In this trial, the effect of mipomersen is tested on LDL-cholesterol levels in patients with severe LDL-hypercholesterolemia and atherosclerosis which are regularly treated by LDL-apheresis. MedDRA version: 17.0 Level: HLGT Classification code 10027424 Term: Metabolic and nutritional disorders congenital System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Trade Name: Kynamro
Product Name: Mipomersen
Product Code: ISIS 301012
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Mipomersen
CAS Number: 629167-92-6
Current Sponsor code: ISIS 30
Sponsors
Hospital of the University of Munich
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. The patient is a male or female, age >/= 18 years. 2. The patient fulfils German criteria for regular LDL-apheresis: a. Established atherosclerosis, b. LDL-cholesterol >/=130 mg/dl despite maximal possible drug therapy. 3. Regular (weekly) LDL-apheresis >/= 3 months; no change in aphere-sis system for 6 weeks. 4. The patient has fasting pre-apheresis LDL-C >/= 130 mg/dL at screening. 5. The patient is receiving a stable, maximally tolerated, lipid-lowering regimen, and is expected to remain on this regimen through the end of treatment, including both: a. A maximally tolerated statin treatment greater than zero, unless the patient has a documented history of statin intoler-ance, stable for at least 12 weeks prior to screening. b. A stable low-fat diet (e.g. NCEP-ATP III therapeutic lowering cholesterol or equivalent). c. Note: Patients may receive another class of lipid-lowering therapy (e.g. cholesterol absorption inhibitors, bile-acid se-questrants, fibrates, niacin, fish oil), as long as it (drug and dose) has been stable for at least 6 weeks prior to screening 6. The patient has a body mass index (BMI) 6 weeks prior to screening. 7. The patient satisfies one of the following criteria: a. Females: Non-pregnant and non-lactating; either surgically sterile, post-menopausal (e.g. one year without menstrual pe-riods), or patient or partner compliant with an acceptable and highly effective contraceptive regimen (a regimen which results in a failure rate of less than 1% per year) for 4 weeks prior to screening, and willing to remain compliant during and for 24 weeks after the last investigational product dose. b. Males: Either surgically sterile or patient or partner is willing to utilize an acceptable and highly effective contraceptive method during and for 24 weeks after the last investigational product dose. 8. Patients with the ability to follow study instructions and likely to attend and complete all required visits. 9. Written informed consent of the patient Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. The patient has experienced MI, percutaneous transluminal coronary intervention (PTCI), CABG, cerebrovascular accident, unstable angina, or acute coronary syndrome within 12 weeks of screening. 2. The patient has a clinically significant arrhythmia that was deemed to be uncontrolled at any time 8% at screening. 4. The patient has New York Heart Association (NYHA) functional clas-sification III or IV heart failure. 5. The patient has systolic blood pressure > 160 mm Hg or diastolic blood pressure > 95 mm Hg at screening (despite antihypertensive medication/therapy). 6. The patient has an active infection requiring systemic antiviral or an-timicrobial therapy unless treatment expected to be completed by day 1. 7. The patient has a positive test for HIV or hepatitis B or C at screen-ing. 8. The patient has any uncontrolled condition that may predispose to secondary hyperlipidemia such as uncontrolled hypothyroidism. 9. The patient has had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated. 10. The patient has clinically significant hepatic (e.g. History of confirmed non-alcoholic steatosis hepatis NASH) or renal disease or Gilbert’s syndrome. 11. The patient has previously received mipomersen treatment. 12. The patient has any of the following laboratory values at screening: a. Serum creatine phosphokinase (CPK) > 3 x upper limit of nor-mal (ULN), b. Alanine aminotransferase (ALT) levels > 1.5 x ULN, c. Serum creatinine > 0.1 mg/dL (> 8.8 µmol/L) above ULN for women, or > 0.2 mg/dL (> 17.7 µmol/L) above ULN for men, d. Proteinuria (> 1000 mg protein / g creatinine on spot urine), e. Total bilirubin > 1.2 x ULN, f. The patient has a fasting TG value >350 mg/dL (3.95 mmol/L). 13. The patient has used any of the following medications within 12 weeks of Screening: a. Cholestin™ (also known as red yeast rice, or monascus pur-pureus extract), b. Anti-obesity medication, c. Chronic systemic corticosteroids or anabolic agents except for replacement therapy. 14. The patient is currently using any of the following medications - unless a stable dose regimen was used for at least 12 weeks prior to screening and the dose and regimen are expected to remain stable un-til the end of treatment: a. Oral anticoagulants (e.g., warfarin; minimal dose adjustments considered to be within usual limits for the patient are allowed per Investigator judgment), b. Hormone replacement therapy, c. Diabetes medications including - but not limited to - sulfony-lureas, metformin and glitazones, with the exception of changes of ± 10 units of insulin, d. Prophylactic antiviral therapy for herpes simplex virus (HSV), e. Oral contraceptives (with the exception of progestagen-only pills), combined injectable contraceptives, and combined con-traceptive rings or patches. 15. 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. 16. The patient has a current or a recent history of d
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives of this study are to prove the concept for efficacy of mipomersen in patients with severe LDL-hypercholesterolemia and atherosclerosis treated by regular LDL-apheresis and to explore the consequent benefits for patients in therapy management. The goal of the first phase is to demonstrate that 6 months of mipomersen treatment reduces LDL-cholesterol in patients on regular LDL-apheresis and with similar side effects as reported in patients not treated by concomitant apheresis therapy and to estimate the extent of reduction. The goal of the second phase is to evaluate the clinical significance of the reduction in terms of possible adaptions in apheresis therapy, i.e. to evaluate in how many patients apheresis duration can be shortened, intervals between two consecutive apherese treatments can be stretched or apheresis can be discontinued. ;Secondary Objective: The secondary objectives are: 1) the evaluation of the safety and tolerability of mipomersen in patients on regular apheresis, 2) the evaluation of mipomersen in patients on regular apheresis on other lipid parameters and 3) the evaluation of pharmacokinetic characteristics of mipomersen in patients on regular apheresis therapy. ;Primary end point(s): Primary Endpoints: Phase 1: The primary efficacy endpoint is the percent change in pre-apheresis LDL-C from baseline (averaged from visits 3-5) to end of phase 1 (averaged from visits 29-31). Outcome measure: Absolute difference of percent change between the two groups. Phase 2: The primary endpoint is a shortened, stretched (from weekly to bi-weekly) or discontinued apheresis therapy. Outcome measure: Absolute differ-ence of success rates between the groups, whereby the success rates are estimated by the fractions of patients with success. ;Timepoint(s) of evaluation of this end point: Phase 1: week 26 Phase 2: week 38 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints: Phase 1: Secondary efficacy endpoints during phase 1 include the percent change in post-apheresis LDL-C as well as in pre- and post-apheresis apolipo-protein B (apo B), total cholesterol (TC), non-high-density lipoprotein choles-terol (non-HDL-C) and lipoprotein a (Lp(a)) from baseline to end of phase 1. Other efficacy endpoints include the percent change in pre- and post-apheresis TG, very low density lipoprotein cholesterol (VLDL-C), LDL/HDL ratio, and high-density lipoprotein cholesterol (HDL-C) from baseline to end of phase 1. Phase 2: The secondary efficacy endpoints will be the patients’ types of success (apheresis may be shortened, stretched (from weekly to biweekly) or discontinued) and a graded or at least linear ordered success score developed on the best type of success a patient has reached. ;Timepoint(s) of evaluation of this end point: Phase 1: week 26 Phase 2: week 38 | — |
Countries
Germany
Contacts
Public ContactProf. Dr. med. Klaus Parhofer
Medizinische Klinik u. Poliklinik II
Outcome results
None listed