Optimizing patient risk stratification for colonoscopy screening and surveillance of colorectal cancer: The role for linked data

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Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

What is the importance of the referral letter in the patient journey? A pilot survey in Western Australia

Background: Access to specialists is mediated by general practitioners in many countries. In these settings, specialists rely on information in referral letters when deciding which cases to schedule for their clinics.,/p\u3e Method: Two-hundred and seven consecutive referral letters to gastroenterologists were scored for the amount of information relayed to the specialist, using a published schedule. The \u27quality\u27 scores for these referral letters were compared for four groups of patients: patients diagnosed with histological lesion, those with no histological lesion, those who failed to attend clinic, or those who had a diagnosis unknown. Forty-two referral letters were generated with a range of quality scores. Four gastroenterologists were asked to identify which letters described patients \u27likely\u27 to have a significant or benign colorectal condition, and whether they could triage the cases for their clinic given only the information in the letters. Results: It was not possible to differentiate which letters related to patients in each of the four categories (P = 0.6). Patients who failed to attend were more symptomatic than those with a histological lesion (35.4 versus 28.2, mean difference 7.14, 95% confidence interval (CI) 14.1 to 0.15, P = 0.045). Patients referred \u27urgently\u27 were not, on the basis of the referral letters, the most symptomatic group (29.7 versus 27, mean difference 2.7, 95% CI -3.4 to 8.8, P = 0.38). The specialists failed to agree on the proportion of cases that could be triaged for their clinics. The cases that could be triaged contained more information (mean 66.38 versus 49.86, mean difference 16, 95% CI 1.3-31.7, P \u3c 0.001). Conclusion: There was no evidence for an association between the amount of information relayed and the diagnosis of a histological lesion. However, more information was helpful when deciding which patients to schedule first. By corollary, patients referred with lesser documentation of their clinical presentation may be denied \u27urgent\u27 access to the gastroenterology clinic

Randomised clinical trial: a placebo-controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease

Background Nexvax2 contains three gluten-derived peptides, intended to tolerize coeliac disease patients to gluten. Sequences cover six epitopes that trigger immune activation in human leucocyte antigen-DQ2.5-positive patients, most notably after an initial dose. Patients experience gastrointestinal symptoms with increases in serum interleukin-2. Consistent with Nexvax2's induction of non-responsiveness, reactivity disappears after repeated doses, or is avoided with gradual dose escalation. Early clinical trials used intradermal dosing, but pharmacokinetics and rapid onset of effect suggest that subcutaneous delivery may also be effective. Aims To document the relative bioavailability of Nevax2 peptides after subcutaneous and intradermal dosing, and the tolerability and ability of subcutaneous dosing to induce non-responsiveness to Nexvax2 peptides. Methods A randomised, double-blind, placebo-controlled study was conducted to assess plasma pharmacokinetics after subcutaneous and intradermal Nexvax2 dosing in HLA DQ2.5-positive patients, who had symptoms after an oral gluten challenge. Randomisation was to semi-weekly Nexvax2 (n = 12) or placebo (n = 2) injections, over a 5-week subcutaneous dose escalation and 2-week maintenance period, the latter with four doses of 900 mu g, two subcutaneous and two intradermal. Post-dose circulating peptide and interleukin-2 levels were assessed. Investigators recorded adverse events experienced by patients. Results Subcutaneous dosing resulted in slightly greater exposure. Interleukin-2 responses were seen with the gluten challenge but not after subcutaneous or intradermal dosing of 900 mu g. Adverse events were generally mild and self-limited. Conclusions Subcutaneous and intradermal dosing of Nexvax2 yield similar bioavailability of constituent peptides; subcutaneous dose escalation avoids an immune response to dominant gluten epitopes

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Background: Nexvax2® is a novel, peptide-based, epitope-specific immunotherapy intended to be administered by regular injections at dose levels that increase the threshold for clinical reactivity to natural exposure to gluten and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients administered fixed intradermal doses of Nexvax2 become unresponsive to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but gastrointestinal symptoms and cytokine release mimicking gluten exposure, that accompany the first dose, limit the maximum tolerated dose to 150. μg. Our aim was to test whether stepwise dose escalation attenuated the first dose effect of Nexvax2 in celiac disease patients. Methods: We conducted a randomized, double-blind, placebo-controlled trial at four community sites in Australia (3) and New Zealand (1) in HLA-DQ2·5 genotype positive adults with celiac disease who were on a gluten-free diet. Participants were assigned to cohort 1 if they were HLA-DQ2·5 homozygotes; other participants were assigned to cohort 2, or to cohort 3 subsequent to completion of cohort 2. Manual central randomization without blocking was used to assign treatment for each cohort. Initially, Nexvax2-treated participants in cohorts 1 and 2 received an intradermal dose of 30. μg (consisting of 10. μg of each constituent peptide), followed by 60. μg, 90. μg, 150. μg, and then eight doses of 300. μg over six weeks, but this was amended to include doses of 3. μg and 9. μg and extended over a total of seven weeks. Nexvax2-treated participants in cohort 3 received doses of 3. μg, 9. μg, 30. μg, 60. μg, 90. μg, 150. μg, 300. μg, 450. μg, 600. μg, 750. μg, and then eight of 900. μg over nine weeks. The dose interval was 3 or 4. days. Participants, care providers, data managers, sponsor personnel, and study site personnel were blinded to treatment assignment. The primary outcome was the number of adverse events and percentage of participants with adverse events during the treatment period. This completed trial is registered with ClinicalTrials.gov, number NCT02528799. Findings: From the 73 participants who we screened from 19 August 2015 to 31 October 2016, 24 did not meet eligibility criteria, and 36 were ultimately randomized and received study drug. For cohort 1, seven participants received Nexvax2 (two with the starting dose of 30. μg and then five at 3. μg) and three received placebo. For cohort 2, 10 participants received Nexvax2 (four with starting dose of 30. μg and then six at 3. μg) and four received placebo. For cohort 3, 10 participants received Nexvax2 and two received placebo. All 36 participants were included in safety and immune analyses, and 33 participants completed treatment and follow-up; in cohort 3, 11 participants were assessed and included in pharmacokinetics and duodenal histology analyses. Whereas the maximum dose of Nexvax2 had previously been limited by adverse events and cytokine release, no such effect was observed when dosing escalated from 3. μg up to 300. μg in HLA-DQ2·5 homozygotes or to 900. μg in HLA-DQ2.5 non-homozygotes. Adverse events with Nexvax2 treatment were less common in cohorts 1 and 2 with the starting dose of 3. μg (72 for 11 participants) than with the starting dose of 30. μg (91 for six participants). Adverse events during the treatment period in placebo-treated participants (46 for nine participants) were similar to those in Nexvax2-treated participants when the starting dose was 3. μg in cohort 1 (16 for five participants), cohort 2 (56 for six participants), and cohort 3 (44 for 10 participants). Two participants in cohort 2 and one in cohort 3 who received Nexvax2 starting at 3. μg did not report any adverse event, while the other 33 participants experienced at least one adverse event. One participant, who was in cohort 1, withdrew from the study due to adverse events, which included abdominal pain graded moderate or severe and associated with nausea after receiving the starting dose of 30. μg and one 60. μg dose. The most common treatment-emergent adverse events in the Nexvax2 participants were headache (52%), diarrhoea (48%), nausea (37%), abdominal pain (26%), and abdominal discomfort (19%). Administration of Nexvax2 at dose levels from 150. μg to 900. μg preceded by dose escalation was not associated with elevations in plasma cytokines at 4. h. Nexvax2 treatment was associated with trends towards improved duodenal histology. Plasma concentrations of Nexvax2 peptides were dose-dependent. Interpretation: We show that antigenic peptides recognized by CD4-positive T cells in an autoimmune disease can be safely administered to patients at high maintenance dose levels without immune activation if preceded by gradual dose escalation. These findings facilitate efficacy studies that test high-dose epitope-specific immunotherapy in celiac disease

Benefits, harms and cost-effectiveness of potential age-extensions to the National Bowel Cancer Screening Program in Australia

BACKGROUND: The Australian National Bowel Cancer Screening Program(NBCSP) is rolling out 2-yearly immunochemical Faecal Occult Blood Test screening in people 50-74 years. This study aimed to evaluate the benefits, harms and cost-effectiveness of extending the NBCSP to younger and/or older ages. METHODS: A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate the fully rolled-out NBCSP and alternative strategies assuming screening starts at 45 or 40 years and/or ceases at 79 or 84 years given three scenarios:(i) perfect adherence(100%), (ii) high adherence(60%), and (ii) low adherence(40%, as currently achieved). RESULTS: The current NBCSP will reduce colorectal cancer incidence(mortality) by 23-51(36-74)% compared to no screening (range reflects participation); extending screening to younger or older ages would result in additional reductions of 2-6(2-9) or 1-3(3-7) percentage points, respectively. With an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS), only screening from 50-74 (incremental cost-effective ratio [ICER]:A$2,984-5,981/LYS) or from 45-74 (ICER:A$17,053-29,512/LYS) remained cost-effective in all participation scenarios. The number-needed-to-colonoscope to prevent a death over the lifetime of a cohort in the current NBCSP is 35-49. Starting at 45 years would increase colonoscopy demand for program-related colonoscopies by 3-14% and be associated with 55-170 additional colonoscopies per additional death prevented. CONCLUSIONS: Starting screening at 45 years could be cost-effective, but it would increase colonoscopy demand and would be associated with a less favourable incremental benefits-to-harms trade-off than screening from 50-74 years. IMPACT: The study underpins recently updated Australian colorectal cancer management guidelines which recommends that the NBCSP continues to offer bowel screening from 50-74 years