Feasibility and economic assessment of chromocolonoscopy for detection of proximal serrated neoplasia within a population-based colorectal cancer screening programme (CONSCOP): an open-label, randomised controlled non-inferiority trial.

BACKGROUND: Most post-colonoscopy interval colorectal cancers are proximal; serrated polyps are often precursors to these cancers and are considered difficult to detect. We assessed the safety, feasibility, and economic effect of chromocolonoscopy on detection of proximal serrated neoplasia. METHODS: We did an open-label, multicentre, randomised, controlled non-inferiority trial including patients from Bowel Screening Wales centres. Participants who tested positive for faecal occult blood and who were eligible for and considered fit to have colonoscopy (patients with known cases of polyposis syndromes, Lynch syndrome, and chronic inflammatory disease were excluded) were randomly assigned (1:1; with the use of minimisation, stratified by centre with an 80:20 random element) to either standard white light colonoscopy (standard group) or chromocolonoscopy (indigo carmine dye [0·2%]; chromocolonoscopy group) using a secure, internet-based, computerised, randomisation system that used centralised, dynamic allocation. Participants were followed up for 1 year and data from index colonoscopies and associated clearance procedures were analysed. All proximal polyps were reviewed by an expert pathologist panel. The main outcome on which power was based was time taken to perform the colonoscopy procedure, defined as from the time when the scope was inserted to withdrawal from the anus, assessed in the per-protocol population. The non-inferiority margin was 15 min. This trial is complete and is registered with ClinicalTrials.gov, number NCT01972451. FINDINGS: Between Nov 20, 2014, and June 16, 2016, 741 (72%) of 1031 patients screened were eligible and consented: 360 were randomly assigned to white light colonoscopy and 381 to chromocolonoscopy. In the chromocolonoscopy group, the procedure took a mean of 36·8 min (SD 15·0), compared with a mean of 30·6 min (13·7) in the standard group (mean difference 6·3 min [95% CI 4·2-8·4] longer with chromocolonoscopy than in the standard group). The mean difference was within the prespecified non-inferiority margin. Detection rates for proximal serrated lesions were significantly higher in the chromocolonoscopy group than in the control group (45 [12%] of 381 patients vs 23 [6%] of 360 patients; odds ratio 1·96 [95% CI 1·16-3·32]; p=0·012). Serious adverse events (four cases of postpolypectomy bleeding [two in each group], and one case of anxiety and hyperventilation [in the chromocolonoscopy group]), colonoscopy quality measures, comfort scores, and sedation were similar between groups. INTERPRETATION: Chromocolonoscopy is feasible within a population-based colorectal cancer screening programme, is safe, and has significantly increased detection of proximal serrated neoplasia and other polyp types compared with standard colonoscopy. Larger randomised trials of chromocolonoscopy, powered for improved detection of significant serrated polyps and for longer-term follow-up to investigate the effect on reduction of interval cancers within screening populations, are warranted. FUNDING: Health and Care Research Wales (RfPPB-1021).

Mycophenolate for persistent complex regional pain syndrome, a parallel, open, randomised, proof of concept trial.

BACKGROUND AND AIMS: Current therapies for persistent complex regional pain syndrome (CRPS) are grossly inadequate. With accruing evidence to support an underlying immunological process and anecdotal evidence suggesting potential efficacy of mycophenolate, we wished to explore the feasibility and effectiveness of this treatment in patients with CRPS. METHODS: A randomised, open, parallel, proof of concept trial was conducted. Patients with Budapest research criteria CRPS of >2-year duration and moderate or high pain intensity (numeric rating scale score ≥5) were enrolled. Eligible patients were randomised 1:1 to openly receive mycophenolate as add-on treatment, or their usual treatment alone, over 5.5 months. They then switched to the other treatment arm for 5.5 months. The main outcome was average the patients' average pain intensity recorded over 14 days, between 5.0 and 5.5 months post randomisation, on 11-point (0-10) numeric rating scales, compared between trial arms. Skin sensitivities and additional outcomes were also assessed. RESULTS: Twelve patients were enrolled. Nine provided outcomes and were analysed for the main outcome. Mycophenolate treatment was significantly more effective than control [drug-group mean (SD): pre: 7.4 (1.2)- post: 5.2 (1.3), n=4, control: pre: 7.7 (1.4)- post: 8.1 (0.9), n=5; -2.8 (95% CI: -4.7, -1.0), p=0.01, analysis of covariance]. There were four treatment responders (to mycophenolate treatment either before, or after switch), whose initial exquisite skin hyper-sensitivities, function and quality of life strongly improved. Side effects including itchiness, skin-cryptitis, increased pain, and increased depression caused 45% of the subjects to stop taking mycophenolate. CONCLUSIONS: Mycophenolate appears to reduce pain intensity and improve quality of life in a subgroup of patients with persistent CRPS. IMPLICATIONS: These results support the feasibility of conducting a definite trial to confirm the efficacy and effect size of mycophenolate treatment for persistent CRPS (EudraCT 2015-000263-14).

Modeling Health State Utility Values in Ankylosing Spondylitis: Comparisons of Direct and Indirect Methods.

OBJECTIVES: Cost-effectiveness analyses of technologies for patients with ankylosing spondylitis frequently require estimates of health utilities as a function of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). METHODS: Linear regression, bespoke mixture models, and generalized ordered probit models were used to model the EuroQol five-dimensional questionnaire as a function of BASDAI and BASFI. Data were drawn from a large UK cohort study (n = 516 with up to five observations) spanning the full range of disease severity. RESULTS: Linear regression was systematically biased. Three- and four-component mixture models and generalized probit models exhibit no such bias and improved fit to the data. The mean, median, mean error, and mean absolute error favored the mixture model approach. Root mean square error favored the generalized ordered probit model approach for the data as a whole. Model fit assessed using these same measures by disease severity quartiles tended to be best using the mixture models. The value of moving from good to poor health may differ substantially according to the chosen method. Simulated data from the mixture and probit models yield a very similar distribution to the original data set. CONCLUSIONS: These results add to a body of evidence that the statistical model used to estimate health utilities matters. Linear models are not appropriate. The four-class bespoke mixture model approach provides the best performing method to estimate the EuroQol five-dimensional questionnaire values from BASDAI and BASFI.