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Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.
Ruban, A, Miras, AD, Glaysher, MA, Goldstone, AP, Prechtl, CG, Johnson, N, Chhina, N, Al-Najim, W, Aldhwayan, M, Klimowska-Nassar, N, et al
Annals of surgery. 2022;(3):440-447
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Abstract
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 Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.
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Effectiveness of different recruitment strategies in an RCT of a surgical device: experience from the Endobarrier trial.
Ruban, A, Prechtl, CG, Glaysher, MA, Chhina, N, Al-Najim, W, Miras, AD, Smith, C, P Goldstone, A, Patel, M, Moore, M, et al
BMJ open. 2019;(11):e032439
Abstract
Recruiting participants into clinical trials is notoriously difficult and poses the greatest challenge when planning any investigative study. Poor recruitment may not only have financial ramifications owing to increased time and resources being spent but could adversely influence the clinical impact of a study if it becomes underpowered. Herein, we present our own experience of recruiting into a nationally funded, multicentre, randomised controlled trial (RCT) of the Endobarrier versus standard medical therapy in obese patients with type 2diabetes. Despite these both being highly prevalent conditions, there were considerable barriers to the effectiveness of different recruitment strategies across each study site. Although recruitment from primary care proved extremely successful at one study site, this largely failed at another site prompting the implementation of multimodal recruitment strategies including a successful media campaign to ensure sufficient participants were enrolled and the study was adequately powered. From this experience, we propose where appropriate the early engagement and investment in media campaigns to enhance recruitment into clinical trials. Trial Registration: ISRCTN30845205.
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Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.
Dorling, J, Abbott, J, Berrington, J, Bosiak, B, Bowler, U, Boyle, E, Embleton, N, Hewer, O, Johnson, S, Juszczak, E, et al
The New England journal of medicine. 2019;(15):1434-1443
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Abstract
BACKGROUND Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).
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Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study.
Shah, MA, Starodub, A, Sharma, S, Berlin, J, Patel, M, Wainberg, ZA, Chaves, J, Gordon, M, Windsor, K, Brachmann, CB, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;(16):3829-3837
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Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in protumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6.Patients and Methods: Three dosages of andecaliximab monotherapy [200, 600, and 1800 mg i.v. every 2 weeks (q2w)] were investigated in patients with advanced solid tumors (n = 13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n = 40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed.Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1,200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were four deaths on study not attributed to andecaliximab treatment. In first-line patients (n = 36), median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI), 5-13.9 months], and the overall response rate (ORR) was 50%. Among all patients (n = 40), median PFS was 7.8 (90% CI, 5.5-13.9) months, and ORR was 48%, with a median duration of response of 8.4 months.Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase III study evaluating mFOLFOX6 ± andecaliximab in this setting is ongoing. Clin Cancer Res; 24(16); 3829-37. ©2018 AACR.
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A Phase II Study of the c-Met Inhibitor Tivantinib in Combination with FOLFOX for the Treatment of Patients with Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction, or Stomach.
Pant, S, Patel, M, Kurkjian, C, Hemphill, B, Flores, M, Thompson, D, Bendell, J
Cancer investigation. 2017;(7):463-472
Abstract
BACKGROUND This phase I/II study was designed to determine the maximum tolerated dose of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors and to evaluate the safety and efficacy of this combination for patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. METHODS Patients with advanced solid tumors for which FOLFOX would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design in phase I. In phase II, patients with advanced GE cancer received standard FOLFOX day 1 and tivantinib (360 mg PO BID) days 1-14 of each 2-week cycle. Restaging occurred every four cycles. The primary phase II endpoint was response rate (RR). RESULTS Forty-nine patients were enrolled (15 on phase I and 34 on phase II). The expansion dose was established as tivantinib 360 mg BID in combination with FOLFOX. Thirty-two phase II patients were treated for a median of eight cycles (range, 1-38), with an overall RR of 38%. Treatment-related toxicities included neutropenia, fatigue, diarrhea, nausea, and peripheral neuropathy. Median progression-free survival (PFS) was 6.1 hmonths with a median time to progression of 7.0 months. Median overall survival was 9.6 months. Two patients remain on study at the time of this analysis. CONCLUSIONS The combination treatment of tivantinib plus FOLFOX in patients with advanced GE cancer showed a response and PFS in the range of historical controls for first-line FOLFOX therapy. However, two patients had extended time on study treatment (36 and 45 cycles) at the time of data cutoff.
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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.
Glaysher, MA, Mohanaruban, A, Prechtl, CG, Goldstone, AP, Miras, AD, Lord, J, Chhina, N, Falaschetti, E, Johnson, NA, Al-Najim, W, et al
BMJ open. 2017;(11):e018598
Abstract
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. TRIAL REGISTRATION NUMBER ISRCTN30845205, ClinicalTrials.gov Identifier NCT02459561.
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Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.
Suttle, AB, Grossmann, KF, Ouellet, D, Richards-Peterson, LE, Aktan, G, Gordon, MS, LoRusso, PM, Infante, JR, Sharma, S, Kendra, K, et al
Journal of clinical pharmacology. 2015;(4):392-400
Abstract
The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.
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Evaluation of CYP3A-mediated drug-drug interactions with romidepsin in patients with advanced cancer.
Laille, E, Patel, M, Jones, SF, Burris, HA, Infante, J, Lemech, C, Liu, L, Arkenau, HT
Journal of clinical pharmacology. 2015;(12):1378-85
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Two multicenter, single-arm, single-infusion, open-label studies were conducted to evaluate the effect of ketoconazole (a strong CYP3A inhibitor) or rifampin (a strong CYP3A inducer) daily for 5 days on the pharmacokinetics (PK) and safety of romidepsin (8 mg/m(2) intravenous 4-hour infusion for the ketoconazole study or a 14 mg/m(2) intravenous 4-hour infusion for the rifampin study) in patients with advanced cancer. Romidepsin coadministered with ketoconazole (400 mg) or rifampin (600 mg) was not bioequivalent to romidepsin alone. With ketoconazole, the mean romidepsin AUC and Cmax were increased by approximately 25% and 10%, respectively. With rifampin, the mean romidepsin AUC and Cmax were unexpectedly increased by approximately 80% and 60%, respectively; this is likely because of inhibition of active liver uptake. For both studies, romidepsin clearance and volume of distribution were decreased, terminal half-life was comparable, and median Tmax was similar. Overall, the safety profile of romidepsin was not altered by coadministration with ketoconazole or rifampin, except that a higher incidence and greater severity of thrombocytopenia was observed when romidepsin was given with rifampin. The use of romidepsin with rifampin and strong CYP3A inducers should be avoided. Toxicity related to romidepsin exposure should be monitored when romidepsin is given with strong CYP3A inhibitors.
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Impact of deceased organ donor demographics and critical care end points on liver transplantation and graft survival rates.
Bloom, MB, Raza, S, Bhakta, A, Ewing, T, Patel, M, Ley, EJ, Margulies, DR, Salim, A, Malinoski, D
Journal of the American College of Surgeons. 2015;(1):38-47
Abstract
BACKGROUND The criteria for organ acceptance remain inconsistent, which limits the ability to standardize critical care practices. We sought to examine predictors of liver graft use and survival to better guide the selection and management of potential organ donors. STUDY DESIGN A prospective observational study of all donors managed by the 8 organ procurement organizations in United Network for Organ Sharing Region 5 was conducted from July 2008 to March 2011. Critical care end points that reflect the normal hemodynamic, acid-base, respiratory, endocrine, and renal status of the donor were collected at 3 time points. Critical care and demographic data associated with liver transplantation and graft survival rates were first determined using univariate analyses, and then logistic regression was used to identify independent predictors of these two outcomes. RESULTS From 961 donors, 730 (76%) livers were transplanted and 694 (95%) were functioning after 74 ± 73 days of follow-up. After regression analysis, donor BMI (odds ratio [OR] = 0.94), male sex (OR = 1.89), glucose <150 mg/dL (OR = 1.97), lower dopamine dose (OR = 0.95), vasopressin use (OR = 1.95), and ejection fraction >50% (OR = 1.77) remained as independent predictors of liver use. Graft survival was associated with lower donor BMI (OR = 0.91) and sodium levels (OR = 0.95). CONCLUSIONS After controlling for donor age, sex, and BMI, both hemodynamic and endocrine critical care end points were associated with increased liver graft use. Both donor BMI and lower sodium levels during the course of donor management were independently predictive of improved graft survival. These results may help guide the management and selection of potential organ donors after neurologic determination of death.
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Quality of life in patients with age-related macular degeneration: results from the VISION study.
Leys, A, Zlateva, G, Shah, SN, Patel, M
Eye (London, England). 2008;(6):792-8
Abstract
PURPOSE To assess the impact of treatment with pegaptanib sodium vs usual care on vision-related quality of life (VRQoL) in patients with age-related macular degeneration (AMD). METHODS VRQoL was a secondary end point in the trial, a prospective, randomized, double-masked, multicentre, dose-ranging study. Three doses of pegaptanib (0.3, 1, and 3 mg) were compared with usual care with respect to changes in VRQoL as indicated by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25), administered at baseline and weeks 30 and 54. Four of the NEI-VFQ 25 domains were prospectively designated as primary: near vision, distance vision, role limitations, and dependency. Between-group differences were assessed using an analysis of covariance model with age, gender, and baseline score as covariates. RESULTS NEI-VFQ 25 data were available for 569 subjects. At week 54, improvements in the distance vision and role limitations domains were greater in pegaptanib than usual care arms. No substantial increase in ocular pain was noted in pegaptanib-treated patients. No clear superiority of any particular dosage strength of pegaptanib was demonstrated, and no significant differences or trends favoured usual care on any domain score or the NEI-VFQ 25 composite score. The greatest VRQoL benefit was seen in responders (lost<3 lines) to treatment. CONCLUSION The VISION trial provided evidence of trends in quality-of-life benefit associated with effective treatment of AMD using pegaptanib. Treatment with pegaptanib is expected to contribute significantly to VRQoL improvement for responder patients.