Safety, Tolerability and Efficacy of Microsomal Triglyceride Protein (MTP) Inhibitor
Primary Purpose
Homozygous Familial Hypercholesterolemia
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Lomitapide
Sponsored by
About this trial
This is an interventional treatment trial for Homozygous Familial Hypercholesterolemia
Eligibility Criteria
Inclusion Criteria:
- Males and females ≥13 years of age
Clinical diagnosis of HoFH AND one of the following (a, b, or c):
- Documented functional mutation in both LDL receptor alleles, OR
- Skin fibroblast LDL receptor activity <20% of normal, OR
- TC >500 mg/dL AND triglycerides < 300 mg/dL AND both parents with documented TC >250 mg/dL
- Body weight ≥40 kg
- Negative screening pregnancy test if female of child-bearing potential
- Subjects must be willing and able to comply with all study-related procedures
- Subjects must be willing and able to go off all lipid-lowering medications, dietary supplements (psyllium preparations) and LDL apheresis within 4 weeks prior to the Baseline visit until the end of the study.
Exclusion Criteria:
- Uncontrolled hypertension defined as: systolic blood pressure >180 mmHg, diastolic blood pressure >95 mmHg
- History of chronic renal insufficiency (serum creatinine >2.5 mg/dL)
- History of liver disease or abnormal LFTs at screening (>3x upper limit of normal [ULN])
- Any major surgical procedure occurring < 3 months prior to the screening visit
- Cardiac insufficiency defined by the New York Heart Association classification as functional Class III or Class IV
- History of a non-skin malignancy within the previous 5 years
- History of alcohol or drug abuse
- Participation in an investigational drug study within 6 weeks prior to the screening visit
- Serious or unstable medical or psychological conditions that, in the opinion of the Investigator, would compromise the patient's safety or successful participation in the study.
Sites / Locations
- University of Pennsylvania
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Lomitapide
Arm Description
This is an open label trial where all patients receive lomitapide (AEGR733/BMS-201038)at escalating doses
Outcomes
Primary Outcome Measures
LDL-C
Percent change in LDL-C compared to Baseline.
Secondary Outcome Measures
Absolute Change From Baseline in Alanine Aminotransferase (ALT)
Absolute change from Baseline in ALT
Absolute Change From Baseline in Aspartate Aminotransferase (AST)
Absolute change from Baseline in AST
Absolute Change From Baseline in Total Bilirubin
Absolute change from Baseline in total bilirubin
Absolute Change From Baseline in Hepatic Fat Percent
Absolute change from Baseline in hepatic fat percent
Absolute Change From Baseline in Forced Expiratory Volume During 1 Second (FEV1)
Absolute change from Baseline in FEV1
Absolute Change From Baseline in Carbon Monoxide Lung Diffusing Capacity (DLCO)(a Pulmonary Function Test)
Absolute change from Baseline in DLCO
Absolute Change From Baseline in Vitamin A
Absolute change from Baseline in vitamin A
Absolute Change From Baseline in Vitamin E
Absolute change from Baseline in vitamin E
Absolute Change From Baseline in Vitamin D
Absolute Change From Baseline in Vitamin D
Absolute Change From Baseline in Ratio of Vitamin E to Total Lipids
Absolute Change From Baseline in ratio of vitamin E to total lipids
Absolute Change From Baseline in Alpha Linoleic Acid (ALA)
Absolute Change From Baseline in ALA
Absolute Change From Baseline in Eicosapentaenoic Acid (EPA)
Absolute Change From Baseline in EPA
Absolute Change From Baseline in Docosahexaenoic Acid (DHA)
Absolute Change From Baseline in DHA
Absolute Change From Baseline in Linoleic Acid (LA)
Absolute Change From Baseline in LA
Full Information
NCT ID
NCT01556906
First Posted
March 7, 2012
Last Updated
April 4, 2013
Sponsor
Aegerion Pharmaceuticals, Inc.
Collaborators
University of Pennsylvania, Doris Duke Charitable Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01556906
Brief Title
Safety, Tolerability and Efficacy of Microsomal Triglyceride Protein (MTP) Inhibitor
Official Title
A Phase II Open Label, Dose-Escalation Study to Determine the Safety, Tolerability and Efficacy of Microsomal Triglyceride Transfer Protein (MTP) Inhibitor BMS-201038 in Patients With Homozygous Familial Hypercholeterolemia
Study Type
Interventional
2. Study Status
Record Verification Date
April 2013
Overall Recruitment Status
Completed
Study Start Date
June 2003 (undefined)
Primary Completion Date
February 2004 (Actual)
Study Completion Date
February 2004 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Aegerion Pharmaceuticals, Inc.
Collaborators
University of Pennsylvania, Doris Duke Charitable Foundation
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary objective of this study is to evaluate the safety and tolerability of 4 doses of lomitapide (AEGR-733; BMS-201038) given as an initial low dose and then escalated through an additional 3 dose levels over a 16-week period.
The secondary objectives of this study included the evaluation of the pharmacodynamics of lomitapide based on:
Percent change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides, and very low density lipoprotein cholesterol (VLDL-C) concentrations at the end of each 4-week dosing period compared to the Baseline value of each parameter at the end of the previous dose phase(s).
Changes in other plasma lipoproteins: apolipoproteins (apo B, apo AI, apo AII, apo CIII, apo E) and lipoprotein a [Lp(a)].
Detailed Description
This is a single center, open-label, Phase 2 clinical trial designed to evaluate the safety, tolerability, and pharmacodynamics of lomitapide in the treatment of patients with homozygous familial hypercholesterolemia (HoFH).
Patients are required to stop all lipid-lowering therapies, including apheresis, within 4 weeks prior to the Baseline visit and throughout the study. Patients are placed on a rigorous low-fat diet (<10% of energy from total dietary fat) at the Screening assessment; dietary counseling by a registered dietitian will be initiated at Screening and will continue at each subsequent study visit.
Patients initially receive 0.03 mg/kg of lomitapide orally every day for 4 weeks. Intra-patient dose escalation to 0.1 mg/kg, 0.3 mg/kg/day and 1.0 mg/kg/day occur every 4 weeks if specific protocol-defined stopping rules related to Grade 3 or 4 toxicities or serious adverse events (SAEs) do not apply.
The study includes 15 study visits over 22 weeks: a Screening visit (Visit 1) conducted within 2 weeks prior to dosing, a Baseline visit (Visit 2) conducted on Day 1 prior to the first dose, 12 visits conducted during the treatment period (Visits 3 through 14), and a Follow-up visit (Visit 15) conducted approximately 4 weeks after the last dose of lomitapide.
Screening and Baseline procedures include medical and medication history, physical examination, vital signs, 12-lead electrocardiogram (ECG), pulmonary function tests (PFTs), safety laboratory tests, fat soluble vitamin levels and a fatty acid profile. Nuclear magnetic resonance spectroscopy (NMRS) of the liver will be conducted at Baseline, at the end of each dosing period, and at the follow up visit to assess hepatic fat content. Baseline efficacy assessment includes a fasting lipid profile (TC, LDL-C [directly measured], VLDL-C, high density lipoprotein-cholesterol [HDL-C], triglycerides, and apolipoproteins [apo B, apo AI, apo AII, apo CIII, apo E] and Lp(a)).
Safety and lipid profile assessments are repeated during the treatment period and at the Follow-up visit conducted 28 days after the last dose of lomitapide.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Homozygous Familial Hypercholesterolemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Lomitapide
Arm Type
Experimental
Arm Description
This is an open label trial where all patients receive lomitapide (AEGR733/BMS-201038)at escalating doses
Intervention Type
Drug
Intervention Name(s)
Lomitapide
Other Intervention Name(s)
AEGR-733, BMS-201038
Intervention Description
Oral administration with escalating doses administered once daily
Primary Outcome Measure Information:
Title
LDL-C
Description
Percent change in LDL-C compared to Baseline.
Time Frame
Up to 16 weeks of treatment comapred to Baseline
Secondary Outcome Measure Information:
Title
Absolute Change From Baseline in Alanine Aminotransferase (ALT)
Description
Absolute change from Baseline in ALT
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Aspartate Aminotransferase (AST)
Description
Absolute change from Baseline in AST
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Total Bilirubin
Description
Absolute change from Baseline in total bilirubin
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Hepatic Fat Percent
Description
Absolute change from Baseline in hepatic fat percent
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Forced Expiratory Volume During 1 Second (FEV1)
Description
Absolute change from Baseline in FEV1
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Carbon Monoxide Lung Diffusing Capacity (DLCO)(a Pulmonary Function Test)
Description
Absolute change from Baseline in DLCO
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Vitamin A
Description
Absolute change from Baseline in vitamin A
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Vitamin E
Description
Absolute change from Baseline in vitamin E
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Vitamin D
Description
Absolute Change From Baseline in Vitamin D
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Ratio of Vitamin E to Total Lipids
Description
Absolute Change From Baseline in ratio of vitamin E to total lipids
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Alpha Linoleic Acid (ALA)
Description
Absolute Change From Baseline in ALA
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Eicosapentaenoic Acid (EPA)
Description
Absolute Change From Baseline in EPA
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Docosahexaenoic Acid (DHA)
Description
Absolute Change From Baseline in DHA
Time Frame
Baseline and 16 weeks of treatment
Title
Absolute Change From Baseline in Linoleic Acid (LA)
Description
Absolute Change From Baseline in LA
Time Frame
Baseline and 16 weeks of treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Males and females ≥13 years of age
Clinical diagnosis of HoFH AND one of the following (a, b, or c):
Documented functional mutation in both LDL receptor alleles, OR
Skin fibroblast LDL receptor activity <20% of normal, OR
TC >500 mg/dL AND triglycerides < 300 mg/dL AND both parents with documented TC >250 mg/dL
Body weight ≥40 kg
Negative screening pregnancy test if female of child-bearing potential
Subjects must be willing and able to comply with all study-related procedures
Subjects must be willing and able to go off all lipid-lowering medications, dietary supplements (psyllium preparations) and LDL apheresis within 4 weeks prior to the Baseline visit until the end of the study.
Exclusion Criteria:
Uncontrolled hypertension defined as: systolic blood pressure >180 mmHg, diastolic blood pressure >95 mmHg
History of chronic renal insufficiency (serum creatinine >2.5 mg/dL)
History of liver disease or abnormal LFTs at screening (>3x upper limit of normal [ULN])
Any major surgical procedure occurring < 3 months prior to the screening visit
Cardiac insufficiency defined by the New York Heart Association classification as functional Class III or Class IV
History of a non-skin malignancy within the previous 5 years
History of alcohol or drug abuse
Participation in an investigational drug study within 6 weeks prior to the screening visit
Serious or unstable medical or psychological conditions that, in the opinion of the Investigator, would compromise the patient's safety or successful participation in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dan J Rader, MD
Organizational Affiliation
University of Pennsylvania
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
17215532
Citation
Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE, Rader DJ. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007 Jan 11;356(2):148-56. doi: 10.1056/NEJMoa061189.
Results Reference
result
Learn more about this trial
Safety, Tolerability and Efficacy of Microsomal Triglyceride Protein (MTP) Inhibitor
We'll reach out to this number within 24 hrs