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Statistically based experimental designs have been available for over a century. However, many preclinical researchers are completely unaware of these methods, and the success of experiments is usually equated only with ' p < 0.05'. By contrast, a well-thought-out experimental design strategy provides data with evidentiary and scientific value. A value-based strategy requires implementation of statistical design principles coupled with basic project management techniques. This article outlines the three phases of a value-based design strategy: proper framing of the research question, statistically based operationalisation through careful selection and structuring of appropriate inputs, and incorporation of methods that minimise bias and process variation. Appropriate study design increases study validity and the evidentiary strength of the results, reduces animal numbers, and reduces waste from noninformative experiments. Statistically based experimental design is thus a key component of the 'Reduction' pillar of the 3R (Replacement, Reduction, Refinement) principles for ethical animal research. [ABSTRACT FROM AUTHOR]

Blinding and randomisation are important methods for increasing the robustness of pre-clinical studies, as incomplete or improper implementation thereof is recognised as a source of bias. Randomisation ensures that any known and unknown covariates introducing bias are randomly distributed over the experimental groups. Thereby, differences between the experimental groups that might otherwise have contributed to false positive or -negative results are diminished. Methods for randomisation range from simple randomisation (e.g. rolling a dice) to advanced randomisation strategies involving the use of specialised software. Blinding on the other hand ensures that researchers are unaware of group allocation during the preparation, execution and acquisition and/or the analysis of the data. This minimises the risk of unintentional influences resulting in bias. Methods for blinding require strong protocols and a team approach. In this review, we outline methods for randomisation and blinding and give practical tips on how to implement them, with a focus on animal studies. [ABSTRACT FROM AUTHOR]

Random treatment assignment is essential in demonstrating a causal relationship between a treatment and the outcome of interest. Randomisation ensures that animals assigned to different treatment groups do not differ from each other systematically, except for the randomly assigned treatment. The randomisation pattern should also dictate the statistical analysis. [ABSTRACT FROM AUTHOR]

According to the norm of policy equipoise, it is permissible to randomly assign participants to two or more interventions in a public policy randomised controlled trial (RCT) when there is meaningful uncertainty among the relevant expert community regarding which intervention is superior. While this norm is gaining traction in the research ethics literature, the idea of interventional superiority remains unclear. Is one intervention superior to another if it is reasonably expected to more effectively realise one outcome of interest, even though there is uncertainty regarding other outcomes of interest? Or, must an intervention be reasonably expected to more effectively realise all outcomes of interest? I address this question in this paper. My aim is to develop and defend an account of interventional superiority for policy RCTs that are authorised, funded, or conducted by government institutions. I defend the greatest value view, according to which one intervention is superior to another if and only if it is reasonably expected to more effectively realise a set of outcomes with greater value. [ABSTRACT FROM AUTHOR]

Integration of different kinds of data is an important issue in archaeological prospection. However, the current methodological approaches are underdeveloped and rarely use the data to their maximum potential. Common approaches to integration in the geophysical sciences are mostly just various forms of comparison. We argue that true integration should involve the mathematical manipulation of input data such that the original values of the input data are changed, or that new variables are produced. To address this important research gap, we present an innovative approach to the analysis of geochemical and geophysical datasets in prospection-focused disciplines. Our approach, which we refer to as "multiscalar integration" to differentiate it from simpler methods, involves the application of mathematical methods and tools to process the data in a unified way. To demonstrate our approach, we focus on integrating geophysical data (magnetometry) with geochemical data (elemental content). Our approach comprises three main stages: Quantification of the data deviation from random distributions, linear modelling of geophysical and geochemical data and integration based on weighting of the different elements derived in previous steps. All the steps of the workflow can be also applied separately and independently as needed or preferred. Our approach is implemented in the R environment for statistical computing. All data, functions and scripts used in the work are available from open access repositories (Zenodo.org and Github.com) so that others can test, modify and apply our proposed methods to new cases and problems. Our approach has the following advantages: (1) It allows the rapid exploration of multiple data sources in an unified way; (2) it can increase the utility of geochemical data across diverse prospection disciplines; (3) it facilitates the identification of links between geochemical and geophysical data (or generally, between point-based and raster data); (4) it innovatively integrates various datasets by weighting the information provided by each; (5) it is simple to apply following a step-by-step framework; (6) the code and workflow is fully open to allow for customization, improvements and additions. [ABSTRACT FROM AUTHOR]

Abstract Background Evidence indicates that trial participants often struggle to understand participant information leaflets (PILs) for clinical trials, including the concept of randomisation. We analysed the language used to describe randomisation in PILs and determine the most understandable and acceptable description through public and participant feedback. Methods We collected 280 PILs/informed consent forms and one video animation from clinical research facilities/clinical trial units in Ireland and the UK. We extracted text on how randomisation was described, plus trial characteristics. We conducted content analysis to group the randomisation phrases inductively. We then excluded phrases that appeared more than once or were very similar to others. The final list of randomisation phrases was then presented to an online panel of participants and the public. Panel members were asked to rate each phrase on a 5-point Likert scale in terms of their understanding of the phrase, confidence in their understanding and acceptability of the phrase. Results Two hundred and eighty PILs and the transcribed text from one video animation represented 229 ongoing or concluded trials. The pragmatic content analysis generated five inductive categories: (1) explanation of why randomisation is required in trials; (2) synonyms for randomisation; (3) comparative randomisation phrases; (4) elaborative phrases for randomisation (5) and phrases that describe the process of randomisation. We had 48 unique phrases, which were shared with 73 participants and members of the public. Phrases that were well understood were not necessarily acceptable. Participants understood, but disliked, comparative phrases that referenced gambling, e.g. toss of a coin, like a lottery, roll of a die. They also disliked phrases that attributed decision-making to computers or automated systems. Participants liked plain language descriptions of what randomisation is and those that did not use comparative phrases. Conclusions Potential trial participants are clear on their likes and dislikes when it comes to describing randomisation in PILs. We make five recommendations for practice.

Objective: Little guidance exists on the conduct of randomised clinical trials (RCT) that seek to randomise patients away from standard of care. We sought to test the technique of network meta‐analysis (NMA) to ascertain best available evidence for the purposes of informing the ethical evaluation of RCTs under these circumstances. We used the example of RCTs for patients with symptomatic, moderate to severe carotid stenosis that seek to compare surgical intervention plus medical therapy (standard of care) versus medical therapy (less than standard of care). Study Design and Setting: Network meta‐analysis of RCTs of adults with symptomatic carotid artery stenosis of 50%–99% who were treated with carotid endarterectomy (CEA), carotid artery stenting (CAS), or medical therapy (MT). The primary outcome was any stroke or death until end of follow‐up, and secondary outcome was 30‐day risk of ipsilateral stroke/death. Results: We analysed eight studies, with 7187 subjects with symptomatic moderate/severe stenosis (50%–99%). CEA was more efficacious than MT (HR = 0.82, 95% credible intervals [95% CrI] = 0.73–0.92) and CAS (HR 0.73, 95% CrI = 0.62–0.85) for the prevention of any stroke/death. At 30 days, the odds of experiencing an ipsilateral stroke/death were significantly lower in the CEA group compared to both MT (OR = 0.58, 95% CrI = 0.47–0.72) and CAS (OR = 0.68, 95% CrI = 0.55–0.83). Conclusion: Our results support the feasibility of using NMA to assess best available evidence to inform the ethical evaluation of RCTs seeking to randomise patients away from standard of care. Our results suggest that a strong argument is required to ethically justify the conduct of RCTs that seek to randomise patients away from standard of care in the setting of symptomatic moderate to severe carotid stenosis. [ABSTRACT FROM AUTHOR]

Abstract Background There exist many different methods of allocating participants to treatment groups during a randomised controlled trial. Although there is research that explores trial characteristics that are associated with the choice of method, there is still a lot of variety in practice not explained. This study used qualitative methods to explore more deeply the motivations behind researchers’ choice of randomisation, and which features of the method they use to evaluate the performance of these methods. Methods Data was collected from online focus groups with various stakeholders involved in the randomisation process. Focus groups were recorded and then transcribed verbatim. A thematic analysis was used to analyse the transcripts. Results Twenty-five participants from twenty clinical trials units across the UK were recruited to take part in one of four focus groups. Four main themes were identified: how randomisation methods are selected; researchers’ opinions of the different methods; which features of the method are desirable and ways to measure method features. Most researchers agree that the randomisation method should be selected based on key trial characteristics; however, for many, a unit standard is in place. Opinions of methods were varied with some participants favouring stratified blocks and others favouring minimisation. This was generally due to researchers’ perception of the effect these methods had on balance and predictability. Generally, predictability was considered more important than balance as adjustments cannot be made for it; however, most researchers felt that the importance of these two methods was dependent on the design of the study. Balance is usually evaluated by tabulating variables by treatment arm and looking for perceived imbalances, predictability was generally considered much harder to measure, partly due to differing definitions. Conclusion There is a wide variety in practice on how randomisation methods are selected and researcher’s opinions on methods. The difference in practice observed when looking at randomisation method selection can be explained by a difference in unit practice, and also by a difference in researchers prioritisation of balance and predictability. The findings of this study show a need for more guidance on randomisation method selection.

BackgroundAs the landscape of haematological malignancies dramatically changes due to diagnostic and therapeutic advances, it is important to evaluate trends in clinical trial designs. The objective of our study was to describe the design of clinical trials for five common haematological malignancies with respect to randomisation and end-points. We also aimed to assess trends over time and examine the relationships of funding source and country of origin to proportions of randomisation and utilisation of clinical end-points.MethodsThis systematic review identified haematological malignancy clinical trials starting in 2015-2020 registered at ClinicalTrials.gov as of 20th February 2021. Trial-related variables including randomisation status, type of primary end-point, and both projected and actual enrolment numbers were captured. Clinical end-points were defined as overall survival and quality of life, while surrogate end-points included all other end-points.ResultsOf 2609 relevant trials included in this analysis, only one-fifth were randomised (538, 21%), with a significant decrease in the proportion of randomised clinical trials from 26% of trials in 2015 to 19% in 2020 (p

Abstract Background The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. Methods Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. Results Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. Conclusions Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. Trial registration ISRCTN27544579, prospectively registered on 22 May 2014

Background: There exist many different methods of allocating participants to treatment groups during a randomised controlled trial. Although there is research that explores trial characteristics that are associated with the choice of method, there is still a lot of variety in practice not explained. This study used qualitative methods to explore more deeply the motivations behind researchers’ choice of randomisation, and which features of the method they use to evaluate the performance of these methods. Methods: Data was collected from online focus groups with various stakeholders involved in the randomisation process. Focus groups were recorded and then transcribed verbatim. A thematic analysis was used to analyse the transcripts. Results: Twenty-five participants from twenty clinical trials units across the UK were recruited to take part in one of four focus groups. Four main themes were identified: how randomisation methods are selected; researchers’ opinions of the different methods; which features of the method are desirable and ways to measure method features. Most researchers agree that the randomisation method should be selected based on key trial characteristics; however, for many, a unit standard is in place. Opinions of methods were varied with some participants favouring stratified blocks and others favouring minimisation. This was generally due to researchers’ perception of the effect these methods had on balance and predictability. Generally, predictability was considered more important than balance as adjustments cannot be made for it; however, most researchers felt that the importance of these two methods was dependent on the design of the study. Balance is usually evaluated by tabulating variables by treatment arm and looking for perceived imbalances, predictability was generally considered much harder to measure, partly due to differing definitions. Conclusion: There is a wide variety in practice on how randomisation methods are selected and researcher’s opinions on methods. The difference in practice observed when looking at randomisation method selection can be explained by a difference in unit practice, and also by a difference in researchers prioritisation of balance and predictability. The findings of this study show a need for more guidance on randomisation method selection. [ABSTRACT FROM AUTHOR]

Simple Summary: This article summarises the international Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial for patients with rhabdomyosarcoma. The trial has multiple research questions relating to chemotherapy and radiotherapy and biological and imaging studies as well as to the introduction of novel drugs for patients with very high-risk disease. The rationale, background, and international collaboration of the trial are explained, and how the data will be used to inform future studies is outlined. The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [18F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results. [ABSTRACT FROM AUTHOR]

Background: The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. Methods: Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. Results: Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. Conclusions: Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. Trial registration: ISRCTN27544579, prospectively registered on 22 May 2014 [ABSTRACT FROM AUTHOR]

Abstract Background When conducting a randomised controlled trial, there exist many different methods to allocate participants, and a vast array of evidence-based opinions on which methods are the most effective at doing this, leading to differing use of these methods. There is also evidence that study characteristics affect the performance of these methods, but it is unknown whether the study design affects researchers’ decision when choosing a method. Methods We conducted a review of papers published in five journals in 2019 to assess which randomisation methods are most commonly being used, as well as identifying which aspects of study design, if any, are associated with the choice of randomisation method. Randomisation methodology use was compared with a similar review conducted in 2014. Results The most used randomisation method in this review is block stratification used in 162/330 trials. A combination of simple, randomisation, block randomisation, stratification and minimisation make up 318/330 trials, with only a small number of more novel methods being used, although this number has increased marginally since 2014. More complex methods such as stratification and minimisation seem to be used in larger multicentre studies. Conclusions Within this review, most methods used can be classified using a combination of simple, block stratification and minimisation, suggesting that there is not much if any increase in the uptake of newer more novel methods. There seems to be a noticeable polarisation of method use, with an increase in the use of simple methods, but an increase in the complexity of more complex methods, with greater numbers of variables included in the analysis, and a greater number of strata.

Abstract Background In the ongoing COVID-19 pandemic, advanced age is a risk factor for a severe clinical course of SARS-CoV-2 infection. Thus, older people may benefit in particular from booster doses with potent vaccines and research should focus on optimal vaccination schedules. In addition to each individual’s medical history, immunosenescence warrants further research in this population. This study investigates vaccine-induced immune response over 1 year. Methods/design EU-COVAT-1-AGED is a randomised controlled, adaptive, multicentre phase II protocol evaluating different booster strategies in individuals aged ≥75 years (n=600) already vaccinated against SARS-CoV-2. The initial protocol foresaw a 3rd vaccination (1st booster) as study intervention. The present modified Part B of this trial foresees testing of mRNA-1273 (Spikevax®) vs. BNT162b2 (Comirnaty®) as 4th vaccination dose (2nd booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and variants. The primary endpoint of the trial is to assess the rate of 2-fold antibody titre increase 14 days after vaccination measured by quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wild-type virus. Secondary endpoints include the changes in neutralising antibody titres (Virus Neutralisation Assay) against wild-type as well as against Variants of Concern (VOC) at 14 days and up to 12 months. T cell response measured by qPCR will be performed in subgroups at 14 days as exploratory endpoint. Biobanking samples are being collected for neutralising antibody titres against potential future VOC. Furthermore, potential correlates between humoral immune response, T cell response and neutralising capacity will be assessed. The primary endpoint analysis will be triggered as soon as for all patients the primary endpoint (14 days after the 4th vaccination dose) has been observed. Discussion The EU-COVAT-1-AGED trial Part B compares immunogenicity and safety of mRNA-1273 (Spikevax®) and BNT162b2 (Comirnaty®) as 4th SARS-CoV-2 vaccine dose in adults ≥75 years of age. The findings of this trial have the potential to optimise the COVID-19 vaccination strategy for this at-risk population. Trial registration ClinicalTrials.gov NCT05160766 . Registered on 16 December 2021. Protocol version: V06_0: 27 July 2022

Introduction: The most frequent and dangerous gastrointestinal emergency in newborns is Necrotising Enterocolitis (NEC). A novel and promising strategy for preventing NEC is enterally given probiotics. Aim: To evaluate the efficacy of probiotics in preterm neonates in the prevention of NEC and to assess the time of achievement of full feeds and duration of Intensive Care Unit (ICU) stay. Materials and Methods: The present study was a parallel design single-centre randomised controlled trial, conducted in Neonatal Intensive Care Unit (NICU), Department of Paediatrics, Kempegowda Institute of Medical Sciences, Bangalore, Karnataka, India, from November 2018 to April 2020. Total of 130 newborns were included after inclusion and exclusion criteria and were randomised into two groups: that is probiotic (group I, n=61) and non probiotic (group II, n=69) groups. The probiotic group was given probiotics with breastmilk and non probiotic group were given only breastmilk. Probiotic (Bifidobacterium breve M16V) 0.5 g was mixed with breastmilk and given twice daily till full feeds were reached. All neonates were followed-up on daily basis for the appearance of features of NEC. Other parameters like time of achievement of full feeds and duration of ICU stay were compared between the two groups. Descriptive and inferential statistical analysis was carried out in the present study. Results: Out of total sample, majority of babies belonged to the gestational age group of 30-33 weeks i.e., 30 (49.2%) in group I and 30 (43.5%) in group II. There were 29 (47.5%) females and 32 (52.5%) males in group I and, 32 (46.4%) females and 37 (53.6%) males in group II. There was a significant reduction of incidence of NEC (p-value=0.024) and earlier achievement of full feeds in the probiotic group (p-value=0.003) when compared to non probiotic group. The mean duration of ICU stay compared between the two groups was not statistically significant (p-value=0.366). Conclusion: Supplementation of probiotics to the preterm Low Birth Weight (LBW) babies helps in the reduction of incidence of NEC and also helps in earlier achievement of full feeds. [ABSTRACT FROM AUTHOR]

We consider the problem of constructing an unconditionally secure cipher for the case when the key length is less than the length of the encrypted message. (Unconditional security means that a computationally unbounded adversary cannot obtain information about the encrypted message without the key). In this article, we propose a cipher based on data compression and randomisation in combination with entropically-secure encryption and apply it to the following two cases: (i) the statistics of encrypted messages are known; and (ii) statistics are unknown, but messages are generated by a Markov chain with known memory (or connectivity). In both cases, the length of the secret key is negligible compared to the length of the message. [ABSTRACT FROM AUTHOR]

Background: Papers describing the results of a randomised trial should include a baseline table that compares the characteristics of randomised groups. Researchers who fraudulently generate trials often unwittingly create baseline tables that are implausibly similar (under-dispersed) or have large differences between groups (over-dispersed). I aimed to create an automated algorithm to screen for under- and over-dispersion in the baseline tables of randomised trials. Methods: Using a cross-sectional study I examined 2,245 randomised controlled trials published in health and medical journals on PubMed Central. I estimated the probability that a trial's baseline summary statistics were under- or over-dispersed using a Bayesian model that examined the distribution of t-statistics for the between-group differences, and compared this with an expected distribution without dispersion. I used a simulation study to test the ability of the model to find under- or over-dispersion and compared its performance with an existing test of dispersion based on a uniform test of p-values. My model combined categorical and continuous summary statistics, whereas the uniform test used only continuous statistics. Results: The algorithm had a relatively good accuracy for extracting the data from baseline tables, matching well on the size of the tables and sample size. Using t-statistics in the Bayesian model out-performed the uniform test of p-values, which had many false positives for skewed, categorical and rounded data that were not under- or over-dispersed. For trials published on PubMed Central, some tables appeared under- or over-dispersed because they had an atypical presentation or had reporting errors. Some trials flagged as under-dispersed had groups with strikingly similar summary statistics. Conclusions: Automated screening for fraud of all submitted trials is challenging due to the widely varying presentation of baseline tables. The Bayesian model could be useful in targeted checks of suspected trials or authors.

The article is devoted to analysing the achievements of the laureates of the Nobel Prize in Economic Sciences in 2021. The author described the methods of natural experiment used by the laureates in their research. Further, the author noted the differences between different types of experiments: laboratory, field, computer and mental (thought, imaginary). The author described details of two of their studies (which have become classic) on the consequences for the labour market of the influx of immigrants and the increase in the minimum wage. The methods and results of the laureates’ research on assessing the consequences of state programs and structural decisions are also analysed. In conclusion, the author considered new experimental and econometric research methods, which the laureates have significantly improved. In particular, it concerns the method of counter samples and an example from the author’s research using this method.

Researchers should ideally conduct clinical trials under a presumption of clinical equipoise, but in fact trial patients will often prefer one or other of the treatments being compared. Receiving an unblinded preferred treatment may affect the study outcome, possibly beneficially, but receiving a non-preferred treatment may induce 'reluctant acquiescence', and poorer outcomes. Even in blinded trials, patients' primary motivation to enrol may be the chance of potentially receiving a desirable experimental treatment, which is otherwise unavailable. Study designs with a higher probability of receiving a preferred treatment (denoted as 'concordance') will be attractive to potential participants, and investigators, because they may improve recruitment and hence enhance study efficiency. Therefore, it is useful to consider the concordance rates associated with various study designs. We consider this question with a focus on comparing the standard, randomised, two-arm, parallel group design with the two-stage randomised patient preference design and Zelen designs; we also mention the fully randomised and partially randomised patient preference designs. For each of these designs, we evaluate the concordance rate as a function of the proportions randomised to the alternative treatments, the distribution of preferences over treatments, and (for the Zelen designs) the proportion of patients who consent to receive their assigned treatment. We also examine the equity of each design, which we define as the similarity between the concordance rates for participants with different treatment preferences. Finally, we contrast each of the alternative designs with the standard design in terms of gain in concordance and change in equity. [ABSTRACT FROM AUTHOR]

Benefits of invasive species management for terrestrial biodiversity are widely expected and promoted in New Zealand. Evidence for this is presented in policy and scientific reviews of the literature, but the robustness and repeatability of the underpinning evidence-base remains poorly understood. We evaluated the design of field-based studies assessing biodiversity responses to invasive species management in 155 peerreviewed articles published in 46 journals from 2010-2019. Each study was assessed against nine principles of experimental design, covering robustness of sampling and avoidance of bias. These principles are important in New Zealand to detect treatment effects from environmental variability driven by underlying gradients such as soil fertility, climate, and disturbance. Across all publications, about half defined the sampling universe (52%) or were unreplicated (54%), whereas most (74%) did not representatively collect data across the sampling universe. Management treatments were specified, with or without only influencing the target species, in 68% of publications. Relatively few studies quantified invasive species (15%) and biodiversity responses (27%) representatively within replicates. Initial conditions and accounting for the effects of experimental implementation were not used in 57% and 84% of publications, respectively. No publications avoided observer/analyst bias using blinding methods, despite this being widely adopted in other scientific fields. We used ordinal logistic regression to understand how these principles varied among categories of biodiversity responses and for major groups of invasive species. Our findings suggest that greater attention to experimental design principles is desirable: supported by researchers, funding agencies, reviewers, and journal editors. Greater resources are not necessarily a solution to these design issues. One alternative is undertaking fewer studies that are individually more expensive because they better adhere to experimental design principles. The challenges of meeting experimental design principles suggests a significant role for other approaches such as systematic monitoring and natural experiments, although many of the design principles we discuss still apply. Our intent in this article is to improve the robustness of future field studies for at least some principles. Robust designs have enduring value, reduce uncertainty, and increase our understanding of when, where and how often the impacts of invasive species on biodiversity are reversible. [ABSTRACT FROM AUTHOR]

A detailed examination of the 1930 Lanarkshire Milk Experiment (LME) by the famous statistician William Sealy Gossett ("Student"), which appeared in Biometrika in 1931, is re-examined from a more modern perspective. The LME had a complicated design whereby 67 schools in Lanarkshire were allocated to receive either raw or pasteurised milk but pupils within the schools were allocated to either receive milk or to act as controls. Student's criticisms are considered in detail and examined in terms of subsequent developments on the design and analysis of experiments, in particular as regards appropriate estimation of standard errors of treatment estimates when an incomplete blocks structure has been used. An analogy with a more modern trial in osteoarthritis is made. Suggestions are made as to how analysis might proceed if the original data were available. Some lessons for observational studies in epidemiology are drawn and it is speculated that hidden clustering structures might be an explanation as to why results may vary from observational study to observational study by more than conventionally calculated standard errors might suggest. [ABSTRACT FROM AUTHOR]

Abstract Background Hand oedema is a common consequence of hand trauma or surgery. There are numerous methods to reduce hand oedema but lack high-quality evidence to support best practice. The primary objective of this pilot trial was to assess study feasibility when comparing treatments for subacute hand oedema after trauma. Methods A parallel two-arm pilot randomised controlled trial was conducted in the hand therapy department at a regional hospital in Norfolk between October 2017 and July 2018. Patients were eligible if 18 years or over, referred to hand therapy with subacute hand oedema. Randomisation was on a 1:1 basis to treatment as usual (TAU) (compression, elevation and massage) or trial treatment (TT) (kinesiology tape, elevation and massage). One blinded assessor completed all assessments (prior to randomisation, 4 and 12 weeks later). Data on study feasibility, adherence and acceptability of treatments were collected. The primary outcome measure was hand volume (volumetry). Patient-rated severity (0–5 Likert scale), hand health profile of the Patient Evaluation Measure (PEM) and quality of life (EQ-5D-5L) were also recorded. Results Forty-five patients were screened for eligibility and 26 consented and were randomised with 13 patients in each treatment arm. Twelve participants were lost to follow-up leaving 7 participants in each group included in the analysis. Assessor blinding was maintained in 64% of participants (9/14). Total mean acceptability scores, out of 100, were higher for TAU (87.9) than TT (76.1). Health resource use results showed TT was marginally cheaper (~£2 per patient) than TAU. Individual adherence ranged between 39 and 100%, with higher levels of overall adherence seen in the TAU group. Four participants (28%) reported adverse effects (TT group n = 3, TAU group n = 1). Conclusion This pilot trial has identified that modifications are required in order to make a full-scale trial feasible. They include a formal assessment of treatment fidelity, research staff assisting with screening and recruitment of participants and multiple blinded assessors at each study site. Whilst not designed as an efficacy trial, it should be acknowledged that the small sample size and high loss to follow-up meant very small numbers were included in the final analysis resulting in wide confidence intervals and therefore low precision in parameter estimates. Trial registration International Standard Randomised Controlled Trial Number: 94083271 . Date of registration 16th August 2017. Trial funding National Institute for Health Research Trainees Co-ordinating Centre (TCC); Grant Codes: CDRF-2014-05-064

Abstract Background A multicentre feasibility trial (MIAMI), comparing outcomes and quality of life of women with multiple ipsilateral breast cancer randomised to therapeutic mammoplasty or mastectomy, was conducted from September 2018 to March 2020. The MIAMI surgical trial aimed to investigate recruitment of sufficient numbers of women. Multidisciplinary teams at 10 breast care centres in the UK identified 190 with MIBC diagnosis; 20 were eligible for trial participation but after being approached only four patients were recruited. A nested qualitative study sought to understand the reasons for this lack of recruitment. Methods Interviews were conducted from November 2019 to September 2020 with 17 staff from eight hospital-based breast care centres that recruited and attempted to recruit to MIAMI; and seven patients from four centres, comprising all patients who were recruited to the trial and some who declined to take part. Interviews were audio-recorded, anonymised and analysed using thematic methods of building codes into themes and sub-themes using the process of constant comparison. Results Overarching themes of (1) influences on equipoise and recruitment and (2) effects of a lack of equipoise were generated. Within these themes, health professional themes described the barriers to recruitment as ‘the treatment landscape has changed’, ‘staff preferences and beliefs’ which influenced equipoise and patient advice; and how different the treatments were for patients. Patient themes of ‘altruism and timing of trial approach’, ‘influences from consultants and others’ and ‘diagnostic journey doubts’ all played a part in whether patients agreed to take part in the trial. Conclusions Barriers to recruiting to breast cancer surgical trials can be significant, especially where there are substantial differences between the treatments being offered and a lack of equipoise communicated by healthcare professionals to patients. Patients can become overwhelmed by numerous requests for participation in research trials and inappropriate timing of trial discussions. Alternative study designs to the gold standard randomised control trial for surgical interventions may be required to provide the high-quality evidence on which to base practice. Trial registration ISRCTN ( ISRCTN17987569 ) registered on April 20, 2018, and ClinicalTrials.gov ( NCT03514654 ).

Background: When conducting a randomised controlled trial, there exist many different methods to allocate participants, and a vast array of evidence-based opinions on which methods are the most effective at doing this, leading to differing use of these methods. There is also evidence that study characteristics affect the performance of these methods, but it is unknown whether the study design affects researchers' decision when choosing a method. Methods: We conducted a review of papers published in five journals in 2019 to assess which randomisation methods are most commonly being used, as well as identifying which aspects of study design, if any, are associated with the choice of randomisation method. Randomisation methodology use was compared with a similar review conducted in 2014. Results: The most used randomisation method in this review is block stratification used in 162/330 trials. A combination of simple, randomisation, block randomisation, stratification and minimisation make up 318/330 trials, with only a small number of more novel methods being used, although this number has increased marginally since 2014. More complex methods such as stratification and minimisation seem to be used in larger multicentre studies. Conclusions: Within this review, most methods used can be classified using a combination of simple, block stratification and minimisation, suggesting that there is not much if any increase in the uptake of newer more novel methods. There seems to be a noticeable polarisation of method use, with an increase in the use of simple methods, but an increase in the complexity of more complex methods, with greater numbers of variables included in the analysis, and a greater number of strata. [ABSTRACT FROM AUTHOR]

Background: In the ongoing COVID-19 pandemic, advanced age is a risk factor for a severe clinical course of SARS-CoV-2 infection. Thus, older people may benefit in particular from booster doses with potent vaccines and research should focus on optimal vaccination schedules. In addition to each individual's medical history, immunosenescence warrants further research in this population. This study investigates vaccine-induced immune response over 1 year.Methods/design: EU-COVAT-1-AGED is a randomised controlled, adaptive, multicentre phase II protocol evaluating different booster strategies in individuals aged ≥75 years (n=600) already vaccinated against SARS-CoV-2. The initial protocol foresaw a 3rd vaccination (1st booster) as study intervention. The present modified Part B of this trial foresees testing of mRNA-1273 (Spikevax®) vs. BNT162b2 (Comirnaty®) as 4th vaccination dose (2nd booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and variants. The primary endpoint of the trial is to assess the rate of 2-fold antibody titre increase 14 days after vaccination measured by quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wild-type virus. Secondary endpoints include the changes in neutralising antibody titres (Virus Neutralisation Assay) against wild-type as well as against Variants of Concern (VOC) at 14 days and up to 12 months. T cell response measured by qPCR will be performed in subgroups at 14 days as exploratory endpoint. Biobanking samples are being collected for neutralising antibody titres against potential future VOC. Furthermore, potential correlates between humoral immune response, T cell response and neutralising capacity will be assessed. The primary endpoint analysis will be triggered as soon as for all patients the primary endpoint (14 days after the 4th vaccination dose) has been observed.Discussion: The EU-COVAT-1-AGED trial Part B compares immunogenicity and safety of mRNA-1273 (Spikevax®) and BNT162b2 (Comirnaty®) as 4th SARS-CoV-2 vaccine dose in adults ≥75 years of age. The findings of this trial have the potential to optimise the COVID-19 vaccination strategy for this at-risk population.Trial Registration: ClinicalTrials.gov NCT05160766 . Registered on 16 December 2021.Protocol Version: V06_0: 27 July 2022. [ABSTRACT FROM AUTHOR]

Abstract Background Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT. Methods/design LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction. The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy. Discussion LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema. Trial registration ClinicalTrials.gov NCT04272827. Registered on February 14, 2020. Trial status Protocol version is 02_0, December 17, 2019

Background: Papers describing the results of a randomised trial should include a baseline table that compares the characteristics of randomised groups. Researchers who fraudulently generate trials often unwittingly create baseline tables that are implausibly similar (under-dispersed) or have large differences between groups (over-dispersed). I aimed to create an automated algorithm to screen for under- and over-dispersion in the baseline tables of randomised trials. Methods: Using a cross-sectional study I examined 2,245 randomised controlled trials published in health and medical journals on PubMed Central. I estimated the probability that a trial's baseline summary statistics were under- or over-dispersed using a Bayesian model that examined the distribution of t-statistics for the between-group differences, and compared this with an expected distribution without dispersion. I used a simulation study to test the ability of the model to find under- or over-dispersion and compared its performance with an existing test of dispersion based on a uniform test of p-values. My model combined categorical and continuous summary statistics, whereas the uniform uniform test used only continuous statistics. Results: The algorithm had a relatively good accuracy for extracting the data from baseline tables, matching well on the size of the tables and sample size. Using t-statistics in the Bayesian model out-performed the uniform test of p-values, which had many false positives for skewed, categorical and rounded data that were not under- or over-dispersed. For trials published on PubMed Central, some tables appeared under- or over-dispersed because they had an atypical presentation or had reporting errors. Some trials flagged as under-dispersed had groups with strikingly similar summary statistics. Conclusions: Automated screening for fraud of all submitted trials is challenging due to the widely varying presentation of baseline tables. The Bayesian model could be useful in targeted checks of suspected trials or authors.

A clinical trial is the gold standard study design to assess the effectiveness of interventions in health care. Yet, often paradoxically, clinicians find that the benefits of the randomized controlled clinical trial cannot be replicated in an actual clinical practice. A tradeoff between practicality and ideal trial requirements is needed to develop a pragmatic clinical trial. The results of a pragmatically constituted trial are more likely to be acceptable to practicing clinicians. The major steps and requirements and practices for a clinical trial by clinicians are summarized in this article. The PICOT format is a helpful approach to summarize research questions that explore the effects of therapy. Next, depending on the feasibility, the study population is selected by using inclusion and exclusion criteria. The needed sample size is calculated from this representative study population by providing clinical data inputs to a statistician. It is essential that chance, all possible forms of bias and confounding factors are eliminated or balanced between the study groups. This is ensured by randomization, proper allocation concealment, and masking. A clinical trial also needs to pass through relevant review boards and should be ethical. The good clinical practice guidelines throw light on this aspect. Finally, it is very important that a clinical trial is reported adequately such that readers understand the trial's design, conduct, analysis and interpretation, and can assess the validity of its results. The CONSORT guidelines are very useful in this regard.

In this paper we introduce the randomised stability constant for abstract inverse problems, as a generalisation of the randomised observability constant, which was studied in the context of observability inequalities for the linear wave equation. We study the main properties of the randomised stability constant and discuss the implications for the practical inversion, which are not straightforward.

Rationale: The coherence theory of truth, the epistemology of evidence-based medicine, mathematical statistics, and axiomatic mathematics., Aims and Objectives: To explore mathematical misconceptions inhering in randomised controlled trial designs, suggest improvements, encourage meta-methodological discussions and call for further interdisciplinary studies., Method: Mathematical-statistical analyses and science-philosophical considerations., Results: Randomisation does not (necessarily) generate equal samples, ergo, outcomes of usual RCTs are not as reliable as they claim. Moreover, ignoring initial sample discrepancies may cause inaccuracies similar to type I and type II errors. Insufficient awareness of these flaws harms final RCT statements about significance and evidence levels, hence their loss of trustworthiness. Statistical parameters such as the standard error of the mean may help to estimate the expected distinction between random samples., Conclusion: Researchers in EBM should be aware of systemic misconceptions in RCT standards. Pre-measurement can reduce shortcomings, e.g. through calculation how sample differences impact on usual RCT processing, or randomisation is given up in favour of mathematical minimisation of sample differences, i.e. optimising statistical sample equality. Moreover, the promising future of dynamic simulation models is highlighted., (© 2024 John Wiley & Sons Ltd.)

Background: Hand oedema is a common consequence of hand trauma or surgery. There are numerous methods to reduce hand oedema but lack high-quality evidence to support best practice. The primary objective of this pilot trial was to assess study feasibility when comparing treatments for subacute hand oedema after trauma. Methods: A parallel two-arm pilot randomised controlled trial was conducted in the hand therapy department at a regional hospital in Norfolk between October 2017 and July 2018. Patients were eligible if 18 years or over, referred to hand therapy with subacute hand oedema. Randomisation was on a 1:1 basis to treatment as usual (TAU) (compression, elevation and massage) or trial treatment (TT) (kinesiology tape, elevation and massage). One blinded assessor completed all assessments (prior to randomisation, 4 and 12 weeks later). Data on study feasibility, adherence and acceptability of treatments were collected. The primary outcome measure was hand volume (volumetry). Patient-rated severity (0–5 Likert scale), hand health profile of the Patient Evaluation Measure (PEM) and quality of life (EQ-5D-5L) were also recorded. Results: Forty-five patients were screened for eligibility and 26 consented and were randomised with 13 patients in each treatment arm. Twelve participants were lost to follow-up leaving 7 participants in each group included in the analysis. Assessor blinding was maintained in 64% of participants (9/14). Total mean acceptability scores, out of 100, were higher for TAU (87.9) than TT (76.1). Health resource use results showed TT was marginally cheaper (~£2 per patient) than TAU. Individual adherence ranged between 39 and 100%, with higher levels of overall adherence seen in the TAU group. Four participants (28%) reported adverse effects (TT group n = 3, TAU group n = 1). Conclusion: This pilot trial has identified that modifications are required in order to make a full-scale trial feasible. They include a formal assessment of treatment fidelity, research staff assisting with screening and recruitment of participants and multiple blinded assessors at each study site. Whilst not designed as an efficacy trial, it should be acknowledged that the small sample size and high loss to follow-up meant very small numbers were included in the final analysis resulting in wide confidence intervals and therefore low precision in parameter estimates. Trial registration: International Standard Randomised Controlled Trial Number: 94083271. Date of registration 16th August 2017. Trial funding: National Institute for Health Research Trainees Co-ordinating Centre (TCC); Grant Codes: CDRF-2014-05-064 [ABSTRACT FROM AUTHOR]

Uncertainty quantification plays an important role in problems that involve inferring a parameter of an initial value problem from observations of the solution. Conrad et al. (Stat Comput 27(4):1065–1082, 2017) proposed randomisation of deterministic time integration methods as a strategy for quantifying uncertainty due to the unknown time discretisation error. We consider this strategy for systems that are described by deterministic, possibly time-dependent operator differential equations defined on a Banach space or a Gelfand triple. Our main results are strong error bounds on the random trajectories measured in Orlicz norms, proven under a weaker assumption on the local truncation error of the underlying deterministic time integration method. Our analysis establishes the theoretical validity of randomised time integration for differential equations in infinite-dimensional settings. [ABSTRACT FROM AUTHOR]

Background: A multicentre feasibility trial (MIAMI), comparing outcomes and quality of life of women with multiple ipsilateral breast cancer randomised to therapeutic mammoplasty or mastectomy, was conducted from September 2018 to March 2020. The MIAMI surgical trial aimed to investigate recruitment of sufficient numbers of women. Multidisciplinary teams at 10 breast care centres in the UK identified 190 with MIBC diagnosis; 20 were eligible for trial participation but after being approached only four patients were recruited. A nested qualitative study sought to understand the reasons for this lack of recruitment. Methods: Interviews were conducted from November 2019 to September 2020 with 17 staff from eight hospital-based breast care centres that recruited and attempted to recruit to MIAMI; and seven patients from four centres, comprising all patients who were recruited to the trial and some who declined to take part. Interviews were audio-recorded, anonymised and analysed using thematic methods of building codes into themes and sub-themes using the process of constant comparison. Results: Overarching themes of (1) influences on equipoise and recruitment and (2) effects of a lack of equipoise were generated. Within these themes, health professional themes described the barriers to recruitment as 'the treatment landscape has changed', 'staff preferences and beliefs' which influenced equipoise and patient advice; and how different the treatments were for patients. Patient themes of 'altruism and timing of trial approach', 'influences from consultants and others' and 'diagnostic journey doubts' all played a part in whether patients agreed to take part in the trial. Conclusions: Barriers to recruiting to breast cancer surgical trials can be significant, especially where there are substantial differences between the treatments being offered and a lack of equipoise communicated by healthcare professionals to patients. Patients can become overwhelmed by numerous requests for participation in research trials and inappropriate timing of trial discussions. Alternative study designs to the gold standard randomised control trial for surgical interventions may be required to provide the high-quality evidence on which to base practice. Trial registration: ISRCTN (ISRCTN17987569) registered on April 20, 2018, and ClinicalTrials.gov (NCT03514654). [ABSTRACT FROM AUTHOR]

ABSTRACT (198): Background: The multi-dose regimen is a known barrier to successful human papillomavirus (HPV) vaccination. Emerging evidence suggests that one vaccine dose could protect against HPV. While there are clear advantages to a single dose schedule, beliefs about vaccine dosage in low and middle income countries (LMICs) are poorly understood. We investigated acceptability of dose-reduction among girls, and parents/guardians of girls, randomised to receive one, two or three doses in an HPV vaccine dose-reduction and immunobridging study (DoRIS trial) in Tanzania. Methods: Semi-structured interviews with girls (n = 19), and parents/guardians of girls (n = 18), enrolled in the study and completing their vaccine course. Results: Most participants said they entrusted decisions about the number of HPV vaccine doses to experts. Random allocation to the different dose groups did not feature highly in the decision to participate in the trial. Given a hypothetical choice, girls generally said they would prefer fewer doses in order to avoid the pain of injections. Parental views were mixed, with most wanting whichever dose was most efficacious. Nonetheless, a few parents equated a higher number of doses with greater protection. Conclusion: Vaccine trials and programmes will need to employ careful messaging to explain that one dose offers sufficient protection against HPV should emerging evidence from ongoing dose-reduction clinical trials support this.

Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time. To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes. We systematically searched PubMed, Embase, PsychINFO and Web of Science. We included registered randomized controlled trials published in journals between January 2015 and December 2019. We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria. Primary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible versus non-susceptible bacteria. Results are described narratively. Of 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients' outcomes were superior when patients with infections due to susceptible and non-susceptible pathogens were compared post hoc (median difference 14%, interquartile range 8%–24%) in trials allowing this comparison (seven antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible versus colistin-resistant carbapenem-resistant Acinetobacter baumannii. When excluding patients with pathogens that were non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in five out of six trials. Trials should perform AST to guide patient inclusion or exclusion from the study and consider the impact of the central laboratory susceptibility results on the study outcomes when using post-hoc reference testing. [ABSTRACT FROM AUTHOR]

Background: Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.Methods/design: LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0-10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction. The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher's exact test in a hierarchical test strategy.Discussion: LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.Trial Registration: ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.Trial Status: Protocol version is 02_0, December 17, 2019. [ABSTRACT FROM AUTHOR]

Abstract Background One important ethical issue in randomised controlled trials (RCTs) is randomisation. Relatively little is known about how participating individuals and communities understand and perceive central aspects of randomisation such as equality, fairness, transparency and accountability in community-based trials. The aim of this study was to understand and explore study communities’ perspectives of the randomisation process in a cluster RCT in rural Zambia studying the effectiveness of different support packages for adolescent girls on early childbearing. Methods In this explorative study, in-depth semi-structured interviews were carried out in 2018 with 14 individuals who took part in the randomisation process of the Research Initiative to Support the Empowerment of Girls (RISE) project in 2016 and two traditional leaders. Two of the districts where the trial is implemented were purposively selected. Interviews were audio recorded and fully transcribed. Data were analysed by coding and describing emergent themes. Results The understanding of the randomisation process varied. Some respondents understood that randomisation was conducted for research purposes, but most of them did not. They had trouble distinguishing research and aid. Generally, respondents perceived the randomisation process as transparent and fair. However, people thought that there should not have been a “lottery” because they wanted all schools to receive equal or balanced benefits of the interventions. Conclusions Randomisation was misunderstood by most respondents. Perceived procedural fairness was easier to realize than substantive fairness. Researchers working on Cluster Randomised Controlled Trials (CRCTs) should consider carefully how to explain randomisation.