Meta-analysis of individual patient data from randomised trials: a review of methods used in practice

Background: Meta-analyses based on individual patient data (IPD) are regarded as the gold standard for systematic reviews. However, the methods used for analysing and presenting results from IPD meta-analyses have received little discussion. Methods We review 44 IPD meta-analyses published during the years 1999–2001. We summarize whether they obtained all the data they sought, what types of approaches were used in the analysis, including assumptions of common or random effects, and how they examined the effects of covariates. Results: Twenty-four out of 44 analyses focused on time-to-event outcomes, and most analyses (28) estimated treatment effects within each trial and then combined the results assuming a common treatment effect across trials. Three analyses failed to stratify by trial, analysing the data is if they came from a single mega-trial. Only nine analyses used random effects methods. Covariate-treatment interactions were generally investigated by subgrouping patients. Seven of the meta-analyses included data from less than 80% of the randomized patients sought, but did not address the resulting potential biases. Conclusions: Although IPD meta-analyses have many advantages in assessing the effects of health care, there are several aspects that could be further developed to make fuller use of the potential of these time-consuming projects. In particular, IPD could be used to more fully investigate the influence of covariates on heterogeneity of treatment effects, both within and between trials. The impact of heterogeneity, or use of random effects, are seldom discussed. There is thus considerable scope for enhancing the methods of analysis and presentation of IPD meta-analysis.

Using historical lesion volume data in the design of a new phase II clinical trial in acute stroke

Background and Purpose-Clinical research into the treatment of acute stroke is complicated, is costly, and has often been unsuccessful. Developments in imaging technology based on computed tomography and magnetic resonance imaging scans offer opportunities for screening experimental therapies during phase II testing so as to deliver only the most promising interventions to phase III. We discuss the design and the appropriate sample size for phase II studies in stroke based on lesion volume. Methods-Determination of the relation between analyses of lesion volumes and of neurologic outcomes is illustrated using data from placebo trial patients from the Virtual International Stroke Trials Archive. The size of an effect on lesion volume that would lead to a clinically relevant treatment effect in terms of a measure, such as modified Rankin score (mRS), is found. The sample size to detect that magnitude of effect on lesion volume is then calculated. Simulation is used to evaluate different criteria for proceeding from phase II to phase III. Results-The odds ratios for mRS correspond roughly to the square root of odds ratios for lesion volume, implying that for equivalent power specifications, sample sizes based on lesion volumes should be about one fourth of those based on mRS. Relaxation of power requirements, appropriate for phase II, lead to further sample size reductions. For example, a phase III trial comparing a novel treatment with placebo with a total sample size of 1518 patients might be motivated from a phase II trial of 126 patients comparing the same 2 treatment arms. Discussion-Definitive phase III trials in stroke should aim to demonstrate significant effects of treatment on clinical outcomes. However, more direct outcomes such as lesion volume can be useful in phase II for determining whether such phase III trials should be undertaken in the first place. (Stroke. 2009;40:1347-1352.)

Improved arthritic knee health in a pilot RCT of phytotherapy

Although practitioner-prescribed 'western' herbal medicine (phytotherapy) is a popular complementary therapy in the UK, no clinical studies have been reported on patient-orientated outcomes. The objective of this pilot study was to investigate the effects of phytotherapy on symptoms of osteoarthritis of the knee. A previous study of Chinese herbal medicine for the treatment of irritable bowel syndrome, published in the Journal of the American Medical Association,(1) acted as a model in the development of the protocol of this investigation. Twenty adults, previously diagnosed with osteoarthritis of the knee, were recruited from two Inner London GP practices into this randomized, double-blind, placebo-controlled, pilot study carried out in a primary-care setting. All subjects were seen in consultation three times by a herbal practitioner who was blinded to the randomization coding. Each subject was prescribed treatment and given lifestyle advice according to usual practice: continuation of conventional medication where applicable, healthy-eating advice and nutrient supplementation, Individualized herbal medicine was prescribed for each patient, but only dispensed for those randomized to active treatment - the remainder were supplied with a placebo. At baseline and outcome (after ten weeks of treatment), subjects completed a food frequency questionnaire and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee health and Measure Yourself Outcome Profile (MYMOP) wellbeing questionnaires. Subjects completing the study per protocol (n = 14) reported an increased intake of wholegrain foods (p = 0.045) and oily fish (p = 0.039) compared to baseline, but no increase in fruit and vegetables and dairy products intakes. There was no difference in the primary outcome measure of knee health assessed as the difference in the mean response (baseline-week 10) in WOMAC score between the two treatment groups. However, there was, compared with baseline, improvement in the active group (n = 9) for the mean WOMAC stiffness sub-score at week 5 (p = 0.035) and week 10 (p = 0.060) but not in the placebo group (n = 5). Furthermore, for the active, but not the placebo group, the mean WOMAC total and sub-scores all showed clinically significant improvement (>= 20%) in knee symptoms at weeks 5 and 10 compared with baseline. Moreover, the mean MYMOP symptom 2 sub-score, mostly relating to osteoarthritis (OA), showed significant improvement at week 5 (p = 0.02) and week 10 (p = 0.008) compared with baseline for the active, but not for the placebo group. This pilot study showed that herbal medicine prescribed for the individual by a herbal practitioner resulted in improvement of symptoms of OA of the knee.

Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study

Background: Osteoarthritis (OA) of the knee is the most prevalent joint disorder. Previous studies suggest that bromelain, a pineapple extract, may be a safer alternative/adjunctive treatment for knee OA than current conventional treatment. Aim: To assess the efficacy of bromelain in treating OA of the knee. Design: Randomized, double-blind placebo-controlled trial. Methods: Subjects (n=47) with a confirmed diagnosis of moderate to severe knee OA were randomized to 12 weeks of bromelain 800 mg/day or placebo, with a 4-week follow-up. Knee (pain, stiffness and function) and quality-of-life symptoms were reported monthly in the WOMAC and SF36 questionnaires, respectively. Adverse events were also recorded. The primary outcome measure was the change in total WOMAC score from baseline to the end of treatment at week 12. Longitudinal models were used to evaluate outcome. Results: Thirty-one patients completed the trial (14 bromelain, 17 placebo). No statistically significant differences were observed between groups for the primary outcome (coefficient 11.16, p=0.27, 95%CI-8.86 to 31.18), nor the WOMAC subscales or SF36. Both treatment groups showed clinically relevant improvement in the WOMAC disability subscale only. Adverse events were generally mild in nature. Discussion: This study suggests that bromelain is not efficacious as an adjunctive treatment of moderate to severe OA, but its limitations support the need for a follow-up study.

Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis

Background: Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation. Objective: We investigated the plant cannabinoids Delta-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors. Methods: A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR analysis confirmed presence of CB1 and CB2 receptors. Results: The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either C81 /C82 antagonists. Conclusion: The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis. (c) 2006 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers

Acute doses of Ginkgo biloba have been shown to improve attention and memory in young, healthy participants, but there has been a lack of investigation into possible effects on executive function. In addition, only one study has investigated the effects of chronic treatment in young volunteers. This study was conducted to compare the effects of ginkgo after acute and chronic treatment on tests of attention, memory and executive function in healthy university students. Using a placebo-controlled double-blind design, in experiment 1, 52 students were randomly allocated to receive a single dose of ginkgo (120 mg, n=26) or placebo (n=26), and were tested 4h later. In experiment 2, 40 students were randomly allocated to receive ginkgo (120 mg/day; n=20) or placebo (n=20) for a 6-week period and were tested at baseline and after 6 weeks of treatment. In both experiments, participants underwent tests of sustained attention, episodic and working memory, mental flexibility and planning, and completed mood rating scales. The acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern-recognition memory task; however, there were no effects on working memory, planning, mental flexibility or mood. After 6 weeks of treatment, there were no significant effects of ginkgo on mood or any of the cognitive tests. In line with the literature, after acute administration ginkgo improved performance in tests of attention and memory. However, there were no effects after 6 weeks, suggesting that tolerance develops to the effects in young, healthy participants.

Controlled trial of the short- and long-term effect of psychological treatment of post-partum depression - 1. Impact on maternal mood!

Background: Psychological interventions for postnatal depression can be beneficial in the short term but their longer-term impact is unknown, Aims To evaluate the long-term effect on maternal mood of three psychological treatments in relation to routine primary care. Method: Women with post-partum depression (n=193)were assigned randomly to one of four conditions: routine primary care, non-directive counselling, cognitive-behavioural therapy or psychodynamic therapy. They were assessed immediately after the treatment phase (at 4.5 months) and at 18 and 60 months post-partum. Results: Compared with the control, ail three treatments had a significant impact at 4.5 months on maternal mood (Edinburgh Postnatal Depression Scale, EPDS). Only psychodynamic therapy produced a rate of reduction in depression (Structured Clinical interview for DSM III-R) significantly superior to that of the control. The benefit of treatment was no longer apparent by 9 months postpartum, treatment did not reduce subsequent episodes of post-partum depression. Conclusions: Psychological intervention for post-partum depression improves maternal mood (EPDS) in the short term. However, this benefit is not superior to spontaneous remission in the long term.

Effective elements of cognitive behaviour therapy for psychosis: results of a novel type of subgroup analysis based on principal stratification

Background. Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology. Method. The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization. Results. Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective. Conclusions. Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment.

Online customer experience in e-retailing: an empirical model of antecedents and outcomes

The theoretical understanding of online shopping behavior has received much attention. Less focus has been given to the formation of the customer experience (CE) that results from online shopper interactions with e-retailers. This study develops and empirically tests a model of the relationship between antecedents and outcomes of online customer experience (OCE) within Internet shopping websites using an international sample. The study identifies and provides operational measures of these variables plus the cognitive and affective components of OCE. The paper makes contributions towards new knowledge and understanding of how e-

Computerized short-term memory treatment for older adults with aphasia

We report on a software prototype designed to deliver a novel term memory treatment for older adults with aphasia. We conducted a review of the prototype with 14 speech and language therapists, to elicit feedback on the potential usefulness of the ultimate application and, particularly, the prototype in terms of its main design features and use by older adults with aphasia. The clinicians’ feedback highlights a number of design considerations relating to the usability, training methods, and appeal of treatment software, which can help engage patients more fully in computerized treatments and improve treatment outcomes.

Radically open-dialectical behavior therapy for adult anorexia nervosa: feasibility and outcomes from an inpatient program

Background Anorexia Nervosa (AN) is a highly life-threatening disorder that is extremely difficult to treat. There is evidence that family-based therapies are effective for adolescent AN, but no treatment has been proven to be clearly effective for adult AN. The methodological challenges associated with studying the disorder have resulted in recommendations that new treatments undergo preliminary testing prior to being evaluated in a randomized clinical trial. The aim of this study was to provide preliminary evidence on the effectiveness of a treatment program based on a novel adaptation of Dialectical Behavior Therapy (DBT) for adult Anorexia Nervosa (Radically Open-DBT; RO-DBT) that conceptualizes AN as a disorder of overcontrol. Methods Forty-seven individuals diagnosed with Anorexia Nervosa-restrictive type (AN-R; mean admission body mass index = 14.43) received the adapted DBT inpatient program (mean length of treatment = 21.7 weeks). Results Seventy-two percent completed the treatment program demonstrating substantial increases in body mass index (BMI; mean change in BMI = 3.57) corresponding to a large effect size (d = 1.91). Thirty-five percent of treatment completers were in full remission, and an additional 55% were in partial remission resulting in an overall response rate of 90%. These same individuals demonstrated significant and large improvements in eating-disorder related psychopathology symptoms (d = 1.17), eating disorder-related quality of life (d = 1.03), and reductions in psychological distress (d = 1.34). Conclusions RO-DBT was associated with significant improvements in weight gain, reductions in eating disorder symptoms, decreases in eating-disorder related psychopathology and increases in eating disorder-related quality of life in a severely underweight sample. These findings provide preliminary support for RO-DBT in treating AN-R suggesting the importance of further evaluation examining long-term outcomes using randomized controlled trial methodology.

An investigation of the shortcomings of the CONSORT 2010 statement for the reporting of group sequential randomised controlled trials: a methodological systematic review

Background It can be argued that adaptive designs are underused in clinical research. We have explored concerns related to inadequate reporting of such trials, which may influence their uptake. Through a careful examination of the literature, we evaluated the standards of reporting of group sequential (GS) randomised controlled trials, one form of a confirmatory adaptive design. Methods We undertook a systematic review, by searching Ovid MEDLINE from the 1st January 2001 to 23rd September 2014, supplemented with trials from an audit study. We included parallel group, confirmatory, GS trials that were prospectively designed using a Frequentist approach. Eligible trials were examined for compliance in their reporting against the CONSORT 2010 checklist. In addition, as part of our evaluation, we developed a supplementary checklist to explicitly capture group sequential specific reporting aspects, and investigated how these are currently being reported. Results Of the 284 screened trials, 68(24%) were eligible. Most trials were published in “high impact” peer-reviewed journals. Examination of trials established that 46(68%) were stopped early, predominantly either for futility or efficacy. Suboptimal reporting compliance was found in general items relating to: access to full trials protocols; methods to generate randomisation list(s); details of randomisation concealment, and its implementation. Benchmarking against the supplementary checklist, GS aspects were largely inadequately reported. Only 3(7%) trials which stopped early reported use of statistical bias correction. Moreover, 52(76%) trials failed to disclose methods used to minimise the risk of operational bias, due to the knowledge or leakage of interim results. Occurrence of changes to trial methods and outcomes could not be determined in most trials, due to inaccessible protocols and amendments. Discussion and Conclusions There are issues with the reporting of GS trials, particularly those specific to the conduct of interim analyses. Suboptimal reporting of bias correction methods could potentially imply most GS trials stopping early are giving biased results of treatment effects. As a result, research consumers may question credibility of findings to change practice when trials are stopped early. These issues could be alleviated through a CONSORT extension. Assurance of scientific rigour through transparent adequate reporting is paramount to the credibility of findings from adaptive trials. Our systematic literature search was restricted to one database due to resource constraints.

The dark side of brand attachment: a conceptual framework of brand attachment's detrimental outcomes

Brand attachment recently has received great attention among practitioners and academics alike. Scholars consider brand attachment a key requisite in consumer-brand relationships that create favourable consumer behaviours such as positive brand attitudes and brand loyalty. Few studies, however, examine the detrimental outcomes of brand attachment. In this paper, we develop a conceptual framework that explores how brand attachment may explain detrimental consumer behaviours, such as oppositional brand loyalty and antibrand actions. We investigate consumers' trash-talking and schadenfreude in brand communities and their subsequent outcomes. Our framework reveals that the link between brand attachment and oppositional brand loyalty is driven by consumers' social identity and sense of rivalry. Furthermore, we put forward that brand attachment leads to anti-brand actions when relationships deteriorate. We identify two factors behind the deterioration: (1) companies' opportunism activities, and (2) incongruity between consumers' values and the brand's values. Theoretical and managerial implications are discussed arising from our emerging 'dark side' brand attachment framework.

Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers (“biomarkers”) of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10–20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2–10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research.

Effects of isoproterenol treatment for 7 days on inflammatory mediators in the rat aorta

The aim of the present study was to evaluate the effect of overstimulation of beta-adrenoceptors on vascular inflammatory mediators. Wistar rats were treated with the beta-adrenoceptor agonist isoproterenol (0.3 mg(.)kg(-1.)day(-1) sc) or vehicle (control) for 7 days. At the end of treatment, the right carotid artery was catheterized for arterial and left ventricular (LV) hemodynamic evaluation. Isoproterenol treatment increased LV weight but did not change hemodynamic parameters. Aortic mRNA and protein expression were quantified by real-time RT-PCR and Western blot analysis, respectively. Isoproterenol enhanced aortic mRNA and protein expression of IL-1 beta (124% and 125%) and IL-6 (231% and 40%) compared with controls but did not change TNF-alpha expression. The nuclear-to-cytoplasmatic protein expression ration of the NF-beta B p65 subunit was increased by isoproterenol treatment (51%); in addition, it reduced the cytoplasmatic expression of I kappa B-alpha (52%) in aortas. An electrophoretic mobility shift assay was performed using the aorta, and increased NF-kappa B DNA binding (31%) was observed in isoproterenol-treated rats compared with controls (P < 0.05). Isoproterenol treatment increased phenylephrine-induced contraction in aortic rigs (P < 0.05), which was significantly reduced by superoxide dismutase (150 U/ml) and sodium salicylate (5 mM). Cotreatment with thalidomide (150 mg(.)kg(-1.)day(-1) for 7 days) also reduced hyperreactivity to phenylephrine induced by isoproterenol. In conclusion, overstimulation of beta-adrenoceptors increased proinflammatory cytokines and upregulated NF-kappa B in the rat aorta. Moreover, local oxidative stress and the proinflammatory state seem to play key roles in the altered vascular reactivity of the rat aorta induced by chronic beta-adrenergic stimulation.