Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT01679197
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 23
• Location: 1
• Arm: 1
• Actual Duration (Months): 45.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study involves research about an investigational medicine called metreleptin. The reason for this study is to find out how metreleptin can improve non-alcoholic steatohepatitis or nonalcoholic fatty liver disease associated with lipodystrophy, a rare disorder associated with abnormal loss of the body's fat tissue. In this study, metreleptin is considered to be investigational for the treatment of lipodystrophy. Metreleptin will be given via injections under the skin. We plan to continue therapy for a period of one year and evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic parameters (e.g. blood cholesterol, liver function, insulin resistance) and body composition characteristics (e.g. the pattern of fat distribution in the body).

Condition or Disease	Intervention/Treatment	Phase
Fatty Liver Disease, Nonalcoholic; Nonalcoholic Steatohepatitis; Lipodystrophy	Drug: Metreleptin	Phase 2

Detailed Description

The goal is to test the efficacy of restorative leptin therapy on the degree of hepatic steatosis and on amelioration of pathological features of NASH/NAFLD. In addition, the study will evaluate the impact of leptin therapy on total body insulin sensitivity and lipid levels as well as energy expenditure. In order to accomplish this aim, we now propose an efficacy study with recombinant human leptin therapy in patients with all forms of lipodystrophy who also have NASH/NAFLD.

1. AIM 1: To determine the efficacy of leptin in promoting amelioration of body composition, hepatic steatosis and histopathological scores in patients with all forms of lipodystrophy and NAFLD/NASH. We will conduct a 1 year, open-label study, to assess the metabolic effects of recombinant human leptin (METRELEPTIN, AztraZeneca, Wilmington, DE). The primary outcome measure will be NASH scores. We will also explore body weight, insulin sensitivity, glucose and lipid control, body composition, and free fatty acid levels.

2. AIM 2: To Investigate molecular effects of leptin therapy. In parallel to our preliminary studies, gene expression will be performed on individuals participating in Aim 1 at baseline and following 1 year of leptin. We will combine this with measures of liver metabolite levels to provide novel insights into alterations in metabolism that occur secondary to leptin therapy. We will also measure plasma metabolites at baseline and after 2 (optional), 24 and 48 weeks of therapy to assess the dynamic changes induced by leptin and correlate these changes with phenotypic measures.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy
• Actual Study Start Date: Oct 8, 2012
• Actual Primary Completion Date: Jul 13, 2016
• Actual Study Completion Date: Jul 13, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Metreleptin	Drug: Metreleptin; Other Names: (originally A100, recombinant-human-methionyl-leptin

Outcome Measures

Primary Outcome Measures

1. Liver Histopathology [1 year]

   Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.

Secondary Outcome Measures

1. Liver Fat by MRI and MR Spectroscopy [1 year]

   All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.

2. Liver Function Tests [1 year]

   AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.

3. Fasting Lipids [1 year]

   Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.

4. Fasting Glucose [1 year]

5. Body Weight [1 year]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 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 [βhCG]) 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 generalized (whole body) or partial (limbs) loss of body fat outside the range of normal variation.

• Alcohol consumption of less than 40 grams/week.

• A liver ultrasound confirming non-alcoholic fatty liver disease, or previous liver biopsy confirming NASH status.

• If ≥ 18 years of age, is able to read, understand and sign the U of M 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 U of M 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 PT 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.

• Very poorly controlled diabetes; HbA1c >10%

• Inability to give informed consent.

• Presence of ESRD, 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.

• Active infection (may be transient).

• 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	48109

Sponsors and Collaborators

• University of Michigan
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Elif Oral, Associate Professor, University of Michigan
• ClinicalTrials.gov Identifier: NCT01679197
• Other Study ID Numbers: MCRU 2834; R01DK088114-02
• First Posted: Sep 5, 2012
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Keywords provided by Elif Oral, Associate Professor, University of Michigan: Nonalcoholic fatty liver disease; NAFLD; Nonalcoholic steatohepatitis; NASH; Lipodystrophy; Leptin; Metreleptin; Hypertriglyceridemia; Diabetes mellitus
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Lipodystrophy

Study Results

Participant Flow

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
Period Title: Overall Study
STARTED	23
COMPLETED	19
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
Overall Participants	23
Age (Count of Participants)
<=18 years	3 13%
Between 18 and 65 years	20 87%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.35 (15.82)
Sex: Female, Male (Count of Participants)
Female	18 78.3%
Male	5 21.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	22 95.7%
African American	1 4.3%
Asian	0 0%
Native American	0 0%
Unknown	0 0%
Decline to answer	0 0%
Region of Enrollment (participants) [Number]
United States	23 100%

Outcome Measures

1. Primary Outcome

Title	Liver Histopathology
Description	Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
Measure Participants	23
Baseline	6 (2)
Month 12	5 (2)

2. Secondary Outcome

Title	Liver Fat by MRI and MR Spectroscopy
Description	All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
Measure Participants	23
Baseline	19.19 (11.11)
Month 12	13.47 (9.02)

3. Secondary Outcome

Title	Liver Function Tests
Description	AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.

Arm/Group Title	Liver Function AST	Liver Function ALT
Arm/Group Description
Measure Participants	23	23
Baseline	41.52 (27.46)	53.22 (37.03)
Month 12	30.37 (14.04)	36 (22.84)

4. Secondary Outcome

Title	Fasting Lipids
Description	Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.

Arm/Group Title	Cholesterol, Total mg/dL	Triglycerides mg/dL	HDL Cholesterol mg/dL	LDL mg/dL
Arm/Group Description	Lipid measurement	Lipid measurement	Lipid measurement	Lipid measurement
Measure Participants	23	23	23	23
Baseline	256.91 (136.87)	1057.48 (1744.89)	35.83 (11.01)	95.39 (48.30)
Month 12	189.11 (64.73)	478.47 (790.85)	33.42 (6.41)	95.95 (32.64)

5. Secondary Outcome

Title	Fasting Glucose
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
Measure Participants	23
Baseline	178.91 (82.36)
Month 12	163.53 (66.79)

6. Secondary Outcome

Title	Body Weight
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
Measure Participants	23
Baseline	77.2 (21.4)
Month 12	75.0 (23.1)

Adverse Events

Arm/Group Title	Treatment
Arm/Group Description	Metreleptin Metreleptin
All Cause Mortality
	Treatment
	Affected / at Risk (%)	# Events
Total	0/23 (0%)
Serious Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	7/23 (30.4%)
Cardiac disorders
Left shoulder pain, atypical chest pain	1/23 (4.3%)	1
Gastrointestinal disorders
Epigastric pain, mild chest pain	1/23 (4.3%)	1
Immune system disorders
Granulomatous tissue reaction	1/23 (4.3%)	1
Metabolism and nutrition disorders
Hypertriglyceridemia	1/23 (4.3%)	1
Secondary diabetes mellitus with keatoacidosis	1/23 (4.3%)	1
Musculoskeletal and connective tissue disorders
Fall, hip fracture	1/23 (4.3%)	1
Chest pain	1/23 (4.3%)	1
Nervous system disorders
Transient ischemic attack vs. cerebrovascular attack vs. complicated migraine	1/23 (4.3%)	1
Bell's palsy left side weakness	1/23 (4.3%)	1
Renal and urinary disorders
UTI abdominal pain	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Bronchial pneumonia	1/23 (4.3%)	1
Surgical and medical procedures
Rectal prolapse surgery	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	22/23 (95.7%)
Blood and lymphatic system disorders
Hypoglycemia	7/23 (30.4%)	12
Gastrointestinal disorders
Diarrhea	5/23 (21.7%)	6
Vomiting	2/23 (8.7%)	3
Abdominal pain/discomfort	3/23 (13%)	3
General disorders
Dizziness	2/23 (8.7%)	2
Nausea	3/23 (13%)	4
Immune system disorders
Upper respiratory tract infection	9/23 (39.1%)	10
Infections and infestations
Cold/Flu-like symptoms	4/23 (17.4%)	4
Musculoskeletal and connective tissue disorders
Muscle cramping	2/23 (8.7%)	2
Fall	2/23 (8.7%)	2
Renal and urinary disorders
Urinary tract infection	2/23 (8.7%)	3
Hematuria	2/23 (8.7%)	2
Respiratory, thoracic and mediastinal disorders
Bronchitis	2/23 (8.7%)	2
Asthma	3/23 (13%)	3
Cough	2/23 (8.7%)	2
Skin and subcutaneous tissue disorders
Alopecia	2/23 (8.7%)	2
Injection site reaction	3/23 (13%)	3
Rash	2/23 (8.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.