CLINICAL PROTOCOL to Investigate the Long-term Safety and Efficacy of Metreleptin in Various Forms of Partial Lipodystrophy

Study Overview
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Brief Summary
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The study investigators' aim is to determine the long term safety and efficacy of Metreleptin (Myalept,) in promoting amelioration of metabolic abnormalities in patients with all forms of partial lipodystrophy. Patients will be offered this protocol under the following condition: Subjects have completed University of Michigan research protocol MB002-014 and have shown improved clinical benefit as judged by clinical criteria set forth in this protocol.

Detailed Description
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Leptin is now an approved therapeutic in the form of Myalept in patients with generalized forms of lipodystrophy. However, it is still under investigation for patients with partial forms of the disease based on FDA decision on February 24, 2014. The study investigators have been carrying out a protocol in patients with partial lipodystrophy, specifically familial partial lipodystrophy. There have been a number of patients who have been treated under this protocol who are not covered by the currently approved label, but who have experienced significant clinical benefit. This study allowed continued treatment of patients with partial forms of lipodystrophy who volunteered and completed treatment under the investigators' completed protocol (MB002-014) and who derived significant clinical benefit as judged by an amelioration of their hemoglobin A1c, triglyceride levels, and/or reduction in their baseline diabetes or lipid therapies that affect quality of life. In this long-term study, there were three individuals whose data were excluded from final data analyses as explained in the results, however all participants were included in the presentation of baseline data as well as tabulated safety data.

Official Title
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CLINICAL PROTOCOL to Investigate the Long-term Safety and Efficacy of Recombinant Human Leptin (METRELEPTIN) in Various Forms of Partial Lipodystrophy

Conditions
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Familial Partial Lipodystrophy, Nonalcoholic Steatohepatitis, NAFLD

Intervention / Treatment
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* Drug: Metreleptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously completed study protocol: o CLINICAL PROTOCOL to investigate the efficacy of recombinant human leptin (METRELEPTIN) in nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD) associated with lipodystrophy, MB002-014 (IRMBED: HUM00058708) Demonstrates clinical benefit as defined by meeting at least one of the following criteria upon completion of the above stated protocols: Reduction of HbA1c ≥ 1.0% or, Reduction of triglycerides ≥ 30% of baseline or, Decrease in insulin requirements ≥ 40% or, Reduction in total NASH score by ≥ 2 points, Significant worsening of metabolic parameters after discontinuation of Metreleptin if discontinuation has been undertaken. A health condition that appears to have significantly improved by metreleptin for which two independent health care providers make a request to prevent drug discontinuation. In addition, the PI has to document absence of contraindications for drug continuation (such as bone marrow suppression). Is male or female ≥ 5 years old at baseline. Is male, female not of childbearing potential, or meets all the following criteria if female of childbearing potential (including perimenopausal women who have had a menstrual period within one year): Not breastfeeding Negative pregnancy test result (human chorionic gonadotropin, beta subunit) at baseline (not applicable to hysterectomized females). Must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate when use consistently and correctly, such as implants, injectables, oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a vasectomized partner) during the entire duration of metreleptin treatment. Has physician-confirmed lipodystrophy as defined by evidence of partial (limbs) loss of body fat outside the range of normal variation. If ≥ 18 years of age, is able to read, understand and sign the University of Michigan institutional review board (IRBMED) approved informed consent form (ICF), communicate with study physician and study team, understand and comply with protocol requirements. If < 18 and ≥ 7 years of age, is able to read, understand and sign the appropriate University of Michigan IRBMED approved assent form and has a parent or legal guardian that is able to read, understand and sign the ICF. If < 7 and ≥ 5 years of age or unable to read, the appropriate assent form must be explained to the child. If previously treated with thiazolidinediones or Vitamin E, stable dose of these medications for at least 3 months. Exclusion Criteria: Presence of advanced liver disease (as evidenced by abnormal synthetic function, abnormal partial thromboplastin time or albumin). Evidence of other etiologies of viral hepatitis. Presence of clinically significant hematologic abnormalities (such as neutropenia and/or lymphadenopathy). Presence of HIV infection. Inability to give informed consent. Presence of end stage renal disease, any type of active cancer, or >class 2 congestive heart failure ((New York Heart Association Functional Classification System), based on medical history and physical examination. Has known allergies to E. coli-derived proteins or hypersensitivity to any component of metreleptin treatment. Any other condition in the opinion of the investigators that may impede successful data collection.

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: Metreleptin<br>Metreleptin open-label | Drug: Metreleptin<br>* MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections<br>* Other names: MyaLept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Fasting Triglyceride Levels | Fasting triglyceride levels after 5 years on metreleptin, measured in mg/dL are compared to fasting triglyceride levels at baseline). The median percent increase (positive numbers) or decrease from baseline is shown, along with the full range. | 5 years on metreleptin or last observation carried forward | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Hemoglobin A1c Levels | Fasting hemoglobin A1c levels after 5 years on metreleptin, measured in % are compared to fasting Hemoglobin levels at baseline). Thus, for example, a change from 10% to 5% would be a -50% change (or 50% decrease). The median percent increase (positive numbers) or decrease from baseline is shown, along with the full range. | 5 years on metreleptin or last observation carried forward |