RESUMEN

This study presents a hybrid (Bayesian-frequentist) approach to sample size re-estimation (SSRE) for cluster randomised trials with continuous outcome data, allowing for uncertainty in the intra-cluster correlation (ICC). In the hybrid framework, pre-trial knowledge about the ICC is captured by placing a Truncated Normal prior on it, which is then updated at an interim analysis using the study data, and used in expected power control. On average, both the hybrid and frequentist approaches mitigate against the implications of misspecifying the ICC at the trial's design stage. In addition, both frameworks lead to SSRE designs with approximate control of the type I error-rate at the desired level. It is clearly demonstrated how the hybrid approach is able to reduce the high variability in the re-estimated sample size observed within the frequentist framework, based on the informativeness of the prior. However, misspecification of a highly informative prior can cause significant power loss. In conclusion, a hybrid approach could offer advantages to cluster randomised trials using SSRE. Specifically, when there is available data or expert opinion to help guide the choice of prior for the ICC, the hybrid approach can reduce the variance of the re-estimated required sample size compared to a frequentist approach. As SSRE is unlikely to be employed when there is substantial amounts of such data available (ie, when a constructed prior is highly informative), the greatest utility of a hybrid approach to SSRE likely lies when there is low-quality evidence available to guide the choice of prior.

RESUMEN

In 2016, we published a conceptual framework outlining the conclusions of our work in defining pilot and feasibility studies. Since then, the CONSORT extension to randomised pilot and feasibility trials has been published and there have been further developments in the pilot study landscape. In this paper, we revisit and extend our framework to incorporate the various feasibility pathways open to researchers, which include internal pilot studies. We consider, with examples, when different approaches to feasibility and pilot studies are more effective and efficient, taking into account the pragmatic decisions that may need to be made. The ethical issues involved in pilot studies are discussed. We end with a consideration of the funders' perspective in making difficult resource decisions to include feasibility work and the policy implications of these; throughout, we provide examples of the uncertainties and compromises that researchers have to navigate to make progress in the most efficient way.

RESUMEN

BACKGROUND: Dental caries is common in young people and has wide-ranging ramifications for health and quality of life. Text messaging interventions show promise as a means to promote oral health behaviour change among young people. This paper reports the internal pilot of the Brushing RemInder 4 Good oral HealTh (BRIGHT) trial, which is evaluating an intervention comprising an oral health classroom lesson and text messages about toothbrushing, on caries in young people. Pilot trial objectives were to evaluate the feasibility and appropriateness of recruitment and data collection methods, the randomisation strategy, and intervention delivery against progression criteria for the main trial. METHODS: This is an internal pilot trial embedded within an assessor-blinded, two-arm, cluster randomised controlled trial. Participants were pupils aged 11-13 years (in year 7/S1 or year 8/S2) in secondary schools in England, Scotland, and Wales with above average pupil eligibility for free school meals. Following completion of pupil baseline questionnaires and dental assessments, year groups within schools were randomised to the intervention or control arm. Approximately 12 weeks later, participants completed a follow-up questionnaire, which included questions about sources of oral health advice to assess intervention contamination between year groups. At the end of the pilot phase, trial conduct was reviewed against pre-specified progression criteria. RESULTS: Ten schools were recruited for the pilot, with 20 year groups and 1073 pupils randomised (average of 54 pupils per year group). Data collection methods and intervention delivery were considered feasible, the response rate to the follow-up questionnaire was over 80%, there was an indication of a positive effect on self-reported toothbrushing, and interest was obtained from 80% of the schools required for the main trial. Despite partial intervention contamination between year groups, within-school randomisation at the level of the year-group was considered appropriate for the main trial, and the sample size was revised to account for partial contamination. Facilitators and barriers to recruitment and data collection were identified and strategies refined for the main trial. CONCLUSIONS: Progression to the main trial of BRIGHT, with some design refinements, was concluded. The internal pilot was an efficient way to determine trial feasibility and optimise trial processes. TRIAL REGISTRATION: ISRCTN registry, ISRCTN12139369 , registered 10/05/2017.

RESUMEN

OBJECTIVE: To assess feasibility and acceptability of a novel, low-cost "Suction Tube Uterine Tamponade" (STUT) treatment for refractory postpartum hemorrhage (PPH). METHODS: We allocated patients with refractory PPH by randomly ordered envelopes to STUT or routine uterine balloon tamponade (UBT, Ellavi free-flow system) in 10 hospitals in South Africa. In the STUT group, a 24FG Levin stomach tube was inserted into the uterine cavity and vacuum created with a vacuum pump or manual vacuum aspiration syringe. RESULTS: For this internal pilot study, 12 participants were allocated to STUT and 12 to UBT. Insertion failed in one of each group and was recorded as difficult in 3/10 STUT and 4/9 UBT insertions respectively (five missing data). There were two laparotomies and one intensive care unit admission in the UBT group. Pain during STUT insertion was graded as none/mild in 9/10 and severe in 1/10. The experience of the STUT procedure was graded as fine in 4/11 and "uncomfortable but acceptable" in 7/11. CONCLUSION: STUT is feasible and acceptable, justifying continuation of our trial. These data will also inform a large World Health Organization trial to test effectiveness of uterine tamponade methods. The numbers are too small to support any clinical recommendation.

Asunto(s)

Hemorragia Posparto , Taponamiento Uterino con Balón , Estudios de Factibilidad , Femenino , Humanos , Proyectos Piloto , Hemorragia Posparto/terapia , Embarazo , Succión , Resultado del Tratamiento , Taponamiento Uterino con Balón/métodos

RESUMEN

BACKGROUND: Return to work (RTW) is achieved by less than 50% of stroke survivors. The rising incidence of stroke among younger people, the UK economic forecast, and clinical drivers highlight the need for stroke survivors to receive support with RTW. However, evidence for this type of support is lacking. This randomised controlled trial (RCT) will investigate whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care (UC) (i.e. usual NHS rehabilitation) is more clinically and cost-effective for supporting post-stroke RTW, than UC alone. METHODS: Seven hundred sixty stroke survivors and their carers will be recruited from approximately 20 NHS stroke services. A 5:4 allocation ratio will be employed to randomise participants to receive ESSVR plus UC, or UC alone. The individually tailored ESSVR intervention will commence within 12 weeks of stroke onset and be delivered for up to 12 months as necessary by trained RETAKE occupational therapists in the community, participants' homes or workplaces, and outpatient/inpatient therapy settings, via telephone, email, or SMS text message. Outcome data will be collected via self-report questionnaires administered by post or online at 3, 6, and 12 months follow-up. The primary outcome will be self-reported RTW and job retention at 12 months (minimum 2 h/week). Secondary outcomes will include mood, function, participation, health-related quality of life, confidence, intervention compliance, health and social care resource use, and mortality. An embedded economic evaluation will estimate cost-effectiveness and cost-utility analyses from National Health Service (NHS) and Personal Social Services (PSS) perspectives. An embedded process evaluation will employ a mixed methods approach to explore ESSVR implementation, contextual factors linked to outcome variation, and factors affecting NHS roll-out. DISCUSSION: This article describes the protocol for a multi-centre RCT evaluating the clinical- and cost-effectiveness of an early vocational rehabilitation intervention aimed at supporting adults to return to work following a stroke. Evidence favouring the ESSVR intervention would support its roll-out in NHS settings. TRIAL REGISTRATION: ISRCTN, ISRCTN12464275 . Registered on 26 February 2018.

Asunto(s)

Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Adulto , Cuidadores , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Rehabilitación Vocacional , Reinserción al Trabajo , Accidente Cerebrovascular/diagnóstico , Sobrevivientes

RESUMEN

BACKGROUND: The aim of the TANDEM trial is to evaluate whether a tailored, psychological cognitive behavioural approach intervention, which links into, and optimises the effects of routine pulmonary rehabilitation (PR), leads to a reduction in mild/moderate anxiety and/or depression in people with moderate, severe or very severe chronic obstructive pulmonary disease. METHODS AND DESIGN: TANDEM is a multi-centre, two-arm, parallel group, pragmatic, individually randomised controlled, superiority trial including an internal pilot. Participants are randomised to receive either the intervention (a tailored psychological intervention plus usual care including referral to PR) or the control (usual care including referral to PR). The designed randomisation ratio is 1.25:1 in favour of the intervention. The multiple-primary outcomes are participant depression and anxiety at 6 months, measured using the Hospital Anxiety and Depression Scale (HADS) depression and anxiety subscales. RESULTS: This article describes the statistical analysis plan (SAP) for the TANDEM trial. In particular, we describe the general analysis principles, how we will handle missing data, the primary and secondary outcomes and how these will be analysed, sensitivity analyses for the multiple-primary outcomes, and any other analyses and data summaries. The SAP was developed and published prior to completion of follow-up of the last participant. TRIAL REGISTRATION: ISRCTN registry ISRCTN59537391. Registered on 20 March 2017.

Asunto(s)

Depresión , Enfermedad Pulmonar Obstructiva Crónica , Ansiedad/diagnóstico , Ansiedad/terapia , Análisis Costo-Beneficio , Depresión/diagnóstico , Depresión/terapia , Humanos , Intervención Psicosocial , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/terapia , Calidad de Vida

RESUMEN

Many late-phase clinical trials recruit subjects at multiple study sites. This introduces a hierarchical structure into the data that can result in a power-loss compared to a more homogeneous single-center trial. Building on a recently proposed approach to sample size determination, we suggest a sample size recalculation procedure for multicenter trials with continuous endpoints. The procedure estimates nuisance parameters at interim from noncomparative data and recalculates the sample size required based on these estimates. In contrast to other sample size calculation methods for multicenter trials, our approach assumes a mixed effects model and does not rely on balanced data within centers. It is therefore advantageous, especially for sample size recalculation at interim. We illustrate the proposed methodology by a study evaluating a diabetes management system. Monte Carlo simulations are carried out to evaluate operation characteristics of the sample size recalculation procedure using comparative as well as noncomparative data, assessing their dependence on parameters such as between-center heterogeneity, residual variance of observations, treatment effect size and number of centers. We compare two different estimators for between-center heterogeneity, an unadjusted and a bias-adjusted estimator, both based on quadratic forms. The type 1 error probability as well as statistical power are close to their nominal levels for all parameter combinations considered in our simulation study for the proposed unadjusted estimator, whereas the adjusted estimator exhibits some type 1 error rate inflation. Overall, the sample size recalculation procedure can be recommended to mitigate risks arising from misspecified nuisance parameters at the planning stage.

Asunto(s)

Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Tamaño de la Muestra , Sesgo , Simulación por Computador , Humanos , Método de Montecarlo , Estudios Multicéntricos como Asunto

RESUMEN

When testing for superiority in a parallel-group setting with a continuous outcome, adjusting for covariates is usually recommended. For this purpose, the analysis of covariance is frequently used, and recently several exact and approximate sample size calculation procedures have been proposed. However, in case of multiple covariates, the planning might pose some practical challenges and pitfalls. Therefore, we propose a method, which allows for blinded re-estimation of the sample size during the course of the trial. Simulations confirm that the proposed method provides reliable results in many practically relevant situations, and applicability is illustrated by a real-life data example.

Asunto(s)

Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación/estadística & datos numéricos , Anestesia General , Sedación Consciente , Interpretación Estadística de Datos , Humanos , Modelos Estadísticos , Tamaño de la Muestra , Accidente Cerebrovascular/terapia , Trombectomía , Resultado del Tratamiento

RESUMEN

BACKGROUND: Internal pilots provide useful information which can help to optimise the running of the main trial. Although some recommendations exist in the literature for the design of internal pilots, little is known about current practice in terms of the specification and also the assessment of progression criteria. The aim of the review is to provide an overview of current practice. METHODS: A cohort of clinical trials with an internal pilot, funded by the National Institute for Health Research (NIHR), Health Technology Assessment programme (HTA), extracted in 2017 was reviewed. Data were extracted from: project descriptions; summary of changes from the first stage; feedback about the full application; monitoring notes; progress report history and protocols, for information about the design and assessment of internal pilots. RESULTS: Fifty-seven studies were reviewed. An internal pilot was first proposed in the early stages of the trial in the majority of cases. Target number for recruitment, rate of randomisation, retention/primary outcome ascertainment rate, rate of treatment adherence and consent rate were included as progression criteria. All but one study was permitted to continue to the main trial; however, 25% did not strictly meet the progression criteria. Changes were made to the design of the main trial for 25% of studies, mainly in terms of conduct of recruitment. CONCLUSIONS: This review provides insight into the process of designing and assessing internal pilots. Progression criteria are sometimes not met; however, committees involved in the reviewing process will recommend continuation to the main trial, usually accompanied by a second review or close monitoring. Recommendations are made to optimise the process.

Asunto(s)

Ensayos Clínicos como Asunto/métodos , Proyectos Piloto , Proyectos de Investigación , Evaluación de la Tecnología Biomédica , Humanos , Reino Unido

RESUMEN

BACKGROUND: With millions of pounds spent annually on medical research in the UK, it is important that studies are spending funds wisely. Internal pilots offer the chance to stop a trial early if it becomes apparent that the study will not be able to recruit enough patients to show whether an intervention is clinically effective. This study aims to assess the use of internal pilots in individually randomised controlled trials funded by the Health Technology Assessment (HTA) programme and to summarise the progression criteria chosen in these trials. METHODS: Studies were identified from reports of the HTA committees' funding decisions from 2012 to 2016. In total, 242 trials were identified of which 134 were eligible to be included in the audit. Protocols for the eligible studies were located on the NIHR Journals website, and if protocols were not available online then study managers were contacted to provide information. RESULTS: Over two-thirds (72.4%) of studies said in their protocol that they would include an internal pilot phase for their study and 37.8% of studies without an internal pilot had done an external pilot study to assess the feasibility of the full study. A typical study with an internal pilot has a target sample size of 510 over 24 months and aims to recruit one-fifth of their total target sample size within the first one-third of their recruitment time. There has been an increase in studies adopting a three-tiered structure for their progression rules in recent years, with 61.5% (16/26) of studies using the system in 2016 compared to just 11.8% (2/17) in 2015. There was also a rise in the number of studies giving a target recruitment rate in their progression criteria: 42.3% (11/26) in 2016 compared to 35.3% (6/17) in 2015. CONCLUSIONS: Progression criteria for an internal pilot are usually well specified but targets vary widely. For the actual criteria, red/amber/green systems have increased in popularity in recent years. Trials should justify the targets they have set, especially where targets are low.

Asunto(s)

Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Auditoría Médica , Proyectos Piloto , Evaluación de la Tecnología Biomédica

Asunto(s)

Simulación por Computador/estadística & datos numéricos , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Esclerosis Múltiple/epidemiología , Método Doble Ciego , Humanos , Estudios Multicéntricos como Asunto/métodos , Esclerosis Múltiple/terapia , Tamaño de la Muestra

RESUMEN

The determination of the sample size required by a crossover trial typically depends on the specification of one or more variance components. Uncertainty about the value of these parameters at the design stage means that there is often a risk a trial may be under- or overpowered. For many study designs, this problem has been addressed by considering adaptive design methodology that allows for the re-estimation of the required sample size during a trial. Here, we propose and compare several approaches for this in multitreatment crossover trials. Specifically, regulators favor reestimation procedures to maintain the blinding of the treatment allocations. We therefore develop blinded estimators for the within and between person variances, following simple or block randomization. We demonstrate that, provided an equal number of patients are allocated to sequences that are balanced for period, the proposed estimators following block randomization are unbiased. We further provide a formula for the bias of the estimators following simple randomization. The performance of these procedures, along with that of an unblinded approach, is then examined utilizing three motivating examples, including one based on a recently completed four-treatment four-period crossover trial. Simulation results show that the performance of the proposed blinded procedures is in many cases similar to that of the unblinded approach, and thus they are an attractive alternative.

Asunto(s)

Biometría/métodos , Ensayos Clínicos como Asunto , Estudios Cruzados , Trasplante de Corazón , Humanos , Estimación de Kaplan-Meier , Modelos Estadísticos , Análisis de Regresión , Tamaño de la Muestra , Estadísticas no Paramétricas

RESUMEN

The ability to accurately estimate the sample size required by a stepped-wedge (SW) cluster randomized trial (CRT) routinely depends upon the specification of several nuisance parameters. If these parameters are misspecified, the trial could be overpowered, leading to increased cost, or underpowered, enhancing the likelihood of a false negative. We address this issue here for cross-sectional SW-CRTs, analyzed with a particular linear-mixed model, by proposing methods for blinded and unblinded sample size reestimation (SSRE). First, blinded estimators for the variance parameters of a SW-CRT analyzed using the Hussey and Hughes model are derived. Following this, procedures for blinded and unblinded SSRE after any time period in a SW-CRT are detailed. The performance of these procedures is then examined and contrasted using two example trial design scenarios. We find that if the two key variance parameters were underspecified by 50%, the SSRE procedures were able to increase power over the conventional SW-CRT design by up to 41%, resulting in an empirical power above the desired level. Thus, though there are practical issues to consider, the performance of the procedures means researchers should consider incorporating SSRE in to future SW-CRTs.

Asunto(s)

Biometría/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Cruzados , Estudios Transversales , Humanos , Incertidumbre

RESUMEN

The importance of subgroup analyses has been increasing due to a growing interest in personalized medicine and targeted therapies. Considering designs with multiple nested subgroups and a continuous endpoint, we develop methods for the analysis and sample size determination. First, we consider the joint distribution of standardized test statistics that correspond to each (sub)population. We derive multivariate exact distributions where possible, providing approximations otherwise. Based on these results, we present sample size calculation procedures. Uncertainties about nuisance parameters which are needed for sample size calculations make the study prone to misspecifications. We discuss how a sample size review can be performed in order to make the study more robust. To this end, we implement an internal pilot study design where the variances and prevalences of the subgroups are reestimated in a blinded fashion and the sample size is recalculated accordingly. Simulations show that the procedures presented here do not inflate the type I error significantly and maintain the prespecified power as long as the sample size of the smallest subgroup is not too small. We pay special attention to the case of small sample sizes and attain a lower boundary for the size of the internal pilot study.

Asunto(s)

Ensayos Clínicos como Asunto , Proyectos Piloto , Proyectos de Investigación , Tamaño de la Muestra , Ensayos Clínicos como Asunto/estadística & datos numéricos , Interpretación Estadística de Datos , Humanos , Modelos Estadísticos

RESUMEN

Prior information is often incorporated informally when planning a clinical trial. Here, we present an approach on how to incorporate prior information, such as data from historical clinical trials, into the nuisance parameter-based sample size re-estimation in a design with an internal pilot study. We focus on trials with continuous endpoints in which the outcome variance is the nuisance parameter. For planning and analyzing the trial, frequentist methods are considered. Moreover, the external information on the variance is summarized by the Bayesian meta-analytic-predictive approach. To incorporate external information into the sample size re-estimation, we propose to update the meta-analytic-predictive prior based on the results of the internal pilot study and to re-estimate the sample size using an estimator from the posterior. By means of a simulation study, we compare the operating characteristics such as power and sample size distribution of the proposed procedure with the traditional sample size re-estimation approach that uses the pooled variance estimator. The simulation study shows that, if no prior-data conflict is present, incorporating external information into the sample size re-estimation improves the operating characteristics compared to the traditional approach. In the case of a prior-data conflict, that is, when the variance of the ongoing clinical trial is unequal to the prior location, the performance of the traditional sample size re-estimation procedure is in general superior, even when the prior information is robustified. When considering to include prior information in sample size re-estimation, the potential gains should be balanced against the risks.

Asunto(s)

Ensayos Clínicos como Asunto/estadística & datos numéricos , Interpretación Estadística de Datos , Modelos Estadísticos , Ensayos Clínicos como Asunto/métodos , Depresión/tratamiento farmacológico , Humanos , Hypericum , Proyectos Piloto , Tamaño de la Muestra

RESUMEN

Just over half of publicly funded trials recruit their target sample size within the planned study duration. When recruitment targets are missed, the funder of a trial is faced with the decision of either committing further resources to the study or risk that a worthwhile treatment effect may be missed by an underpowered final analysis. To avoid this challenging situation, when there is insufficient prior evidence to support predicted recruitment rates, funders now require feasibility assessments to be performed in the early stages of trials. Progression criteria are usually specified and agreed with the funder ahead of time. To date, however, the progression rules used are typically ad hoc. In addition, rules routinely permit adaptations to recruitment strategies but do not stipulate criteria for evaluating their effectiveness. In this paper, we develop a framework for planning and designing internal pilot studies which permit a trial to be stopped early if recruitment is disappointing or to continue to full recruitment if enrolment during the feasibility phase is adequate. This framework enables a progression rule to be pre-specified and agreed upon prior to starting a trial. The novel two-stage designs stipulate that if neither of these situations arises, adaptations to recruitment should be made and subsequently evaluated to establish whether they have been successful. We derive optimal progression rules for internal pilot studies which minimise the expected trial overrun and maintain a high probability of completing the study when the recruitment rate is adequate. The advantages of this procedure are illustrated using a real trial example.

Asunto(s)

Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación , Tamaño de la Muestra , Ciática/tratamiento farmacológico , Esteroides/administración & dosificación , Evaluación de la Discapacidad , Humanos , Inyecciones Epidurales , Estudios Multicéntricos como Asunto , Proyectos Piloto

RESUMEN

Blinded sample size reassessment is a popular means to control the power in clinical trials if no reliable information on nuisance parameters is available in the planning phase. We investigate how sample size reassessment based on blinded interim data affects the properties of point estimates and confidence intervals for parallel group superiority trials comparing the means of a normal endpoint. We evaluate the properties of two standard reassessment rules that are based on the sample size formula of the z-test, derive the worst case reassessment rule that maximizes the absolute mean bias and obtain an upper bound for the mean bias of the treatment effect estimate.

Asunto(s)

Tamaño de la Muestra , Algoritmos , Sesgo , Ensayos Clínicos como Asunto/estadística & datos numéricos , Modelos Estadísticos , Proyectos Piloto , Proyectos de Investigación

RESUMEN

In this article, we study blinded sample size re-estimation in the 'gold standard' design with internal pilot study for normally distributed outcomes. The 'gold standard' design is a three-arm clinical trial design that includes an active and a placebo control in addition to an experimental treatment. We focus on the absolute margin approach to hypothesis testing in three-arm trials at which the non-inferiority of the experimental treatment and the assay sensitivity are assessed by pairwise comparisons. We compare several blinded sample size re-estimation procedures in a simulation study assessing operating characteristics including power and type I error. We find that sample size re-estimation based on the popular one-sample variance estimator results in overpowered trials. Moreover, sample size re-estimation based on unbiased variance estimators such as the Xing-Ganju variance estimator results in underpowered trials, as it is expected because an overestimation of the variance and thus the sample size is in general required for the re-estimation procedure to eventually meet the target power. To overcome this problem, we propose an inflation factor for the sample size re-estimation with the Xing-Ganju variance estimator and show that this approach results in adequately powered trials. Because of favorable features of the Xing-Ganju variance estimator such as unbiasedness and a distribution independent of the group means, the inflation factor does not depend on the nuisance parameter and, therefore, can be calculated prior to a trial. Moreover, we prove that the sample size re-estimation based on the Xing-Ganju variance estimator does not bias the effect estimate. Copyright © 2017 John Wiley & Sons, Ltd.

Asunto(s)

Ensayos Clínicos como Asunto/métodos , Modelos Estadísticos , Tamaño de la Muestra , Simulación por Computador , Humanos , Método de Montecarlo , Proyectos Piloto , Placebos , Reproducibilidad de los Resultados , Proyectos de Investigación

RESUMEN

BACKGROUND: Endometriosis is associated with the growth of endometrium in ectopic sites mainly within the pelvis. This results in inflammation and scarring, causing pain and impaired quality of life. Endometriotic lesions can be excised or ablated surgically, but the risk of recurrence is high. A Heath Technology Assessment commissioning call in 2011 sought applications for trials aimed at evaluating long-term effectiveness of postoperative, long-acting, reversible contraceptives (LARCs) in preventing recurrence of endometriosis. A survey of gynaecologists indicated that there was no consensus about which LARC (Levonorgestrel Intrauterine System (LNG-IUS) or depot medroxyprogesterone acetate injection (DMPA)) or comparator (combined oral contraceptive pill (COCP) or no treatment) should be evaluated. Hence, we designed a 'flexible-entry' internal pilot to assess whether a four-arm trial was feasible including a possible design adaption based on pilot findings. METHODS: In this pilot, women could be randomised to two, three or four treatment options provided that one was a LARC and one was a non-LARC. An assessment of feasibility based on recruitment to these options and a revised substantive trial design was considered by an independent oversight committee. RESULTS: The study ran for 1 year from April 2014 and 77 women were randomised. Only 5 (6%) women accepted randomisation to all groups, with 63 (82%) having a LARC preference and 55 (71%) a non-LARC preference. Four-way and three-way designs were ruled out with a two-way LARC versus COCP design, stratified by prerandomisation choice of LARC and optional subrandomisation to LNG-IUS versus DMPA considered a feasible substantive study. CONCLUSIONS: Multi-arm studies are potentially efficient as they can answer multiple questions simultaneously but are difficult to recruit to if there are strong patient or clinician preferences. A flexible approach to randomisation in a pilot phase can be used to assess feasibility of such studies and modify a trial design based on chosen recruitment options, but trialists should consider carefully any practical arrangements should groups need to be dropped during a study. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number, ISRCTN97865475 . Registered on 20 March 2014.

Asunto(s)

Anticonceptivos Hormonales Orales/administración & dosificación , Endometriosis/tratamiento farmacológico , Levonorgestrel/administración & dosificación , Acetato de Medroxiprogesterona/administración & dosificación , Progestinas/administración & dosificación , Prevención Secundaria/métodos , Adolescente , Adulto , Protocolos Clínicos , Anticonceptivos Hormonales Orales/efectos adversos , Preparaciones de Acción Retardada , Endometriosis/diagnóstico , Endometriosis/cirugía , Estudios de Factibilidad , Femenino , Humanos , Inyecciones , Dispositivos Intrauterinos , Laparoscopía , Levonorgestrel/efectos adversos , Acetato de Medroxiprogesterona/efectos adversos , Persona de Mediana Edad , Selección de Paciente , Proyectos Piloto , Progestinas/efectos adversos , Recurrencia , Proyectos de Investigación , Factores de Tiempo , Resultado del Tratamiento , Reino Unido , Adulto Joven

RESUMEN

We consider clinical trials with a binary composite endpoint where the trial is successful when a significant result is achieved for the composite or one prespecified main component. Appropriate sample size planning is challenging in this situation, as in addition to the Type I error rate, power, and target difference the overall event rates and the correlation between the test statistics have to be defined. Reliable estimates of these quantities, however, are usually hard to obtain and therefore there is a high risk to not achieve the intended power in a fixed sample size design. In this article, we propose an internal pilot study design where the nuisance parameters are estimated in a blinded way at an interim stage and where the sample size is then revised accordingly. We investigate the characteristics of the proposed design with respect to the actual Type I error rate, power, and sample size. The application of this design is illustrated by a clinical trial example.

Asunto(s)

Ensayos Clínicos como Asunto , Proyectos de Investigación , Tamaño de la Muestra , Humanos , Proyectos Piloto