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

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT02654977
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arm: 1
• Actual Duration (Months): 49.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Familial Partial Lipodystrophy; Nonalcoholic Steatohepatitis; NAFLD	Drug: Metreleptin	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CLINICAL PROTOCOL to Investigate the Long-term Safety and Efficacy of Recombinant Human Leptin (METRELEPTIN) in Various Forms of Partial Lipodystrophy
• Actual Study Start Date: Sep 29, 2015
• Actual Primary Completion Date: Nov 14, 2019
• Actual Study Completion Date: Nov 14, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metreleptin Metreleptin open-label	Drug: Metreleptin; MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections; Other Names: MyaLept

Outcome Measures

Primary Outcome Measures

1. Percent Change in Fasting Triglyceride Levels [5 years on metreleptin or last observation carried forward]

   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.

Secondary Outcome Measures

1. Percent Change in Hemoglobin A1c Levels [5 years on metreleptin or last observation carried forward]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48105

Sponsors and Collaborators

• University of Michigan

Investigators

• Principal Investigator: Elif A Oral, MD, University of Michigan

Study Documents (Full-Text)

• Study Protocol - Aug 7, 2020

More Information

Publications

None provided.

• Responsible Party: Elif Oral, Professor, Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT02654977
• Other Study ID Numbers: HUM00093399
• First Posted: Jan 13, 2016
• Last Update Posted: Nov 24, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Lipodystrophy, Familial Partial; Lipodystrophy

Study Results

Participant Flow

Arm/Group Title	Metreleptin
Arm/Group Description	Metreleptin open-label Metreleptin: MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections
Period Title: Overall Study
STARTED	11
COMPLETED	4
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Metreleptin
Arm/Group Description	Metreleptin open-label Metreleptin: MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections
Overall Participants	11
Age (Count of Participants)
<=18 years	3 27.3%
Between 18 and 65 years	8 72.7%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	11 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 18.2%
Not Hispanic or Latino	9 81.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	11 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Baseline triglyceride value (mg/dL) [Median (Full Range) ]
Median (Full Range) [mg/dL]	204
Baseline hemoglobin A1c value (%) [Median (Full Range) ]
Median (Full Range) [%]	8.4

Outcome Measures

1. Primary Outcome

Title	Percent Change in Fasting Triglyceride Levels
Description	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.
Time Frame	5 years on metreleptin or last observation carried forward

Outcome Measure Data

Analysis Population Description

Participants with immediate drop out, SAE withdrawal or death were excluded from analysis.

Arm/Group Title	Metreleptin
Arm/Group Description	Metreleptin open-label Metreleptin: MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections
Measure Participants	8
Median (Full Range) [percentage of change from baseline]	55.76

2. Secondary Outcome

Title	Percent Change in Hemoglobin A1c Levels
Description	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.
Time Frame	5 years on metreleptin or last observation carried forward

Outcome Measure Data

Analysis Population Description

Percent change in hemoglobin A1c levels (hemoglobin A1c levels are measured in %) Participants with immediate drop out, SAE withdrawal or death were excluded from analysis.

Arm/Group Title	Metreleptin
Arm/Group Description	Metreleptin open-label Metreleptin: MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections
Measure Participants	8
Median (Full Range) [percentage of change from baseline]	2.55

Adverse Events

Time Frame	5 years (from baseline visit to year 5 study visit or date of study participant early termination)
Arm/Group Title	Metreleptin
Arm/Group Description	Metreleptin open-label Metreleptin: MyaLept (Recombinant-methionyl Human Leptin (r-metHuLeptin) METRELEPTIN) subcutaneous injections
All Cause Mortality
	Metreleptin
	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)
Serious Adverse Events
	Metreleptin
	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)
Cardiac disorders
chest pain with elevated troponin	1/11 (9.1%)	2
atrial flutter	1/11 (9.1%)	1
sudden cardiac death	1/11 (9.1%)	1
chronic heart failure exacerbation	1/11 (9.1%)	1
Endocrine disorders
onset of type 1 diabetes	1/11 (9.1%)	1
diabetic ketoacidosis	1/11 (9.1%)	4
hypokalemia	1/11 (9.1%)	1
pancreatitis	1/11 (9.1%)	2
Gastrointestinal disorders
abdominal pain	1/11 (9.1%)	2
splenic flexure colitis fluid collection	1/11 (9.1%)	1
splenic laceration	1/11 (9.1%)	1
cholecystitis	1/11 (9.1%)	1
esophageal spasms	1/11 (9.1%)	1
Hepatobiliary disorders
autoimmune hepatitis	1/11 (9.1%)	1
Immune system disorders
metreleptin neutralizing antibodies	1/11 (9.1%)	1
Infections and infestations
clinical sepsis	1/11 (9.1%)	1
Metabolism and nutrition disorders
hyperglycemia	1/11 (9.1%)	1
Onset of hypertriglyceridemia	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
left shoulder pain	1/11 (9.1%)	1
multiple rib fractures	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
labia majora dermatofibrosarcoma protuberans	1/11 (9.1%)	1
Nervous system disorders
nonepilogenic seizures	1/11 (9.1%)	1
dizziness	1/11 (9.1%)	1
Reproductive system and breast disorders
uterine bleeding	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
pleural effusion	2/11 (18.2%)	2
acute hypoxia	1/11 (9.1%)	1
shortness of breath	1/11 (9.1%)	2
Surgical and medical procedures
anterior cervical discectomy	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	Metreleptin
	Affected / at Risk (%)	# Events
Total	11/11 (100%)
Blood and lymphatic system disorders
elevated blood platelets	2/11 (18.2%)	2
increased blood protein levels	1/11 (9.1%)	1
Cardiac disorders
cardiac chest pain	1/11 (9.1%)	1
abnormal stress test	1/11 (9.1%)	1
Endocrine disorders
weight loss	1/11 (9.1%)	1
hypoglycemia	2/11 (18.2%)	4
worsening vitamin D deficiency	1/11 (9.1%)	1
worsening diabetes	1/11 (9.1%)	1
increase in appetite	1/11 (9.1%)	1
low blood iron level	1/11 (9.1%)	1
increased creatitine levels	1/11 (9.1%)	1
Eye disorders
retinopathy lesion	1/11 (9.1%)	1
Gastrointestinal disorders
acid reflux	1/11 (9.1%)	1
nausea	1/11 (9.1%)	2
vomiting	1/11 (9.1%)	1
abdominal pain	3/11 (27.3%)	3
worsening of fecal incontinence	1/11 (9.1%)	1
Infections and infestations
sinus infection	1/11 (9.1%)	1
cold	3/11 (27.3%)	3
cellutitus	2/11 (18.2%)	5
strep throat	1/11 (9.1%)	1
urinary tract infection	3/11 (27.3%)	5
upper respiratory tract infection	3/11 (27.3%)	3
bronchitis	2/11 (18.2%)	2
vaginal yeast infection	1/11 (9.1%)	3
infected tooth	1/11 (9.1%)	1
kidney infection	1/11 (9.1%)	1
viral illness	1/11 (9.1%)	1
blocked parotid gland	1/11 (9.1%)	1
Metabolism and nutrition disorders
elevated liver function tests	1/11 (9.1%)	1
elevated low density cholesterol	1/11 (9.1%)	1
thyroid nodules	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
worsening of chronic back pain	2/11 (18.2%)	2
extremity weakness	2/11 (18.2%)	2
worsening weakness	1/11 (9.1%)	1
knee pain	1/11 (9.1%)	1
Spinal pain	1/11 (9.1%)	1
worsening of restless leg syndrome	1/11 (9.1%)	1
right wrist pain	1/11 (9.1%)	1
right wrist numbness	1/11 (9.1%)	1
lower right leg numbness	1/11 (9.1%)	1
frozen shoulder	1/11 (9.1%)	1
leg pain	1/11 (9.1%)	1
ostearthritis dissicans	1/11 (9.1%)	1
Nervous system disorders
hyperesthesia	1/11 (9.1%)	1
headache	1/11 (9.1%)	1
worsening imbalance	1/11 (9.1%)	1
Psychiatric disorders
intermittent suicidal ideation	1/11 (9.1%)	1
worsening depression	3/11 (27.3%)	3
worsening anxiety	1/11 (9.1%)	1
Renal and urinary disorders
kidney stone	1/11 (9.1%)	1
Reproductive system and breast disorders
vaginal spotting	1/11 (9.1%)	1
irregular periods	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
lung nodule	1/11 (9.1%)	1
worsening cough	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
reticular rash	2/11 (18.2%)	2

Limitations/Caveats

Definitive conclusions cannot be drawn from sample sizes as small as the four individuals who completed the trial period.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.