Clinical trial NCT00085982: Effect of Metreleptin Therapy in the Treatment of Severe Insulin Resistance
Official title: Phase II Trial of Effect of Metreleptin Therapy in Severe Insulin Resistance
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Severe Insulin Resistance
Keywords: Rabson Mendenhall
Type B Insulin Resistance
Type A Insulin Resistance
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2004-06-21
Enrollment: 11
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Eligibility 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.

Primary outcomes:
measure: Change in HbA1C
timeFrame: Change at month 12 from baseline
Secondary outcomes:
measure: Change in Fasting Insulin Level
timeFrame: Change at month 12 from baseline
measure: Change in Fasting Blood Glucose
timeFrame: Change at month 12 from baseline
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Rebecca J Brown, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, Walter PJ, Lightbourne M, Brown RJ. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest. 2020 Jul 1;130(7):3592-3602. doi: 10.1172/JCI135431.
citation: Okawa MC, Cochran E, Lightbourne M, Brown RJ. Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function. J Clin Endocrinol Metab. 2022 Feb 17;107(3):e1032-e1046. doi: 10.1210/clinem/dgab782.
citation: Brown RJ, Cochran E, Gorden P. Metreleptin improves blood glucose in patients with insulin receptor mutations. J Clin Endocrinol Metab. 2013 Nov;98(11):E1749-56. doi: 10.1210/jc.2013-2317. Epub 2013 Aug 22.