Web-based alcohol screening and brief intervention for Māori and non-Māori: the New Zealand e-SBINZ trials

BACKGROUND: Hazardous alcohol consumption is a leading modifiable cause of mortality and morbidity among young people. Screening and brief intervention (SBI) is a key strategy to reduce alcohol-related harm in the community, and web-based approaches (e-SBI) have advantages over practitioner-delivered approaches, being cheaper, more acceptable, administrable remotely and infinitely scalable. An efficacy trial in a university population showed a 10-minute intervention could reduce drinking by 11% for 6 months or more among 17-24 year-old undergraduate hazardous drinkers. The e-SBINZ study is designed to examine the effectiveness of e-SBI across a range of universities and among Māori and non-Māori students in New Zealand. METHODS/DESIGN: The e-SBINZ study comprises two parallel, double blind, multi-site, individually randomised controlled trials. This paper outlines the background and design of the trial, which is recruiting 17-24 year-old students from seven of New Zealand's eight universities. Māori and non-Māori students are being sampled separately and are invited by e-mail to complete a web questionnaire including the AUDIT-C. Those who score >4 will be randomly allocated to no further contact until follow-up (control) or to assessment and personalised feedback (intervention) via computer. Follow-up assessment will occur 5 months later in second semester. Recruitment, consent, randomisation, intervention and follow-up are all online. Primary outcomes are (i) total alcohol consumption, (ii) frequency of drinking, (iii) amount consumed per typical drinking occasion, (iv) the proportions exceeding medical guidelines for acute and chronic harm, and (v) scores on an academic problems scale. DISCUSSION: The trial will provide information on the effectiveness of e-SBI in reducing hazardous alcohol consumption across diverse university student populations with separate effect estimates for Māori and non-Māori students. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12610000279022.

Nucleic acid-based aptamers: applications, development and clinical trials

Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases.

Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Effect of increasing dietary calcium through supplements and dairy food on body weight and body composition: a meta-analysis of randomised controlled trials

This meta-analysis of randomised controlled trials assessed the effect of Ca on body weight and body composition through supplementation or increasing dairy food intake. Forty-one studies met the inclusion criteria (including fifty-one trial arms; thirty-one with dairy foods (n 2091), twenty with Ca supplements (n 2711). Ca intake was approximately 900 mg/d higher in the supplement groups compared with control. In the dairy group, Ca intake was approximately 1300 mg/d. Ca supplementation did not significantly affect body weight (mean change ( - 0·17, 95 % CI - 0·70, 0·37) kg) or body fat (mean change ( - 0·19, 95 % CI - 0·51, 0·13) kg) compared to control. Similarly, increased dairy food intake did not affect body weight ( - 0·06, 95 % CI - 0·54, 0·43) kg or body fat change ( - 0·36, 95 % CI - 0·80, 0·09) kg compared to control. Sub-analyses revealed that dairy supplementation resulted in no change in body weight (nineteen studies, n 1010) ( - 0·32, 95 % CI - 0·93, 0·30 kg, P= 0·31), but a greater reduction in body fat (thirteen studies, n 564) ( - 0·96, 95 % CI - 1·46, - 0·46 kg, P < 0·001) in the presence of energy restriction over a mean of 4 months compared to control. Increasing dietary Ca intake by 900 mg/d as supplements or increasing dairy intake to approximately 3 servings daily (approximately 1300 mg of Ca/d) is not an effective weight reduction strategy in adults. There is, however, an indication that approximately 3 servings of dairy may facilitate fat loss on weight reduction diets in the short term.

Trials and tribulations with electronic medication adherence monitoring in kidney transplantation

Medication adherence in kidney transplantation is critical to prevent graft rejection. Testing interventions designed to support patients to take their prescribed medications following a kidney transplant require an accurate measure of medication adherence. In research, the available methods for measuring medication adherence include self-report, pill counts, prescription refill records, surrogate measures of medication adherence and medication bottles with a microchip-embedded cap to record bottle openings. Medication bottles with a microchip-embedded cap are currently regarded as the gold standard measure. This commentary outlines the challenges in measuring medication adherence using electronic medication monitoring of kidney transplant patients recruited from five sites. The challenges included obtaining unanimous stakeholder support for using this method, agreement on an index medication to measure, adequate preparation of the patient and training of pharmacy staff, and how to analyze data when periods of time were not recorded using the electronic adherence measure. Provision of this information will enable hospital and community pharmacists to implement approaches that promote the effective use of this adherence measure for optimal patient outcomes.

The relationship between suicide and violence in schizophrenia: analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset

Background

Suicide and violence often co-occur in the general population as well as in mentally ill individuals. Few studies, however, have assessed whether these suicidal behaviors are predictive of violence risk in mental illness.

Aims

The aim of this study is to investigate whether suicidal behaviors, including suicidal ideation, threats, and attempts, are significantly associated with increased violence risk in individuals with schizophrenia.

Method

Data for these analyses were obtained from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, a randomized controlled trial of antipsychotic medication in 1460 adults with schizophrenia. Univariate Cox regression analyses were used to calculate hazard ratios (HRs) for suicidal ideation, threats, and attempts. Multivariate analyses were conducted to adjust for common confounding factors, including: age, alcohol or drug misuse, major depression, antisocial personality disorder, depression, hostility, positive symptom, and poor impulse control scores. Tests of discrimination, calibration, and reclassification assessed the incremental predictive validity of suicidal behaviors for the prediction of violence risk.

Results

Suicidal threats and attempts were significantly associated with violence in both males and females with schizophrenia with little change following adjustment for common confounders. Only suicidal threats, however, were associated with a significant increase in incremental validity beyond age, diagnosis with a comorbid substance use disorder, and recent violent behavior.

Conclusions

Suicidal threats are independently associated with violence risk in both males and females with schizophrenia, and may improve violence risk prediction.

Adding a new anticoagulant or antiplatelet agent for patient receiving aspirin after an acute coronary syndrome? - Results from a pairwise and network meta-analysis of randomized-controlled trials

 Objectives: To synthesize the efficacy and safety outcomes from randomized-controlled trials (RCTs) regarding new oral anticoagulant, protease-activated receptor-1 (PAR-1) antagonist, and warfarin adjunctive to aspirin for patients after acute coronary syndrome (ACS) via pair-wise and network meta-analyses.
Methods: A comprehensive literature search was performed in Embase, Medline, Cochrane Library Web of Knowledge, and Scopus. The pair-wise meta-analysis was undertaken respectively to each agent/treatment category via Revmen 5.1. In order to estimate the relative efficacy of each agent/treatment category whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using both fixed- and random-effects model. Covariate analysis was performed to explore the effects of length of follow-up and age of subject on the final results.
Results: In total, 23 RCTs were included in the meta-analysis. As shown by the results (OR,95%CI) for the pair-wise meta-analysis, new oral anticoagulants (0.85, [0.78, 0.93] and 3.04, [2.21, 4.19]), PAR-1 antagonists (0.80, [0.52, 1.22] and 1.55, [1.25, 1.93]) and warfarin (0.87, [0.74, 1.02] and 1.77, [1.46, 2.14]) might be able to provide better outcome in the incidences of major adverse events (MAE) but with higher bleeding risk comparing to aspirin treatment alone. Based on the model fit assessment, the random-effects model was adopted. The network meta-analysis (treatment effect comparing to aspirin lone) identified ximelagatran (-0.3044, [-0.8601, 0.2502]), dabigatran (-0.2144, [-0.8666, 0.4525]), rivoroxaban (-0.2179, [-0.5986, 0.1628]) and vorapaxar (-0.2272, [-0.81, 0.1664]) produced better improvements in MAE incidences whereas vorapaxar (0.3764, [-0.4444, 1.124]), warfarin (0.663, [0.3375, 1.037]), ximelagatran (0.7509, [-0.4164, 2.002]) and apixaban (0.8594, [-0.0049, 1.7]) produced less major bleeding events. The indirect comparisons among drug category (difference in incidence comparing to aspirin lone) showed new oral anticoagulants (-0.1974, [-0.284, -0.111]) and PAR-1 antagonists (-0.1239, [-0.215, -0.033]) to besuperior to warfarin (-0.1004, [-0.166, -0.035]) in the occurrences of MAE whereas PAR-1 antagonists (0.4292, [0.2123, 0.6476]) afforded better outcomes in major bleeding events against warfarin (0.5742, [0.3889, 0.7619]) and new oral anticoagulants (1.169, [0.8667, 1.485]).
Conclusion: Based on the study results, we cannot recommend the routine administration of new oral anticoagulant as add-on treatment for patients after ACS. However, for ACS patients comorbid with atrial fibrillation, new oral anticoagulant might be superior to warfarin in both efficacy and safety outcomes.

The use of mixed methods in drug discovery: integrating qualitative methods into clinical trials

Contemporary methods in clinical trials are pivoted around hypothesis confirmation, not generation. This is a problem for new drug discovery, since the pharmacokinetic or receptor profile of most novel agents do not link to pathophysiology, which is very poorly understood. Therefore, it is difficult to impute the therapeutic potential of a candidate agent. Most psychotropic agents were discovered serendipitously, either through careful clinical observation or by researchers finding unexpected associations in datasets. Methods that increase the ability to detect latent signals in data are needed. These include mixed methods that incorporate qualitative methods into randomized controlled trials.

This chapter proposes a methodology for the integration of mixed methods in clinical trials, fusing qualitative and quantitative methods, and presents an exemplar using this approach.

Mixed methods show potential for signal detection, hypothesis generation, and associations that may be otherwise undetected in traditional clinical trials.

Family-based interventions for reducing sedentary time in youth: a systematic review of randomized controlled trials

Family involvement in interventions to reduce sedentary time may help foster appropriate long-term screen-based habits in children. This review systematically synthesized evidence from randomized controlled trials of interventions with a family component that targeted reduction of sedentary time, including TV viewing, video games and computer use, in children. MEDLINE, PubMed, PsycInfo, CINAHL and Embase were searched from inception through March 2012. Seventeen articles were considered eligible and included in the review. Studies were judged to be at low-to-moderate risk of bias. Despite inconsistent study results, level of parental involvement, rather than the setting itself, appeared an important determinant of intervention success. Studies including a parental component of medium-to-high intensity were consistently associated with statistically significant changes in sedentary behaviours. Participant age was also identified as a determinant of intervention outcomes; all three studies conducted in pre-school children demonstrated significant decreases in sedentary time. Finally, TV exposure appeared to be related to changes in energy intake rather than physical activity. Future studies should assess the effects of greater parental involvement and child age on success of sedentary behaviour interventions. More research is required to better understand the relationship between screen time and health behaviours, particularly energy intake.

Assessing randomised clinical trials of cognitive and exposure therapies for gambling disorders : a systematic review

Aims: Problem or pathological gambling is associated with significant disruption to the individual, family and community with a range of adverse outcomes, including legal, financial and mental health impairment. It occurs more frequently in younger populations, and comorbid conditions are common. Cognitive–behaviour therapy (CBT) is the most empirically established class of treatments for problematic gambling. This article reports on a systematic review and evaluation of randomised clinical trials (RCTs) concerning two core techniques of CBT: cognitive and behavioural (exposure-based) therapies. Methods: PsycINFO, MEDLINE and the Cochrane library were searched from database inception to December 2012. The CONsolidated Standards Of Reporting Trials (CONSORT) for non-pharmacological treatments was used to evaluate each study. Results: The initial search identified 104 references. After two screening phases, seven RCTs evaluating either cognitive (n = 3), exposure (n = 3) or both (n = 1) interventions remained. The studies were published between 1983 and 2003 and conducted across Australia, Canada, and Spain. On average, approximately 31% of CONSORT items were rated as ‘absent’ for each study and more than 52% rated as ‘present with some limitations’. For all studies, 70.83% of items rated as ‘absent’ were in the methods section. Conclusions: The findings from this review of randomised clinical trials involving cognitive and exposure-based treatments for gambling disorders show that the current evidence base is limited. Trials with low risk of bias are needed to be reported before recommendations are given on their effectiveness and clinicians can appraise their potential utility with confidence.

Does sleep education change sleep parameters? Comparing sleep education trials for middle school students in Australia and New Zealand

Background: Adolescents suffer daytime consequences from sleep loss. Sleep education programs have been developed in an attempt to increase sleep knowledge and/or duration. This paper presents data from three trials of the Aus-tralian Centre for Education in Sleep (ACES) program for adolescents.

Methods: The ACES program was delivered to 69 Australian adolescents in a pre-post cross-sectional design (mean age 15.2) and 29 New Zealand adolescents in a randomised control trial (mean age 14.8 years). Assessments in sleep parame-ters were undertaken at baseline and post intervention.

Results: Where sleep knowledge was evaluated (Australian trials), significant improvements were shown in all trials (All p <0.05). Where sleep duration was assessed (New Zealand trial) significant improvements were found in week and weekend sleep duration [F(1, 27)=4.26, p=0.04). Both, students and teachers found the program feasible, interesting, and educational.

Conclusions: ACES sleep education programmes can improve both sleep knowledge and sleep duration in adolescents. Improving the programme so sleep knowledge attained equates to actual sleep behaviour change are areas for future direc-tion. Collectively these findings provide encouraging signs that adolescents can improve their sleep knowledge and behav-iour with sleep education which bodes well for sleep-related health and psycho-social issues.

Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials

BACKGROUND: In epidemiological studies, statins appear to benefit mood, and there are now some randomized controlled trials examining the efficacy of statins. However, the role of statins in depression remains uncertain. Thus the aim of this paper was to assess the effect of statins on depressive symptoms by performing a meta-analysis of all double-blind, randomized, placebo controlled clinical trials (RCT) conducted in subjects with depression. METHODS: A systematic search was executed using PubMed and ClinicalTrials.gov in November 30th, 2015 for all double-blind, RCT of statins versus placebo in persons with depressive symptoms. Sixty-seven potential articles were identified through search of electronic databases, of those three met inclusion criteria and were included in the meta-analysis. The outcome measure was change in Hamilton Depression Rating Scale (HDRS) scores associated with statin use. A meta-analysis was conducted and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. GRADE was used to assess study quality. RESULTS: The three articles included provided data on 165 participants with moderate to severe depression. Of these, 82 were randomized to statins as an adjuvant therapy to antidepressant treatment (i.e., citalopram or fluoxetine) and 83 to the placebo arm. All studies were double-blind RCTs, with a follow-up of 6-12 weeks. The statin agents evaluated were lovastatin, atorvastatin, and simvastatin. When compared to placebo, statins, as add-on to treatment as usual, largely improved depressive symptoms as assessed by the HDRS (SMD=-0.73, 95% IC -1.04 to -0.42, p<0.001, 3 between-group comparisons, n=165). No serious adverse effects were reported. CONCLUSIONS: Our results suggest that adjunctive treatment with statins could be useful for the treatment of depressive symptoms. Additional double-blind, randomised, placebo-controlled trials are necessary to settle the matter.

The science of the COAG coordinated care trials

Objectives: To explicate the organisational change agenda of the COAG coordinated care trials within the Australian health system and to illuminate the role of science in this process. Methods and Results: This article briefly outlines the COAG coordinated care trial aims and the effect of the trial as a change initiative in rural South Australia. It is proposed that although the formal trial outcomes are still not clear, the trial had significant impact upon health service delivery in some sites. The trial involved standard research methods with control and intervention groups and with key hypotheses being tested to compare the costs and service utilization profile of intervention and control groups. Formal results indicate that costs were not significantly different between intervention and control groups across all sites, but that the trial, nonetheless, had a powerful impact on the attitude and behaviours of service providers in the rural trial on Eyre Peninsula in particular. Some of the key structural changes now in place are outlined. Conclusions: The COAG trial has had many and varied impacts upon those organisations and individual providers involved with it. It is argued here that since successive initiatives had been implemented before final evaluation results were published, other agendas were served by the trial apart from those of standard scientific research and hypothesis testing. That is, the main impact of the coordinated care trial in Eyre Region at least has been change by stealth, and not through scientific research and demonstration. Implications: The COAG trials have set in train a series of structural and procedural changes in the methods of delivery and management of primary health care systems; changes that are embodied in the Enhanced Primary Care packages (EPC) and other initiatives recently introduced by the Commonwealth Government. These changes have occurred and are occurring across the system without formal evidence as to their efficacy, suggesting that other financial motives are driving these new approaches apart from the goal of improving health outcomes for consumers. Also, if science is to be used in this way to drive policy and procedural change ahead of actual outcome evidence, it is important that we examine the more subtle agendas of such research projects in future if the integrity of the scientific method is to be maintained. The occurrence of such phenomena questions the very foundation of scientific endeavour and weakens the application of scientific principles in the arena of social and political science.