Designing clinical trials for a complex disease: Pediatric obesity

Introduction

The prevalence of obesity has increased rapidly worldwide in adults and children. In the US over 14 million children, including 22% of adolescents, meet criteria for obesity, according to the American Academy of Pediatrics. The most common cause of obesity in children and adolescents is a caloric imbalance with excess calories consumed without being spent through activity. Efforts to treat pediatric obesity typically involve increasing exercise and improving dietary intake. This has had limited success on long-term weight loss. With the increasing development of drug treatments for obesity in adults in recent years, sponsors may wish to investigate possible pediatric obesity treatments. In this blog, we outline some of the considerations for the design and execution of pediatric obesity studies.

Obesity in childhood

Obesity is a complex disease involving multiple factors such as genetics, biology, physiology and social factors. Pediatric obesity is further complicated by family, developmental and societal factors that clinicians need to consider when choosing a treatment. Many of the behaviours around food and activity are developed in early childhood, led by parents and caregivers. However, these behaviours can change throughout our lives with physical, cognitive, social and developmental changes. For younger children and infants, parents and caregivers decide which foods to provide. These may include highly processed, calorie dense food. Conversely, parents who overly restrict food may result in children to overconsuming processed foods when they reach school age or adolescence. Physical activity also changes throughout childhood due to school schedules and technology use. Video games, smartphone and computer use in adolescence can further limit opportunities for physical activity.¹

Patient selection considerations

When selecting participants for a pediatric trial, sponsors must weigh the risk of exposure to the study drug against the consequences of continued obesity. Alongside this are the factors which should be considered in patient selection for any pediatric trial: age, severity of the condition, pubertal maturity and whether the patient has comorbid conditions. FDA guidance recommends identifying the causes of obesity through a medical assessment as well as screening for comorbidities including glucose intolerance and hypertension. Medication can be considered for children as young as six years old who have severe obesity according to the European Medicines Agency (EMA). Trials for older and younger children should be performed separately because of their different cognitive and developmental stages. For younger children there will be more parental involvement than for adolescents.

Comorbidities and endpoint selection

Pediatric obesity has a number of associated comorbidities and patients may be using other medications. Some of these medications may affect weight, including selective serotonin reuptake inhibitors, stimulants, insulin and metformin. Obesity is also associated with a number of liver abnormalities known as metabolic-dysfunction associated steatotic liver disease (MASLD). Central obesity, insulin resistance, type 2 diabetes, dyslipidaemia and hypertension are associated with MASLD. Obesity is a risk factor for obstructive sleep apnoea for children and adolescents. This leads to disordered sleep and impacts school performance, behaviour and social engagement. Children and teenagers with obesity may also deal with psychosocial issues such as depression, social isolation, bullying, low self-esteem and reduced quality of life. Obesity may be stigmatised and compared to non-obese peers, young people with obesity are more likely to be bullied at school. The emotional and psychological effects of childhood obesity can continue much later in life.

In pediatric obesity trials, primary endpoint selection goes beyond the standard benchmarks of adult trials. Regulatory agencies provide limited guidance. Consequently, there is a lot of debate about what may be appropriate. Some proposals are to present data to allow comparison of efficacy for example the absolute and percentage change in BMI, change in percentage the 95th BMI percentile, or change in percentage of the median. Novel endpoints beyond weight loss could be linked to improvements in some of the various metabolic, orthopaedic, psychological or endocrinologic comorbidities.

Overcoming challenges to patient enrolment and retention

Parents often underestimate their children’s weight and associated comorbidities. Parents who do not recognise their children are overweight are less likely to provide the necessary support to help their children achieve a healthy weight.² Reaching these parents and educating them about the negative health impacts of childhood obesity is a prerequisite to their clinical trial enrolment. Childhood obesity is also more prevalent in some groups such as Hispanic and non-Hispanic Black children.³ These groups tend to be clinical trial naïve or hesitant and their enrolment in clinical trials is relatively low. Sponsors should consider a study campaign designed to support diversity and inclusivity. Selection of study sites should be informed by their accessibility to these groups. Mobile research units could be used to support enrolment and retention for people unable to travel.

Creating engaging educational materials for parents and children is essential to explain the importance of the study and their roles in participating. During study design sponsors should be aware of the possible burdens of on-site visits, fasting labs, blood draws, patient reported outcomes and other requirements. Limiting these burdens or offering alternatives that reduce them may help with patient retention. These could include using home health visits, electronic tools to record patient-reported outcomes and providing pain- and anxiety-reducing tools.

Sponsors should also give participants and their caregivers strategies to manage unwanted side effects such as nausea and diarrhoea. Potential concerns about suicidal thoughts or actions should be addressed in discussion and with supporting materials. Questions and conversations throughout the trial should be encouraged and supported by the study team.

Conclusion

Treating the growing problem of childhood obesity calls for exploring new approaches and treatments. Developing these treatments will require gathering safety and efficacy data through well-designed clinical trials. Pediatric clinical trials need to be designed and executed by experienced teams following regulatory guidelines. These teams and their trials need to be patient-centric to ensure they can enrol and retain pediatric patients with their caregivers’ support.

Contact us to explore how ICON can support your pediatric clinical trial requirements.

This article was first published on Pharmafocus on 4 June 2024.

References

¹ Hampl SE, Hassink SG, Skinner AC, et al. Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity. Pediatrics. 2023;151(2).

² Abbas N, Rouaiheb H, Saliba J, El‑Bikai R. Childhood obesity: Facts and parental perceptions. World Acad Sci J. 2023;5(6):38.

³ Childhood Obesity Facts. https://www.cdc.gov/obesity/childhood-obesity-facts/childhood-obesity-facts.html. Updated April 2 2024. Accessed 18 November, 2024.