Hypothalamic Obesity Following Craniopharyngioma Surgery: A Pilot Trial of Combined Metformin and Diazoxide Therapy
Condition: Hypothalamic Obesity
MeSH terms: Craniopharyngioma; Adamantinoma; Obesity
Study type: Interventional
Phase: Phase 2

Summary: 
      To study the effect of combined diazoxide-metformin therapy on body weight in youth with
      hypothalamic obesity following treatment for craniopharyngioma. A secondary objective is to
      evaluate changes in insulin resistance (IR), beta-cell function, features of the metabolic
      syndrome, muscle metabolism and intramyocellular lipid.

      Hypothesis: Treatment with diazoxide and metformin will result in weight loss or slowed
      weight gain and improved metabolic profile, compared to pretreatment levels.
    

Detailed description: 
      46 children under the age of 22 years have been treated surgically for craniopharyngioma
      tumor and are currently followed at the Hospital for Sick Children, Toronto. Approximately
      50% are obese (BMI ≥ 95th percentile for age and gender assessed from the updated Centre for
      Disease Control growth charts), all of whom have panhypopituitarism requiring hormone
      replacement therapy. These children are assessed regularly in Endocrine Clinic and also are
      invited to attend a comprehensive care clinic for evaluation by an endocrinologist (Principal
      Investigator), neurosurgical clinical nurse practitioner, dietitian, exercise physiologist,
      psychologist and social worker to provide multi-disciplinary dietary and exercise
      consultation and psychological counseling for weight related concerns. This clinic will
      provide the infrastructure for recruitment and follow-up of study patients. Recruitment of
      eight subjects for this pilot study will occur over 6 months from patients attending the
      comprehensive clinic. This number was chosen as it is equivalent to the number chosen in the
      pilot study of octreotide by Lustig which showed beneficial changes in body mass index with
      treatment.

      This study evaluates a novel combination therapy in children with hypothalamic obesity at
      very high risk for complications. Evaluation of insulin resistance and metabolic changes on
      therapy will allow a better understanding of how insulin secretion relates to weight gain in
      this population. Successful therapy in a pilot setting will provide necessary data for a
      larger randomized trial in individuals with hypothalamic obesity including children with
      craniopharyngioma and others with damage to the hypothalamus secondary to other tumors,
      surgery or cranial irradiation.
    

Intervention name(s): Diazoxide; Metformin
Intervention type(s): Drug; Drug
Intervention description(s): Diazoxide will be initiated at half the dose (100 mg per day) for 2 weeks to allow the insulin sensitizing action of metformin to take effect. Dosage will be increased to 200mg daily, divided twice daily with meals for 6 months.; Metformin will be initiated at 500 mg twice daily and increased to 1000 mg twice daily over a one week period to minimize gastrointestinal side effects. the 2000mg is to be taken with meals for 6 months.
Other intervention name(s): Proglycem; Novo-metformin
Intervention MeSH terms: Metformin; Diazoxide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Craniopharyngioma surgery; Hypothalamic Obesity; Children; Combined Diazoxide and Metformin