E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Arterial inflammation in subjects with elevated lipoprotein a (Lp[a]) |
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E.1.1.1 | Medical condition in easily understood language |
Arterial inflammation in subjects with elevated lipoprotein a (Lp[a]) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051615 |
E.1.2 | Term | Atherosclerotic cardiovascular disease |
E.1.2 | System Organ Class | 100000004866 |
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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 |
The primary objective is to assess the effects of four 250 mg 3G10 once monthly intravenous injections on monocyte function ex vivo. |
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E.2.2 | Secondary objectives of the trial |
Primary objective The primary objective is to assess the effects of four 250 mg 3G10 once monthly intravenous injections on monocyte function ex vivo. Secondary objectives To assess functional effects of 3G10 on arterial inflammation in vivo To assess 3G10 effects on arterial stiffness To assess the safety and tolerability of 3G10 Exploratory objectives To assess the effects of 3G10 on heart function and LFR in a subgroup of the study population To study the pharmacodynamics of 3G10 by scavenger receptor and adhesion molecule expression on circulating monocytes and other circulating biomarkers To study the pharmacokinetics of 3G10 To further assess 3G10 effects on arterial stiffness over time To further assess functional effects of 3G10 on arterial inflammation in vivo To study the change in plasma protein patterns
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of a signed written informed consent 2. Lp(a) above 50 mg/dL at screening 3. Male or female, ≥ 50 years of age at screening 4. Weight of at least 63 kg and maximum 125 kg at screening (dose = 2-4 mg/kg body weight)
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E.4 | Principal exclusion criteria |
1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the result or the subject’s ability to participate in the study 2. Illness (including common colds) for the last 4 weeks before Visit 3 and Visit 4 3. Medical history of myocardial infarction (MI) or stroke within 12 months of screening 4. Ongoing or paroxysmal atrial fibrillation 5. Clinically overt heart failure 6. Hypertension defined as ≥180/100 mmHg 7. Diabetes mellitus 8. Ongoing treatment with statins or PCSK9 inhibitor Except when: • Statin is prescribed for primary prevention and Lp(a) >50 mg/dl and LDLc >100 mg/dL (2.5 mmol/L). • Statin and/or PCSK9, or other lipid lowering medication, are prescribed for secondary prevention, and Lp(a) >50 mg/dL. 9. Systemic autoimmune diseases requiring treatment 10. Cancer, excluding basal cell carcinoma, within the last five years 11. Medical PET, SPECT, abdominal or thoracic CT examination during the previous 12 months’ time period 12. Conditions contraindicating MRI such as, but not limited to, claustrophobia, having a history of brain or heart surgery and pacemaker implantation, permanent make-up, past or present occupation as metalworker or welder. Having metallic implants that cannot be declared safe under the employed MRI scanning conditions, or which will significantly degrade MRI scan quality. 13. Positive HIV or hepatitis test 14. Clinically significant abnormal findings in haematology or clinical chemistry at screening or any value ≥ 3 times the upper limit of normal haematology or clinical chemistry at screening 15. The subject is unable to understand the written and verbal instructions 16. Pregnant or breast feeding women. A negative urine pregnancy test must be demonstrated in females at screening. The females must be of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal defined as 12 month of amenorrhea (in questionable cases a blood sample with simultaneous determination of follicle stimulating hormone 25 150 IE/L and estradiol <200 pmol/L is confirmatory). The male subjects must agree to use condom in combination with use of contraceptive methods with failure rate of <1% to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of dosing until 3 months after last dosing of the IMP. 17. History or current drug or alcohol abuse which in the opinion of the Investigator should preclude participation in the study 18. Subjects who have participated in any other clinical study that included drug treatment within 3 months of the administration of investigational product in this study 19. Subjects who have received any type of vaccination within 21 days before dosing or who anticipate the need for vaccination before the end of the study 20. Plasma donation within one month of screening or any blood donation/blood loss >450 mL during 3 months prior to screening 21. Subjects who have planned any scheduled invasive treatment/surgical procedure during the whole study 22. Investigator considers subject unlikely to comply with study procedures, restrictions and requirements 23. History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses. 24. Recent (<1 month prior to screening) or current treatment with medications that may have a significant effect on plaque inflammation, including oral, rectal, or subcutaneous/intramuscular injected corticosteroids and immunosuppressive medications (e.g. cyclosporine, methotrexate, tacrolimus, azathioprine, anti-thymocyte globulin, sirolimus, anti-TNF agents such as infliximab, anti-IL6 therapy such as tocilizumab, or anti-IL1 therapy such as anakinra)
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in TEM in monocytes isolated from treated subjects from baseline to visit 11 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints Change in TBRmax in common carotid arteries by fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) from baseline to Visit 11 Change in PWV (m/sec) assessed by Sphygmocor Xcel from baseline to Visit 11
Safety endpoints Safety and tolerability: AEs/SAEs, vital signs, physical examination, ECG and laboratory assessments including haematology, clinical chemistry and immunogenicity
Exploratory endpoints Change from baseline in cardiac variables and LFR variables, as assessed by MRI, in a subgroup of the study population IgM anti-PC level, other circulating biomarkers, monocyte adhesion markers and scavenger receptors assessed by fluorescence-activated cell sorting (FACS) over time Pharmacokinetics: 3G10 serum levels Arterial stiffness variables, assessed by Sphygmocor Xcel TBRmean (carotid and aorta), TBRgluc (carotid and aorta) and TBRmax (aorta) assessed by 18F-FDG PET/CT Change in protein pattern from baseline to Visit 11 as assessed by proteomics measurements
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints are evaluated from baseline to Visit 11
Safety endpoints: Adverse events (AE) will be assessed from administration of study drug until end of study visit. ECG will be assessed at screening and pre-dose as well as post dose at dosing visits. Vital signs and physical examination will be assessed during all visits to the clinic. Safety blood samples will be assessed at all visit to the clinic. Immunogenicity will be assessed pre-dose at each dosing visit dosing and at the end of study visit.
Exploratory endpoints will be presented showing observed values and changes from baseline at each available visit/assessment |
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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) | 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 | 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 | 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 | 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 | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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Last visit of the last subject in 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 | 3 |
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 | 3 |