Efficacy and Safety of Phentermine/Topiramate in Youth With Hypothalamic Obesity
Status: Not yet recruiting

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. In this pilot trial, our objective is to gather key preliminary data about phentermine/topiramate (Ph/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.

Preliminary assessments of safety, adverse events, dosing (Aim 1), as well as of efficacy (% BMI loss, Aim 2) will be made in a 28-week parallel-arm double-blinded Phase 2 placebo-controlled clinical trial in 12-28-year-old individuals with HO.

Eligibility:
- EligibilityCriteria: Inclusion Criteria:  Males and Females; Ages 12-28 years (inclusive) History of rapid weight gain related to tumor onset or treatment, as assessed by an experienced endocrinologist (for example, change in BMI z-score > 0.2 and/or BMI +5% during the first 6 months following tumor treatment) Obesity (BMI > 95th%ile for age/sex using CDC 2000 reference for under 18; BMI > 30 kg/m2 for 18+ years) Recent evidence of hypothalamic injury by brain MRI with central review; >6 months status-post definitive therapy (surgery, chemotherapy, or radiation); no major operations/surgeries planned during the study period. Stable on pituitary replacement* and/or appetite-modulating medications (including stimulants) for at least 2 months. *Adjustments of less than 25% (<25%) are permitted to hydrocortisone, growth hormone or thyroid hormone. Sex steroids and DDAVP are exempt. Post-menarchal females must use a highly effective form of contraception, unless hypogonadotropic hypogonadism is documented. All participating females will have pregnancy testing as outlined in the protocol. Participants must be able to communicate well with the investigative team, must comply with requirements of the study, and be able to provide written informed consent and/or assent for individuals less than 18y with consent of a parent/legal guardian.  Exclusion Criteria:  Contraindication to Phentermine or Topiramate, as assessed using current package inserts. Including: History of glaucoma and known hyperthyroidism. Known history of metabolic acidosis, low bicarbonate on screening laboratory (below lower limit of normal), or clinically significant bone disease requiring medication (not calcium or vitamin D). Current or recent (<14 days) use of monoamine oxidase inhibitor. Known hypersensitivity to sympathomimetic amines. Clinically significant cardiovascular conditions, as defined as any of the following: i) elevated blood pressure, defined as >97%ile for age, sex and height for adult participants abnormal blood pressure is defined as Stage 2 hypertension (systolic BP > 160 mm Hg or diastolic BP > 100 mm Hg); ii) history of cardiac arrhythmia or arrhythmia detected on screening ECG; iii) history of heart failure and/or cardiomyopathy; iv) prolonged QTc interval (QTc > 460 msec), and/or long QT syndrome phenotype and/or positive genotype for long QT syndrome pathogenic; v) history of cardiac disease including coronary artery disease. Females who are pregnant, breastfeeding, or planning to become pregnant during the trial. "Brittle" diabetes insipidus (in the opinion of the referring endocrinologist, e.g. requiring frequent hospitalizations and/or frequent abnormal sodium values). Diabetes mellitus requiring insulin/secretagogue. HbA1c > 8.5% at Screening. Clinically significant liver disease and/or known severe hepatic impairment. ALT > 3 x Upper Limit of Normal (ULN) AST > 3 x ULN Clinically significant kidney disease. GFR<60 ml/min/1.73m2 History of seizure in the 12 months prior to Screening. History of substance abuse, depression of moderate or greater severity, psychiatric disorder and/or suicidality. History of abdominal surgery including gastric bypass. Current use of supra-physiologic steroids. History of allergy or sensitivity to test agents. Including individuals with known aspirin allergy or hypersensitivity and/or known allergy to FD&C Yellow No. 5 (tartrazine). Concurrent use carbonic anhydrase inhibitor. New weight management medication (or more than 5% decrease in weight over prior 2 months on any current, stable regimen), new stimulant, and/or investigational medication within 2 months prior to Screening, and/or plans to initiate new weight management regimen. Cognitive impairment that, in the opinion of the investigator, precludes participation in the study. Individuals considered, in the Investigator's opinion, otherwise not suitable to participate in the study. - HealthyVolunteers: No - Gender: All - MinimumAge: 12 Years - MaximumAge: 28 Years - StdAgeList: Child, Adult