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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Jill Hamilton, The Hospital for Sick Children
ClinicalTrials.gov Identifier:
NCT00892073
First received: April 30, 2009
Last updated: August 14, 2013
Last verified: August 2013
  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 Intervention Phase
Hypothalamic Obesity
Drug: Diazoxide
Drug: Metformin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Combined Diazoxide and Metformin Therapy in Children With Hypothalamic Obesity Secondary to Craniopharyngioma: A Pilot Study

Resource links provided by NLM:


Further study details as provided by The Hospital for Sick Children:

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 ]

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 ]

Enrollment: 9
Study Start Date: May 2006
Study Completion Date: January 2008
Primary Completion Date: January 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   9 Years to 22 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00892073

Locations
Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada
Sponsors and Collaborators
The Hospital for Sick Children
Investigators
Principal Investigator: Jill Hamilton, MD The Hospital for Sick Children
  More Information

No publications provided

Responsible Party: Jill Hamilton, Staff Endocrinologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT00892073     History of Changes
Other Study ID Numbers: 1000008879, 9427-H1117-120C
Study First Received: April 30, 2009
Last Updated: August 14, 2013
Health Authority: Canada: Health Canada

Keywords provided by The Hospital for Sick Children:
Craniopharyngioma surgery
Hypothalamic Obesity
Children
Combined Diazoxide and Metformin

Additional relevant MeSH terms:
Adamantinoma
Craniopharyngioma
Obesity
Body Weight
Bone Diseases
Bone Neoplasms
Musculoskeletal Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Nutrition Disorders
Overnutrition
Overweight
Signs and Symptoms
Diazoxide
Metformin
Antihypertensive Agents
Cardiovascular Agents
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on November 19, 2014