Effect of Metreleptin Therapy in the Treatment of Severe Insulin Resistance

Study Overview
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Brief Summary
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Study Description: Patients with mutations of the insulin receptor have diabetes that is challenging to control with conventional therapies, leading to early morbidity and mortality. We hypothesize that recombinant leptin (metreleptin) in these patients will improve glycemia control. Objectives: Primary Objective: To determine if 1 year of metreleptin will improve glycemia control in patients with genetic defects of the insulin receptor. Secondary Objectives: To determine mechanisms by which metreleptin improves glycemia. Endpoints: Primary Endpoint: Hemoglobin A1c. Secondary Endpoints: fasting plasma glucose, fasting insulin/C-peptide, glucose/insulin/C-peptide area under the curve during oral glucose tolerance test. Study Population: 20 male or female patients with mutations of the insulin receptor, age (Bullet)5 years, at the NIH Clinical Center. Description of Sites/Facilities Enrolling Participants: Description of Study Intervention: NIH Clinical Center Open label study of metreleptin, 0.2 mg/kg/day (max dose 0.24 mg/kg/day).

Detailed Description
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Study Description: Patients with mutations of the insulin receptor have diabetes that is challenging to control with conventional therapies, leading to early morbidity and mortality. We hypothesize that recombinant leptin (metreleptin) in these patients will improve glycemia control. Objectives: Primary Objective: To determine if 1 year of metreleptin will improve glycemia control in patients with genetic defects of the insulin receptor. Secondary Objectives: To determine mechanisms by which metreleptin improves glycemia. Endpoints: Primary Endpoint: Hemoglobin A1c. Secondary Endpoints: fasting plasma glucose, fasting insulin/C-peptide, glucose/insulin/C-peptide area under the curve during oral glucose tolerance test. Study Population: 20 male or female patients with mutations of the insulin receptor, age (Bullet)5 years, at the NIH Clinical Center. Description of Sites/Facilities Enrolling Participants: Description of Study Intervention: NIH Clinical Center Open label study of metreleptin, 0.2 mg/kg/day (max dose 0.24 mg/kg/day).

Official Title
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Phase II Trial of Effect of Metreleptin Therapy in Severe Insulin Resistance

Conditions
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Severe Insulin Resistance

Intervention / Treatment
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* Drug: Metreleptin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Provision of signed and dated informed consent form Male or female, aged > 5 years Clinically significant, severe insulin resistance caused by a known or suspected defect in the insulin receptor Presence of at least one of the following metabolic abnormalities: Fasting insulin >30 micro U/ml, or Presence of diabetes as defined by the 2006 American Diabetes Association (ADA) criteria: Fasting plasma glucose >= 126 mg/dL 2 hour plasma glucose >= 200 mg/dL following a 75 gram (1.75g/kg if less than 40kg) oral glucose load, or Diabetic symptoms with a random plasma glucose >= 200 mg/dL EXCLUSION CRITERIA: Pregnant at time of enrollment, women in their reproductive years who do not use an effective method of birth control, and women currently nursing or lactating within 6 weeks of having completed nursing. Known infectious liver disease Known HIV infection Current alcohol or substance abuse Active tuberculosis Use of anorexigenic drugs Other conditions which in the opinion of the clinical investigators would impede completion of the study. Subjects who have a known hypersensitivity to E. Coli derived proteins.

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leptin Treatment<br>300 mg of study drug administered via subcutaneous (SC) injections. | Drug: Metreleptin<br>* Administered SC twice/day to achieve physiological concentrations that will be effective in improving the severe state of insulin resistance seen in patients with genetic defects on their insulin receptor mutation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1C | Change in HbA1C at month 12 from baseline. | Change at month 12 from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Insulin Level | Change in fasting insulin level at month 12 from baseline | Change at month 12 from baseline | 
| Change in Fasting Blood Glucose | Change in fasting blood glucose at month 12 from baseline. | Change at month 12 from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rabson Mendenhall, Type B Insulin Resistance, Type A Insulin Resistance