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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00892073
Recruitment Status : Completed
First Posted : May 4, 2009
Last Update Posted : November 17, 2017
Information provided by (Responsible Party):
Jill Hamilton, The Hospital for Sick Children

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.

Condition or disease Intervention/treatment Phase
Hypothalamic Obesity Drug: Diazoxide Drug: Metformin Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combined Diazoxide and Metformin Therapy in Children With Hypothalamic Obesity Secondary to Craniopharyngioma: A Pilot Study
Study Start Date : May 2006
Actual Primary Completion Date : January 2008
Actual Study Completion Date : January 2008

Arm Intervention/treatment
Experimental: Diazoxide and Metformin Therapy 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 Name: Proglycem

Drug: 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 Name: Novo-metformin

Primary Outcome Measures :
  1. Change in BMI and BMI SDS (calculated using for Disease Control formula - 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 ]

Secondary Outcome Measures :
  1. Insulin secretion [ Time Frame: Baseline to 6 months ]
  2. Insulin resistance [ Time Frame: Baseline to 6 months ]
  3. Lipid profile [ Time Frame: Baseline to 6 months ]
  4. Adiponectin [ Time Frame: Baseline to 6 months ]
  5. Leptin [ Time Frame: Baseline to 6 months ]
  6. Features of the metabolic syndrome [ Time Frame: Baseline to 6 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   9 Years to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00892073

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Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada
Sponsors and Collaborators
The Hospital for Sick Children
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Principal Investigator: Jill Hamilton, MD The Hospital for Sick Children
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Responsible Party: Jill Hamilton, Staff Endocrinologist, The Hospital for Sick Children Identifier: NCT00892073    
Other Study ID Numbers: 1000008879
First Posted: May 4, 2009    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017
Keywords provided by Jill Hamilton, The Hospital for Sick Children:
Craniopharyngioma surgery
Hypothalamic Obesity
Combined Diazoxide and Metformin
Additional relevant MeSH terms:
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Nutrition Disorders
Body Weight
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Bone Neoplasms
Neoplasms by Site
Bone Diseases
Musculoskeletal Diseases
Hypoglycemic Agents
Physiological Effects of Drugs
Antihypertensive Agents
Vasodilator Agents