Sample-targeted clinical trial adaptation

Clinical trial adaptation refers to any adjustment of the trial protocol after the onset of the trial. The main goal is to make the process of introducing new medical interventions to patients more efficient by reducing the cost and the time associated with evaluating their safety and efficacy. The principal question is how should adaptation be performed so as to minimize the chance of distorting the outcome of the trial. We propose a novel method for achieving this. Unlike previous work our approach focuses on trial adaptation by sample size adjustment. We adopt a recently proposed stratification framework based on collected auxiliary data and show that this information together with the primary measured variables can be used to make a probabilistically informed choice of the particular sub-group a sample should be removed from. Experiments on simulated data are used to illustrate the effectiveness of our method and its application in practice.Comment: AAAI Conference on Artificial Intelligence, 201

Integrating Phase 2 into Phase 3 based on an Intermediate Endpoint While Accounting for a Cure Proportion -- with an Application to the Design of a Clinical Trial in Acute Myeloid Leukemia

For a trial with primary endpoint overall survival for a molecule with curative potential, statistical methods that rely on the proportional hazards assumption may underestimate the power and the time to final analysis. We show how a cure proportion model can be used to get the necessary number of events and appropriate timing via simulation. If Phase 1 results for the new drug are exceptional and/or the medical need in the target population is high, a Phase 3 trial might be initiated after Phase 1. Building in a futility interim analysis into such a pivotal trial may mitigate the uncertainty of moving directly to Phase 3. However, if cure is possible, overall survival might not be mature enough at the interim to support a futility decision. We propose to base this decision on an intermediate endpoint that is sufficiently associated with survival. Planning for such an interim can be interpreted as making a randomized Phase 2 trial a part of the pivotal trial: if stopped at the interim, the trial data would be analyzed and a decision on a subsequent Phase 3 trial would be made. If the trial continues at the interim then the Phase 3 trial is already underway. To select a futility boundary, a mechanistic simulation model that connects the intermediate endpoint and survival is proposed. We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia, discuss historical data that informed the simulation model, and operational challenges when implementing it.Comment: 23 pages, 3 figures, 3 tables. All code is available on github: https://github.com/numbersman77/integratePhase2.gi

Adaptation of an evidence-based cardiovascular health intervention for rural African Americans in the Southeast

Background: African Americans (AA) living in the southeast United States have the highest prevalence of cardiovascular diseases (CVD) and rural minorities bear a significant burden of co-occurring CVD risk factors. Few evidence-based interventions (EBI) address social and physical environmental barriers in rural minority communities. We used intervention mapping together with community-based participatory research (CBPR) principles to adapt objectives of a multi-component CVD lifestyle EBI to fit the needs of a rural AA community. We sought to describe the process of using CPBR to adapt an EBI using intervention mapping to an AA rural setting and to identify and document the adaptations mapped onto the EBI and how they enhance the intervention to meet community needs. Methods: Focus groups, dyadic interviews, and organizational web-based surveys were used to assess content interest, retention strategies, and incorporation of auxiliary components to the EBI. Using CBPR principles, community and academic stakeholders met weekly to collaboratively integrate formative research findings into the intervention mapping process. We used a framework developed by Wilstey Stirman et al. to document changes. Results: Key changes were made to the content, context, and training and evaluation components of the existing EBI. A matrix including behavioral objectives from the original EBI and new objectives was developed. Categories of objectives included physical activity, nutrition, alcohol, and tobacco divided into three levels, namely, individual, interpersonal, and environmental. Conclusions: Intervention mapping integrated with principles of CBPR is an efficient and flexible process for adapting a comprehensive and culturally appropriate lifestyle EBI for a rural AA community context

A systematic review of recommended modifications of CBT for people with cognitive impairments following brain injury

Due to diverse cognitive, emotional and interpersonal changes that can follow brain injury, psychological therapies often need to be adapted to suit the complex needs of this population. The aims of the study were to synthesise published recommendations for therapy modifications following brain injury from non-progressive traumatic, vascular, or metabolic causes and to determine how often such modifications have been applied to cognitive behavioural therapy (CBT) for post-injury emotional adjustment problems. A systematic review and narrative synthesis of therapy modifications recommended in review articles and reported in intervention studies was undertaken. Database and manual searches identified 688 unique papers of which eight review articles and 16 intervention studies met inclusion criteria. The review articles were thematically analysed and a checklist of commonly recommended modifications composed. The checklist items clustered under themes of: therapeutic education and formulation; attention; communication; memory; and executive functioning. When this checklist was applied to the intervention studies, memory aids and an emphasis on socialising patients to the CBT model were most frequently reported as adaptations. It was concluded that the inconsistent reporting of psychological therapy adaptations for people with brain injury is a barrier to developing effective and replicable therapies. We present a comprehensive account of potential modifications that should be used to guide future research and practice

Inhaled nitric oxide as an adjunct to neonatal resuscitation in premature infants: a pilot, double blind, randomized controlled trial.

BackgroundNitric oxide (NO) plays an important role in normal postnatal transition. Our aims were to determine whether adding inhaled NO (iNO) decreases supplemental oxygen exposure in preterm infants requiring positive pressure ventilation (PPV) during resuscitation and to study iNO effects on heart rate (HR), oxygen saturation (SpO2), and need for intubation during the first 20 min of life.MethodsThis was a pilot, double-blind, randomized, placebo-controlled trial. Infants 25 0/7-31 6/7 weeks' gestational age requiring PPV with supplemental oxygen during resuscitation were enrolled. PPV was initiated with either oxygen (FiO2-0.30) + iNO at 20 ppm (iNO group) or oxygen (FiO2-0.30) + nitrogen (placebo group). Oxygen was titrated targeting defined SpO2 per current guidelines. After 10 min, iNO/nitrogen was weaned stepwise per protocol and terminated at 17 min.ResultsTwenty-eight infants were studied (14 per group). The mean gestational age in both groups was similar. Cumulative FiO2 and rate of exposure to high FiO2 (>0.60) were significantly lower in the iNO group. There were no differences in HR, SpO2, and need for intubation.ConclusionsAdministration of iNO as an adjunct during neonatal resuscitation is feasible without side effects. It diminishes exposure to high levels of supplemental oxygen

Attention control comparisons with SLT for people with aphasia following stroke: methodological concerns raised following a systematic review

Objective: Attention control comparisons in trials of stroke rehabilitation require care to minimize the risk of comparison choice bias. We compared the similarities and differences in SLT and social support control interventions for people with aphasia. Data sources: Trial data from the 2016 Cochrane systematic review of SLT for aphasia after stroke. Methods: Direct and indirect comparisons between SLT, social support and no therapy controls. We double-data extracted intervention details using the template for intervention description and replication. Standardized mean differences and risk ratios (95% confidence intervals (CIs)) were calculated. Results: Seven trials compared SLT with social support (n  =  447). Interventions were matched in format, frequency, intensity, duration and dose. Procedures and materials were often shared across interventions. Social support providers received specialist training and support. Targeted language rehabilitation was only described in therapy interventions. Higher drop-out (P  =  0.005, odds ratio (OR) 0.51, 95% CI 0.32–0.81) and non-adherence to social support interventions (P  <  0.00001, OR 0.18, 95% CI 0.09–0.37) indicated an imbalance in completion rates increasing the risk of control comparison bias. Conclusion: Distinctions between social support and therapy interventions were eroded. Theoretically based language rehabilitation was the remaining difference in therapy interventions. Social support is an important adjunct to formal language rehabilitation. Therapists should continue to enable those close to the person with aphasia to provide tailored communication support, functional language stimulation and opportunities to apply rehabilitation gains. Systematic group differences in completion rates is a design-related risk of bias in outcomes observed

A systematic review of school-based alcohol and other drug prevention programs

Background: Alcohol use in adolescents constitutes a major public health concern. Europe is the heaviest drinking region of the world. Several school-based alcohol prevention programs have been developed but it is not clear whether they are really effective. The present study was aimed at identifying the typology with the best evidence of effectiveness in European studies. Methods: A systematic search of meta-analyses and/or randomized controlled trials (RCTs) on interventions school-based prevention programs aimed at preventing alcohol consumption or changing the attitudes to consume alcohol. Results: A meta-analysis published in 2011 and 12 RCTs more recently published were identified. The meta-analysis evaluated 53 RCTs but only 11.3% of them were conducted in Europe. Globally, 23 RCTs (43.4%) showed some evidence of effectiveness, and 30 RCTs (56.6%) did not find significant difference between the groups. According to the conclusions of the meta-analysis, the Unplugged program should be considered as a practice option in Europe. Among the other 12 RCTs, 42% were conducted in Europe. Globally, 7 studies (58.3%) achieved positive results, and 5 studies (41.7%) did not find significant differences or produced a mixed pattern of results. Three of the 5 European trials (60%) used the Unplugged program with positive results. Conclusion: Even if further studies should be conducted to confirm these results, Unplugged appears to be the prevention project with the best evidence of effectiveness in European studies

The Herts and Minds study: feasibility of a randomised controlled trial of Mentalizationbased Treatment versus usual care to support the wellbeing of children in foster care

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background: There is a lack of well-designed randomized controlled trials (RCTs) to investigate the efficacy of psychological therapies for children in foster care with emotional and behavioural difficulties. Mentalization-based therapy (MBT) focuses on supporting the carer-child relationship by promoting reflective capacity. This study examined the feasibility and acceptability of an RCT of MBT, delivered in a family-format, for children who are in foster care in the UK. Method: Herts and Minds was a phase II, blinded feasibility RCT with follow-up of at 12 and 24 weeks post-randomisation. Participants were children (age 5-16) in foster care referred to a targeted mental health service, who had some level of difficulty as identified by the Strengths and Difficulties Questionnaire (SDQ). Aims were to assess: the feasibility of recruitment processes and study uptake; capacity to train mental health practitioners to deliver MBT to an acceptable level of treatment integrity; establish acceptability and credibility of MBT as an intervention for children in foster care; establish feasibility and acceptability to participants of conducting an RCT; and estimate the likely treatment efficacy effect size. Participants were randomly allocated to either MBT (n = 15) or Usual Clinical Care (UCC) (n = 21) individually or in sibling groups. A range of qualitative and quantitative data was gathered to assess feasibility. Results: Feasibility was established with regard to: capacity to recruit participants to a study; capacity to train mental health practitioners to deliver MBT to an acceptable level of treatment integrity; acceptability and credibility of MBT; and feasibility and acceptability to participants of conducting an RCT. A number of issues made it difficult to estimate a likely treatment efficacy effect size. Conclusion: With modifications, it is feasible to run an RCT of MBT for children in foster care. Both the therapy and research design were acceptable to participants, but modifications may be needed regarding both the timing of assessments and the identification of appropriate primary outcome measures. Given the lack of evidenced based therapies for this population, such a trial would be a significant contribution to the field. Findings may be useful for other groups planning clinical trials of psychological therapies for children in foster care. Trial registration: ISRCTN 90349442. The trial was retrospectively registered on 6 May 2016.Peer reviewedFinal Published versio