A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 as Add-on Therapy in Homozygous Familial Hypercholesterolemia Subjects

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2005-003449-15-GB
• Date of registration: 09/03/2007
• Prospective Registration: Yes
• Primary sponsor: Genzyme Europe B.V.
• Public title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 as Add-on Therapy in Homozygous Familial Hypercholesterolemia Subjects
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 as Add-on Therapy in Homozygous Familial Hypercholesterolemia Subjects - RADICHOL I
• Date of first enrolment: 12/07/2007
• Target sample size: 50
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-003449-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Contacts

• Name: Genzyme Europe B.V.
• Affiliation: Genzyme Europe B.V.

• Name: Genzyme Europe B.V.
• Affiliation: Genzyme Europe B.V.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female subjects age = 12 years, > Tanner Stage 2
2. Body weight = 40 kg
3. Diagnosis of HoFH determined by at least one of the criteria below*:
a. History of genetic testing confirming two mutated alleles at the LDL receptor
gene locus, OR
b, Documented history of untreated LDL-C greater than 500 mg/dL (13 mmol/L)
AND at least one of the criteria below:
i. Tendinous and/or cutaneous xanthoma prior to age 10 years
ii. Documentation of elevated LDL-C > 190 mg/dL (4.9 mmol/L) prior to
lipid-lowering therapy consistent with HeFH in both parents. In case a
parent is not available, a history of coronary artery disease in a first degree
male relative of the parent younger than 55 years or first degree female
relative of the parent younger than 60 years is acceptable
*Note: Inclusion of subjects who meet the clinical criteria for HoFH, but have a
genetic diagnosis other than HoFH must be discussed with the Key Sponsor
Contact prior to enrollment.
4. Satisfy one of the following:
a. Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal,
abstinent, or subject or partner compliant with an acceptable contraceptive
regimen for 4 weeks prior to, during, and 6 months after the last study drug
dose
b. Males: Surgically sterile, abstinent or subject or partner is utilizing an
acceptable contraceptive method during and 6 months after the last study drug
dose
Please refer to Restriction on Lifestyle for acceptable contraceptive methods
5. For subjects on allowed lipid-lowering therapies (i.e., statins, cholesterol
absorption inhibitors, bile-acid sequestrants, and niacin), the dose and regimen of
the therapies must be stable for at least 12 weeks prior to Screening and the
subject must be expected to remain on the same dose and regimen throughout the
study
6. On stable low-fat diet (e.g., NCEP-ATP III diet, Appendix 2) beginning at least
8 weeks prior to the first dose of study drug and willing to maintain the diet
throughout the study
7. Stable weight (± 4 kg) for > 6 weeks prior to Screening for adult subjects
(= 18 years)
8. Fasting LDL-C = 130 mg/dL (3.4 mmol/L) and triglycerides (TG) < 350 mg/dL
(4.0 mmol/L) at Screening
9. Given informed consent, or, in the case of minors, the subject’s parent/legal
guardian must be capable and willing of giving informed consent, and, if
appropriate for the subject’s age, the subject must be capable of giving
assent/consent for study participation
Are the trial subjects under 18? yes
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:
1. Myocardial infarction (MI), percutaneous transluminal coronary intervention, or
coronary artery bypass graft surgery within 12 weeks prior to Screening, or
cerebrovascular accident within 24 weeks prior to Screening. Subjects with
adequately treated stable angina, per Investigator assessment, may be included
2. Congestive heart failure defined by New York Heart Association (NYHA)
Classes III or IV
3. Active infection requiring antiviral or antimicrobial therapy
4. Positive test for HIV or hepatitis B or C at Screening
5. Uncontrolled hypothyroidism, other uncontrolled endocrine disease or any
uncontrolled condition that may predispose to secondary hyperlipidemia
6. Diabetes mellitus that is inadequately controlled (HbA1c > 8.0%), or newly
diagnosed (within 12 weeks), or a change in antidiabetic pharmacotherapy (i.e.,
change in dosage [with the exception of ± 10 units of insulin] or the addition of
new medication) within 8 weeks of Screening
7. Disorders of the hematologic, digestive, or central nervous systems including
degenerative disease that would limit study evaluation or participation
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the
skin that has been adequately treated
9. Serum creatine phosphokinase (CPK) = 3 x upper limit of normal (ULN)
10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >
1.5 x ULN, unless pre-approved by Key Sponsor Contact
11. History of significant hepatic disease including liver cirrhosis, or documented
liver steatosis prior to Screening
12. History of significant renal disease, or abnormal creatinine or proteinuria at
Screening, unless pre-approved by Key Sponsor Contact
13. Current use of the following medications:
a. Anti-obesity medications (e.g., orlistat, sibutramine), or has discontinued
treatment < 12 weeks prior to Screening
b. Fibrates within 8 weeks of Screening
c. Systemic corticosteroids or anabolic agents within 6 weeks of Screening*
*Note: Concomitant therapy of oral corticosteroids used as replacement
therapy for pituitary/adrenal disease as well as inhaled steroid therapy (e.g.,
Pulmicort®), or intra-articular, or topical may be acceptable; however, the
subject must be on a stable regimen for at least 4 weeks prior to Screening.
All exceptions should be discussed with the Key Sponsor Contact.
14. Current use of the following medications unless the dose has been stable for
> 12 weeks prior to Screening and is expected to be stable and the subject agrees
to continue this regimen for the duration of the study:
a. cardiovascular medications (e.g., beta-blockers, calcium-channel blockers,
ACE inhibitors, nitrates, a-adrenergic blockers, thiazide diuretics, or
angiotensin II receptor antagonists)
b. fish oils
c. Cholestin™ (also known as red yeast rice, or mo

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Reduction of low density lipoprotein C (LDL-C) in Homozygous Familial Hypercholesterolemia (HoFH)
MedDRA version: 9.1 Level: LLT Classification code 10057080 Term: Homozygous familial hypercholesterolemia

Intervention(s)

Product Name: ISIS 301012
Product Code: ISIS 301012
Pharmaceutical Form: Solution for injection
Current Sponsor code: ISIS 301012
Other descriptive name: ISIS 301012 phosphorothioate oligonucleotide
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: To evaluate in HoFH subjects treated for 26 weeks with ISIS 301012 added on to stable lipid-lowering therapy:
1) The incremental apo B lowering efficacy of ISIS 301012
2) The incremental total cholesterol lowering efficacy of ISIS 301012
3) The incremental non-HDL-C lowering efficacy of ISIS 301012
4) The incremental effects of ISIS 301012 on TG, VLDL-C, HDL-C, apo A-1, Lp(a), lipoprotein subclasses, and hsCRP

Main Objective: To evaluate the incremental LDL-C lowering efficacy of ISIS 301012 at Week 28 in homozygous familial hypercholesterolemia (HoFH) subjects treated for 26 weeks with ISIS 301012 added on to stable lipid-lowering therapy

Primary end point(s): Efficacy:
Percent reduction in LDL-C from baseline at Week 28 (or LOCF)

Safety:
All AEs and SAEs
Platelets, liver transaminases, renal function tests
Other laboratory results
Vital signs and ECG

Secondary ID(s)

301012-CS5

Source(s) of Monetary Support

Genzyme Europe B.V.

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 01/06/2016
• Date Completed: 25/03/2009
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-003449-15/results