Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)

• Sponsor: Elif Oral (Other)
• Overall Status: Completed
• CT.gov ID: NCT00596934
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), University of Michigan (Other)
• Enrollment: 9
• Location: 1
• Arm: 1
• Duration (Months): 36.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Nonalcoholic steatohepatitis (or NASH) is known to be caused by deposition of fat in the liver and development of scarring. This condition occurs more frequently in overweight and obese persons. It is often associated with resistance to the actions of insulin hormone. Fat cells secrete a hormone called leptin. Recently, we have learned that obese or overweight persons make too much leptin, which may contribute to insulin resistance. Paradoxically, patients who do not have any fat cells, also have insulin resistance. In these patients, insulin resistance is caused by the absence of leptin and leptin replacement significantly improves insulin resistance and fat deposition in the liver. In an earlier study, we determined the leptin levels in patients with NASH and how these levels are related to body fat levels as well as responsiveness to insulin. We saw that a subgroup of patients with NASH have relatively low levels of leptin in contrast to the amount of body fat they had. We now would like to see if restoring leptin levels to normal will improve the disease process in these patients. Our study patients will be male patients, aged between 18 and 65 (inclusive), who do not have any other cause for their liver disease. We have put some restrictions in body size such that a spectrum of patients from normal weight to obese range would be included. They will also demonstrate low leptin levels (levels similar to only 25% of normal population). We will use a genetically engineered form of leptin manufactured by Amylin Inc. 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 and body composition characteristics that we examined in our earlier study. We expect that patients with low blood leptin levels will show improvement in their liver disease and insulin resistance when their blood leptin levels are restored to normal.

Condition or Disease	Intervention/Treatment	Phase
Fatty Liver Disease, Nonalcoholic	Drug: metreleptin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nonalcoholic Steatohepatitis: is Leptin an Etiological Factor (Phase 2).
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metreleptin treatment group Treatment group	Drug: metreleptin; 0.1 mg/kg/day once a day via subcutaneous injections; Other Names: (originally A100, recombinant-human-Methionyl-leptin

Outcome Measures

Primary Outcome Measures

1. Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months [1 year]

   Non-alcoholic steatohepatitis (NASH) score after approximately one year of treatment with metreleptin. Total NASH scores can range from 0 to 14. The higher the NASH score the more severe the liver disease.

Secondary Outcome Measures

1. Body Weight at 12 Months [1 year]

   Body weight (kg) after one year of treatment on metreleptin for patients that completed 12 months of metreleptin treatment.

2. Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months [1 year]

   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.

3. Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months [1 year]

   ALT value in subjects that completed 12 months of metreleptin treatment.

4. Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months [1 year]

   AST value in subjects that completed 12 months of metreleptin treatment.

5. Fasting Glucose Value at 12 Months [1 year]

   Fasting glucose value in subjects that completed 12 months of metreleptin treatment.

6. Fasting Triglycerides Value at 12 Months [1 year]

   Fasting triglyceride value in subjects that completed 12 months of metreleptin treatment.

7. Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months [1 year]

   HOMA values in subjects that completed 12 months of metreleptin treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Biopsy proven NASH

• Circulating fasting leptin <9 ng/mL (staggered criteria for different BMI levels)

Exclusion Criteria:

• Presence of advanced liver disease (as evidenced by abnormal synthetic function, abnormal prothrombin time or albumin)

• Presence of clinical lipodystrophy

• Presence of other liver disease

• Presence of clinical diabetes (fasting >126 mg/dL or 2 hour post 75 g-glucose >200 mg/dL or random glucose >200 mg/dL with presence of diabetes symptoms or known history of diabetes)

• Any medication for treatment of NASH or obesity

• Presence of HIV

• 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

• Presence of any other condition that limits life expectancy to <2 years

• Active infection (may be transient)

• 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

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

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• PIs Web site

Publications

None provided.

• Responsible Party: Elif Oral, Associate Prof of Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT00596934
• Other Study ID Numbers: R03DK074488; R03DK074488; Protocol 2145 (MCRU); Amylin Protocol 20050119; DRDA 643938K3
• First Posted: Jan 17, 2008
• Last Update Posted: Nov 24, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Elif Oral, Associate Prof of Medicine, University of Michigan: Nonalcoholic fatty liver disease; Insulin resistance; Obesity; Leptin therapy; NASH
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease

Study Results

Participant Flow

Recruitment Details	Patient recruitment occurred from February 2007 and concluded in October 2007.
Pre-assignment Detail	One of ten enrolled participants screen failed during baseline visit, liver biopsy showed no non-alcoholic steatohepatitis. Therefore he is not included in any tables or analyses.

Arm/Group Title	NASH02
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Period Title: Overall Study
STARTED	9
COMPLETED	7
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Overall Participants	9
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	44.3
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	9 100%
Region of Enrollment (participants) [Number]
United States	9 100%
Non-alcoholic steatohepatitis (NASH) score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.1 (3.3)
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	90.9 (9.0)
Liver fat percentage by Magnetic Resonance Imaging (MRI - Dixon method) (liver fat percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [liver fat percentage]	19.0 (7.7)
Liver function test: Alanine aminotransferase (ALT) (IU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [IU/L]	50.9 (19.4)
Liver function test: Aspartate aminotransferase (AST) (IU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [IU/L]	33.5 (13.3)
Fasting glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	98.1 (7.2)
Insulin Resistance: homeostatic model assessment (HOMA) (mU/L x mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mU/L x mg/dL]	7.4 (3.2)
Fasting triglycerides (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	129.4 (66.2)

Outcome Measures

1. Primary Outcome

Title	Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months
Description	Non-alcoholic steatohepatitis (NASH) score after approximately one year of treatment with metreleptin. Total NASH scores can range from 0 to 14. The higher the NASH score the more severe the liver disease.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Individuals who completed the year of metreleptin treatment and had follow-up liver biopsies after one year.

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [units on a scale]	5 (1.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments	Differences in each collected parameter will be evaluated using a paired t-test. If data are skewed such as in triglyceride levels, nonparametric tests will be used. P<0.05 will be considered significant. If a significant difference can be demonstrated between baseline and 1-year results, a large scale, placebo-controlled trial will be designed using the data obtained from this pilot study
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Body Weight at 12 Months
Description	Body weight (kg) after one year of treatment on metreleptin for patients that completed 12 months of metreleptin treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Subjects that completed 12 months of metreleptin treatment.

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin: 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [kg]	86.4 (9.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months
Description	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

[Not Specified]

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [liver fat percentage]	13.7 (9.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	p = 0.074
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months
Description	ALT value in subjects that completed 12 months of metreleptin treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

7 subjects who completed 12 months of metreleptin treatment.

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [IU/L]	44.3 (29.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months
Description	AST value in subjects that completed 12 months of metreleptin treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

7 subjects who completed 12 months of metreleptin treatment.

Arm/Group Title	Metreleptin Treatment Group
Arm/Group Description	Treatment group metreleptin: 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [IU/L]	34.9 (13.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Fasting Glucose Value at 12 Months
Description	Fasting glucose value in subjects that completed 12 months of metreleptin treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

7 subjects who completed 12 months of metreleptin treatment.

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [mg/dL]	92.1 (5.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Fasting Triglycerides Value at 12 Months
Description	Fasting triglyceride value in subjects that completed 12 months of metreleptin treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

7 subjects who completed 12 months of metreleptin treatment.

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [mg/dL]	146.4 (75.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments	p-value = 0.195.
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months
Description	HOMA values in subjects that completed 12 months of metreleptin treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

7 subjects who completed 12 months of metreleptin treatment.

Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
Measure Participants	7
Mean (Standard Deviation) [mU/L x mg/dL]	4.1 (3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metreleptin Treatment Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	13 months from patient baseline appointment.
Adverse Event Reporting Description	Adverse event data collected from patient's baseline study appointment till one month following patient's 12 month study appointment.
Arm/Group Title	Metreleptin Treatment Arm
Arm/Group Description	Treatment group metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections
All Cause Mortality
	Metreleptin Treatment Arm
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Metreleptin Treatment Arm
	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)
Blood and lymphatic system disorders
toxoplasmosis	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	Metreleptin Treatment Arm
	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)
Blood and lymphatic system disorders
right sternocleidomastoid lymphadenopathy	1/9 (11.1%)	1
right axilla lymphadenopathy	1/9 (11.1%)	1
Musculoskeletal and connective tissue disorders
left side muscle pain	1/9 (11.1%)	1
Nervous system disorders
vertigo	1/9 (11.1%)	1
Renal and urinary disorders
polyuria	1/9 (11.1%)	1
haematuria	1/9 (11.1%)	1
Reproductive system and breast disorders
rectal pressure with ejaculation	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
actinic keratoses	1/9 (11.1%)	10

Limitations/Caveats

This is a non-blinded, non-placebo controlled proof of concept trial. Out of the 9 patients, there were 7 completers.

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.