E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
GENETICALLY DEFINED FAMILIAL PRIMARY HYPOALPHALIPOPROTEINEMIA (FPHA mutation in ApoA1 and/or ABCA1 gene) |
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E.1.1.1 | Medical condition in easily understood language |
Very low HDL-C level and either mutations in your ApoA-I or/and ABCA1 gene |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019185 |
E.1.2 | Term | HDL cholesterol decreased |
E.1.2 | System Organ Class | 100000004848 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of 24 weeks treatment with CER-001 on carotid Mean Vessel Wall Area (MVWA) as compared to placebo using 3T magnetic resonance imaging (3T-MRI);
To evaluate the safety and tolerability of CER-001 administered for 24 weeks
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of 8 weeks and 48 weeks treatment with CER-001 on MVWA as compared to placebo using 3T-MRI;
To evaluate the effect of 8 weeks, 24 weeks and 48 weeks treatment with CER-001 on femoral artery as compared to placebo using 3T-MRI;
To evaluate the effect of 24 weeks treatment with CER-001 in the target (plaque) to background (blood) ratio (TBR) from an index vessel (either right carotid, left carotid) based on the standardized 18FDG uptake measured with PET/CT;
To evaluate safety and tolerability of CER-001 administered for 48 weeks
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with ApoA-1 < 70 mg/dL and with suspected homozygous or heterozygous mutation in the ABCA1, and/or ApoA-1 genes confirmed by genetic testing, will be eligible for this study. Additionally, background symptomatic or asymptomatic cardiovascular disease should be present as such:
· For symptomatic cardiovascular disease: i)history of cardio or cerebrovascular events, ii)diagnosed coronary artery disease (CAD), iii) diagnosed carotid or peripheral stenosis, iiv)previous myocardial revascularisation - percutaneous coronary intervention (PCI), or
coronary artery bypass graft (CABG).
· For asymptomatic cardiovascular disease: patients with subclinical atherosclerosis diagnosed using imaging methods such as i) Doppler ultrasound, ii) B-mode ultrasonography – measurement of carotid intima media thickness, iii) intravascular ultrasonography, iv) Computed Tomography, v) Magnetic Resonance Imaging
Eligible patients must meet the following criteria before they are enrolled in the study:
1. Male and female patients, aged 18 and above.
2. Female patients who are not either surgically sterilized (e.g., tubal ligation or removal of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year) must agree to use one of the following forms of contraception from screening until 90 days after the completion of the study medication: (1) systemic hormonal treatment (2) an IUD which was implanted at least 2 months prior to screening or (3) "double-barrier" contraception (condom, diaphragm and spermicide are each considered a barrier), or (4) agree to remain sexually abstinent during the entire study period (when contraception is not acceptable for cultural or religious beliefs)
3. Sign written informed consent after the scope and nature of the investigation have been explained to them before screening evaluations and willing to comply with the study restrictions
4. Are fluent in the language of the investigator, study staff (including raters), and the informed consent
5. Diagnosis of genetically confirmed HDL-c deficiency due to defects in genes coding for e.g. ABCA1 and/or ApoA-1
6. Stable doses of lipid lowering therapies for at least 6 weeks prior to baseline procedures |
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E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA
Patients meeting any one of the following criteria are not eligible for the study:
1. Patient with LCAT mutation will be excluded
2. Patient who experienced a cardiovascular event within 6 months prior to the onset of screening
3. Patient who experienced stroke or other cerebrovascular event within 1 year prior to the onset of screening
4. Patients with triglycerides level above 500 mg/dL
5. The patient has evidence of clinically significant, uncontrolled or unstable cardiovascular, renal, hepatic (incl. AST or ALT at or above 3x ULN, or bilirubin at or above 2x ULN), gastrointestinal, hematologic, immunological, neurological, endocrine, metabolic or pulmonary disease (as determined by medical history, clinical laboratory or ECG results, or physical examination) or any other medical disorder that would increase the risk associated with taking study medication or would confound the interpretation of study results.
6. Patients with a body mass index (BMI) < 17 kg/m2 or > 40 kg/m2
7. Patients with severe anemia defined as hemoglobin level below or equal to 10 g/dL
8. Any clinically significant abnormal laboratory data, vital signs, physical examination at screening or baseline, which in the opinion of the investigator, would interfere with safety assessments
9. Clinically significant ECG abnormality at screening, including sinus bradycardia (resting heart rate < 50 beats per minute), 2nd or 3rd degree atrioventricular block, prolonged QTc (QTcF ≥ 450 ms in males and ≥ 470 ms in females) history of congenital long QT syndromes, or risk of Torsades de Pointes because of family history of sudden death, etc.
10. Positive result on the serum pregnancy test or are breast feeding at screening, or intend to become pregnant during the course of the trial
11. Male intending to get a child during the study
12. Likely to be unreliable as a study participant based on the Investigator's (or designee’s) knowledge of the patient (e.g., alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis)
13. Symptomatic (NYHA Class II or greater) congestive heart failure requiring and persisting despite appropriate medical treatment
14. Uncontrolled blood pressure: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg at screening or any other pre-randomization visit
15. Uncontrolled diabetes mellitus defined as HbA1c >10%
16. Unexplained creatine phosphokinase level > 3 times the ULN
17. History of malignancy during the 3 years prior to screening, with the exception of basal cell carcinoma of the skin
18. Current alcohol or drug abuse or history thereof within 5 years prior to screening
19. Contraindication to MRI scanning such as imbedded metal (e.g., schrapnel), implanted metal objects (e.g., pacemaker), claustrophobia.
20. Participated in any investigational study or taken an investigational drug within 30 days (or 5 times the half-life of the investigational drug, whatever is longer)
21. Ever received CER-001 within 6 months from the onset of screening
22. Medically non-compliant in the management of their disease in the investigator’s opinion
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E.5 End points |
E.5.1 | Primary end point(s) |
PRIMARY EFFICACY PARAMETER:
The primary efficacy parameter of this study will be the change from baseline after 24 weeks treatment with CER-001 on carotid Mean Vessel Wall Area (MVWA) as compared to placebo using 3T-MRI when administered to patients with genetically defined FPHA.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks treatment with CER-001 |
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E.5.2 | Secondary end point(s) |
SECONDARY EFFICACY PARAMETERS:
• Change from baseline after 8 week and 48 week treatment with CER-001 on MVWA as compared to placebo using 3T-MRI when administered to patients with genetically defined FPHA.
• Change from baseline after 8, 24 and 48 week treatment with CER-001 on femoral artery as compared to placebo using 3T-MRI when administered to patients with genetically defined FPHA.
• Change from baseline at 24 weeks in the TBR from an index vessel (either right carotid or left carotid) based on the standardized 18FDG uptake measured with PET/CT in patients with genetically defined FPHA.
SECONDARY SAFETY PARAMETERS:
• 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 anti-ApoA-1 antibody.
• Incidence of cardiovascular events.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 8, 24 and 48 week treatment with CER-001 |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
Belgium |
Brazil |
Canada |
France |
Israel |
Italy |
Netherlands |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
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 | 11 |