Hypothalamic Obesity Following Craniopharyngioma Surgery: A Pilot Trial of Combined Metformin and Diazoxide Therapy | RxWiki

Hypothalamic Obesity Following Craniopharyngioma Surgery: A Pilot Trial of Combined Metformin and Diazoxide Therapy

Overview[ - collapse ][ - ]

Purpose	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.
Condition	Hypothalamic Obesity
Intervention	Drug: Diazoxide Drug: Metformin
Phase	Phase 2
Sponsor	The Hospital for Sick Children
Responsible Party	The Hospital for Sick Children
ClinicalTrials.gov Identifier	NCT00892073
First Received	April 30, 2009
Last Updated	August 14, 2013
Last verified	August 2013

Tracking Information[ + expand ][ + ]

First Received Date	April 30, 2009
Last Updated Date	August 14, 2013
Start Date	May 2006
Estimated Primary Completion Date	January 2008
Current Primary Outcome Measures	Change in BMI and BMI SDS (calculated using for Disease Control formula - www.cdc.gov.doc) over 6 months of treatment compared to change in BMI and BMI SDS over 6 month 'run-in' period (prior to study start) [Time Frame: 6 months prior to baseline, Baseline, 6 months after baseline] [Designated as safety issue: No]
Current Secondary Outcome Measures	Insulin secretion [Time Frame: Baseline to 6 months] [Designated as safety issue: No] Insulin resistance [Time Frame: Baseline to 6 months] [Designated as safety issue: No] Lipid profile [Time Frame: Baseline to 6 months] [Designated as safety issue: No] Adiponectin [Time Frame: Baseline to 6 months] [Designated as safety issue: No] Leptin [Time Frame: Baseline to 6 months] [Designated as safety issue: No] Features of the metabolic syndrome [Time Frame: Baseline to 6 months] [Designated as safety issue: No]

Descriptive Information[ + expand ][ + ]

Brief Title	Hypothalamic Obesity Following Craniopharyngioma Surgery: A Pilot Trial of Combined Metformin and Diazoxide Therapy
Official Title	Combined Diazoxide and Metformin Therapy in Children With Hypothalamic Obesity Secondary to Craniopharyngioma: A Pilot Study
Brief 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.
Study Type	Interventional
Study Phase	Phase 2
Study Design	Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Hypothalamic Obesity
Intervention	Drug: Diazoxide 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. Other Names: ProglycemDrug: Metformin 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 Names: Novo-metformin
Study Arm (s)	Experimental: Diazoxide and Metformin Therapy

Recruitment Information[ + expand ][ + ]

Recruitment Status	Completed
Estimated Enrollment	9
Estimated Completion Date	January 2008
Estimated Primary Completion Date	January 2008
Eligibility Criteria	Inclusion Criteria: - Craniopharyngioma at least one year following surgery - Evidence of at least one other endocrinopathy of hypothalamic origin - Stable hormone replacement therapy (with one or more of thyroxine hydrocortisone, DDAVP, sex steroids and GH) - Obesity, defined as weight >120% Ideal Body Weight (IBW) or BMI > 27 kg/m2, with normal weight for height before tumour diagnosis and weight gain >2SD above mean for age for 1 year following tumour treatment (41). - Age 9 -22 years - Minimum of 6 months of standard diet and exercise intervention (run-in period). This was chosen to allow a period of prospective measurements to establish individual baseline slope of change in BMI SDS prior to initiation of active treatment with diazoxide and metformin. Exclusion Criteria: - Contraindications for Metformin or Diazoxide use (history or evidence of cardiac, renal, or progressive hepatic disease , diabetes or hypoxic conditions) - Pharmacologic doses of glucocorticoids or use of other medications known to affect glucose metabolism (e.g. beta-blockers, oral hypoglycemics) - Growth hormone (GH) initiation in the preceding 6 months or planned initiation in the next 6 months (to rule out potential confounding effect of GH on weight / body composition and glucose metabolism). - Use of other weight loss medications - Inability of the family and/or patient to comply with study protocol - Non English speaking
Gender	Both
Ages	9 Years
Accepts Healthy Volunteers	No
Contacts	Not Provided
Location Countries	Canada

Administrative Information[ + expand ][ + ]

NCT Number	NCT00892073
Other Study ID Numbers	1000008879
Has Data Monitoring Committee	Yes
Information Provided By	The Hospital for Sick Children
Study Sponsor	The Hospital for Sick Children
Collaborators	Not Provided
Investigators	Principal Investigator: Jill Hamilton, MD The Hospital for Sick Children
Verification Date	August 2013

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