Industry Insight

Alan Baldridge and Heather Peterson from ICON consider the prevalence of paediatric obesity and assess clinical trials of its treatments

According to the American Academy of Pediatrics over 14 million children in the US, including 22% of adolescents, meet criteria for obesity. Until recently, interventions for overweight and obese children were focused on increasing caloric expenditure through exercise and improving dietary caloric intake (both quantity and quality of food choice). These interventions have had limited success on long-term weight loss and prevention of associated morbidities.

Obesity is a complex interplay of biology, physiology, genetics, social and societal factors. Paediatric obesity is complicated by the interplay of family, societal, developmental and physiologic factorsthatmustbeconsideredwhenimplementing new therapies in the paediatric age group. The most common cause of obesity throughout childhood and adolescence is an inequity in energy balance; that is, excess caloric intake without appropriate caloric expenditure.

Children develop behaviours associated with eating and activity that evolve throughout their lives. These behaviours transition from parent-directed to self-directed control due to physical, cognitive, communicative, social and developmental progress. While parents and caregivers determine what food is available to infants and younger children, recent trends have increased the consumption of calorie dense, highly processed food. Also, meal sizes have increased with pressure to finish the complete meal. Paradoxically, parents with excessive concern about healthy diet or highly restrictive food practices may promote over-consumption of highly palatable foods when available to school-age and adolescent children. Limited physical activity and sedentary behaviour associated with school schedules and technology limit caloric expenditure. During the adolescent years, more sedentary behaviours such as video game and computer use can further limit physical exercise.1

In determining the target population for paediatric obesity pharmacotherapy clinical trials, one must balance the risks of study drug exposure against the consequences of persistent obesity. Factors to consider include age, severity of obesity, pubertal maturation and the presence or absence of comorbid conditions. The US Food and Drug Administration (FDA) guidance document for industry in developing products for weight management, in reference to the paediatric population, recommends a medical assessment to identify genetic or endocrinologic causes of obesity, as well as to screen for comorbidities including dyslipidaemia, hypertension and glucose intolerance. The European Medicines Agency (EMA) suggests that medication could be considered for children with severe obesity as young as six years of age. Also, it should be recognised that separate trials of older and younger children should be performed owing to the unique cognitive and developmental features of children vs adolescents. Different lifestyle modification therapy strategies should be used and more parental involvement for younger children.

The FDA recommends that initial obesity pharmacotherapy trials include participants with a BMI greater than the 95th percentile and with more than one weight-related comorbid condition; and once a satisfactory risk/benefit additive or synergistic effect has been determined. Due to the common comorbidity and increased healthcare utilisation of paediatric obese patients, it isnotun common forpotentially eligible participants to be using other medications. These medications may have weight-altering effects. Examples of these medications include selective serotonin reuptake inhibitors, atypical antipsychotic medications, stimulants, insulin, metformin and hormonal contraception. Researchers should strive to strike a balance between a ‘clean’ evaluation of obesity pharmacotherapy and the need for general isability to clinical care and the ability to recruit into a proposed trial.

Primary endpoint selection for paediatric obesity trials goes beyond the standard benchmarks for adult trials. There is still much discussion on what endpoints are most appropriate in paediatric studies with limited guidance available from regulatory agencies. Some have proposed that data be presented in a variety of ways to allow adequate comparison of efficacy eg, absolute and percentage of change in BMI, change in percentage of the 95th BMI percentile, change in percentage of the median.

Childhood obesity is associated with a variety of metabolic, orthopaedic, endocrinologic and psychological sequalae. Each of these outcomes could be a novel endpoint beyond weight loss in paediatric weight loss trials. Obesity is an independent risk factor for obstructive sleep apnoea (OSA) in children and adolescents. Obstructive sleep apnoea leads to disordered sleep, school performance issues, behaviour concerns and social consequences.2 Children with OSA do better than adolescents and adults with OSA in terms of cardiovascular stress or metabolic syndrome. However, in children, behavioural and neurocognitive dysfunction are the most critical and frequent end-organ morbidities associated with OSA and can lead to school and social dysfunction. In adolescents, obesity and OSA can cause oxidative systemic stress and inflammation. When seen concurrently, these can result in more severe metabolic dysfunction and cardiovascular outcomes later in adulthood.

Obesity is related to a clinical spectrum of liver abnormalities known as metabolic-dysfunction associated steatotic liver disease (MASLD).

MASLD includes steatosis (increased liver fat without inflammation) and MASH (increased liver fat with inflammation and hepatic injury). MASLD is closely associated with metabolic syndrome including central obesity, insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and acanthosis nigricans.

Obese children and adolescents may experience psychosocial sequelae, including depression, bullying, social isolation, diminished self-esteem, behavioural problems, dissatisfaction with body image and reduced quality of life. Compared with normal-weight counterparts, being overweight or obese is one of the most common reasons children and adolescents are bullied at school. The consequence of stigma, bullying and teasing related to childhood obesity are pervasive and can have severe implications for emotional and physical health and performance that can persist later in life.

It is far too common for parents or caregivers of overweight or obese children to underestimate their child’s weight status and acknowledgement of associated comorbidities. In addition, parents often deflect concerns of their child becoming overweight.3 This often leads to little or no motivation to seek support or encourage positive change in dietary or lifestyle modifications that can negatively impact clinical trial enrolment.

Childhood obesity prevalence is highest among Hispanic and non-Hispanic Black children, and these families also tend to be clinical trial naïve or  demonstrate clinical trial hesitancy.4 Enrolment of these diverse populations into clinical trials is known to be relatively low. In order to increase diversity, consideration should be given to creating a branded study campaign that supports diversity and inclusivity to create interest and promote these individuals to ask questions. Assess the placement of study centres to allow accessibility for all. Diversity of the principal investigators selected for study will enhance trust among those with clinical trial hesitancy. Host community events to provide education and awareness in a non-threatening environment. Deploy mobile research units to support enrolment and retention for those unable to travel to study centres.

When developing study designs for children and adolescents in obesity studies be mindful of the expectations placed on them. Consider the number of on-site visits, fasting labs, blood draws, extended PK visits, patient reported outcomes and diaries that will need to be completed. Reduce the associated burden by offering home health, electronic means to complete patient-reported outcomes (PROs) and diaries, and offer anxiety and pain-reducing tools. 

To support adherence and gain the buy-in of the participants, it is essential to create educational materials to help them understand the importance of each task asked of them. Ensure the participants and families clearly understand the big picture of clinical trial participation and how their participation has the potential to improve treatment options for others like them. Offer intensive behaviour and lifestyle modification counselling for the family unit. Recent AAP guidance recommends a minimum of 26 hours of face-to-face family-based treatment over a twelve-month period. Offer small incentives or rewards to recognise milestones met and celebrate the participant with gratitude for the time they’ve devoted to study participation.

Lastly, take into account the negative publicity surrounding many obesity medications and experimental treatments. Address this head-on by providing supplemental strategies to alleviate unwanted side effects associated with gastrointestinal upset, such as nausea and diarrhoea. Discuss potential concerns of suicidal thoughts or actions and provide supportive materials to caregivers and participants for reference, encourage questions and support ongoing conversations.

With the continuing increase in the number of medications in development to treat obesity, it will be important to focus on evaluating the agents in paediatric patients. Generating safety and efficacy data from well-designed, controlled clinical trials is the only mechanism to characterise the features of those likely to respond and the duration of treatment required to sustain that response. Because of the novel aspects of paediatric obesity care, paediatric pharmacotherapy, paediatric clinical trials need to be carefully designed by experienced teams with expertise following appropriate regulatory guidelines.