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

• Sponsor: Aegerion Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01556906
• Collaborator: University of Pennsylvania (Other), Doris Duke Charitable Foundation (Other)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 8
• Patients Per Site Per Month: 0.7

Study Details

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)].

Condition or Disease	Intervention/Treatment	Phase
Homozygous Familial Hypercholesterolemia	Drug: Lomitapide	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Jun 1, 2003
• Actual Primary Completion Date: Feb 1, 2004
• Actual Study Completion Date: Feb 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lomitapide This is an open label trial where all patients receive lomitapide (AEGR733/BMS-201038)at escalating doses	Drug: Lomitapide; Oral administration with escalating doses administered once daily; Other Names: AEGR-733 BMS-201038

Outcome Measures

Primary Outcome Measures

1. LDL-C [Up to 16 weeks of treatment comapred to Baseline]

   Percent change in LDL-C compared to Baseline.

Secondary Outcome Measures

1. Absolute Change From Baseline in Alanine Aminotransferase (ALT) [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in ALT

2. Absolute Change From Baseline in Aspartate Aminotransferase (AST) [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in AST

3. Absolute Change From Baseline in Total Bilirubin [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in total bilirubin

4. Absolute Change From Baseline in Hepatic Fat Percent [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in hepatic fat percent

5. Absolute Change From Baseline in Forced Expiratory Volume During 1 Second (FEV1) [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in FEV1

6. 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

7. Absolute Change From Baseline in Vitamin A [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in vitamin A

8. Absolute Change From Baseline in Vitamin E [Baseline and 16 weeks of treatment]

   Absolute change from Baseline in vitamin E

9. Absolute Change From Baseline in Vitamin D [Baseline and 16 weeks of treatment]

   Absolute Change From Baseline in Vitamin D

10. 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

11. Absolute Change From Baseline in Alpha Linoleic Acid (ALA) [Baseline and 16 weeks of treatment]

    Absolute Change From Baseline in ALA

12. Absolute Change From Baseline in Eicosapentaenoic Acid (EPA) [Baseline and 16 weeks of treatment]

    Absolute Change From Baseline in EPA

13. Absolute Change From Baseline in Docosahexaenoic Acid (DHA) [Baseline and 16 weeks of treatment]

    Absolute Change From Baseline in DHA

14. Absolute Change From Baseline in Linoleic Acid (LA) [Baseline and 16 weeks of treatment]

    Absolute Change From Baseline in LA

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Body weight ≥40 kg

2. Negative screening pregnancy test if female of child-bearing potential

3. Subjects must be willing and able to comply with all study-related procedures

4. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Aegerion Pharmaceuticals, Inc.
• University of Pennsylvania
• Doris Duke Charitable Foundation

Investigators

• Principal Investigator: Dan J Rader, MD, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Aegerion Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01556906
• Other Study ID Numbers: UP1001
• First Posted: Mar 19, 2012
• Last Update Posted: Apr 10, 2013
• Last Verified: Apr 1, 2013

• Additional relevant MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia

Study Results

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.

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Overall Participants	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.7 (9.43)
Sex: Female, Male (Count of Participants)
Female	3 50%
Male	3 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 16.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	3 50%
More than one race	0 0%
Unknown or Not Reported	2 33.3%
Region of Enrollment (participants) [Number]
United States	6 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [percentage change in LDL-C]	-50.94 (9.311)

2. Secondary Outcome

Title	Absolute Change From Baseline in Alanine Aminotransferase (ALT)
Description	Absolute change from Baseline in ALT
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [U/L]	91.2 (85.53)

3. Secondary Outcome

Title	Absolute Change From Baseline in Aspartate Aminotransferase (AST)
Description	Absolute change from Baseline in AST
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [U/L]	37.5 (32.51)

4. Secondary Outcome

Title	Absolute Change From Baseline in Total Bilirubin
Description	Absolute change from Baseline in total bilirubin
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [mg/dL]	-0.25 (0.274)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [percent of hapatic fat]	19.3 (12.92)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [Liters]	0.070 (0.2406)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [mL CO/min/mm Hg]	-3.020 (5.3246)

8. Secondary Outcome

Title	Absolute Change From Baseline in Vitamin A
Description	Absolute change from Baseline in vitamin A
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [µmol/L]	-0.35 (0.847)

9. Secondary Outcome

Title	Absolute Change From Baseline in Vitamin E
Description	Absolute change from Baseline in vitamin E
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [umol/L]	-94.35 (130.797)

10. Secondary Outcome

Title	Absolute Change From Baseline in Vitamin D
Description	Absolute Change From Baseline in Vitamin D
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [nmol/L]	-6.57 (10.712)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [ratio]	-0.0 (1.71)

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [mg/mL]	0.06 (0.045)

13. Secondary Outcome

Title	Absolute Change From Baseline in Eicosapentaenoic Acid (EPA)
Description	Absolute Change From Baseline in EPA
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [mg/mL]	-0.08 (0.079)

14. Secondary Outcome

Title	Absolute Change From Baseline in Docosahexaenoic Acid (DHA)
Description	Absolute Change From Baseline in DHA
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [mg/mL]	-0.08 (0.045)

15. Secondary Outcome

Title	Absolute Change From Baseline in Linoleic Acid (LA)
Description	Absolute Change From Baseline in LA
Time Frame	Baseline and 16 weeks of treatment

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [mg/mL]	-2.9 (1.51)

Adverse Events

Time Frame	First dose through 28 days post-treatment
Arm/Group Title	Lomitapide Escalated
Arm/Group Description	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.
All Cause Mortality
	Lomitapide Escalated
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lomitapide Escalated
	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)
Reproductive system and breast disorders
Breast mass	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Lomitapide Escalated
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Eye disorders
Eye disorders	1/6 (16.7%)
Gastrointestinal disorders
Diarrhoea	5/6 (83.3%)
Nausea	2/6 (33.3%)
Vomiting	2/6 (33.3%)
Dyspepsia	1/6 (16.7%)
Abdominal pain upper	2/6 (33.3%)
Constipation	1/6 (16.7%)
General disorders
Fatigue	2/6 (33.3%)
Asthenia	1/6 (16.7%)
Chest pain	1/6 (16.7%)
Infections and infestations
Rhinitis	1/6 (16.7%)
Injury, poisoning and procedural complications
Contusion	1/6 (16.7%)
Scratch	1/6 (16.7%)
Investigations
Alinine aminotransferase increased	3/6 (50%)
Aspartate aminotransferase increased	3/6 (50%)
International normalized ratio increased	2/6 (33.3%)
Prothrombin time prolonged	1/6 (16.7%)
Metabolism and nutrition disorders
Decreased appetite	1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/6 (33.3%)
Myalgia	1/6 (16.7%)
Neck pain	1/6 (16.7%)
Pain in extremity	1/6 (16.7%)
Nervous system disorders
Headache	3/6 (50%)
Dizziness	1/6 (16.7%)
Renal and urinary disorders
Haemoglobinuria	1/6 (16.7%)
Reproductive system and breast disorders
Breast mass	1/6 (16.7%)
Ovarian cyst	1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	4/6 (66.7%)
Nasal congestion	2/6 (33.3%)
Lung disorder	4/6 (66.7%)
Cough	2/6 (33.3%)
Dyspnoea	1/6 (16.7%)
Sneezing	1/6 (16.7%)
Skin and subcutaneous tissue disorders
Xanthoma	1/6 (16.7%)
Acne	1/6 (16.7%)
Hyperhidrosis	1/6 (16.7%)
Rash	1/6 (16.7%)
Vascular disorders
Hot flush	1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Information is unavailable.