SUMMARY
Hypothalamic obesity (HO) refers to the substantial weight gain that often complicates hypothalamic brain
tumors. Children with this treatment-recalcitrant form of obesity have excess rates of metabolic sequelae
compared to otherwise healthy children with similar obesity, and later experience excess mortality related to
cardiometabolic disease. Our team has made important progress in recent trials. In our 36-week placebo-
controlled trial (ECHO, NCT02664441), participants receiving exenatide, a glucagon-like peptide-1 receptor
agonist (GLP1RA), demonstrated a larger reduction in body fat than those receiving placebo. While these results
are encouraging, in 50% of participants, BMI did not decrease with exenatide, highlighting the need to address
treatment non-response. Another pharmacologic option tested by our team is intranasal oxytocin (OXT), which
has had success in our case studies and reassuring safety. However, in a recently concluded cross-over study,
we observed a nominal, not statistically significant, within-subject weight loss of -0.6 kg attributable to OXT as
compared to placebo (NCT02849743), but suggestions of benefit for anxiety and impulsivity. These trials
highlight our team's experience and our commitment to developing evidence-supported, individualized
approaches to address the problem of treatment non-response in HO. In future, we envision pursuing an
innovative sequential multiple assignment randomized trial (SMART) design. A SMART is a multi-staged clinical
trial where at each stage, individuals are re-randomized to the next intervention based on accumulated
information about response to the previous intervention. HO is particularly suited to a SMART as non-responders
may benefit from alternative and/or combination interventions. Moreover, the SMART allows for the identification
of biomarkers, such as hypothalamic injury on MRI, to support optimal and efficient treatment planning. In this
pilot trial, our objective is to gather key preliminary data about phentermine/topiramate (Ph/T), a promising option
containing a sympathomimetic amine (Ph) combined with an appetite-suppressive epilepsy drug (T) that is FDA-
approved for “common” obesity but has never been tested in HO. The subset of individuals with HO who
experience hyperphagia or excess daytime sleepiness may benefit from the Ph/T-induced decrease in appetite
and increase in alertness. We will make preliminary assessments of safety, adverse events and dosing (Aim 1),
as well as efficacy (% BMI loss, Aim 2) in a 27-week parallel-arm double-blinded Phase 2 randomized placebo-
controlled clinical trial in 12-25-year-old individuals with HO, following the FDA-approved dose titration. We will
also measure the proportion of individuals who experience 5% or 2.5% decrease in BMI, explore effects of Ph/T
on body fat, eating, autonomic tone, and cognition, and will bank biological samples for future mechanistic
analyses. Semi-structured exit interviews with participants and caregivers will help to explain treatment response
or non-response, experience of adverse events, and impressions of trial participation. We will next design a
SMART to include GLP1RA, Ph/T, and/or other novel therapies like OXT alone and/or in combination for HO.
