Clinical Trials Register

Summary
EudraCT Number:	2005-003449-15
Sponsor's Protocol Code Number:	301012-CS5
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-03-09
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2005-003449-15

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

RADICHOL I

A.4.1

Sponsor's protocol code number

301012-CS5

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Genzyme Europe B.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Genzyme Europe B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Genzyme Europe B.V.
B.5.2	Functional name of contact point	Genzyme Europe B.V.
B.5.3	Address:
B.5.3.1	Street Address	Gooimeer 10
B.5.3.2	Town/ city	Naarden
B.5.3.3	Post code	1411 DD
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31356991200

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ISIS 301012
D.3.2	Product code	ISIS 301012
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ISIS 301012
D.3.9.3	Other descriptive name	ISIS 301012 phosphorothioate oligonucleotide
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Reduction of low density lipoprotein C (LDL-C) in Homozygous Familial Hypercholesterolemia (HoFH)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10057080
E.1.2	Term	Homozygous familial hypercholesterolemia

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal 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, α-adrenergic blockers, thiazide diuretics, or
angiotensin II receptor antagonists)
b. fish oils
c. Cholestin™ (also known as red yeast rice, or monascus purpureus extract)
d. over-the-counter therapies known to affect serum lipids (e.g., psyllium, other
fiber-based laxatives, phytosterol margarines)
15. Current use of oral anticoagulants (e.g. warfarin), unless the dose has been stable
for > 4 weeks prior to Screening and regular clinical laboratory monitoring is
performed
16. Current use of cyclical hormones unless the dose has been stable for > 12 weeks
prior to Screening and is expected to be stable for the duration of the study
17. Treatment with another investigational drug, biological agent, or device within
4 weeks of Screening or five half-lives of study agent, whichever is longer
18. Currently receiving apheresis treatments or last apheresis treatment was within
8 weeks of Screening
19. Recent history of, or current drug or alcohol abuse, or unwilling to limit alcohol
consumption for the entire duration of the study, including follow-up: male
subjects to a maximum of two drinks (20 g) per day, and 8 drinks (80 g) per week;
female subjects to a maximum of one drink (10 g) per day, and four drinks (40 g)
per week
20. Unwillingness to comply with study procedures, including follow-up, as specified
by this protocol, or unwillingness to cooperate fully with the Investigator
21. Have any other conditions which, in the opinion of the Investigator, would make
the subject unsuitable for enrollment, or could interfere with the subject
participating in or completing the study

E.5 End points

E.5.1

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Not applicable

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

In the case of minors, the subject's parent or 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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Refer to protocol

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2007-03-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-07-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2009-03-20

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