|E.1 Medical condition or disease under investigation |
|E.1.1||Medical condition(s) being investigated || |
|Familial Dysbetalipoproteinemia |
|E.1.1.1||Medical condition in easily understood language || |
|Familial Dysbetalipoproteinemia |
|E.1.1.2||Therapeutic area ||Diseases [C] - Cardiovascular Diseases [C14] |
|MedDRA Classification |
|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 evaluate the effect of 12 weeks subcutaneous evolocumab (140 mg pre-filled pen every 2 weeks) compared to placebo on fasting and post fat load non-HDL-C levels in 30 patients with FD, in a multicenter, randomized, placebo-controlled, double-blind, crossover study |
|E.2.2||Secondary objectives of the trial || |
|- To evaluate the effect of 12 weeks evolocumab compared to placebo on fasting and post fat load TC, LDL-C (directly measured), HDL-C, TG and ApoB in patients with FD. |
- To evaluate the effect of 12 weeks evolocumab compared to placebo on the change from baseline in fasting and post fat load non-HDL-C, TC, LDL-C (directly measured), HDL-C, TG and ApoB in patients with FD.
- To evaluate the effect of 12 weeks evolocumab on fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL and HDL) concentrations and composition (triglycerides, cholesterol and apolipoproteins) compared with placebo in patients with FD.
-To evaluate the effect of 12 weeks evolocumab on post fat load ApoB48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) compared with placebo in patients with FD.
- To evaluate the occurrence of adverse events by evolocumab compared to placebo in patients with FD.
|E.2.3||Trial contains a sub-study || No |
|E.3||Principal inclusion criteria || |
|1. Patients diagnosed with Familial Dysbetalipoproteinemia; |
*ε2ε2 genotype or dominant APOE mutation genotype (confirmed by genotyping or isoelectric focusing) with any lipid-lowering treatment at a stable dose for at least three months and non-HDL-C >1.6 mmol/L or;
*Patients with ε2ε2 genotype or dominant APOE mutation (confirmed by genotyping or isoelectric focusing) without lipid-lowering treatment and with an ApoB/TC ratio < 0.15.
2. >18 years old (on the day of signing informed consent).
3. Women are postmenopausal and not receiving hormone therapy (including cyclic and non-cyclical hormone replacement therapy or any estrogen antagonist/agonist). Postmenopausal status is defined as:
*no menses for ≥3 years or;
*no menses for ≥1 year but <3 years and confirmed by FSH levels elevated into the postmenopausal range (15-150 IU/L).
4. Willingness to maintain a stable diet for the duration of the study.
5. Understanding of the study procedures, alternative treatments available, and risks
involved with the study and voluntarily agreement to participate by giving written
|E.4||Principal exclusion criteria|| |
|1. Intolerance, known allergy or hypersensitivity to evolocumab (or other PCSK-9 monoclonal antibodies) or any of the components of the medication. |
2. Current or prior exposure to evolocumab or another PCSK9-inhibitor mAb in the past 12 weeks.
3. Unable or unwilling to drink an oral fat load.
4. Uncontrolled diabetes as defined by a HbA1c >69 mmol/L at visit 1 (screening visit).
5. BMI >40 kg/m2 at visit 1 (screening visit).
6. Uncontrolled blood pressure with systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at visit 1 (screening visit).
7. Increased hepatic enzymes, defined as alanine transaminase (ALAT) or aspartate transaminase (ASAT) >3 times the ULN, or active liver disease defined as cirrhosis or Child Pugh B and C, or history of chronic active hepatitis B or C; participants with documented resolution after treatment are permitted.
8. Impaired renal function, defined by an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2, and/or need of renal placement therapy or other clinically significant renal disease.
9. (Sub)clinical hypothyroidism: defined as TSH >5.0 mcl/U/mL at visit 1 (screening visit).
10. Increased levels of creatinine kinase defined as >3 times the ULN at visit 1 (screening visit).
11. Increased fasting levels of triglycerides defined as >10 mmol/L at visit 1 (screening visit).
12. History of organ transplantation and/or use of immunosuppressive medication.
13. Use of fish oil or red yeast rice <6 weeks prior to the study.
14. Active malignancy (<2 year prior to informed consent), except non-melanoma skin cancer or carcinoma in situ of the cervix.
15. Known infection with Human Immunodeficiency Virus (HIV) or AIDS.
16. Known celiac disease or other disorder associated with significant intestinal malabsorption.
17. Known galactose-intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.
18. Alcohol use, defined as >14 alcoholic consumptions per week for women and >21 alcohol consumptions per week for men. One alcohol consumption unit is defined as follows: 350 mL beer, 150 mL wine or 45 mL alcohol for mixed drinks.
19. Current participation or participation in a study with an investigational compound or device within 30 days of signing informed consent.
20. Any medical, social or physiological circumstance which interferes the study, based on judgement by the principal investigator.
|E.5 End points |
|E.5.1||Primary end point(s)|| |
|The primary endpoint is non-HDL-C AUC. |
|E.5.1.1||Timepoint(s) of evaluation of this end point|| |
|After 12 weeks of treatment |
|E.5.2||Secondary end point(s)|| |
|1. Fasting levels, AUC and iAUC of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB, as well as fasting non-HDL-cholesterol. |
2. Percentage change from baseline and absolute difference in fasting and post fat load non-HDL-cholesterol, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB.
3. Fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL, HDL) concentrations and composition (triglycerides, cholesterol, ApoB and apolipoproteins).
4. Post fat load ApoB 48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) and proteins involved in postprandial lipid metabolism.
|E.5.2.1||Timepoint(s) of evaluation of this end point|| |
|After 12 weeks of treatment |
|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|| No |
|E.6.5||Efficacy|| No |
|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.22.214.171.124||Other trial type description|| |
|E.7.2||Therapeutic exploratory (Phase II)|| No |
|E.7.3||Therapeutic confirmatory (Phase III)|| No |
|E.7.4||Therapeutic use (Phase IV)|| Yes |
|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 || Yes |
|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 || 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||4 |
|E.8.5||The trial involves multiple Member States|| No |
|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 || |
|Last telephone contact with last subject (patients are contacted by telephone 8 weeks after the last visit to the hospital, to follow-up on any side-effects/complaints). |
|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||4 |
|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||4 |