Salima Punja

Long-acting versus short-acting methylphenidate for paediatric ADHD: a systematic review and meta-analysis of comparative efficacy.

Objective To synthesise existing knowledge of the efficacy and safety of long-acting versus short-acting methylphenidate for paediatric attention deficit hyperactivity disorder (ADHD). Design Systematic review and meta-analysis. Data sources Electronic literature search of CENTRAL, MEDLINE, PreMEDLINE, CINAHL, EMBASE, PsychINFO, Scopus and Web of Science for articles published in the English language between 1950 and 2012. Reference lists of included studies were checked for additional studies. Study selection Randomised controlled trials of paediatric ADHD patients (<18 years), comparing a long-acting methylphenidate form to a short-acting methylphenidate form. Data extraction Two authors independently selected trials, extracted data and assessed risk of bias. Continuous outcomes were compared using standardised mean differences (SMDs) between treatment groups. Adverse events were compared using risk differences between treatment groups. Heterogeneity was explored by subgroup analysis based on the type of long-acting formulation used. Results Thirteen RCTs were included; data from 882 participants contributed to the analysis. Meta-analysis of three studies which used parent ratings to report on hyperactivity/impulsivity had an SMD of −0.30 (95% CI −0.51 to −0.08) favouring the long-acting forms. In contrast, three studies used teacher ratings to report on hyperactivity and had an SMD of 0.29 (95% CI 0.05 to 0.52) favouring the short-acting methylphenidate. In addition, subgroup analysis of three studies which used parent ratings to report on inattention/overactivity indicate that the osmotic release oral system generation long-acting formulation was favoured with an SMD of −0.35 (95% CI −0.52 to −0.17), while the second generation showed less efficacy than the short-acting formulation with an SMD of 0.42 (95% CI 0.17 to 0.68). The long-acting formulations presented with slightly more total reported adverse events (n=578) as compared with the short-acting formulation (n=566). Conclusions The findings from this systematic review indicate that the long-acting forms have a modest effect on the severity of inattention/overactivity and hyperactivity/impulsivity according to parent reports, whereas the short-acting methylphenidate was preferred according to teacher reports for hyperactivity.

N-of-1 trials are a tapestry of heterogeneity

OBJECTIVES To summarize the methods of design, analysis, and meta-analysis used in N-of-1 trials. STUDY DESIGN AND SETTING Electronic search for English language articles published from 1950 to 2013. N-of-1 trials were selected if they followed an ABAB design and if they assessed a health intervention for a medical condition. Elements of design, analysis, and meta-analysis were extracted. RESULTS We included 100 reports representing 1,995 participants. N-of-1 trials have been conducted in over 50 health conditions. Most reports incorporated the use of elements that maintain methodological rigor, including randomization, blinding, and formal outcome assessment; however, many failed to address trial registration, funding source, and adverse events. Most reports statistically analyzed individual N-of-1 trials; however, only a small proportion of included series meta-analyzed their results. CONCLUSIONS N-of-1 trials have the ability to assess treatment response in individual participants and can be used for a variety of health interventions for a wide range of medical conditions in both clinical and research settings. Considerable heterogeneity exists in the methods used in N-of-1 trials.

N-of-1 trials can be aggregated to generate group mean treatment effects: a systematic review and meta-analysis

OBJECTIVES To evaluate how data from n-of-1 trials may be used in systematic reviews and meta-analyses by examining the effects of amphetamine and methylphenidate for attention-deficit hyperactivity disorder (ADHD). STUDY DESIGN AND SETTING Electronic search of MEDLINE, EMBASE, and PsychINFO for English language articles published from 1950 to 2013. N-of-1 trials of pediatric participants with ADHD that assessed either amphetamine or methylphenidate vs. placebo were included. The primary outcome was improvement of core symptoms of ADHD, which was assessed by multiple rating scales. Studies with obtainable individual participant data were included in the meta-analysis. Weighted mean differences were computed using a random-effects model. RESULTS Nine studies were included in the amphetamine-placebo comparison and 10 in the methylphenidate-placebo comparison. Meta-analyses were consistently in favor of amphetamine in 10 of 11 ADHD symptom domains and methylphenidate in 7 of 12 symptom domains. A high degree of heterogeneity across participant treatment response was observed. CONCLUSIONS Meta-analysis of n-of-1 trials suggests that amphetamine and methylphenidate are effective treatments for pediatric ADHD. Synthesizing n-of-1 trials enables assessment of individual responses to treatment as well as aggregate summaries across individuals and studies. It offers a promising general approach with applications across diverse treatments and disorders.

N-of-1 Trials: Individualized Medication Effectiveness Tests

Evidence-based management of chronic diseases presents a unique set of challenges. Results from randomized controlled trials (RCTs), often considered the “gold standard” of research evidence, are often not well suited to the realities of clinical practice given patient heterogeneity, comorbidities, and the use of multiple concurrent therapies. In fact, RCTs may exclude the majority of patients seen in routine clinical practice [1]. In addition, evidence is lacking on the long-term effectiveness, comparative effectiveness, and additive effectiveness of many therapies for chronic conditions. This lack of relevant evidence can limit a clinician’s ability to make evidence-based decisions.

The history and development of N-of-1 trials

‘Trials of therapy’, in which physicians ‘try out’ treatments and assess patients’ responses, are long-established, common elements of routine medical practice. Because ‘trials of therapy’ are usually informal, they may only be reported if treatments are associated with dramatic changes in a patient’s condition – whether by improvement or deterioration. Our understanding of bias suggests that informal ‘trials of therapy’ – comparisons of patients’ condition before and after treatment – do not provide a trustworthy basis for inferring treatment effects. More sophisticated comparisons are usually needed: for example, comparing a patient’s responses when treatments are given or withheld (‘crossed over’) and conducting formal assessment of outcomes. In 1676, Richard Wiseman (a surgeon to King Charles II) reported an unplanned experiment. He had prescribed a pair of laced stockings for a patient suffering from leg oedema. The stockings had reduced the oedema to the extent that the patient ‘was able to walk to his closet, and take the air in his coach, and was well pleased with them’. However, someone suggested to the patient that the stockings might do him harm and persuaded him to remove them. His legs swelled up, he became confined to bed again and developed leg ulcers. Dr Wiseman waited six weeks for the ulcers to heal, restored the laced stockings, with the result that the patient recovered. A century after Wiseman’s crude crossover trial of laced stockings, Caleb Parry, a doctor in Bath, England, published a more formal, planned use of between two and six crossover periods of variable duration in 13 patients, to compare the purgative effects of three varieties of rhubarb. Parry was unable to find any advantage of the more costly Turkish rhubarb compared with English rhubarb. Parry’s ‘trials of therapy’ were important in having used at least two crossovers, but he took no steps to ensure that his andhis patients’ assessments of the treatment effects were not influenced by his or the patients’ knowledgeof the type of rhubarb being given.Fourteen years later, also in Bath, JohnHaygarth compared the effects on rheumatism of a metal ‘tractor’ with a matched wooden (placebo) tractor. This demonstrated that the assumed treatment effects of the metal tractor resulted from patients’ imagination. Haygarth’s study made clear that informal ‘trials of therapy’ can be plagued by false positives (due to placebo effects, physicians’ and patients’ desires to please, the pre-existing expectations of both parties and natural history). And they can also result in false negatives (patients destined to deteriorate and the intervention resulting in them remaining stable). Although more than a century passed after Haygarth before Paul Martini set out principles for designing unbiased crossover trials in his 69-page book, it appears that it was not until 1953 that serious scientific consideration was given to how controlled trials in individual patients could complement traditional parallel group trials. Hogben and Sim recognised that:

Rhodiola Rosea for Mental and Physical Fatigue in Nursing Students: A Randomized Controlled Trial

Background Fatigue is one of many unintended consequences of shift work in the nursing profession. Natural health products (NHPs) for fatigue are becoming an increasingly popular topic of clinical study; one such NHP is Rhodiola rosea. A well-designed, rigorously conducted randomized controlled trial is required before therapeutic claims for this product can be made. Objective To compare the efficacy of R. rosea with placebo for reducing fatigue in nursing students on shift work. Design A parallel-group randomized, double-blinded, placebo-controlled trial of 18–55 year old students from the Faculty of Nursing from the University of Alberta, participating in clinical rotations between January 2011 and September 2011. Interventions Participants were randomized to take 364 mg of either R. rosea or identical placebo at the start of their wakeful period and up to one additional capsule within the following four hours on a daily basis over a 42-day period. Outcomes The primary outcome was reduction in fatigue over the 42-day trial period measured using the Vitality-subscale of the RAND-36, cross-validated by the visual analogue scale for fatigue (VAS-F). Secondary outcomes included health-related quality of life, individualized outcomes assessment, and adverse events. Results A total of 48 participants were randomized to R. rosea (n = 24) or placebo (n = 24). The mean change in scores on the Vitality-subscale was significantly different between the study groups at day 42 in favor of placebo (−17.3 (95% CI −30.6, −3.9), p = 0.011), The mean change in scores on the VAS-F was also significantly difference between study groups at day 42 in favour of placebo (1.9 (95% CI 0.4, 3.5), p = 0.015). Total number of adverse events did not differ between R. rosea and placebo groups. Conclusion This study indicates that among nursing students on shift work, a 42-day course of R. Rosea compared with placebo worsened fatigue; however, the results should be interpreted with caution. Trial Registration Clinicaltrials.gov NCT01278992

Protocol for a systematic review of N-of-1 trial protocol guidelines and protocol reporting guidelines

BackgroundN-of-1 trials are multiple cross-over trials done in individual participants, generating individual treatment effect information. While reporting guidelines for the CONSORT Extension for N-of-1 trials (CENT) and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) already exist, there is no standardized recommendation for the reporting of N-of-1 trial protocols.ObjectiveThe objective of this study is to evaluate current literature on N-of-1 design and reporting to identify key elements of rigorous N-of-1 protocol design.MethodsWe will conduct a systematic search for all N-of-1 trial guidelines and protocol-reporting guidelines published in peer-reviewed literature. We will search Medline, Embase, PsycINFO, CINAHL, the Cochrane Methodology Register, CENTRAL, and the NHS Economic Evaluation Database. Eligible articles will contain explicit guidance on N-of-1 protocol construction or reporting. Two reviewers will independently screen all titles and abstracts and then undertake full-text reviews of potential articles to determine eligibility. One reviewer will perform data extraction of selected articles, checked by the second reviewer. Data analysis will ascertain common features of N-of-1 trial protocols and compare them to the SPIRIT and CENT items.DiscussionThis systematic review assesses recommendations on the design and reporting of N-of-1 trial protocols. These findings will inform an international Delphi development process for an N-of-1 trial protocol reporting guideline. The development of this guideline is critical for improving the quality of N-of-1 protocols, leading to improvements in the quality of published N-of-1 trial research.

Establishing a Comprehensive Pediatric Integrative Oncology Program

The use of complementary and alternative medicine (CAM) by adult and pediatric oncology patients is highly prevalent around the world. Surveys in Europe, Japan, Singapore, and the United States have demonstrated substantial use, with 40–91 % of adult cancer patients choosing CAM as part of their treatment (Molassiotis et al. 2006; Hyodo et al. 2005; Shih et al. 2008; Yates et al. 2005). Pediatric CAM use is also high, as confirmed by a recent systematic review of 28 studies of pediatric cancer patients from 14 countries (Yates et al. 2005). The prevalence of pediatric CAM use ranged from 6 to 91 %, with the most popular therapies being herbal remedies, nutritional interventions, and faith healing (Bishop et al. 2010). This increased use of CAM has been associated with a concurrent rise in adult and pediatric academic integrative medicine centers, where CAM research and education complement clinical initiatives with a common mission to provide high-quality, evidence-based care.