The impact of introducing alcohol-free beer options in bars and public houses on alcohol sales and revenue: A randomised crossover field trial.

AIMS: The study aimed to estimate the impact of introducing a draught alcohol-free beer, thereby increasing the relative availability of these products, on alcohol sales and monetary takings in bars and pubs in England. DESIGN: Randomised crossover field trial. SETTING: England. PARTICIPANTS: Fourteen venues that did not previously sell draught alcohol-free beer. INTERVENTION AND COMPARATOR: Venues completed two intervention periods and two control periods in a randomised order over 8 weeks. Intervention periods involved replacing one draught alcoholic beer with an alcohol-free beer. Control periods operated business as usual. MEASUREMENTS: The primary outcome was mean weekly volume (in litres) of draught alcoholic beer sold. The secondary outcome was mean weekly revenue [in GBP (£)] from all drinks. Analyses adjusted for randomised order, special events, season and busyness. FINDINGS: The adjusted mean difference in weekly sales of draught alcoholic beer was -20 L [95% confidence interval (CI) = -41 to +0.4], equivalent to a 4% reduction (95% CI = 8% reduction to 0.1% increase) in the volume of alcoholic draught beer sold when draught alcohol-free beer was available. Excluding venues that failed at least one fidelity check resulted in an adjusted mean difference of -29 L per week (95% CI = -53 to -5), equivalent to a 5% reduction (95% CI = 8% reduction to 0.8% reduction). The adjusted mean difference in weekly revenue was +61 GBP per week (95% CI = -328 to +450), equivalent to a 1% increase (95% CI = 5% decrease to 7% increase) when draught alcohol-free beer was available. CONCLUSIONS: Introducing a draught alcohol-free beer in bars and pubs in England reduced the volume of draught alcoholic beer sold by 4% to 5%, with no evidence of the intervention impacting net revenue.

Impact on wine sales of removing the largest serving size by the glass: An A-B-A reversal trial in 21 pubs, bars, and restaurants in England.

BACKGROUND: Interventions that alter aspects of the physical environments in which unhealthy behaviours occur have the potential to change behaviour at scale, i.e., across populations, and thereby decrease the risk of several diseases. One set of such interventions involves reducing serving sizes, which could reduce alcohol consumption. The effect of modifying the available range of serving sizes of wine in a real-world setting is unknown. We aimed to assess the impact on the volume of wine sold of removing the largest serving size by the glass from the options available in licensed premises. METHODS AND FINDINGS: The study was conducted between September 2021 and May 2022 in 21 licensed premises in England that sold wine by the glass in serving sizes greater than 125 ml (i.e., 175 ml or 250 ml) and used an electronic point of sale till system. It used an A-B-A reversal design, set over 3 four-weekly periods. "A" represented the nonintervention periods during which standard serving sizes were served and "B" the intervention period when the largest serving size for a glass of wine was removed from the existing range in each establishment: 250 ml (18 premises) or 175 ml (3 premises). The primary outcome was the daily volume of wine sold, extracted from sales data. Twenty-one premises completed the study, 20 of which did so per protocol and were included in the primary analysis. After adjusting for prespecified covariates, the intervention resulted in -420·8 millilitres (ml) (95% confidence intervals (CIs) -681·4 to -160·2 p = 0·002) or -7·6% (95% CI -12·3%, -2·9%) less wine being sold per day. There was no evidence that sales of beer and cider or total daily revenues changed but the study was not powered to detect differences in these outcomes. The main study limitation is that we were unable to assess the sales of other alcoholic drinks apart from wine, beer, and cider, estimated to comprise approximately 30% of alcoholic drinks sold in participating premises. CONCLUSIONS: Removing the largest serving size of wine by the glass from those available reduced the volume of wine sold. This promising intervention for decreasing alcohol consumption across populations merits consideration as part of alcohol licensing regulations. TRIAL REGISTRATION: ISRCTN https://doi.org/10.1186/ISRCTN33169631; OSF https://osf.io/xkgdb.

Impact of health warning labels and calorie labels on selection and purchasing of alcoholic and non-alcoholic drinks: A randomized controlled trial.

AIMS: To estimate the impact on selection and actual purchasing of (a) health warning labels (text-only and image-and-text) on alcoholic drinks and (b) calorie labels on alcoholic and non-alcoholic drinks. DESIGN: Parallel-groups randomised controlled trial. SETTING: Drinks were selected in a simulated online supermarket, before being purchased in an actual online supermarket. PARTICIPANTS: Adults in England and Wales who regularly consumed and purchased beer or wine online (n = 651). Six hundred and eight participants completed the study and were included in the primary analysis. INTERVENTIONS: Participants were randomized to one of six groups in a between-subjects three [health warning labels (HWLs) (i): image-and-text HWL; (ii) text-only HWL; (iii) no HWL] × 2 (calorie labels: present versus absent) factorial design (n per group 103-113). MEASUREMENTS: The primary outcome measure was the number of alcohol units selected (with intention to purchase); secondary outcomes included alcohol units purchased and calories selected and purchased. There was no time limit for selection. For purchasing, participants were directed to purchase their drinks immediately (although they were allowed up to 2 weeks to do so). FINDINGS: There was no evidence of main effects for either (a) HWLs or (b) calorie labels on the number of alcohol units selected (HWLs: F(2,599) = 0.406, P = 0.666; calorie labels: F(1,599) = 0.002, P = 0.961). There was also no evidence of an interaction between HWLs and calorie labels, and no evidence of an overall difference on any secondary outcomes. In pre-specified subgroup analyses comparing the 'calorie label only' group (n = 101) with the 'no label' group (n = 104) there was no evidence that calorie labels reduced the number of calories selected (unadjusted means: 1913 calories versus 2203, P = 0.643). Among the 75% of participants who went on to purchase drinks, those in the 'calorie label only' group (n = 74) purchased fewer calories than those in the 'no label' group (n = 79) (unadjusted means: 1532 versus 2090, P = 0.028). CONCLUSIONS: There was no evidence that health warning labels reduced the number of alcohol units selected or purchased in an online retail context. There was some evidence suggesting that calorie labels on alcoholic and non-alcoholic drinks may reduce calories purchased from both types of drinks.

Impact on alcohol selection and online purchasing of changing the proportion of available non-alcoholic versus alcoholic drinks: A randomised controlled trial.

BACKGROUND: Increasing the availability of non-alcoholic options is a promising population-level intervention to reduce alcohol consumption, currently unassessed in naturalistic settings. This study in an online retail context aimed to estimate the impact of increasing the proportion of non-alcoholic (relative to alcoholic) drinks, on selection and purchasing of alcohol. METHODS AND RESULTS: Adults (n = 737) residing in England and Wales who regularly purchased alcohol online were recruited between March and July 2021. Participants were randomly assigned to one of 3 groups: "25% non-alcoholic/75% alcoholic"; "50% non-alcoholic/50% alcoholic"; and "75% non-alcoholic/25% alcoholic," then selected drinks in a simulated online supermarket, before purchasing them in an actual online supermarket. The primary outcome was the number of alcohol units selected (with intention to purchase); secondary outcomes included actual purchasing. A total of 607 participants (60% female, mean age = 38 years [range: 18 to 76]) completed the study and were included in the primary analysis. In the first part of a hurdle model, a greater proportion of participants in the "75% non-alcoholic" group did not select any alcohol (13.1%) compared to the "25% non-alcoholic" group (3.4%; 95% confidence interval [CI] -2.09, -0.63; p < 0.001). There was no evidence of a difference between the "75% non-alcoholic" and the "50% non-alcoholic" (7.2%) groups (95% CI 0.10, 1.34; p = 0.022) or between the "50% non-alcoholic" and the "25% non-alcoholic" groups (95% CI -1.44, 0.17; p = 0.121). In the second part of a hurdle model in participants (559/607) selecting any drinks containing alcohol, the "75% non-alcoholic" group selected fewer alcohol units compared to the "50% non-alcoholic" (95% CI -0.44, -0.14; p < 0.001) and "25% non-alcoholic" (95% CI -0.54, -0.24; p < 0.001) groups, with no evidence of a difference between the "50% non-alcoholic" and "25% non-alcoholic" groups (95% CI -0.24, 0.05; p = 0.178). Overall, across all participants, 17.46 units (95% CI 15.24, 19.68) were selected in the "75% non-alcoholic" group; 25.51 units (95% CI 22.60, 28.43) in the "50% non-alcoholic" group; and 29.40 units (95% CI 26.39, 32.42) in the "25% non-alcoholic" group. This corresponds to 8.1 fewer units (a 32% reduction) in the "75% non-alcoholic" compared to the "50% non-alcoholic" group, and 11.9 fewer alcohol units (41% reduction) compared to the "25% non-alcoholic" group; 3.9 fewer units (13% reduction) were selected in the "50% non-alcoholic" group than in the "25% non-alcoholic" group. For all other outcomes, alcohol selection and purchasing were consistently lowest in the "75% non-alcoholic" group. Study limitations include the setting not being entirely naturalistic due to using a simulated online supermarket as well as an actual online supermarket, and that there was substantial dropout between selection and purchasing. CONCLUSIONS: This study provides evidence that substantially increasing the proportion of non-alcoholic drinks-from 25% to 50% or 75%-meaningfully reduces alcohol selection and purchasing. Further studies are warranted to assess whether these effects are realised in a range of real-world settings. TRIAL REGISTRATION: ISRCTN: 11004483; OSF: https://osf.io/qfupw.

Cigarette pack size and consumption: a randomized cross-over trial.

BACKGROUND AND AIMS: Smoking fewer cigarettes per day may increase the chances of stopping smoking. Capping the number of cigarettes per pack is a promising policy option, but the causal impact of such a change is unknown. This study aimed to test the hypothesis that lowering cigarette pack sizes from 25 to 20 reduces the number of cigarettes smoked. DESIGN: This randomized controlled cross-over trial had two 14-day intervention periods with an intervening 7-day period of usual behaviour. Participants purchased their own cigarettes. They were instructed to smoke their usual brand from either one of two sizes of pack in each of two 14-day intervention periods: (a) 25 cigarettes and (b) 20 cigarettes. Participants were randomized to the order in which they smoked from the two pack sizes (a-b; b-a). SETTING: Canada. PARTICIPANTS: Participants were adult smokers who smoked from pack sizes of 25, recruited between July 2020 and June 2021. Of 252 randomized, 240 (95%) completed the study and 236 (94%) provided sufficient data for the primary analysis. MEASUREMENTS: Cigarettes smoked per participant per day. FINDINGS: Participants smoked fewer cigarettes per day from packs of 20 cigarettes [n = 234, mean = 15.7 standard deviation (SD) = 7.1] than from packs of 25 (n = 235, mean = 16.9, SD = 7.1). After adjusting for pre-specified covariates (baseline consumption and heaviness of smoking), modelling estimated that participants smoked 1.3 fewer cigarettes per day [95% confidence interval (CI) = -1.7 to -0.9], equivalent to 7.6% fewer (95% CI = -10.1 to -5.2%) from packs of 20 cigarettes. CONCLUSIONS: Smoking from packs of 20 compared with 25 cigarettes reduced the number of cigarettes smoked per day.

Impact of e-cigarette retail displays on attitudes to smoking and vaping in children: an online experimental study.

OBJECTIVES: To estimate the impact of electronic cigarette (e-cigarette) retail display exposure on attitudes to smoking and vaping (susceptibility to tobacco smoking and using e-cigarettes, and perceptions of the harms of smoking and e-cigarette use). DESIGN: Between-subjects randomised experiment using a 2 (e-cigarette retail display visibility: high vs low)×2 (proportion of e-cigarette images: 75% vs 25%) factorial design. SETTING: Online via the Qualtrics survey platform. PARTICIPANTS: UK children aged 13-17 years (n=1034), recruited through a research agency. INTERVENTION: Participants viewed 12 images of retail displays that contained e-cigarette display images or unrelated product images. E-cigarette display images were either high or low visibility, based on a conspicuousness score. Participants were randomised to one of four groups, with e-cigarette display visibility and proportion of e-cigarette images, compared with images of unrelated products, manipulated: (1) 75% e-cigarettes, high visibility; (2) 25% e-cigarettes, high visibility; (3) 75% e-cigarettes, low visibility; (4) 25% e-cigarettes, low visibility. MAIN OUTCOME MEASURES: The primary outcome was susceptibility to smoking (among never smokers only). Secondary outcomes were susceptibility to using e-cigarettes (among never vapers only), and perceptions of smoking and e-cigarette harm (all participants). RESULTS: Neither e-cigarette retail display visibility, nor the proportion of e-cigarette images displayed, appeared to influence susceptibility to smoking (visibility: OR=0.84, 95% CI 0.62 to 1.13, p=0.24; proportion: OR=1.34, 95% CI 1.00 to 1.82, p=0.054 (reference: low visibility, not susceptible)).Planned subgroup analyses indicated that exposure to a higher proportion of e-cigarette images increased susceptibility to smoking among children who visited retail stores more regularly (n=524, OR=1.59, 95% CI 1.04 to 2.43, p=0.034), and those who passed the attention check (n=880, OR=1.43, 95% CI 1.03 to 1.98, p=0.031).In addition, neither e-cigarette retail display visibility nor the proportion of e-cigarette images displayed, appeared to influence susceptibility to using e-cigarettes (visibility: OR=1.07, 95% CI 0.80 to 1.43, p=0.65; proportion: OR=1.22, 95% CI 0.91 to 1.64, p=0.18).Greater visibility of e-cigarette retail displays reduced perceived harm of smoking (mean difference (MD)=-0.19, 95% CI -0.34 to -0.04, p=0.016). There was no evidence that the proportion of e-cigarette images displayed had an effect (MD=-0.07, 95% CI -0.22 to 0.09, p=0.40).Perceived harm of e-cigarette use did not appear to be affected by e-cigarette retail display visibility (MD=-0.12, 95% CI -0.28 to 0.05, p=0.16) or by the proportion of e-cigarette images displayed (MD=-0.10, 95% CI -0.26 to 0.07, p=0.24). CONCLUSIONS: There is no evidence in the full sample to suggest that children's susceptibility to smoking is increased by exposure to higher visibility e-cigarette retail displays, or to a higher proportion of e-cigarette images. However, for regular store visitors or those paying more attention, viewing a higher proportion of e-cigarette images increased susceptibility to smoking. In addition, viewing higher visibility e-cigarette images reduced perceived harm of smoking. A review of the current regulatory discrepancy between tobacco and e-cigarette point-of-sale marketing is warranted. TRIAL REGISTRATION NUMBER: ISRCTN18215632.

Evaluation of physical activity calorie equivalent (PACE) labels' impact on energy purchased in cafeterias: A stepped-wedge randomised controlled trial.

BACKGROUND: A recent meta-analysis suggested that using physical activity calorie equivalent (PACE) labels results in people selecting and consuming less energy. However, the meta-analysis included only 1 study in a naturalistic setting, conducted in 4 convenience stores. We therefore aimed to estimate the effect of PACE labels on energy purchased in worksite cafeterias in the context of a randomised study design. METHODS AND FINDINGS: A stepped-wedge randomised controlled trial (RCT) was conducted to investigate the effect of PACE labels (which include kcal content and minutes of walking required to expend the energy content of the labelled food) on energy purchased. The setting was 10 worksite cafeterias in England, which were randomised to the order in which they introduced PACE labels on selected food and drinks following a baseline period. There were approximately 19,000 workers employed at the sites, 72% male, with an average age of 40. The study ran for 12 weeks (06 April 2021 to 28 June 2021) with over 250,000 transactions recorded on electronic tills. The primary outcome was total energy (kcal) purchased from intervention items per day. The secondary outcomes were: energy purchased from non-intervention items per day, total energy purchased per day, and revenue. Regression models showed no evidence of an overall effect on energy purchased from intervention items, -1,934 kcals per site per day (95% CI -5,131 to 1,262), p = 0.236, during the intervention relative to baseline, equivalent to -5 kcals per transaction (95% CI -14 to 4). There was also no evidence for an effect on energy purchased from non-intervention items, -5 kcals per site per day (95% CI -513 to 504), p = 0.986, equivalent to 0 kcals per transaction (95% CI -1 to 1), and no clear evidence for total energy purchased -2,899 kcals per site (95% CI -5,810 to 11), p = 0.051, equivalent to -8 kcals per transaction (95% CI -16 to 0). Study limitations include using energy purchased and not energy consumed as the primary outcome and access only to transaction-level sales, rather than individual-level data. CONCLUSION: Overall, the evidence was consistent with PACE labels not changing energy purchased in worksite cafeterias. There was considerable variation in effects between cafeterias, suggesting important unmeasured moderators. TRIAL REGISTRATION: The study was prospectively registered on ISRCTN (date: 30.03.21; ISRCTN31315776).

Practical guidance for planning resources required to support publicly-funded adaptive clinical trials.

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.

Impact of wine bottle and glass sizes on wine consumption at home: a within- and between- households randomized controlled trial.

BACKGROUND AND AIMS: Reducing alcohol consumption across populations would decrease the risk of a range of diseases, including many cancers, cardiovascular disease and Type 2 diabetes. The aim of the current study was to estimate the impact of using smaller bottles (37.5- versus 75-cl) and glasses (290 versus 370 ml) on consuming wine at home. DESIGN: Randomized controlled trial of households with cross-over randomization to bottle size and parallel randomization to glass size. SETTING: UK households. PARTICIPANTS: A total of 260 households consuming at least two 75-cl bottles of wine each week, recruited from the general population through a research agency. The majority consisted of adults who were white and of higher socio-economic position. INTERVENTION: Households were randomized to the order in which they purchased wine in 37.5- or 75-cl bottles, to consume during two 14-day intervention periods, and further randomized to receive smaller (290 ml) or larger (350 ml) glasses to use during both intervention periods. MEASUREMENTS: Volume (ml) of study wine consumed at the end of each 14-day intervention period, measured using photographs of purchased bottles, weighed on study scales. FINDINGS: Of the randomized households, 217 of 260 (83%) completed the study as per protocol and were included in the primary analysis. There was weak evidence that smaller bottles reduced consumption: after accounting for pre-specified covariates, households consumed on average 145.7 ml (3.6%) less wine when drinking from smaller bottles than from larger bottles [95% confidence intervals (CI) = -335.5 to 43. ml; -8.3 to 1.1%; P = 0.137; Bayes factor (BF) = 2.00]. The evidence for the effect of smaller glasses was stronger: households consumed on average 253.3 ml (6.5%) less wine when drinking from smaller glasses than from larger glasses (95% CI = -517 to 10 ml; -13.2 to 0.3%; P = 0.065; BF = 2.96). CONCLUSIONS: Using smaller glasses to drink wine at home may reduce consumption. Greater uncertainty remains around the possible effect of drinking from smaller bottles.

Effect of health warning labels on motivation towards energy-dense snack foods: Two experimental studies.

Health warning labels (HWLs) show promise in reducing motivation towards energy-dense snack foods. Understanding the underlying mechanisms could optimise their effectiveness. In two experimental studies in general population samples (Study 1 n = 90; Study 2 n = 1382), we compared the effects of HWLs and irrelevant aversive labels (IALs) on implicit (approach) motivation towards unhealthy snacks, using an approach-avoidance task (Study 1), and a manikin task (Study 2). We also assessed explicit motivation towards unhealthy snacks using food selection tasks. We examined whether labelling effects on motivation arose from the creation of outcome-dependent associations between the food and its health consequences or from simple, non-specific aversive associations. Both label types reduced motivation towards snack foods but only when the label was physically present. HWLs and IALs showed similar effects on implicit motivation, although HWLs reduced explicit motivation more than IALs. Thus, aversive HWLs appear to act both through low level associative mechanisms affecting implicit motivation, and by additionally emphasizing explicit causal links to health outcomes thereby affecting explicitly motivated choice behaviours.

Public support for policies to improve population and planetary health: A population-based online experiment assessing impact of communicating evidence of multiple versus single benefits.

BACKGROUND: Effective interventions for reducing the consumption of products that harm population and planetary health often lack public support, impeding implementation. Communicating evidence of policies' effectiveness can increase public support but there is uncertainty about the most effective ways of communicating this evidence. Some policies have multiple benefits such as both improving health and the environment. This study assesses whether communicating evidence of multiple versus single benefits of a policy increases its support. METHOD: Participants (n = 4616) nationally representative of the British population were randomised to one of 24 groups in an online experiment with a 4 × 3 × 2 between-subjects factorial design. The messages that participants viewed differed according to the evidence they communicated (no message, effectiveness for changing behaviour, effectiveness for changing behaviour + one policy benefit, effectiveness for changing behaviour + three policy benefits), type of policy (taxation, availability) and the target behaviour (consumption of energy-dense food, alcohol, or meat). The primary outcome was policy support. RESULTS: In a full factorial ANOVA, there was a significant main effect of communicating evidence of effectiveness on policy support, which was similar across policies and behaviours. Communicating three benefits increased support relative to communicating one benefit (d = 0.15; p = 0.01). Communicating one benefit increased support compared to providing evidence for changing behaviour alone (d = 0.13; p = 0.004) or no message (d = 0.11 p = 0.022). CONCLUSION: Communicating evidence of a policy's benefits increases support for policy action across different behaviours and policies. Presenting multiple benefits of policies enhances public support.

Glassware design and drinking behaviours: a review of impact and mechanisms using a new typology of drinking behaviours.

Much of the global burden of disease is attributable to unhealthy behaviour, including excessive consumption of alcohol and sugar-sweetened beverages. Developing effective methods to change these drinking behaviours could inform policies to improve population health. In line with an increasing interest in environmental-level interventions - i.e., changing the environment in which a behaviour occurs in order to change the behaviour of interest - this review first describes the existing evidence of the impact of glassware design (including capacity and shape) on drinking behaviours (e.g., at the 'micro' level - including sip size, as well as at the macro level - including amount consumed). The roles of two sets of possible underlying mechanisms - perception and affordance - are also explored. Finally, this review sets out a provisional typology of drinking behaviours to enable more systematic approaches to the study of these behaviours. While there is a paucity of evidence - in particular on measures of consumption - this growing evidence base suggests promising targets for novel interventions involving glassware design to reduce the consumption of drinks that harm health.Trial registration: ISRCTN.org identifier: ISRCTN10456720.

Size and shape of plates and size of wine glasses and bottles: impact on self-serving of food and alcohol.

BACKGROUND: The physical properties of tableware could influence selection and consumption of food and alcohol. There is considerable uncertainty, however, around the potential effects of different sizes and shapes of tableware on how much food and alcohol people self-serve. These studies aimed to estimate the impact of: 1. Plate size and shape on amount of food self-served; 2.Wine glass and bottle size on amount of wine self-poured. METHODS: 140 adults participated in two laboratory studies-each using randomised within-subjects factorial designs-where they self-served food (Study 1) and wine (Study 2): Study 1: 3 plate sizes (small; medium; large) × 2 plate shapes (circular; square). Study 2: 3 wine glass sizes (small; medium; large) × 2 wine bottle sizes (75 cl; 50 cl). RESULTS: Study 1: There was a main effect of plate size: less was self-served on small (76 g less, p < 0.001) and medium (41 g less, p < 0.001) plates, compared to large plates. There was no evidence for a main effect of plate shape (p = 0.46) or a size and shape interaction (p = 0.47). Study 2: There was a main effect of glass size: less was self-served in small (34 ml less, p < 0.001) and medium (17 ml less, p < 0.001) glasses, compared to large glasses. There was no evidence of a main effect of bottle size (p = 0.20) or a glass and bottle size interaction (p = 0.18). CONCLUSIONS: Smaller tableware (i.e. plates and wine glasses) decreases the amount of food and wine self-served in an initial serving. Future studies are required to generate estimates on selection and consumption in real world settings when numerous servings are possible. Protocol registration information: OSF ( https://osf.io/dj3c6/ ) and ISRCTN ( https://doi.org/10.1186/ISRCTN66774780 ).

Costs and staffing resource requirements for adaptive clinical trials: quantitative and qualitative results from the Costing Adaptive Trials project.

BACKGROUND: Adaptive designs offer great promise in improving the efficiency and patient-benefit of clinical trials. An important barrier to further increased use is a lack of understanding about which additional resources are required to conduct a high-quality adaptive clinical trial, compared to a traditional fixed design. The Costing Adaptive Trials (CAT) project investigated which additional resources may be required to support adaptive trials. METHODS: We conducted a mock costing exercise amongst seven Clinical Trials Units (CTUs) in the UK. Five scenarios were developed, derived from funded clinical trials, where a non-adaptive version and an adaptive version were described. Each scenario represented a different type of adaptive design. CTU staff were asked to provide the costs and staff time they estimated would be needed to support the trial, categorised into specified areas (e.g. statistics, data management, trial management). This was calculated separately for the non-adaptive and adaptive version of the trial, allowing paired comparisons. Interviews with 10 CTU staff who had completed the costing exercise were conducted by qualitative researchers to explore reasons for similarities and differences. RESULTS: Estimated resources associated with conducting an adaptive trial were always (moderately) higher than for the non-adaptive equivalent. The median increase was between 2 and 4% for all scenarios, except for sample size re-estimation which was 26.5% (as the adaptive design could lead to a lengthened study period). The highest increase was for statistical staff, with lower increases for data management and trial management staff. The percentage increase in resources varied across different CTUs. The interviews identified possible explanations for differences, including (1) experience in adaptive trials, (2) the complexity of the non-adaptive and adaptive design, and (3) the extent of non-trial specific core infrastructure funding the CTU had. CONCLUSIONS: This work sheds light on additional resources required to adequately support a high-quality adaptive trial. The percentage increase in costs for supporting an adaptive trial was generally modest and should not be a barrier to adaptive designs being cost-effective to use in practice. Informed by the results of this research, guidance for investigators and funders will be developed on appropriately resourcing adaptive trials.

Cigarette pack size and consumption: an adaptive randomised controlled trial.

BACKGROUND: Observational evidence suggests that cigarette pack size - the number of cigarettes in a single pack - is associated with consumption but experimental evidence of a causal relationship is lacking. The tobacco industry is introducing increasingly large packs, in the absence of maximum cigarette pack size regulation. In Australia, the minimum pack size is 20 but packs of up to 50 cigarettes are available. We aimed to estimate the impact on smoking of reducing cigarette pack sizes from ≥25 to 20 cigarettes per pack. METHOD: A two-stage adaptive parallel group RCT in which Australian smokers who usually purchase packs containing ≥25 cigarettes were randomised to use only packs containing either 20 (intervention) or their usual packs (control) for four weeks. The primary outcome, the average number of cigarettes smoked per day, was measured through collecting all finished cigarette packs, labelled with the number of cigarettes participants smoked. An interim sample size re-estimation was used to evaluate the possibility of detecting a meaningful difference in the primary outcome. RESULTS: The interim analysis, conducted when 124 participants had been randomised, suggested 1122 additional participants needed to be randomised for sufficient power to detect a meaningful effect. This exceeded pre-specified criteria for feasible recruitment, and data collection was terminated accordingly. Analysis of complete data (n = 79) indicated that the mean cigarettes smoked per day was 15.9 (SD = 8.5) in the intervention arm and 16.8 (SD = 6.7) among controls (difference - 0.9: 95%CI = - 4.3, 2.6). CONCLUSION: It remains unclear whether reducing cigarette pack sizes from ≥25 to 20 cigarettes reduces cigarette consumption. Importantly, the results of this study provide no evidence that capping cigarette pack sizes would be ineffective at reducing smoking. The limitations identified in this study can inform a more efficient RCT, which is urgently required to address the dearth of experimental evidence on the impact of large cigarette pack sizes on smoking. TRIAL REGISTRATION: https://doi.org/10.1186/ISRCTN34202533.

Straight-sided beer and cider glasses to reduce alcohol sales for on-site consumption: A randomised crossover trial in bars.

BACKGROUND: Straight-sided glasses can slow the rate of lager consumption in a laboratory setting compared with curved glasses. Slower drinking rates may lower overall alcohol consumption. Glass shape is therefore a potential target for intervention. The aim of this randomised crossover trial was to estimate the impact of serving draught beer and cider in straight-sided glasses, compared with usual, predominantly curved glasses, on alcohol sales for on-site consumption in bars. METHODS: Twenty-four bars in England completed two intervention periods (A) and two control periods (B) in a randomised order: 1) BABA; 2) BAAB; 3) ABBA; or 4) ABAB. Each period lasted two weeks and involved serving draught beer and cider in either straight-sided glasses (A) or the venue's usual glasses (≥75% curved; B). The primary outcome was the mean volume (in litres) of draught beer and cider sold weekly, compared between A and B periods using a paired-samples t-test on aggregate data. A regression model adjusted for season, order, special events, and busyness. FINDINGS: Mean weekly volume sales of draught beer and cider was 690·9 L (SD 491·3 L) across A periods and 732·5 L (SD 501·0 L) across B periods. The adjusted mean difference (A minus B) was 8·9 L per week (95% CI -45·5 to 63·3; p = 0·737). INTERPRETATION: This study provides no clear evidence that using straight-sided glasses, compared with usual, predominantly curved glasses, reduces the volume of draught beer and cider sold for on-site consumption in bars.

Order of meals at the counter and distance between options affect student cafeteria vegetarian sales.

Altering the order in which meals are presented at cafeteria counters has been proposed as a way of lowering meat consumption, but remains largely untested. To address this, we undertook two experimental studies involving 105,143 meal selections in the cafeterias of a British university. Placing vegetarian options first on the counter consistently increased their sales when choices were widely separated (>1.5 m; vegetarian sales as a percentage of total meal sales increased by 4.6 and 6.2 percentage points) but there was no evidence of an effect when the options were close together (<1.0 m). This suggests that order effects depend on the physical distance between options.

Impact of increasing vegetarian availability on meal selection and sales in cafeterias.

Shifting people in higher income countries toward more plant-based diets would protect the natural environment and improve population health. Research in other domains suggests altering the physical environments in which people make decisions ("nudging") holds promise for achieving socially desirable behavior change. Here, we examine the impact of attempting to nudge meal selection by increasing the proportion of vegetarian meals offered in a year-long large-scale series of observational and experimental field studies. Anonymized individual-level data from 94,644 meals purchased in 2017 were collected from 3 cafeterias at an English university. Doubling the proportion of vegetarian meals available from 25 to 50% (e.g., from 1 in 4 to 2 in 4 options) increased vegetarian meal sales (and decreased meat meal sales) by 14.9 and 14.5 percentage points in the observational study (2 cafeterias) and by 7.8 percentage points in the experimental study (1 cafeteria), equivalent to proportional increases in vegetarian meal sales of 61.8%, 78.8%, and 40.8%, respectively. Linking sales data to participants' previous meal purchases revealed that the largest effects were found in the quartile of diners with the lowest prior levels of vegetarian meal selection. Moreover, serving more vegetarian options had little impact on overall sales and did not lead to detectable rebound effects: Vegetarian sales were not lower at other mealtimes. These results provide robust evidence to support the potential for simple changes to catering practices to make an important contribution to achieving more sustainable diets at the population level.

A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function.

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic. CONCLUSION: Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.

Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.