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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01556906

Enrollment

Registered

2012-03-19

Start date

2003-06-30

Completion date

2004-02-29

Last updated

2013-04-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Homozygous Familial Hypercholesterolemia

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.

Interventions

DRUGLomitapide

Oral administration with escalating doses administered once daily

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

13 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
LDL-C	Up to 16 weeks of treatment comapred to Baseline	Percent change in LDL-C compared to Baseline.

Secondary

Measure	Time frame	Description
Absolute Change From Baseline in Aspartate Aminotransferase (AST)	Baseline and 16 weeks of treatment	Absolute change from Baseline in AST
Absolute Change From Baseline in Total Bilirubin	Baseline and 16 weeks of treatment	Absolute change from Baseline in total bilirubin
Absolute Change From Baseline in Hepatic Fat Percent	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)	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)	Baseline and 16 weeks of treatment	Absolute change from Baseline in DLCO
Absolute Change From Baseline in Vitamin A	Baseline and 16 weeks of treatment	Absolute change from Baseline in vitamin A
Absolute Change From Baseline in Alanine Aminotransferase (ALT)	Baseline and 16 weeks of treatment	Absolute change from Baseline in ALT
Absolute Change From Baseline in Vitamin D	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	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)	Baseline and 16 weeks of treatment	Absolute Change From Baseline in ALA
Absolute Change From Baseline in Eicosapentaenoic Acid (EPA)	Baseline and 16 weeks of treatment	Absolute Change From Baseline in EPA
Absolute Change From Baseline in Docosahexaenoic Acid (DHA)	Baseline and 16 weeks of treatment	Absolute Change From Baseline in DHA
Absolute Change From Baseline in Linoleic Acid (LA)	Baseline and 16 weeks of treatment	Absolute Change From Baseline in LA
Absolute Change From Baseline in Vitamin E	Baseline and 16 weeks of treatment	Absolute change from Baseline in vitamin E

Countries

United States

Participant flow

Recruitment details

The study was performed from 05 Jun 2003 to 16 Feb 2004. The study was performed at a single medical clinic.

Participants by arm

Arm	Count
Lomitapide Escalated Lomitapide initiated with an oral dose of 0.03 mg/kg/day for 4 weeks and then escalated through an additional 3 dose levels (0.1, 0.3, and 1.0 mg/kg/day) every 4 weeks over a 16-week period.	6
Total	6

Baseline characteristics

Characteristic	Lomitapide Escalated
Age Continuous	25.7 years STANDARD_DEVIATION 9.43
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	3 Participants
Region of Enrollment United States	6 participants
Sex: Female, Male Female	3 Participants
Sex: Female, Male Male	3 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	6 / 6
serious Total, serious adverse events	1 / 6

Outcome results

Primary