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Abstract: This paper describes the application of a translational research model in developing The Trial Using Motivational Interviewing and Positive Affect and Self-Affirmation in African-Americans with Hypertension (TRIUMPH), a theoretically-based, randomized controlled trial. TRIUMPH targets blood pressure control among African-Americans with hypertension in a community health center and public hospital setting. TRIUMPH applies positive affect, self-affirmation, and motivational interviewing as strategies to increase medication adherence and blood pressure control. A total of 220 participants were recruited in TRIUMPH and are currently being followed. This paper provides a detailed description of the theoretical framework and study design of TRIUMPH and concludes with a critical reflection of the lessons learned in the process of implementing a health behavior intervention in a community-based setting. TRIUMPH provides a model for incorporating the translational science research paradigm to conducting pragmatic behavioral trials in a real-world setting in a vulnerable population. Lessons learned through interactions with our community partners reinforce the value of community engagement in research. [Copyright &y& Elsevier]

Current guidelines recommend behavioral intervention to achieve a modest weight loss (e.g., 3–5%) as a first-line obesity treatment. Online behavioral obesity treatment, delivered via the Rx Weight Loss (RxWL) program, produces clinically significant initial weight losses. However, the program's pragmatic utility in routine medical care has yet to be tested. Further, additional research is needed to determine how best to extend the RxWL program to facilitate weight loss maintenance. This paper summarizes methods for a pragmatic trial aimed at identifying optimal methods for implementation of RxWL in primary care and evaluating relative effectiveness of two approaches to weight loss maintenance. RxWL will be implemented in a network of approximately 60 primary care clinics. Implementation outcomes (program uptake and completion metrics) will be compared between a Basic Implementation Intervention consisting primarily of access to RxWL, and an Enhanced Implementation Intervention with additional training in strategies for motivating and supporting patients in their use of RxWL and online clinician support tools for tracking patient progress. Second, two intervention approaches (Monthly Lessons versus Refresher Courses) within the RxWL patient platform will be tested against an educational control condition, and effects on 1-year weight loss maintenance will be compared. This study will provide essential information about the feasibility and utility of online obesity treatment in primary care. It will provide novel information on two approaches to weight loss maintenance for patients in this setting. This project fills key gaps in evidence regarding best practices for obesity treatment in primary care. [ABSTRACT FROM AUTHOR]

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. [ABSTRACT FROM AUTHOR]

Background Fruit and vegetable (F&V) consumption is an important contributor to chronic disease prevention. However, most Americans do not eat adequate amounts. The worksite is an advantageous setting to reach large, diverse segments of the population with interventions to increase F&V intake, but research gaps exist. No studies have evaluated the implementation of mobile F&V markets at worksites nor compared the effectiveness of such markets with or without nutrition education. Methods This paper describes the protocol for Good to Go (GTG), a cluster randomized trial to evaluate F&V intake change in employees from worksites randomized into three experimental arms: discount, fresh F&V markets (Access Only arm); markets plus educational components including campaigns, cooking demonstrations, videos, newsletters, and a web site (Access Plus arm); and an attention placebo comparison intervention on physical activity and stress reduction (Comparison). Secondary aims include: 1) Process evaluation to determine costs, reach, fidelity, and dose as well as the relationship of these variables with changes in F&V intake; 2) Applying a mediating variable framework to examine relationships of psychosocial factors/determinants with changes in F&V consumption; and 3) Cost effectiveness analysis of the different intervention arms. Discussion The GTG study will fill important research gaps in the field by implementing a rigorous cluster randomized trial to evaluate the efficacy of an innovative environmental intervention providing access and availability to F&V at the worksite and whether this access intervention is further enhanced by accompanying educational interventions. GTG will provide an important contribution to public health research and practice. Trial registration number NCT02729675 , ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Drug addiction is a chronic, devastating, but treatable disorder. A core principle of drug addiction treatment states that no single treatment is appropriate for everyone (NIDA, 2012); treatments need to adjust based on patient characteristics and response in order to be maximally effective. For cocaine use disorders (CUD), specifically, the most potent intervention currently available for initiating abstinence is behavior therapy using contingency management (CM) procedures, with early cessation being a robust predictor of future abstinence. This raises two key questions for treatment development research: First, can we significantly improve initial CM response rates with targeted adjunctive interventions? Second, for individuals who fail to achieve initial abstinence with CM, is pharmacotherapy an effective augmentation strategy? This paper describes how a sequential, multiple assignment, randomized trial (SMART) design has advantages over a fixed-intervention approach when it comes to collecting data needed to answer both questions. The first aim will examine whether Acceptance and Commitment Therapy (ACT) in combination with CM increases initial abstinence response rates (i.e., 2 consecutive weeks of cocaine-negative urine screens). The second aim will examine whether ACT + CM in combination with modafinil promotes abstinence achievement in initial non-responders. Results are expected to inform how we tailor treatment of CUD to maximize outcomes. [ABSTRACT FROM AUTHOR]

Urolithiasis or urinary stone disease has been estimated to affect about 1 in 11 Americans. Patients with urinary stone disease commonly present to the emergency department for management of their acute pain. In addition to providing analgesia, administration of drug (medical expulsive therapy) is often prescribed to assist passage of the urinary stone. In this methodology paper, we describe the design of a prospective, multi-center, randomized, double-blind placebo controlled clinical trial of the alpha-adrenergic blocker, tamsulosin, to evaluate its effectiveness as medical expulsive therapy. In addition, we describe the unique challenges of conducting a trial of this type within the setting of the emergency department. [ABSTRACT FROM AUTHOR]

Background Although suicide ranks 10th as a cause of death in the United States, and 1st among active military personnel, there are surprisingly few evidence-based therapies addressing suicidality, and development of new treatments is limited. This paper describes a clinical trial testing a novel therapy for reducing suicide risk in military veterans. The intervention, Mindfulness-Based Cognitive Therapy for Preventing Suicide Behavior (MBCT-S), is a 10-week group intervention adapted from an existing treatment for depression (Mindfulness-Based Cognitive Therapy – MBCT). MBCT-S incorporates the Safety Planning Intervention, which is currently implemented throughout the Veterans Health Administration (VHA) for veterans at high suicide risk. Methods MBCT-S is being tested in a VHA setting using an intention-to-treat, two-group randomized trial design in which 164 high suicide risk veterans are randomized to either VHA Treatment As Usual (TAU; n = 82) or TAU + MBCT-S (n = 82). Our primary outcome measure, suicide-related event, defined to include suicide preparatory behaviors, self-harm behavior with suicidal or indeterminate intent, suicide-related hospitalizations and Emergency Department (ED) visits, will be measured through five assessments administered by blinded assessors between baseline and 12 months post-baseline. We will measure suicide attempts and suicide deaths as a secondary outcome, because of their anticipated low incidence during the study period. Secondary outcomes also include severity of suicidal ideation, hopelessness and depression. Significance This study has the potential to significantly enhance the quality and efficiency of VHA care for veterans at suicide risk and to substantially improve the quality of life for veterans and their families. [ABSTRACT FROM AUTHOR]

Despite the availability of efficacious treatments, only half of patients with hypertension achieve adequate blood pressure (BP) control. This paper describes the protocol and baseline subject characteristics of a 2-arm, 18-month randomized clinical trial of titrated disease management (TDM) for patients with pharmaceutically-treated hypertension for whom systolic blood pressure (SBP) is not controlled (≥ 140 mm Hg for non-diabetic or ≥ 130 mm Hg for diabetic patients). The trial is being conducted among patients of four clinic locations associated with a Veterans Affairs Medical Center. An intervention arm has a TDM strategy in which patients' hypertension control at baseline, 6, and 12 months determines the resource intensity of disease management. Intensity levels include: a low-intensity strategy utilizing a licensed practical nurse to provide bi-monthly, non-tailored behavioral support calls to patients whose SBP comes under control; medium-intensity strategy utilizing a registered nurse to provide monthly tailored behavioral support telephone calls plus home BP monitoring; and high-intensity strategy utilizing a pharmacist to provide monthly tailored behavioral support telephone calls, home BP monitoring, and pharmacist-directed medication management. Control arm patients receive the low-intensity strategy regardless of BP control. The primary outcome is SBP. There are 385 randomized (192 intervention; 193 control) veterans that are predominately older (mean age 63.5 years) men (92.5%). 61.8% are African American, and the mean baseline SBP for all subjects is 143.6 mm Hg. This trial will determine if a disease management program that is titrated by matching the intensity of resources to patients' BP control leads to superior outcomes compared to a low-intensity management strategy. [ABSTRACT FROM AUTHOR]

Background Depressive and anxiety disorders contribute to a high disease burden. This paper investigates whether concise formats of cognitive behavioral- and/or pharmacotherapy are equivalent with longer standard care in the treatment of depressive and/or anxiety disorders in secondary mental health care. Methods A pragmatic randomized controlled equivalence trial was conducted at five Dutch outpatient Mental Healthcare Centers (MHCs) of the Regional Mental Health Provider (RMHP) ‘Rivierduinen’. Patients (aged 18–65 years) with a mild to moderate anxiety and/or depressive disorder, were randomly allocated to concise or standard care. Data were collected at baseline, 3, 6 and 12 months by Routine Outcome Monitoring (ROM). Primary outcomes were the Brief Symptom Inventory (BSI) and the Web Screening Questionnaire (WSQ). We used Generalized Estimating Equations (GEE) to assess outcomes. Results Between March 2010 and December 2012, 182 patients, were enrolled ( n = 89 standard care; n = 93 concise care). Both intention-to-treat and per-protocol analyses demonstrated equivalence of concise care and standard care at all time points. Severity of illness reduced, and both treatments improved patient’s general health status and subdomains of quality of life. Moreover, in concise care, the beneficial effects started earlier. Discussion Concise care has the potential to be a feasible and promising alternative to longer standard secondary mental health care in the treatment of outpatients with a mild to moderate depressive and/or anxiety disorder. For future research, we recommend adhering more strictly to the concise treatment protocols to further explore the beneficial effects of the concise treatment. The study is registered in the Netherlands Trial Register, number NTR2590. Clinicaltrials.gov identifier: NCT01643642 . [ABSTRACT FROM AUTHOR]

Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N -acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18–50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. [ABSTRACT FROM AUTHOR]

Background Depression during pregnancy has been demonstrated to be predictive of low birthweight, prematurity, and postpartum depression. These adverse outcomes potentially have lasting effects on maternal and child well-being. Socio-economically disadvantaged women are twice as likely as middle-class women to meet diagnostic criteria for antenatal major depression (MDD), but have proven difficult to engage and retain in treatment. Collaborative care treatment models for depression have not been evaluated for racially/ethnically diverse, pregnant women on Medicaid receiving care in a public health system. This paper describes the design, methodology, culturally relevant enhancements, and implementation of a randomized controlled trial of depression care management compared to public health Maternity Support Services (MSS). Methods Pregnant, public health patients, > 18 years with a likely diagnosis of MDD or dysthymia, measured respectively by the Patient Health Questionnaire-9 (PHQ-9) or the Mini-International Neuropsychiatric Interview (MINI), were randomized to the intervention or to public health MSS. The primary outcome was reduction in depression severity from baseline during pregnancy to 18-months post-baseline (one-year postpartum). Baseline results 168 women with likely MDD (96.4%) and/or dysthymia (24.4%) were randomized. Average age was 27.6 years and gestational age was 22.4 weeks; 58.3% racial/ethnic minority; 71.4% unmarried; 22% no high school degree/GED; 65.3% unemployed; 42.1% making < $10,000 annually; 80.4% having recurrent depression; 64.6% PTSD, and 72% unplanned pregnancy. Conclusions A collaborative care team, including a psychiatrist, psychologist, project manager, and 3 social workers, met weekly, collaborated with the patients' obstetrics providers, and monitored depression severity using an electronic tracking system. Potential sustainability of the intervention within a public health system requires further study. [ABSTRACT FROM AUTHOR]

Abstract: Background: A crucial part in the development of any intervention is the preliminary work carried out prior to a large-scale definitive trial. However, the definitions of these terms are not clear cut and many authors redefine them. Because of this, the terms feasibility and pilot are often misused. Aim: To provide an introduction to the topic area of pilot and feasibility trials and draw together the work of others in the area on defining what is a pilot or feasibility study. Methods: This study used a review of definitions and advice from the published literature and from funders' websites. Examples are used to show evidence of good practice and poor practice. Results: We found that researchers use different terms to describe the various stages of the research process. Some define the terms feasibility and pilot as being different whereas others argue that these terms are synonymous. All reflective papers agree that feasibility/pilot studies should not test treatment comparisons nor estimate feasible effect sizes. However, this is not universally observed in practice. Summary: We believe that the term ‘feasibility’ should be used as an overarching term for preliminary studies and the term ‘pilot’ refers to a specific type of study which resembles the intended trial in aspects such as, having a control group and randomisation. However, studies labelled ‘pilot’ should have different aims and objectives to main trials and also should include an intention for future work. Researchers should not use the title ‘pilot’ for a trial which evaluates a treatment effect. [Copyright &y& Elsevier]

Abstract: Obesity prevention in children offers a unique window of opportunity to establish healthful eating and physical activity behaviors to maintain a healthful body weight and avoid the adverse proximal and distal long-term health consequences of obesity. Given that obesity is the result of a complex interaction between biological, behavioral, family-based, and community environmental factors, intervention at multiple levels and across multiple settings is critical for both short- and long-term effectiveness. The Minnesota NET-Works (Now Everybody Together for Amazing and Healthful Kids) study is one of four obesity prevention and/or treatment trials that are part of the Childhood Obesity Prevention and Treatment (COPTR) Consortium. The goal of the NET-Works study is to evaluate an intervention that integrates home, community, primary care and neighborhood strategies to promote healthful eating, activity patterns, and body weight among low income, racially/ethnically diverse preschool-age children. Critical to the success of this intervention is the creation of linkages among the settings to support parents in making home environment and parenting behavior changes to foster healthful child growth. Five hundred racially/ethnically diverse, two–four year old children and their parent or primary caregiver will be randomized to the multi-component intervention or to a usual care comparison group for a three-year period. This paper describes the study design, measurement and intervention protocols, and statistical analysis plan for the NET-Works trial. [Copyright &y& Elsevier]

Abstract: Background: Women have higher rates of depression and often experience depression symptoms during critical reproductive periods, including adolescence, pregnancy, postpartum, and menopause. Collaborative care intervention models for mood disorders in patients receiving care in an OB-GYN clinic setting have not been evaluated. Study design and methodology for a randomized controlled trial of collaborative care depression management versus usual care in OB-GYN clinics and the details of the adapted collaborative care intervention and model implementation are described in this paper. Methods: Women over age 18years with clinically significant symptoms of depression, as measured by a Patient Health Questionnaire-9 (PHQ-9) score ≥10 and a clinical diagnosis of major depression or dysthymia, were randomized to the study intervention or to usual care and were followed for 18months. The primary outcome assessed was change over time in the SCL-20 depression scale between baseline and 12months. Baseline Results: Two hundred five women were randomized: 57% white, 20% African American, 9% Asian or Pacific Islander, 7% Hispanic, and 6% Native American. Mean age was 39years. 4.6% were pregnant and 7.5% were within 12months postpartum. The majority were single (52%), and 95% had at least the equivalent of a high school diploma. Almost all patients met DSM IV criteria for major depression (99%) and approximately 33% met criteria for dysthymia. Conclusions: An OB-GYN collaborative care team, including a social worker, a psychiatrist, and an OB-GYN physician, who met weekly and used an electronic tracking system for patients was the essential element of the proposed depression care treatment model described here. Further study of models that improve quality of depression care that are adapted to the unique OB-GYN setting is needed. [Copyright &y& Elsevier]

Abstract: This paper describes the rationale and design of the vanguard for the Comparison of Depression Interventions after Acute Coronary Syndrome (CODIACS), a multicenter, randomized, controlled trial of a patient preference‐based, stepped care protocol for persistent depressive symptoms after acute coronary syndrome (ACS). The overall aim of the vanguard phase was to determine whether the patient-preference, stepped care protocol, which is based on the intervention used in the recent Coronary Psychosocial Evaluation Studies (COPES) trial, was feasible in patients with recent ACS who were recruited from 5 geographically diverse sites. Innovative design features of this trial include randomization to either initial patient-preference of treatment or to a referred care arm in which the primary care provider decided upon care. Additionally, delivery of psychotherapy was accomplished by telephone, or webcam, depending upon patient preference. The vanguard phase provides estimates of eligibility and screening/enrollment ratios, patient acceptance of screening, and retention. In this report, we describe the innovative features and the baseline results of the vanguard phase of CODIACS. The data from this vanguard study will be used to finalize planning for a large, phase III clinical trial designed to evaluate the effect of treatment on depressive symptoms, coronary events, and death. [Copyright &y& Elsevier]

Abstract: Background: Antidepressants are often the first-line treatment for depression but only one third of patients respond fully to pharmacotherapy. This paper describes the protocol for a randomised controlled trial (RCT) designed to evaluate the clinical and cost effectiveness of cognitive behavioural therapy (CBT) as an adjunct to pharmacotherapy for patients with treatment resistant depression in primary care. Methods/design: CoBalT is a two parallel group multi-centre pragmatic RCT. Eligible participants were those who: (i) were aged 18–75years; (ii) were currently taking antidepressant medication (for at least 6weeks at an adequate dose); (iii) scored ≥14 on the Beck Depression Inventory (BDI-II); (iv) had adhered to their medication; and (v) met ICD-10 criteria for depression (assessed using the Clinical Interview Schedule — revised version). Those who gave written informed consent were randomised to one of two treatment groups: usual care or usual care plus CBT. The primary outcome is depressive symptoms assessed using the BDI-II at 6months post-randomisation. Secondary outcomes measured at 6 and 12months include quality of life, antidepressant use and health care utilisation. Outcomes will be analysed on an intention-to-treat basis. Discussion: The CoBalT trial will provide evidence on the clinical and cost effectiveness of CBT as an adjunct to antidepressant medication in the treatment of depression that has not responded to pharmacotherapy. Given the move to widen access to ‘talking therapies’, the results of this study will be timely. [Copyright &y& Elsevier]

Abstract: Modified Zelen''s approach is a randomization technique useful in multi-center trials where balance in treatment assignments within a center is desired. It has great balancing properties in a study with equal allocation to several treatment arms. This technique can also be used in studies with unequal allocation, where it would provide an allocation ratio close to the targeted one within centers as well as across centers. However, the implementation of the modified Zelen''s approach for unequal allocation involves more than just imposing a constraint on within-center imbalance in treatment assignments, as is the case with equal allocation. Failure to account for this might provide a potential for accidental bias and (even in a double-blind study) selection and evaluation bias. The naive expansion of the modified Zelen''s approach to unequal allocation can also lead to a shift in the re-randomization distribution of the between-group difference in treatment means. This paper will explain why and will offer an easy way to expand the modified Zelen''s approach to unequal allocation that allows one to avoid these issues. The expansion to unequal allocation of another very useful in multi-center trials technique where partial blocks of supplies are sent to the centers will be offered. [Copyright &y& Elsevier]

Abstract: Subgroup analyses in clinical trials are becoming increasingly important. In cancer research more and more targeted therapies are explored and probably only a portion of the whole population will benefit from them. Subgroups of interest can be analyzed in several ways, but a correction of the type I error probability is needed in order to appropriately draw conclusions. Often a conservative Bonferroni approach is taken where the total significance level is distributed (equally or unequally) over the analysis including all patients (overall analysis) and the subgroup analysis. However, more efficient methods are available that take into account the correlation that exists between the test statistics for the overall and the subgroup analysis. The latter approaches are very appealing but have not found their way into practice. The aim of this paper is to show that these methods are the same as the methods used when dealing with interim analyses, i.e., group sequential methods, and hence standard software can be used to calculate the appropriate significance levels. Further, we show that this correction can be applied even when the size of the subgroup is unknown until the end of the trial. Using a simulation study with survival data, we also show that the familywise error rate is well controlled, even with small sample sizes. We hope that this will promote the use of these methods in future cancer clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Trials of many (>2) treatments are common, particularly double-blind dose finding trials in Phase IIb where trials of four or more treatments are often seen. Such trials will almost certainly be conducted at multiple centres given the sponsor''s desire to speed up the development program. When conducting such multicentre trials, the study team will always have to consider the question of whether the randomisation of the trial is to be stratified or balanced in some way by participating centre. In addressing this question there are three considerations: the impact on power, predictability and medication supply requirements. This paper will describe the use of alternative complex list based randomisation solutions that have been recently developed and implemented; two of the solutions have not previously been presented or published. The techniques maintain various degrees of control over treatment allocations at the centre and study as a whole; consequently the methods help with conserving supplies of medication. Simulation evidence will be presented for each technique. [Copyright &y& Elsevier]

Abstract: The purpose of this paper is to evaluate the efficacy and safety of recombinant human hepatocyte growth factor (rh-HGF) for liver failure (LF) using meta-analysis of data from the literature involving available randomized controlled trials of rh-HGF plus comprehensive therapy (CT) compared with that of CT alone (Therapy I versus II) in treating LF. We searched the Cochrane Library, MEDLINE, EMBASE, CBMdisc, and CNKI as well as employing manual searches. Based on our search criteria, we found 21 trials, involving 5902 patients. Our results showed that Therapy I, compared with therapy II, significantly reduced the overall mortality (RR=0.62; 95% CI, 0.59–0.66; p =0.0001). Compared to two clinical types of LF (acute and acute-on-chronic), therapy I perhaps had significant effect on mortality due to sub-acute LF, RR and 95% CI were 0.76 [0.65, 0.89], 0.66 [0.60, 0.74], and 0.58 [0.53, 0.64], respectively. Additionally, there was a reduction in mortality of patients that had evidence for an early stage of LF compared to the two other clinical stages of LF (Middle and Advanced); RR and 95% CI were 0.34 [0.24, 0.49], 0.49 [0.44, 0.55], and 0.87 [0.82, 0.93], respectively. No serious adverse events were reported. We conclude that Therapy I may reduce mortality in LF, especially in sub-acute LF and the early stage of LF. However, considering the strength of the evidence, additional randomized controlled trials are needed before Therapy I can be recommended routinely. [Copyright &y& Elsevier]

Abstract: Blinding is an important design feature of randomised trials that may reduce bias in the results, compared to the situation where blinding is not possible or is not maintained. The literature provides some guidance for the evaluation of blinding in ongoing or completed studies, but the question of pre-trial assessment of the potential for unblinding has not been addressed. This paper describes the design and analysis of a prototype experiment for the pre-trial assessment of blinding in a drug trial. This work was motivated by a trial using antibiotic therapy, in which the investigators were concerned about the possibility of subjects being able to differentiate active medication from placebo, and thus become unblinded to their treatment assignment. A small experiment was mounted in which participants had to divide a random mixture of tablets into two groups. Statistical methods were developed to calculate the probability of a given number of similar tablets being classified into the same group by chance, with a modification to allow for some participants having constrained their responses to have equal numbers of tablets in each group. Differentiation of tablets by taste (the initial concern of the investigators) was not statistically different from chance. A smaller set of data on differentiation by appearance (a possibility not originally considered) had borderline statistical significance. After reviewing all these results, the investigators decided to proceed with the study without modifying the tablets, in part because subjects in the study would be unlikely to compare the two types of medication side-by-side. Our results suggest that blinding might sometimes be compromised in unexpected ways. Whenever possible, we suggest that similar and larger such experiments be carried out before the trial to assess whether blinding might be compromised. The methods proposed here could easily be adapted to evaluate the results of such experiments. [Copyright &y& Elsevier]