E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
homozygous familial hypercholesterolemia |
|
E.1.1.1 | Medical condition in easily understood language |
genetic defect for high cholesterol in blood |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the impact of 12 intravnous infusions of 8 mg/kg CER-001 given at 2-week intervals on descending thoracic aorta and carotid plaque volume, determined from vessel wall volume of diseased arterial segments using 3T magnetic resonance imaging (3TMRI). |
|
E.2.2 | Secondary objectives of the trial |
Absolute change from baseline in carotid plaque volume. Absolute change in baseline in descending thoracid aorta plaque volume. Percent change from baseline in carotid plaque lipid rich necrotic core volume, carotid plauqe calcium volume and coratid intraplaque hemorrhage. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject or Subject guardian must sign the informed consent, and subject must sign assent if applicable, as approved by the EC prior to performance of any screening procedures
2. Male or female subject 12 years or older
3.Females of childbearing potential that agree and commit to use an acceptable form of birth control for the entire study. Acceptable forms of birth control for this study are defined as a barrier method plus hormonal therapy (implants, injections, oral contraceptives and IUDs) or abstinence.
4. Subject diagnosis of Homozygous FH defined as:
• Genetic testing on record classifying the subject as Homozygous FH
-or-
•Genetic testing on record classifying the subject as Compound Heterozygous FH
with accompanying phenotypical criteria of:
• a history of LDL-C ≥220 mg/dl (5.69 mmol/L) while receiving maximally tolerated lipid-lowering therapy with <15% response
-and-
•LDLC above the 90th percentile in ≥2 firstdegree relatives
-and-
• the presence of tendinous xanthomas and/or manifestations of premature
coronary heart disease or corneal arcus.
5. Subject must be willing to participate in the study and comply with all protocol
requirements, including willingness to:
• Undergo two baseline contrastenhanced 3TMRI evaluations separated by about 510 days.
• Return to the clinic every two weeks for a total of twelve IV infusions of study drug.
• Return to the clinic at the end of the study for a followup contrastenhanced 3TMRI procedure. |
|
E.4 | Principal exclusion criteria |
1. Subjects weighing more than 100 kg at Screening.
2. Subjects with significant health problems in the recent past including blood disorders, cancer, or digestive problems but not cardiovascular disease as manifested in inclusion criteria #3 above.
3. Females who are prenant, breastfeeding, or plan to become pregnant during the study.
4. Subject has known major hematologic, renal [serum creatinine > 2.0 mg/dL (180 μmol/L)], hepatic (liver enzymes greater than twice the upper limits of normal for the performing laboratory), metabolic, gastrointestinal or endocrine dysfunction in the judgment of the Investigator
5. Any clinically significant medical condition or presence of any laboratory abnormality performed prior to randomization that is considered by the investigator to be clinically important and could interfere with the conduct of the study.
6. Subject is likely to be unreliable as a study participant based on then Investigator's (or designee’s) knowledge of the subject (e.g., alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis).
7. Subject has a contraindication to MRI scanning such as imbedded metal (e.g., schrapnel), implanted metal objects (e.g., pacemaker), claustrophobia, allergy to gadolinium chelate contrast or severe renal insufficiency (e.g., GFR < 30mL/min/1.73m2) that would preclude the use of contrastenhanced 3TMRI.
8. Subject has participated in any investigational drug study within 30 days prior to randomization, or expects to participate in any other investigational drug study during his/her planned participation in this study. The last dose of any investigational product must have been taken at least 30 days prior to the first dose of CER001.
9. Subject has previously participated in this study or another study involving
CER001. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Percent change from baseline to follow-up in carotid plaque volume measured as arterial wall volume of diseased portions of the arterial wall using 3TMRI. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and 1-3 weeks after last infusion. |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints will include:
Absolute change from baseline to followup in carotid plaque volume.
Percent change and absolute change from baseline to followup in descending
thoracic aorta plaque volume.
Percent change and absolute change from baseline to followup in total descending
thoracic aorta plus carotid plaque volume.
Percent change from baseline in carotid plaque lipid –rich necrotic core volume.
Percent change from baseline in carotid plaque calcium volume.
Percent change from baseline in carotid intraplaque hemorrhage (IPH).
Most severe % stenosis of right and of left carotid arteries by magnetic resonance angiography (MRA) or by noncontrast MRI luminal area reduction if MRA is not available.
Minimum thickness of carotid fibrous cap in carotids with a stenosis >50%.
The safety endpoints in this study include:
Incidence and severity of AEs from routine monitoring;
Incidence of abnormalities and changes from baseline in clinical laboratory parameters from testing of blood and urine, including biomarkers for immunogenicity;
Incidence of adverse changes from baseline vital sign values; and
Incidence of adverse changes from baseline physical examinations.
Minimum thickness of carotid fibrous cap in carotids with a stenosis >50%. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoints: Baseline and 1-3 weeks after last infusion.
Safety Endpoints: From Visit 3 (first drug infusion) through to Visit 15, 1-3 weeks after last drug infusion. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 | No |
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 |
Canada |
Italy |
Netherlands |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
Last visit of the last subject undergoing the trial |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |