Effect of Mipomersen on LDL-Cholesterol Levels in Patients Treated by Regular Apheresis (MICA)

Effect of Mipomersen on LDL-Cholesterol Levels in Patients With Severe LDL-Hypercholesterolemia and Atherosclerosis Treated by Regular LDL-Apheresis

Elevated LDL-cholesterol is a major risk factor for heart disease. In patients with heart disease LDL-cholesterol should be lowered to levels below 70 mg/dl to prevent progression of disease. In most patients life style modification together with lipid lowering drug therapy is sufficient to achieve this goal. In some patients with severe forms of hypercholesterolemia, this may not be sufficient to reach goals and regular lipid apheresis (a costly and time intensive form of therapy) may be performed. Mipomersen is a new drug (apoB antisense oligonucleotide) that can lower LDL-cholesterol even in the most severe forms of LDL-hypercholesterolemia by 25-47%. It is unknown whether and to what extent mipomersen can decrease LDL-cholesterol in patients treated with regular apheresis. Phase 1 of the study will test how 6 months of weekly therapy with mipomersen affects LDL-cholesterol in patients with severe LDL-hypercholesterolemia treated with regular apheresis. Phase 2 will test in how many patients this will result in a meaningful reduction of apheresis time, apheresis frequency or if apheresis can be stopped completely.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis; LDL-hypercholesterolemia
• Intervention / Treatment: Drug: mipomersen

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Munich, Germany, 81377
    • University Munich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The patient fulfils German criteria for regular LDL-apheresis
• Regular (weekly) LDL-apheresis >/= 3 months
• The patient has fasting pre-apheresis LDL-C >/= 130 mg/dL at screening.
• The patient is receiving a stable, maximally tolerated, lipid-lowering regimen
• The patient has a body mass index (BMI) </= 40 kg/m2 with weight stable (± 4 kg) for > 6 weeks prior to screening.
• Written informed consent of the patient

Exclusion Criteria:

• The patient has experienced MI, percutaneous transluminal coronary intervention (PTCI), CABG, cerebrovascular accident, unstable angina, or acute coronary syndrome within 12 weeks of screening.
• The patient has insulin-dependent diabetes mellitus (Type 1), or if Type 2 diabetes, HbA1c > 8% at screening.
• The patient has New York Heart Association (NYHA) functional classification III or IV heart failure.
• The patient has systolic blood pressure > 160 mm Hg or diastolic blood pressure > 95 mm Hg at screening (despite antihypertensive medication/therapy).
• The patient has an active infection requiring systemic antiviral or antimicrobial therapy unless treatment expected to be completed by day 1.
• The patient has a positive test for HIV or hepatitis B or C at screening.
• The patient has any uncontrolled condition that may predispose to secondary hyperlipidemia such as uncontrolled hypothyroidism.
• The patient has had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated.
• The patient has clinically significant hepatic (e.g. History of confirmed non-alcoholic steatohepatitis NASH) or renal disease or Gilbert's syndrome.
• The patient has previously received mipomersen treatment.
• The patient is on chronic systemic corticosteroids or anabolic agents except for replacement therapy.
• The patient has received treatment with another investigational drug, biological agent, or device within 4 weeks of screening or 5 half-lives of the study agent, whichever is longer.
• The patient has a current or a recent history of drug or alcohol abuse, or unwillingness to limit alcohol consumption to within moderate limits (maximum 20 g alcohol per day and 80 g alcohol per week for males; maximum 10 g alcohol per day and 40 g alcohol per week for females).
• Patient not able to give consent.
• Patient without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial.
• Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
• Simultaneous participation in another clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to the beginning of the clinical trial.
• Patient with a physical or psychiatric condition which at the investigator's discretion may put the patient at risk, may confound the trial results, or may interfere with the patient's participation in this clinical trial
• Known or persistent abuse of medication, drugs or alcohol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mipomersen; Patients randomized to this arm will receive mipomersen 200 mg weekly	Drug: mipomersen; mipomersen 200 mg subcutaneously every week for 37 weeks (phase 1: 26 weeks; phase 2: 11 weeks)
No Intervention: Control; patients randomized to this arm will receive no additional drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pre-apheresis LDL-cholesterol (phase 1 of the study)	pre-apheresis LDL-cholesterol concentration will be averaged from 3 subsequent aphereses (exactly 1 week apart) before initiation of mipomersen therapy and after 6 months of weekly apheresis therapy; apheresis conditions will not be changed.	6 months
Fraction of patients in whom apheresis conditions can be modified (phase 2 of the study)	In phase 2 of the study mipomersen will be given weekly. It will be evaluated in what fraction of patients this results in a decrease of apheresis time, apheresis frequency or stopping of apheresis.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in other lipid parameters	a number of additional lipid parameters will be evaluated before and during mipomersen therapy	6 months
Number of participants with adverse events		9 months (phase 1 and 2 of the study)
Plasma concentrations of mipomersen	pharmacokinetic sampling will be obtained following mipomersen administration at different time points during the study.	4 days after injection

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: May 12, 2012
• First Submitted That Met QC Criteria: May 12, 2012
• First Posted (Estimate): May 15, 2012

Study Record Updates

• Last Update Posted (Estimate): September 2, 2015
• Last Update Submitted That Met QC Criteria: September 1, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: hypercholesterolemia; peripheral arterial disease; coronary heart disease; apheresis; cerebrovascular disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Mipomersen
• Other Study ID Numbers: MICA