Efficacy and Safety of Phentermine/Topiramate in Youth With Hypothalamic Obesity

Eligibility Criteria

• 1. Males and Females; Ages 12-28 years (inclusive)
• 2. 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)
• 3. Obesity (BMI \> 95th%ile for age/sex using CDC 2000 reference for under 18; BMI \> 30 kg/m2 for 18+ years)
• 4. 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.
• 5. 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.
• 6. 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.
• 7. 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.
• 1. Contraindication to Phentermine or Topiramate, as assessed using current package inserts. Including: History of glaucoma and known hyperthyroidism.
• 2. 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).
• 3. Current or recent (\<14 days) use of monoamine oxidase inhibitor.
• 4. Known hypersensitivity to sympathomimetic amines.
• 5. 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.
• 6. Females who are pregnant, breastfeeding, or planning to become pregnant during the trial.
• 7. "Brittle" diabetes insipidus (in the opinion of the referring endocrinologist, e.g. requiring frequent hospitalizations and/or frequent abnormal sodium values).
• 8. Diabetes mellitus requiring insulin/secretagogue. HbA1c \> 8.5% at Screening.
• 9. Clinically significant liver disease and/or known severe hepatic impairment. ALT \> 3 x Upper Limit of Normal (ULN) AST \> 3 x ULN
• 10. Clinically significant kidney disease. GFR\<60 ml/min/1.73m2
• 11. History of seizure in the 12 months prior to Screening.
• 12. History of substance abuse, depression of moderate or greater severity, psychiatric disorder and/or suicidality.
• 13. History of abdominal surgery including gastric bypass.
• 14. Current use of supra-physiologic steroids.
• 15. 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).
• 16. Concurrent use carbonic anhydrase inhibitor.
• 17. 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.
• 18. Cognitive impairment that, in the opinion of the investigator, precludes participation in the study.
• 19. Individuals considered, in the Investigator's opinion, otherwise not suitable to participate in the study.