Active Control Intervention Research Articles

White Matter Integrity Declined Over 6-Months, but Dance Intervention Improved Integrity of the Fornix of Older Adults

Degeneration of cerebral white matter (WM), or structural disconnection, is one of the major neural mechanisms driving age-related decline in cognitive functions, such as processing speed. Past cross-sectional studies have demonstrated beneficial effects of greater cardiorespiratory fitness, physical activity, cognitive training, social engagement, and nutrition on cognitive functioning and brain health in aging. Here, we collected diffusion magnetic resonance (MRI) imaging data from 174 older (age 60–79) adults to study the effects of 6-months lifestyle interventions on WM integrity. Healthy but low-active participants were randomized into Dance, Walking, Walking + Nutrition, and Active Control (stretching and toning) intervention groups (NCT01472744 on ClinicalTrials.gov). Only in the fornix there was a time × intervention group interaction of change in WM integrity: integrity declined over 6 months in all groups but increased in the Dance group. Integrity in the fornix at baseline was associated with better processing speed, however, change in fornix integrity did not correlate with change in processing speed. Next, we observed a decline in WM integrity across the majority of brain regions in all participants, regardless of the intervention group. This suggests that the aging of the brain is detectable on the scale of 6-months, which highlights the urgency of finding effective interventions to slow down this process. Magnitude of WM decline increased with age and decline in prefrontal WM was of lesser magnitude in older adults spending less time sedentary and more engaging in moderate-to-vigorous physical activity. In addition, our findings support the anterior-to-posterior gradient of greater-to-lesser decline, but only in the in the corpus callosum. Together, our findings suggest that combining physical, cognitive, and social engagement (dance) may help maintain or improve WM health and more physically active lifestyle is associated with slower WM decline. This study emphasizes the importance of a physically active and socially engaging lifestyle among aging adults.

The effectiveness of Robot-Assisted Gait Training versus conventional therapy on mobility in severely disabled progressIve MultiplE sclerosis patients (RAGTIME): study protocol for a randomized controlled trial

BackgroundGait and mobility impairments affect the quality of life (QoL) of patients with progressive multiple sclerosis (MS). Robot-assisted gait training (RAGT) is an effective rehabilitative treatment but evidence of its superiority compared to other options is lacking. Furthermore, the response to rehabilitation is multidimensional, person-specific and possibly involves functional reorganization processes. The aims of this study are: (1) to test the effectiveness on gait speed, mobility, balance, fatigue and QoL of RAGT compared to conventional therapy (CT) in progressive MS and (2) to explore changes of clinical and circulating biomarkers of neural plasticity.MethodsThis will be a parallel-group, randomized controlled trial design with the assessor blinded to the group allocation of participants. Ninety-eight (49 per arm) progressive MS patients (EDSS scale 6–7) will be randomly assigned to receive twelve 2-h training sessions over a 4-week period (three sessions/week) of either: (1) RAGT intervention on a robotic-driven gait orthosis (Lokomat, Hocoma, Switzerland). The training parameters (torque of the knee and hip drives, treadmill speed, body weight support) are set during the first session and progressively adjusted during training progression or (2) individual conventional physiotherapy focusing on over-ground walking training performed with the habitual walking device. The same assessors will perform outcome measurements at four time points: baseline (before the first intervention session); intermediate (after six training sessions); end of treatment (after the completion of 12 sessions); and follow-up (after 3 months from the end of the training program). The primary outcome is gait speed, assessed by the Timed 25-Foot Walk Test. We will also assess walking endurance, balance, depression, fatigue and QoL as well as instrumental laboratory markers (muscle metabolism, cerebral venous hemodynamics, cortical activation) and circulating laboratory markers (rare circulating cell populations pro and anti-inflammatory cytokines/chemokines, growth factors, neurotrophic factors, coagulation factors, other plasma proteins suggested by transcriptomic analysis and metabolic parameters).DiscussionThe RAGT training is expected to improve mobility compared to the active control intervention in progressive MS. Unique to this study is the analysis of various potential markers of plasticity in relation with clinical outcomes.Trial registrationClinicalTrials.gov, identifier: NCT02421731. Registered on 19 January 2015 (retrospectively registered).

Acupuncture for the Treatment of Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

Neuropathy and its associated pain pose great therapeutic challenges. While there has been a recent surge in acupuncture use and research, little remains known about its effects on nerve function. This review aims to assess the efficacy of acupuncture in the treatment of neuropathy of various etiologies. The Medline, AMED, Cochrane, Scopus, CINAHL, and clintrials.gov databases were systematically searched from inception to July 2015. Randomized controlled trials (RCTs) assessing acupuncture's efficacy for poly- and mononeuropathy were reviewed. Parallel and crossover RCTs focused on acupuncture's efficacy were reviewed and screened for eligibility. The Scale for Assessing Scientific Quality of Investigations in Complementary and Alternative Medicine was used to assess RCT quality. RCTs with score of >9 and active control treatments such as sham acupuncture or medical therapy were included. Fifteen studies were included: 13 original RCTs, a long-term follow-up, and a re-analysis of a prior RCT. The selected RCTs studied acupuncture for neuropathy caused by diabetes, Bell's palsy, carpal tunnel syndrome, human immunodeficiency virus (HIV), and idiopathic conditions. Acupuncture regimens, control conditions, and outcome measures differed among studies, and various methodological issues were identified. Still, the majority of RCTs showed benefit for acupuncture over control in the treatment of diabetic neuropathy, Bell's palsy, and carpal tunnel syndrome. Acupuncture is probably effective in the treatment of HIV-related neuropathy, and there is insufficient evidence for its benefits in idiopathic neuropathy. Acupuncture appears to improve nerve conduction study parameters in both sensory and motor nerves. Meta-analyses were conducted on all diabetic neuropathy and Bell's palsy individual subject data (six RCTs; a total of 680 subjects) using a summary estimate random effects model, which showed combined odds ratio of 4.23 (95% confidence interval 2.3-7.8; p < 0.001) favoring acupuncture over control for neuropathic symptoms. Acupuncture is beneficial in some peripheral neuropathies, but more rigorously designed studies using sham-acupuncture control are needed to characterize its effect and optimal use better.

Disruptive behaviour may hinder the acquisition of daily living skills for youth with autism spectrum disorder

ABSTRACT FROM: Scahill L, Bearss K, Lecavalier L, et al. Effect of parent training on adaptive behavior in children with autism spectrum disorder and disruptive behavior: results of a randomized...

Adaptive working memory strategy training in early Alzheimer's disease: randomised controlled trial.

BackgroundInterventions that improve cognitive function in Alzheimer's disease are urgently required.AimsTo assess whether a novel cognitive training paradigm based on ‘chunking’ improves working memory and general cognitive function, and is associated with reorganisation of functional activity in prefrontal and parietal cortices (trial registration: ISRCTN43007027).MethodThirty patients with mild Alzheimer's disease were randomly allocated to receive 18 sessions of 30 min of either adaptive chunking training or an active control intervention over approximately 8 weeks. Pre- and post-intervention functional magnetic resonance imaging (fMRI) scans were also conducted.ResultsAdaptive chunking training led to significant improvements in verbal working memory and untrained clinical measures of general cognitive function. Further, fMRI revealed a bilateral reduction in task-related lateral prefrontal and parietal cortex activation in the training group compared with controls.ConclusionsChunking-based cognitive training is a simple and potentially scalable intervention to improve cognitive function in early Alzheimer's disease.

Mindfulness‐based stress reduction (MBSR) for improving health, quality of life and social functioning in adults: a systematic review and meta‐analysis

This review summarizes all studies that compare the effect of a MBSR program to a control group intervention, in which the participants had been randomly allocated to be in either the MBSR group or a control group. The review summarizes the results in two categories. First, where the effect of the MBSR program was compared to an inactive group (either a wait list group or one receiving ordinary care also received by the MBSR group). Second, where MBSR was compared with an alternative active group intervention. Based on this review it is reasonable to consider MBSR a moderately well-documented method for helping adults improve their health and cope better with the challenges and stress that life brings. New research should improve the way the trials are conducted addressing the pitfalls in research on mind-body interventions.

Impact of a Mindfulness-Based Weight-Loss Intervention on Sleep Quality Among Adults with Obesity: Data from the SHINE Randomized Controlled Trial.

Sleep disturbance is a common problem among adults with obesity. Mindfulness interventions have been shown to improve sleep quality in various populations but have not been investigated in adults with obesity. The aim of this study was to compare the effects of a mindfulness-based weight-loss intervention with an active control on self-reported sleep quality among adults with obesity. This study was a secondary analysis of a randomized controlled trial and included 194 adults with a body mass index in the range 30-45 kg/m2. The treatment intervention included mindfulness-based eating and stress-management practices, and the active control intervention included training in progressive muscle relaxation (PMR). Both groups received identical diet and exercise guidelines in 17 group sessions conducted over 5.5 months that were matched for time, attention, and social support. The primary outcome of this analysis was between-group change in self-reported sleep quality, which was assessed using the Pittsburgh Sleep Quality Index (PSQI) global score at baseline and at 6, 12, and 18 months. Between-group differences in mean PSQI change scores in the mindfulness group (n = 100) compared to the control group (n = 94) were -0.27 (-0.68, 1.22; p = 0.58) at 6 months, -0.57 (-0.35, 1.50; p = 0.22) at 12 months, and -0.50 (-0.53, 1.53; p = 0.34) at 18 months, all in the direction of more sleep improvement in the mindfulness group but none reaching statistical significance. In the mindfulness group, average weekly minutes of meditation practice time was associated with improved sleep quality from baseline to 6 months. No statistically significant evidence was found that a weight-loss program that incorporates mindfulness improves self-reported sleep quality compared to a control diet/exercise intervention that included PMR. Within the mindfulness group, average weekly minutes of mindfulness practice was associated with improved sleep quality.

Cognitive–behavioral versus non-directive therapy for preschoolers with severe nighttime fears and sleep-related problems

ObjectiveTo compare the efficacy of a developmentally appropriate cognitive–behavioral therapy protocol for preschoolers with severe nighttime fears and sleep-related problems, with an active control treatment. MethodsNinety children aged four to six years (63% boys) with severe nighttime fears and their parents were randomized to either cognitive–behavioral therapy including parent involved play (CBT-PIP) or to a structurally equivalent non-directive treatment (TEPT; triadic expressive play therapy). Treatment conditions were also equivalent in parent- and child-rated credibility and expectancy, and in therapist-rated compliance. Children and parents were assessed at baseline, during the first intervention week and four weeks after treatment. Measures included actigraphy, daily sleep logs, structured diagnostic interviews and parent questionnaires. ResultsSignificant reductions were observed in nighttime fears and objectively and subjectively measured sleep disruptions in both intervention groups following treatment. Parent reports indicated more advantageous outcomes for CBT-PIP compared to TEPT, with greater reductions in sleep problems and co-sleeping as well as higher customer satisfaction in the former group. ConclusionsWhile CBT-PIP showed no significant advantage compared to the active control in reducing fears or in improving objectively measured sleep, it was significantly more beneficial in reducing the adverse behavioral features of nighttime fears.

Meditation awareness training for the treatment of fibromyalgia syndrome: A randomized controlled trial.

The purpose of this study was to conduct the first randomized controlled trial (RCT) to evaluate the effectiveness of a second-generation mindfulness-based intervention (SG-MBI) for treating fibromyalgia syndrome (FMS). Compared to first-generation mindfulness-based interventions, SG-MBIs are more acknowledging of the spiritual aspect of mindfulness. A RCT employing intent-to-treat analysis. Adults with FMS received an 8-week SG-MBI known as meditation awareness training (MAT; n=74) or an active control intervention known as cognitive behaviour theory for groups (n=74). Assessments were performed at pre-, post-, and 6-month follow-up phases. Meditation awareness training participants demonstrated significant and sustained improvements over control group participants in FMS symptomatology, pain perception, sleep quality, psychological distress, non-attachment (to self, symptoms, and environment), and civic engagement. A mediation analysis found that (1) civic engagement partially mediated treatment effects for all outcome variables, (2) non-attachment partially mediated treatment effects for psychological distress and sleep quality, and (3) non-attachment almost fully mediated treatment effects for FMS symptomatology and pain perception. Average daily time spent in meditation was found to be a significant predictor of changes in all outcome variables. Meditation awareness training may be a suitable treatment for adults with FMS and appears to ameliorate FMS symptomatology and pain perception by reducing attachment to self. Statement of contribution What is already known on this subject? Designing interventions to treat fibromyalgia syndrome (FMS) continues to be a challenge. There is growing interest into the applications of mindfulness-based interventions for treating FMS. Second-generation mindfulness-based interventions (SG-MBIs) are a key new direction in mindfulness research. What does this study add? Meditation awareness training - an SG-MBI - resulted in significant reductions in FMS symptomatology. SG-MBIs recognize the spiritual aspect of mindfulness and may have a role in the treatment of FMS.

Vedolizumab Efficacy Exposure-Response Relationship for Ulcerative Colitis Patients (GEMINI I) Based on Causal Inference Analysis

Introduction: Vedolizumab (VDZ) is efficacious for the treatment of moderate-severe active ulcerative colitis (UC). It is hypothesized that individuals with high drug clearance may be less likely to achieve positive efficacy outcomes. The aim of this analysis was to evaluate if higher induction exposures of VDZ are associated with improved efficacy outcomes in UC. Methods: Data from a Phase 3 VDZ clinical trial (GEMINI I) included week 6 outcomes, Partial Mayo Score (PMS), Clinical Response (CR), and Clinical Remission (RM), individual-specific covariates, and individual-predicted plasma VDZ concentrations and clearances based on a prior population pharmacokinetic (PK) analysis. The limited dose-ranging information in this study yielded the potential for confounded causal inference about the exposure-response (E-R) relationship, and therefore, a propensity score based case-matching analysis was conducted. A logistic propensity score model was fit to the collection of treated subjects and all controls using all measured covariates as predictors. Matches between active treatment subjects and controls were based on a propensity score caliper of 0.2 times the standard deviation. Quartiles of clearances and predicted Week 6 and steady-state trough VDZ concentrations were compared with outcomes for both unmatched and case-matched data. Results: E-R relationships for all exposure metrics and each outcome were evident in the quartile analysis of the raw data, although relationships were more robust for Week 6 PMS and CR endpoints than for RM. After case-matching adjustment for potential confounding, a clear E-R relationship was still evident for the PMS and CR endpoints. VDZ clearance >0.14 L/day was associated with diminished efficacy outcomes (PMS decrease 37.1 mcg/mL, Week 14 trough, >18.4 mcg/mL, steady state trough >12.7 mcg/mL. Conclusion: The estimated E-R relationships will inform the design of future studies evaluating the impact of dose individualization on clinical outcomes in UC patients with high clearance.

A Systematic Review and Meta-Analysis of Randomized and Nonrandomized Trials of Clinical Emotional Freedom Techniques (EFT) for the Treatment of Depression

Among a group of therapies collectively known as energy psychology (EP), emotional freedom techniques (EFT) is the most widely practiced. Clinical EFT is an evidence-based practice combining elements of cognitive and exposure therapies with the manual stimulation of acupuncture points (acupoints). Lacking is a recent quantitative meta-analysis that enhances understanding of the variability and clinical significance of outcomes after clinical EFT treatment in reducing depression. All studies (2005-2015) evaluating EFT for sufferers of depression were identified by electronic search; these included both outcome studies and randomized controlled trials (RCTs). Our focus was depressive symptoms as measured by a variety of psychometric questionnaires and scales. We used meta-analysis to calculate effect sizes at three time points including posttest, follow-ups less than 90 days, and follow-ups more than 90 days. In total, 20 studies were qualified for inclusion, 12 RCTs and 8 outcome studies. The number of participants treated with EFT included N = 461 in outcome studies and N = 398 in RCTs. Clinical EFT showed a large effect size in the treatment of depression in RCTs. At posttest, Cohen׳s d for RCTs was 1.85 and for outcome studies was 0.70. Effect sizes for follow-ups less than 90 days were 1.21, and for ≥ 90 days were 1.11. EFT were more efficacious than diaphragmatic breathing (DB) and supportive interview (SI) in posttest measurements (P = .06 versus DB, P < .001 versus SI), and sleep hygiene education (SHE) at follow-up (P = .036). No significant treatment effect difference between EFT and eye movement desensitization and reprocessing (EMDR) was found. EFT were superior to treatment as usual (TAU), and efficacious in treatment time frames ranging from 1 to 10 sessions. The mean of symptom reductions across all studies was -41%. The results show that Clinical EFT were highly effective in reducing depressive symptoms in a variety of populations and settings. EFT were equal or superior to TAU and other active treatment controls. The posttest effect size for EFT (d = 1.31) was larger than that measured in meta-analyses of antidepressant drug trials and psychotherapy studies. EFT produced large treatment effects whether delivered in group or individual format, and participants maintained their gains over time. This meta-analysis extends the existing literature through facilitation of a better understanding of the variability and clinical significance of depression improvement subsequent to EFT treatment.

Feasibility and Outcomes of an Internet-Based Mindfulness Training Program: A Pilot Randomized Controlled Trial.

BackgroundInterventions based on meditation and mindfulness techniques have been shown to reduce stress and increase psychological well-being in a wide variety of populations. Self-administrated Internet-based mindfulness training programs have the potential to be a convenient, cost-effective, easily disseminated, and accessible alternative to group-based programs.ObjectiveThis randomized controlled pilot trial with 90 university students in Stockholm, Sweden, explored the feasibility, usability, acceptability, and outcomes of an 8-week Internet-based mindfulness training program.MethodsParticipants were randomly assigned to either an intervention (n=46) or an active control condition (n=44). Intervention participants were invited to an Internet-based 8-week mindfulness program, and control participants were invited to an Internet-based 4-week expressive writing program. The programs were automated apart from weekly reminders via email. Main outcomes in pre- and postassessments were psychological well-being and depression symptoms. To assess the participant’s experiences, those completing the full programs were asked to fill out an assessment questionnaire and 8 of the participants were interviewed using a semistructured interview guide. Descriptive and inferential statistics, as well as content analysis, were performed.ResultsIn the mindfulness program, 28 out of 46 students (60%) completed the first week and 18 out of 46 (39%) completed the full program. In the expressive writing program, 35 out of 44 students (80%) completed the first week and 31 out of 44 (70%) completed the full program. There was no statistically significantly stronger intervention effect for the mindfulness intervention compared to the active control intervention. Those completing the mindfulness group reported high satisfaction with the program. Most of those interviewed were satisfied with the layout and technique and with the support provided by the study coordinators. More frequent contact with study coordinators was suggested as a way to improve program adherence and completion. Most participants considered the program to be meaningful and helpful but also challenging. The flexibility in performing the exercises at a suitable time and place was appreciated. A major difficulty was, however, finding enough time to practice.ConclusionsThe program was usable, acceptable, and showed potential for increasing psychological well-being for those completing it. However, additional modification of the program might be needed to increase retention and compliance.ClinicalTrialClinicalTrials.gov NCT02062762; https://clinicaltrials.gov/ct2/show/NCT0206276 (Archived by WebCite at http://www.webcitation.org/6j9I5SGJ4)

Three-Year Follow-Up of Insomnia and Hypnotics after Controlled Internet Treatment for Insomnia.

To investigate the long-term effects of therapist-guided Internet-based insomnia treatment on insomnia severity and sleep medication use, compared with active control. This study was an 8 week randomized controlled trial with follow-up posttreatment and at 6, 12, and 36 months, set at the Internet Psychiatry Clinic, Stockholm, Sweden. Participants were 148 media-recruited nondepressed adults with insomnia. Interventions were Guided Internet-based cognitive behavioral therapy for insomnia (ICBT-i) or active control treatment (ICBT-ctrl). Primary outcome was insomnia severity, measured with the Insomnia Severity Index. Secondary outcomes were sleep medication use and use of other treatments. The large pretreatment to posttreatment improvements in insomnia severity of the ICBT-i group were maintained during follow-up. ICBT-ctrl exhibited significantly less improvement posttreatment (between-Cohen d = 0.85), but after 12 and 36 months, there was no longer a significant difference. The within-group effect sizes from pretreatment to the 36-months follow-up were 1.6 (ICBT-i) and 1.7 (ICBT-ctrl), and 74% of the interviewed participants no longer had insomnia diagnosis after 36 mo. ICBT-ctrl used significantly more sleep medication (P = 0.017) and underwent significantly more other insomnia treatments (P < 0.001) during the follow-up period. The large improvements in the ICBT-i group were maintained after 36 months, corroborating that CBT for insomnia has long-term effects. After 36 months, the groups did not differ in insomnia severity, but ICBT-ctrl had used more sleep medication and undergone more other additional insomnia treatments during the follow-up period. The trial was registered, together with a parallel trial, at Clinicaltrials.gov as "Internet-CBT for Insomnia" registration ID: NCT01256099.

Value-Based Hypothesis Testing for Cardiac Device Clinical Trials: A Pathway for Accelerated Reimbursement Decisions.

Medical device sponsors seeking to introduce innovative devices in the United States must clear 2 regulatory hurdles. First, they must provide evidence demonstrating reasonable assurance of safety and effectiveness for adjudication and marketing approval by the Food and Drug Administration (FDA). Second, they must apply for reimbursement coverage through the Centers for Medicare and Medicaid Services (CMS). This second step is based on a different metric that requires demonstration that treatment using the device is reasonable and necessary. Typically, decisions for reimbursement coverage lag well behind the FDA approval for marketing and may result in substantial delays to the availability of some novel therapies. In interventional cardiology, recent examples include a 6-month wait for a coverage with evidence decision after an already-belated FDA approval for the first transcatheter aortic valve and the only recently final reimbursement decision for the Watchman (Boston Scientific, Marlborough, MA) left atrial occlusion device, almost 11 months after FDA-marketing approval. These delays arise in part from the incomplete overlap between safety/effectiveness and reasonable/necessary standards. Pivotal clinical trials are typically designed to support the safety and effectiveness assessment but may lack data necessary to characterize reasonable and necessary. Although reasonable and necessary does not have a strict regulatory definition, it connotes added healthcare value, defined as improved quality of outcome relative to cost.1,2 Harmonizing these goals in clinical trial designs will accelerate the clinical introduction of important new technology. This study will examine the limitations of current cardiac device clinical trials and explore methods for incorporating value-based hypotheses into the design of these studies. Given the frequent requirement for active treatment controls and the difficulty in proving superiority of incremental changes in new devices, noninferiority trial designs have become the mainstay of cardiac device clinical trials. In addition to demonstrating that a new device …

A protocol for a randomised active-controlled trial to evaluate the effects of an online mindfulness intervention on executive control, critical thinking and key thinking dispositions in a university student sample.

BackgroundWhile most modern research focuses on the clinical benefits of mindfulness, an emerging body of work suggests that mindfulness can facilitate self-regulation of everyday thinking in typically developing individuals. This behaviour is best captured using critical thinking assessments. The aim of this paper is to describe a rigorous, pre-registered study which will investigate the effect of an online mindfulness intervention on Executive Functioning, critical thinking skills and associated thinking dispositions.MethodThe design employed is a randomised-controlled 2 (condition) X 2 (time) parallel-group design which is explanatory in nature. A sample of at least 60 participants will be recruited from the pool of students at NUI Galway, with those between the ages of 18 and 65 with an adequate level of English included. Participants will be randomly assigned following screening, using block randomisation with a fixed block of 6 and a 1:1 ratio, to either the mindfulness meditation group or a sham meditation group. Both groups will be given access to the Headspace app. This is an app which provides guided meditations to users. Participants in each group will receive unique codes granting access to either the experimental or active-control intervention materials. Group allocation will be double-blinded. The primary outcome measures will assess mindfulness, executive functioning, critical thinking, actively open-minded thinking and need for cognition. Secondary outcome measures will assess eudaimonic and hedonic wellbeing, positive and negative affect, and real-world outcomes. These will be measured at baseline and at the end of the intervention. Manipulation checks will assess adherence to the intervention, meditation quality and task difficulty and enjoyment.DiscussionIf this intervention proves effective, it will show the potential of mindfulness practice to facilitate everyday critical thinking and should stimulate more interest in this line of research. If ineffective, claims regarding mindfulness and thinking skills should be tempered. This research was funded by a Galway Doctoral Research Scholarship awarded to the first author and was facilitated by Headspace Inc. who provided the intervention materials. The trial is registered in the ISRCTN registry and any protocol amendments will be recorded there (RCT ID: ISRCTN16588423. Registered 7th January 2016).

Bayesian methods for the design and analysis of noninferiority trials

ABSTRACTThe gold standard for evaluating treatment efficacy of a medical product is a placebo-controlled trial. However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efficacy is through a noninferiority (NI) study where a test treatment is compared to an active control treatment. The minimal objective of such a study is to determine whether the test treatment is superior to placebo. An assumption is made that if the active control treatment remains efficacious, as was observed when it was compared against placebo, then a test treatment that has comparable efficacy with the active control, within a certain range, must also be superior to placebo. Because of this assumption, the design, implementation, and analysis of NI trials present challenges for sponsors and regulators. In designing and analyzing NI trials, substantial historical data are often required on the active control treatment and placebo. Bayesian approaches provide a natural framework for synthesizing the historical data in the form of prior distributions that can effectively be used in design and analysis of a NI clinical trial. Despite a flurry of recent research activities in the area of Bayesian approaches in medical product development, there are still substantial gaps in recognition and acceptance of Bayesian approaches in NI trial design and analysis. The Bayesian Scientific Working Group of the Drug Information Association provides a coordinated effort to target the education and implementation issues on Bayesian approaches for NI trials. In this article, we provide a review of both frequentist and Bayesian approaches in NI trials, and elaborate on the implementation for two common Bayesian methods including hierarchical prior method and meta-analytic-predictive approach. Simulations are conducted to investigate the properties of the Bayesian methods, and some real clinical trial examples are presented for illustration.

Acceptance and Efficacy of Metacognitive Training (MCT) on Positive Symptoms and Delusions in Patients With Schizophrenia: A Meta-analysis Taking Into Account Important Moderators.

Metacognitive training (MCT) is a new, widely used intervention for psychosis. The present meta-analysis examines the efficacy of MCT in schizophrenia. Fifteen studies comparing effects of MCT on positive symptoms, delusions or acceptance of MCT with a control group were included in this meta-analysis. These studies comprised a total of 408 patients in the MCT condition and 399 in the control condition. The moderating effects of masking of outcome assessment, randomization, incomplete outcome data, use of an active control intervention, and individual vs group MCT were investigated. Possible effects of sensitivity analyses and publication bias were also examined. The results show a significant overall effect of MCT for positive symptoms (g = -0.34, 95% CI [-0.53, -0.15]), delusions (g = -0.41, 95% CI [-0.74, -0.07]) and acceptance of the intervention (g = -0.84, 95% CI [-1.37, -0.31]). Using only studies being at low risk for bias regarding randomization, masking and incomplete outcome data reduced effect sizes for positive symptoms and delusions (g = -0.28, 95% CI [-0.50, -0.06] and g = -0.18, 95% CI [-0.43, 0.06]), respectively. This meta-analysis demonstrates that MCT exerts a small to moderate effect on delusions and positive symptoms and a large effect on acceptance of the intervention. The effect on delusions is reduced, but remains significant when potential biases are considered.

Can early counselling and support for Alzheimer′s disease caregivers reduce burden? Study protocol for a multicenter randomized controlled trial

Background: The activity of caregiving for people affected with Alzheimer's disease (AD) is associated with an augmentation in health problems (anxiety, depression, stress, increased mortality), as well as in social and financial problems. Different methods of counselling, to reduce caregiver anxiety and depression, have been shown to be effective. Methods/Design: This study will be a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) controlled superiority trial with two parallel groups. Two hundred and sixty-four caregivers of AD patients will be randomly allocated to the modified Mittelmann psychosocial intervention or an educational intervention. The treatment will consist of 6 hours of counselling and psychosocial support to caregivers, administered by psychologists, along with a specific telephone support service, whereas the active control treatment will be 6 hours of general information about AD. The primary endpoint is change in caregiver burden measured with the Zarit Burden Interview. Secondary endpoints comprise caregiver depression, anxiety and quality of life. All endpoints will be measured at baseline, 6, 12 and 24 months post treatment. Discussion: The results of this trial will be helpful to supply the efficacy of early counselling and psychosocial support for AD caregivers and offer in-depth useful information for stakholders and policy makers to implement strategies for caregivers. Trial registration: Clinical Trials.gov identifier: NCT02685787; registered on 6 February 2016. Ethics: This trial has been approved by Umbria Ethical Review Committee, Italy and will be performed in accordance with the norms on Good Clinical Practice and the Helsinki Declaration. Informed consent: Written informed consent will be obtained from the caregivers.

A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia

A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia

Mindfulness-based cognitive therapy (MBCT) reduces the association between depressive symptoms and suicidal cognitions in patients with a history of suicidal depression.

Objective: In patients with a history of suicidal depression, recurrence of depressive symptoms can easily reactivate suicidal thinking. In this study, we investigated whether training in mindfulness, which is aimed at helping patients “decenter” from negative thinking, could help weaken the link between depressive symptoms and suicidal cognitions. Method: Analyses were based on data from a recent randomized controlled trial, in which previously suicidal patients were allocated to mindfulness-based cognitive therapy (MBCT), an active control treatment, cognitive psychoeducation (CPE), which did not include any meditation practice, or treatment as usual (TAU). After the end of the treatment phase, we compared the associations between depressive symptoms, as assessed through self-reports on the Beck Depression Inventory–II (Beck, Steer, & Brown, 1996), and suicidal thinking, as assessed through the Suicidal Cognitions Scale (Rudd et al., 2001). Results: In patients with minimal to moderate symptoms at the time of assessment, comparisons of the correlations between depressive symptoms and suicidal cognitions showed significant differences between the groups. Although suicidal cognitions were significantly related to levels of symptoms in the 2 control groups, there was no such relation in the MBCT group. Conclusion: The findings suggest that, in patients with a history of suicidal depression, training in mindfulness can help to weaken the association between depressive symptoms and suicidal thinking, and thus reduce an important vulnerability for relapse to suicidal depression.