Severe Insulin Resistance
Conditions
Keywords
Rabson Mendenhall, Type B Insulin Resistance, Type A Insulin Resistance
Brief summary
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
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).
Interventions
DRUGMetreleptin
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
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1C | Change at month 12 from baseline | Change in HbA1C at month 12 from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Blood Glucose | Change at month 12 from baseline | Change in fasting blood glucose at month 12 from baseline. |
| Change in Fasting Insulin Level | Change at month 12 from baseline | Change in fasting insulin level at month 12 from baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Leptin Treatment 300 mg of study drug administered via SC injections.
Metreleptin: 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 | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Leptin Treatment |
|---|---|
| A1c | 10.38 percent STANDARD_DEVIATION 1.17 |
| Age, Continuous | 13.12 years STANDARD_DEVIATION 5.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Fasting blood glucose | 155.27 mg/dL STANDARD_DEVIATION 71.22 |
| Fasting Insulin | 597.26 mcU/mL STANDARD_DEVIATION 787.15 |
| Race/Ethnicity, Customized Race African | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race Caucasian | 7 Participants |
| Race/Ethnicity, Customized Race Filipino | 2 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 7 / 11 |
| serious Total, serious adverse events | 5 / 11 |
Outcome results
Primary
Change in HbA1C
Change in HbA1C at month 12 from baseline.
Time frame: Change at month 12 from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leptin Treatment | Change in HbA1C | -0.336 percent | Standard Deviation 1.921 |
Secondary
Change in Fasting Blood Glucose
Change in fasting blood glucose at month 12 from baseline.
Time frame: Change at month 12 from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leptin Treatment | Change in Fasting Blood Glucose | -6.91 mg/dL | Standard Deviation 86.1 |
Secondary
Change in Fasting Insulin Level
Change in fasting insulin level at month 12 from baseline
Time frame: Change at month 12 from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leptin Treatment | Change in Fasting Insulin Level | -58.31 mcU/mL | Standard Deviation 85.21 |