Patrina Caldwell

Clinical trials in children.

The imperative to undertake randomised trials in children arises from extraordinary advances in basic biomedical sciences, needing a matching commitment to translational research if child health is to reap the benefits from this new knowledge. Unfortunately, many prescribed treatments for children have not been adequately tested in children, sometimes resulting in harmful treatments being given and beneficial treatments being withheld. Government, industry, funding agencies, and clinicians are responsible for research priorities being adult-focused because of the greater burden of disease in adults, coupled with financial and marketing considerations. This bias has meant that the equal rights of children to participate in trials has not always been recognised. This is changing, however, as the need for clinical trials in children has been increasingly recognised by the scientific community and broader public, leading to new legislation in some countries making trials of interventions mandatory in children as well as adults before drug approval is given. Trials in children are more challenging than those in adults. The pool of eligible children entering trials is often small because many conditions are uncommon in children, and the threshold for gaining consent is often higher and more complex because parents have to make decisions about trial participation on behalf of their child. Uncertain about what is best, despite supporting the notion of trials in principle, parents and paediatricians generally opt for the new intervention or for standard care rather than trial participation. In this review, we explore issues relating to trial participation for children and suggest some strategies for improving the conduct of clinical trials involving children.

Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children

BACKGROUND Antibiotics are widely administered to children with the intention of preventing urinary tract infection, but adequately powered, placebo-controlled trials regarding efficacy are lacking. This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy prevents urinary tract infection in predisposed children. METHODS We randomly assigned children under the age of 18 years who had had one or more microbiologically proven urinary tract infections to receive either daily trimethoprim-sulfamethoxazole suspension (as 2 mg of trimethoprim plus 10 mg of sulfamethoxazole per kilogram of body weight) or placebo for 12 months. The primary outcome was microbiologically confirmed symptomatic urinary tract infection. Intention-to-treat analyses were performed with the use of time-to-event data. RESULTS From December 1998 to March 2007, a total of 576 children (of 780 planned) underwent randomization. The median age at entry was 14 months; 64% of the patients were girls, 42% had known vesicoureteral reflux (at least grade III in 53% of these patients), and 71% were enrolled after the first diagnosis of urinary tract infection. During the study, urinary tract infection developed in 36 of 288 patients (13%) in the group receiving trimethoprim-sulfamethoxazole (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% confidence interval, 0.40 to 0.93; P = 0.02 by the log-rank test). In the antibiotic group, the reduction in the absolute risk of urinary tract infection (6 percentage points) appeared to be consistent across all subgroups of patients (P > or = 0.20 for all interactions). CONCLUSIONS Long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children. The treatment effect appeared to be consistent but modest across subgroups. (Australian New Zealand Clinical Trials Registry number, ACTRN12608000470392.)

Clinical trials in children

Safety and efficacy data on many medicines used in children are surprisingly scarce. As a result children are sometimes given ineffective medicines or medicines with unknown harmful side effects. Better and more relevant clinical trials in children are needed to increase our knowledge of the effects of medicines and to prevent the delayed or non-use of beneficial therapies. Clinical trials provide reliable evidence of treatment effects by rigorous controlled testing of interventions on human subjects. Paediatric trials are more challenging to conduct than trials in adults because of the paucity of funding, uniqueness of children and particular ethical concerns. Although current regulations and initiatives are improving the scope, quantity and quality of trials in children, there are still deficiencies that need to be addressed to accelerate radically equitable access to evidence-based therapies in children.

The frequency of constipation in children with nocturnal enuresis: a comparison with parental reporting

Aims:  To identify the prevalence of constipation in children with nocturnal enuresis presenting to a tertiary paediatric outpatient service and to assess parental and clinician recognition of constipation.

StaR Child Health: Developing Evidence-Based Guidance for the Design, Conduct, and Reporting of Pediatric Trials

* Abbreviations: DMC — : data monitoring committee SDG — : standard development group StaR Child Health — : Standards for Research in Child Health WHO — : World Health Organization “Lack of research, poor research, and poorly reported research are violations of children’s human rights,” declared Dr Richard Horton in his plenary address to the audience of the first summit of Standards for Research in (StaR) Child Health. StaR Child Health was founded in 2009 to address the paucity and shortcomings of pediatric clinical trials. This initiative involves international experts who are dedicated to developing practical, evidence-based standards to enhance the reliability and relevance of pediatric clinical research. Through a systematic “knowledge to action” plan, StaR Child Health will make efforts to improve and expand the evidence-base for child health across the world. This article introduces the StaR Child Health agenda, the 11 initial priority topics that have been identified, and methods used to address these issues. Approximately 180 participants, including representatives from the World Health Organization (WHO), the US Food and Drug Administration, and the European Medicines Agency, gathered in Amsterdam for the first StaR Child Health summit in October 2009 (Table 1). The summit was held on the eve of the 20th anniversary of the adoption of the United Nations Convention on the Rights of the Child, which recognizes the right of all children “to the enjoyment of the highest attainable standard of health.”1 One impediment to achieving this universal right is the paucity and well documented shortcomings of pediatric research and more specifically clinical trials.2 It is recognized that the quantity, quality, and relevance of data involving children are substantially lower than for adults,3–5 despite data demonstrating that inadequate testing of interventions in children can result in ineffective or harmful treatments being offered or beneficial treatments being withheld.6 View this table: TABLE 1 Chronology of Key Events for StaR Child Health The mission of StaR Child Health is to improve the design, conduct, and reporting of … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

Risk factors for nocturnal enuresis in school-age children.

PURPOSE Although nocturnal enuresis is common in children, its etiology is multifactorial and not fully understood. We evaluated potential risk factors for presence and severity of nocturnal enuresis. MATERIALS AND METHODS A validated, reproducible questionnaire was distributed to 8,230 school children in Sydney, Australia. Nocturnal enuresis was defined as any wetting in the previous month and categorized as mild (1 to 6 nights), moderate (7 or more nights but less than nightly) or severe (nightly). RESULTS Parents of 2,856 children (mean +/- SD age 7.3 +/- 1.3 years) completed the questionnaire (response rate 35%). Overall prevalence of nocturnal enuresis was 18.2%, with 12.3% of patients having mild, 2.5% moderate and 3.6% severe enuresis. Multivariate analysis showed that daytime incontinence (OR 4.8, 95% CI 2.9 to 7.9), encopresis (OR 2.7, 95% CI 1.6 to 4.4), bladder dysfunction (OR 3.6, 95% CI 2.4 to 5.3) and male gender (OR 2.0, 95% CI 1.3 to 3.1) were associated with severe nocturnal enuresis after adjustment for age. Emotional stressors (OR 2.3, 95% CI 1.2 to 4.2) and social concerns (OR 2.4, 95% CI 1.2 to 4.5) were associated with moderate nocturnal enuresis only. CONCLUSIONS Encopresis and daytime incontinence are significant modifiable risk factors for nocturnal enuresis. Expressed as population attributable risk, 23% of nocturnal enuresis is associated with encopresis and daytime incontinence. Psychosocial factors appear to contribute to moderate but not severe nocturnal enuresis.

Standard 1: Consent and Recruitment

A 4-year-old boy with a serious metabolic disorder is eligible for a trial of a new enzyme replacement, the first potential option to treat this disease. His parents have little understanding of the disease or trial, even with careful explanation, but eventually they consent to entry in the trial. The treating clinician doubts whether their consent is valid. This and similar dilemmas face pediatricians in research every day. Many of the therapeutic options for children have not been tested with the rigor applied to similar treatments in adults. This highlights the need for research to improve the evidence base of childrens medicine, for more pediatricians to undertake research, and for more children and families to participate.1 … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

Factors Influencing Quality of Life in Children With Urinary Incontinence

PURPOSE We evaluated quality of life in children with urinary incontinence using a disease specific tool (Pediatric Incontinence Questionnaire) and determined factors that decrease quality of life in affected children. MATERIALS AND METHODS The Pediatric Incontinence Questionnaire was self-administered by children 6 to16 years old with urinary incontinence while attending outpatient clinics at a tertiary pediatric hospital in Australia between October 2009 and May 2010. A weighted summative quality of life score with a range of 1.75 to 7 (7 being lowest quality of life) was generated, and patient characteristics (age, gender, ethnicity, symptom severity) were evaluated as potential predictors. RESULTS Of 146 children invited to participate 138 consented (response rate 95%). About half of the participants (77) were boys, and mean patient age was 10 years. Girls had a lower quality of life than boys (mean score 3.60 vs 3.31, 95% CI 0.10-0.57, p=0.04), and nonwhite children had a lower quality of life than white children (3.97 vs 3.35, 95% CI 0.23-0.99, p<0.01). Older age (r=0.21, p=0.01) but not increasing symptom severity (r=0.15, p=0.09) or underlying chronic disease (difference 0.12, p=0.91) was correlated to decreased quality of life. Multivariate regression analysis demonstrated that older age, nonwhite ethnicity and female gender were independent predictors of decreased quality of life. CONCLUSIONS Older age, female gender and nonwhite ethnicity are associated with a lower disease specific quality of life in children with urinary incontinence. Clinicians need to be aware of the differential effect of urinary incontinence in children of different ages and ethnic backgrounds.

Teaching by humiliation and mistreatment of medical students in clinical rotations: a pilot study

Objective: To generate a contemporary understanding of “teaching by humiliation” as experienced by medical students in Australia.

Management of nocturnal enuresis

#### Summary points #### Sources and selection criteria We searched Medline, Embase, and the Cochrane Database of Systematic Reviews using the search terms “enuresis” or “bedwetting” as keywords. Systematic reviews, meta-analyses, population based studies, randomised controlled trials, and studies published in the past five years were prioritised. Nocturnal enuresis (enuresis or bedwetting) is the most common type of urinary incontinence in children. Depending on the definition, prevalence is 8-20% for 5 year olds, 1.5-10% for 10 year olds, and 0.5-2% for adults, with 2.6% of 7.5 year old children wetting on two or more nights a week.1 Prevalence seems to be similar worldwide. Here, we review current knowledge about the treatment of this common condition. Nocturnal enuresis is intermittent involuntary voiding during sleep in the absence of physical disease in a child aged 5 years or more. A minimum of one episode a month for at least three months is required for the diagnosis to be made.2 A large epidemiological study showed that nocturnal enuresis is more common in males at all ages, and is more likely to persist in those with frequent wetting.3 Nocturnal enuresis is usually idiopathic and is commonly associated with daytime urinary incontinence (seen in 3.3% of 7.5 year olds in a large epidemiological study1), faecal incontinence, and chronic constipation. In …