The Arclight vs. traditional ophthalmoscope:a cross-over trial

BACKGROUND/OBJECTIVES: To compare skill acquisition of the new, cost-effective Arclight ophthalmoscope, with the traditional ophthalmoscope (TO), in medical students with no prior experience of ophthalmoscopy. SUBJECTS/METHODS: University of Dundee medical students took part in a cross-over trial. Students were divided into two groups and were alternately taught each device using a video tutorial. In period one, Group A was taught the TO first; Group B was taught the Arclight. They were then assessed using simulated objective, structured, clinical, examinations, examining four model heads with lettered fundal photographs of varying sizes of font. Groups crossed over following a 2-week washout period and were taught the second device and reassessed. A questionnaire was distributed to ascertain students’ opinions and preferences. RESULTS: Forty medical students participated. Overall, 92.5% of students performed better with the Arclight, irrespective of cross-over trial period. The mean difference in score in period one of the cross-over trial was 16.77 (95% CI: 11.63–21.93), with students performing better with the Arclight (p < 0.0001). The mean difference in score in period two was 8.02 (95% CI: 4.52–11.52), with students performing better with the Arclight (p < 0.0001). In addition, performance with the TO improved by 52.9% following initial exposure to the Arclight. The Arclight was the preferred device by 82.5% of students, and 82.5% of students would choose this device for future practice. CONCLUSION: Students performed better with and preferred the Arclight ophthalmoscope. The Arclight could be considered as a suitable alternative to the TO used for training medical students

Assessing the commonly used assumptions in estimating the principal causal effect in clinical trials

In addition to the average treatment effect (ATE) for all randomized patients, sometimes it is important to understand the ATE for a principal stratum, a subset of patients defined by one or more post-baseline variables. For example, what is the ATE for those patients who could be compliant with the experimental treatment? Commonly used assumptions include monotonicity, principal ignorability, and cross-world assumptions of principal ignorability and principal strata independence. Most of these assumptions cannot be evaluated in clinical trials with parallel treatment arms. In this article, we evaluate these assumptions through a 2x2 cross-over study in which the potential outcomes under both treatments can be observed, provided there are no carry-over and study period effects. From this example, it seemed the monotonicity assumption and the within-treatment principal ignorability assumptions did not hold well. On the other hand, the assumptions of cross-world principal ignorability and cross-world principal stratum independence conditional on baseline covaraites seemed to hold well. With the latter assumptions, we estimated the ATE for principal strata, defined by whether the blood glucose standard deviation increased in each treatment period, without relying on the cross-over feature. These estimates were very close to the ATE estimate when exploiting the cross-over feature of the trial. To the best of our knowledge, this article is the first attempt to evaluate the plausibility of commonly used assumptions for estimating ATE for principal strata using the setting of a cross-over trial.Comment: 25 pages, 4 table

A double-blind placebo-controlled cross-over clinical trial of DONepezil In Posterior cortical atrophy due to underlying Alzheimer's Disease: DONIPAD study.

BACKGROUND: The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease. METHODS: A single-centre, double-blind, placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto-occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 × 2 cross-over trial was used. RESULTS: Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one subject. Nightmares and vivid dreams occurred in 8/18 subjects (44%), and were statistically more frequent during treatment with donepezil. CONCLUSIONS: In this small study, there was no statistically significant treatment effect of donepezil on the primary outcome measure (MMSE score at 12 weeks) in PCA patients, who appear to be particularly susceptible to the development of nightmares and vivid dreams when treated. TRIAL REGISTRATION: Trial registration: Current Controlled Trials ISRCTN22636071 . Retrospectively registered 19 May 2010

Consumption of a high-fat meal containing cheese compared with a vegan alternative lowers postprandial C-reactive protein in overweight and obese individuals with metabolic abnormalities: a randomised controlled cross-over study.

Dietary recommendations suggest decreased consumption of SFA to minimise CVD risk; however, not all foods rich in SFA are equivalent. To evaluate the effects of SFA in a dairy food matrix, as Cheddar cheese, v. SFA from a vegan-alternative test meal on postprandial inflammatory markers, a randomised controlled cross-over trial was conducted in twenty overweight or obese adults with metabolic abnormalities. Individuals consumed two isoenergetic high-fat mixed meals separated by a 1- to 2-week washout period. Serum was collected at baseline, and at 1, 3 and 6 h postprandially and analysed for inflammatory markers (IL-6, IL-8, IL-10, IL-17, IL-18, TNFα, monocyte chemotactic protein-1 (MCP-1)), acute-phase proteins C-reactive protein (CRP) and serum amyloid-A (SAA), cellular adhesion molecules and blood lipids, glucose and insulin. Following both high-fat test meals, postprandial TAG concentrations rose steadily (P &lt; 0·05) without a decrease by 6 h. The incremental AUC (iAUC) for CRP was significantly lower (P &lt; 0·05) in response to the cheese compared with the vegan-alternative test meal. A treatment effect was not observed for any other inflammatory markers; however, for both test meals, multiple markers significantly changed from baseline over the 6 h postprandial period (IL-6, IL-8, IL-18, TNFα, MCP-1, SAA). Saturated fat in the form of a cheese matrix reduced the iAUC for CRP compared with a vegan-alternative test meal during the postprandial 6 h period. The study is registered at clinicaltrials.gov under NCT01803633

Effect of tart cherry juice on risk of gout attacks: protocol for a randomised controlled trial

Introduction: Gout is a painful form of inflammatory arthritis associated with several comorbidities, particularly cardiovascular disease. Cherries, which are rich in anti-inflammatory and antioxidative bioactive compounds, are proposed to be efficacious in preventing and treating gout, but recommendations to patients are conflicting. Cherry consumption has been demonstrated to lower serum urate levels and inflammation in several small studies. One observational case cross-over study reported that cherry consumption was associated with reduced risk of recurrent gout attacks. This preliminary evidence requires substantiation. The proposed randomised clinical trial aims to test the effect of consumption of tart cherry juice on risk of gout attacks. Methods and analysis: This 12-month, parallel, double-blind, randomised, placebo-controlled trial will recruit 120 individuals (aged 18–80 years) with a clinical diagnosis of gout who have self-reported a gout flare in the previous year. Participants will be randomly assigned to an intervention group, which will receive Montmorency tart cherry juice daily for a 12-month period, or a corresponding placebo group, which will receive a cherry-flavoured placebo drink. The primary study outcome is change in frequency of self-reported gout attacks. Secondary outcome measures include attack intensity, serum urate concentration, fractional excretion of uric acid, biomarkers of inflammation, blood lipids and other markers of cardiovascular risk. Other secondary outcome measures will be changes in physical activity and functional status. Statistical analysis will be conducted on an intention-to-treat basis. Ethics and dissemination: This study has been granted ethical approval by the National Research Ethics Service, Yorkshire and The Humber—Leeds West Research Ethics Committee (ref: 18/SW/0262). Results of the trial will be submitted for publication in a peer-reviewed journal. Trial registration number: NCT03621215

Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.

PURPOSE:The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS:This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500&nbsp;mg, 3000&nbsp;mg and 4500&nbsp;mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS:Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0&nbsp;min. Administering 4500&nbsp;mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9&nbsp;min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION:The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500&nbsp;mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION:https://clinicaltrials.gov/ct2/show/NCT02758015

What type of cluster randomized trial for which setting?

The cluster randomized trial allows a randomized evaluation when it is either not possible to randomize the individual or randomizing individuals would put the trial at high risk of contamination across treatment arms. There are many variations of the cluster randomized design, including the parallel design with or without baseline measures, the cluster randomized cross-over design, the stepped-wedge cluster randomized design, and more recently-developed variants such as the batched stepped-wedge design and the staircase design. Once it has been clearly established that there is a need for cluster randomization, one ever important question is which form the cluster design should take. If a design in which time is split into multiple trial periods is to be adopted (e.g. as in a stepped-wedge), researchers must decide whether the same participants should be measured in multiple trial periods (cohort sampling); or if different participants should be measured in each period (continual recruitment or cross-sectional sampling). Here we outline the different possible options and weigh up the pros and cons of the different design choices, which revolve around statistical efficiency, study logistics and the assumptions required

Effects of low dose morphine on perceived sleep quality in patients with refractory breathlessness : a hypothesis generating study

© 2015 Asian Pacific Society of Respirology. Background and objective The management of chronic refractory breathlessness is one of the indications for regular low-dose (≤30 mg/24 h) oral sustained release morphine. Morphine may disrupt sleep in some conditions and improve sleep quality in others. This study aimed to determine any signal of regular, low-dose morphine on perceived sleep disruption due to breathlessness and perceived sleep quality. Methods This is a secondary analysis of data from 38 participants with refractory breathlessness (30 male; 33 with COPD) aged 76 ± 0.9 years who completed a double-blind, randomized, placebo-controlled, cross-over study in which they received 20 mg oral sustained release morphine daily and placebo for 4 days each. Participant ratings of sleep disruption due to breathlessness and perceived sleep quality were obtained daily throughout the 8-day trial. Results Perceived sleep disruption due to breathlessness over the 4-day period ranged between 13% and 32% of participants for placebo and 13% and 26% for morphine, decreasing by each day of the study during the morphine arm. Most participants reported 'very good' or 'quite good' sleep throughout the trial and were less likely to perceive poor sleep quality during the morphine arm (odds ratio = 0.55, 95% confidence interval: 0.34-0.88, P = 0.01). Participants who reported decreased breathlessness during the 4 days on morphine were also likely to report improved sleep quality with morphine (P = 0.039). Conclusion Four days of low-dose morphine improved perceived sleep quality in elderly participants with refractory breathlessness. Regular low-dose morphine targeted to reduce refractory breathlessness may yield associated benefits by reducing sleep disruption and improving sleep quality

What type of cluster randomized trial for which setting?

The cluster randomized trial allows a randomized evaluation when it is either not possible to randomize the individual or randomizing individuals would put the trial at high risk of contamination across treatment arms. There are many variations of the cluster randomized design, including the parallel design with or without baseline measures, the cluster randomized cross-over design, the stepped-wedge cluster randomized design, and more recently-developed variants such as the batched stepped-wedge design and the staircase design. Once it has been clearly established that there is a need for cluster randomization, one ever important question is which form the cluster design should take. If a design in which time is split into multiple trial periods is to be adopted (e.g. as in a stepped-wedge), researchers must decide whether the same participants should be measured in multiple trial periods (cohort sampling); or if different participants should be measured in each period (continual recruitment or cross-sectional sampling). Here we outline the different possible options and weigh up the pros and cons of the different design choices, which revolve around statistical efficiency, study logistics and the assumptions required.</p

The dog-leg: an alternative to a cross-over design for pragmatic clinical trials in relatively stable populations

Background: A cross-over trial design is more powerful than a parallel groups design, but requires that treatment effects do not carry over from one period of the trial to the next. We focus here on interventions in chronic disease populations where the control is routine care: in such cases we cannot assume the intervention effect is easily washed out in crossing over from the experimental intervention back to the control. Methods: We introduce an alternative trial design for these situations, and investigate its performance. One group is assessed before and after the experimental intervention, whereas two other groups provide respective, independent treatment comparisons in each period. We call this a dog-leg design because of the pattern of assessments in the three groups. The dog-leg design is reminiscent of a stepped wedge design, but with a reduced schedule of assessments and with the notable difference that not all groups receive the intervention. Results: If the correlation between baseline and follow-up is <0.72, the dog-leg design is more efficient than a parallel groups design with a baseline assessment. The dog-leg design also requires fewer assessments in total than a parallel groups design where participants are only assessed once, at follow-up. Conclusions: The dog-leg design is simple, and has some attractive properties. Though there is a risk of differential attrition in the three arms, the design’s good performance relative to alternatives makes it a useful addition to the methodologist’s toolkit