5) energy intake (EI), and 6) mean glucose and measures of glucose variability during continuous glucose monitoring. RESULTS: GOP infusion was well tolerated over the 4-week period. There was a greater weight loss (P = 0.025) with GOP (mean change -4.4 [95% CI -5.3, -3.5] kg) versus saline (-2.5 [-4.1, -0.9] kg). GOP led to a greater improvement (P = 0.0026) in fructosamine (-44.1 [-62.7, -25.5] µmol/L) versus saline (-11.7 [-18.9, -4.5] µmol/L). Despite a smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose tolerance after a mixed-meal stimulus and reduced glycemic variability compared with RYGB and VLCD. CONCLUSIONS: GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Journal article

Behary P, Tharakan G, Alexiadou K, Johnson NA, Albrechtsen NJW, Cuenco J, Hope D, Dhillo W, Minnion JS, Frost G, Le Roux C, Purkayastha S, Moorthy K, Holst JJ, Ahmed A, Prevost T, Bloom S, Tan TMMet al., 2019, Combined GLP-1, Oxyntomodulin, and Peptide YY Improves Glycaemia and Body Weight in Obesity and Type 2 Diabetes: A Randomized, Single-Blinded Study, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Glaysher M, Mohanaruban A, Prechtl CG, Goldstone AP, Miras AD, Lord J, Chhina N, Falaschetti E, Johnson NA, Al-Najim W, smith C, Li JV, Patel M, Ahmed AR, Moore M, Poulter NR, Bloom S, Darzi A, Le Roux C, Byrne JP, teare Jet al., 2017, A randomised controlled trial of a duodenal-jejunal bypass sleeve device (EndoBarrier) compared with standard medical therapy for the management of obese subjects with type 2 diabetes mellitus, BMJ Open, Vol: 7, ISSN: 2044-6055

Introduction The prevalence of obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), is increasing. Exclusion of the foregut, as occurs in Roux-en-Y gastric bypass, has a key role in the metabolic improvements that occur following bariatric surgery, which are independent of weight loss. Endoscopically placed duodenal-jejunal bypass sleeve devices, such as the EndoBarrier (GI Dynamics, Lexington, Massachusetts, USA), have been designed to create an impermeable barrier between chyme exiting the stomach and the mucosa of the duodenum and proximal jejunum. The non-surgical and reversible nature of these devices represents an attractive therapeutic option for patients with obesity and T2DM by potentially improving glycaemic control and reducing their weight.Methods and analysis In this multicentre, randomised, controlled, non-blinded trial, male and female patients aged 18–65 years with a body mass index 30–50 kg/m2 and inadequately controlled T2DM on oral antihyperglycaemic medications (glycosylated haemoglobin (HbA1c) 58–97 mmol/mol) will be randomised in a 1:1 ratio to receive either the EndoBarrier device (n=80) for 12 months or conventional medical therapy, diet and exercise (n=80). The primary outcome measure will be a reduction in HbA1c by 20% at 12 months. Secondary outcome measures will include percentage weight loss, change in cardiovascular risk factors and medications, quality of life, cost, quality-adjusted life years accrued and adverse events. Three additional subgroups will investigate the mechanisms behind the effect of the EndoBarrier device, looking at changes in gut hormones, metabolites, bile acids, microbiome, food hedonics and preferences, taste, brain reward system responses to food, eating and addictive behaviours, body fat content, insulin sensitivity, and intestinal tissue gene expression.

Journal article

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