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Safety, Tolerability and Efficacy of Microsomal Triglyceride Protein (MTP) Inhibitor

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01556906
Recruitment Status : Completed
First Posted : March 19, 2012
Results First Posted : February 22, 2013
Last Update Posted : April 10, 2013
Sponsor:
Collaborators:
University of Pennsylvania
Doris Duke Charitable Foundation
Information provided by (Responsible Party):
Aegerion Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE March 7, 2012
First Posted Date  ICMJE March 19, 2012
Results First Submitted Date  ICMJE January 18, 2013
Results First Posted Date  ICMJE February 22, 2013
Last Update Posted Date April 10, 2013
Study Start Date  ICMJE June 2003
Actual Primary Completion Date February 2004   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 18, 2013)
LDL-C [ Time Frame: Up to 16 weeks of treatment comapred to Baseline ]
Percent change in LDL-C compared to Baseline.
Original Primary Outcome Measures  ICMJE
 (submitted: March 16, 2012)
LDL-C [ Time Frame: Up to 16 weeks of treatment comapred to Baseline ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 4, 2013)
  • Absolute Change From Baseline in Alanine Aminotransferase (ALT) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in ALT
  • Absolute Change From Baseline in Aspartate Aminotransferase (AST) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in AST
  • Absolute Change From Baseline in Total Bilirubin [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in total bilirubin
  • Absolute Change From Baseline in Hepatic Fat Percent [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in hepatic fat percent
  • Absolute Change From Baseline in Forced Expiratory Volume During 1 Second (FEV1) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in FEV1
  • Absolute Change From Baseline in Carbon Monoxide Lung Diffusing Capacity (DLCO)(a Pulmonary Function Test) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in DLCO
  • Absolute Change From Baseline in Vitamin A [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in vitamin A
  • Absolute Change From Baseline in Vitamin E [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute change from Baseline in vitamin E
  • Absolute Change From Baseline in Vitamin D [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute Change From Baseline in Vitamin D
  • Absolute Change From Baseline in Ratio of Vitamin E to Total Lipids [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute Change From Baseline in ratio of vitamin E to total lipids
  • Absolute Change From Baseline in Alpha Linoleic Acid (ALA) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute Change From Baseline in ALA
  • Absolute Change From Baseline in Eicosapentaenoic Acid (EPA) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute Change From Baseline in EPA
  • Absolute Change From Baseline in Docosahexaenoic Acid (DHA) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute Change From Baseline in DHA
  • Absolute Change From Baseline in Linoleic Acid (LA) [ Time Frame: Baseline and 16 weeks of treatment ]
    Absolute Change From Baseline in LA
Original Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2012)
  • Liver function tests [ Time Frame: Through 16 weeks compared to baseline ]
  • Hepatic Fat as measured by NMRS [ Time Frame: Up to 16 weeks compared to baseline ]
  • Pulmonary function tests [ Time Frame: Up to 16 weeks compared to baseline ]
  • Number of adverse events [ Time Frame: Up to 16 weeks ]
  • Fat Soluble nutrients [ Time Frame: up to 16 weeks ]
  • Type of Adverse Event [ Time Frame: Up to 16 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability and Efficacy of Microsomal Triglyceride Protein (MTP) Inhibitor
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Homozygous Familial Hypercholesterolemia
Intervention  ICMJE Drug: Lomitapide
Oral administration with escalating doses administered once daily
Other Names:
  • AEGR-733
  • BMS-201038
Study Arms  ICMJE Experimental: Lomitapide
This is an open label trial where all patients receive lomitapide (AEGR733/BMS-201038)at escalating doses
Intervention: Drug: Lomitapide
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 16, 2012)
6
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 2004
Actual Primary Completion Date February 2004   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Males and females ≥13 years of age
  2. 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
  3. Body weight ≥40 kg
  4. Negative screening pregnancy test if female of child-bearing potential
  5. Subjects must be willing and able to comply with all study-related procedures
  6. 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:

  1. Uncontrolled hypertension defined as: systolic blood pressure >180 mmHg, diastolic blood pressure >95 mmHg
  2. History of chronic renal insufficiency (serum creatinine >2.5 mg/dL)
  3. History of liver disease or abnormal LFTs at screening (>3x upper limit of normal [ULN])
  4. Any major surgical procedure occurring < 3 months prior to the screening visit
  5. Cardiac insufficiency defined by the New York Heart Association classification as functional Class III or Class IV
  6. History of a non-skin malignancy within the previous 5 years
  7. History of alcohol or drug abuse
  8. Participation in an investigational drug study within 6 weeks prior to the screening visit
  9. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 13 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01556906
Other Study ID Numbers  ICMJE UP1001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Aegerion Pharmaceuticals, Inc.
Study Sponsor  ICMJE Aegerion Pharmaceuticals, Inc.
Collaborators  ICMJE
  • University of Pennsylvania
  • Doris Duke Charitable Foundation
Investigators  ICMJE
Principal Investigator: Dan J Rader, MD University of Pennsylvania
PRS Account Aegerion Pharmaceuticals, Inc.
Verification Date April 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP