Summary
EudraCT Number:2018-003476-12
Sponsor's Protocol Code Number:UMCU-VASC-CO-002
National Competent Authority:Netherlands - Competent Authority
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2019-08-01
Trial results
A. Protocol Information
A.1Member State ConcernedNetherlands - Competent Authority
A.2EudraCT number2018-003476-12
A.3Full title of the trial
A multicenter, randomized, double-blind, placebo-controlled, crossover trial to evaluate the effects of evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids in patients with Familial Dysbetalipoproteinemia
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
EVOLVE-FD: Effects of EVOLocumab VErsus placebo added to standard lipid-lowering therapy on fasting and post fat load lipids in patients with Familial Dysbetalipoproteinemia
EVOLVE-FD: Effect van EVOLocumab VErsus placebo toegevoegd aan standaard lipiden verlagende therapie op nuchtere en niet-nuchtere lipidenwaarden in patiënten met Familial Dysbetalipoproteinemie.
A.3.2Name or abbreviated title of the trial where available
EVOLVE-FD
A.4.1Sponsor's protocol code numberUMCU-VASC-CO-002
A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03811223
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorUniversity Medical Center Utrecht
B.1.3.4CountryNetherlands
B.3.1 and B.3.2Status of the sponsorNon-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAmgen
B.4.2CountryNetherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationUniversity Medical Center Utrecht
B.5.2Functional name of contact pointFrank LJ Visseren
B.5.3 Address:
B.5.3.1Street AddressHeidelberglaan 100
B.5.3.2Town/ cityUtrecht
B.5.3.3Post code3508 GA
B.5.3.4CountryNetherlands
B.5.6E-mail[email protected]
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name Repatha 140 mg (evolocumab)
D.2.1.1.2Name of the Marketing Authorisation holderAmgen
D.2.1.2Country which granted the Marketing AuthorisationNetherlands
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameRepatha
D.3.4Pharmaceutical form Solution for injection in pre-filled pen
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPSubcutaneous use
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product Yes
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
D.8 Placebo: 1
D.8.1Is a Placebo used in this Trial?Yes
D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled pen
D.8.4Route of administration of the placeboSubcutaneous use
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Familial Dysbetalipoproteinemia
E.1.1.1Medical condition in easily understood language
Familial Dysbetalipoproteinemia
E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
MedDRA Classification
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
E.3Principal 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
informed consent.
E.4Principal 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.5.1Primary end point(s)
The primary endpoint is non-HDL-C AUC.
E.5.1.1Timepoint(s) of evaluation of this end point
After 12 weeks of treatment
E.5.2Secondary 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.5.2.1Timepoint(s) of evaluation of this end point
After 12 weeks of treatment
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety No
E.6.5Efficacy No
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response No
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other No
E.7.1.3.1Other trial type description
E.7.2Therapeutic exploratory (Phase II) No
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) Yes
E.8 Design of the trial
E.8.1Controlled Yes
E.8.1.1Randomised Yes
E.8.1.2Open No
E.8.1.3Single blind No
E.8.1.4Double blind Yes
E.8.1.5Parallel group No
E.8.1.6Cross over Yes
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) No
E.8.2.2Placebo Yes
E.8.2.3Other No
E.8.2.4Number of treatment arms in the trial2
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.8.4.1Number of sites anticipated in Member State concerned4
E.8.5The trial involves multiple Member States No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial 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.8.9.1In the Member State concerned years1
E.8.9.1In the Member State concerned months4
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years1
E.8.9.2In all countries concerned by the trial months4
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 15
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 15
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations No
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception No
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state30
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)
None
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2019-08-01
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2019-09-12
P. End of Trial
P.End of Trial StatusOngoing