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)
Primary Purpose
Familial Dysbetalipoproteinemia, Hyperlipoproteinemia Type III
Status
Unknown status
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Evolocumab Auto-Injector [Repatha]
Placebos
Sponsored by
About this trial
This is an interventional treatment trial for Familial Dysbetalipoproteinemia focused on measuring Postprandial hyperlipidemia, Evolocumab, PCSK9 monoclonal antibody
Eligibility Criteria
Inclusion criteria:
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.
- >18 years old (on the day of signing informed consent).
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).
- Willingness to maintain a stable diet for the duration of the study.
- Understanding of the study procedures, alternative treatments available, and risks involved with the study and voluntarily agreement to participate by giving written informed consent.
Exclusion criteria:
- Intolerance, known allergy or hypersensitivity to evolocumab (or other PCSK-9 monoclonal antibodies), latex or any of the components of the medication.
- Current or prior exposure to evolocumab or another PCSK9-inhibitor mAb in the past 12 weeks.
- Unable or unwilling to drink an oral fat load.
- Premenopausal women.
- Uncontrolled diabetes as defined by a HbA1c >69 mmol/mol.
- BMI >40 kg/m2.
- Uncontrolled blood pressure with systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg.
- Increased hepatic enzymes, defined as alanine transaminase (ALAT) or aspartate transaminase (ASAT) >3 times the ULN, or active liver disease defined as non alcoholic steatohepatitis (NASH), cirrhosis or Child Pugh B and C, or history of chronic active hepatitis B or C; subjects with documented resolution after treatment are permitted.
- 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.
- (Sub)clinical hypothyroidism defined as TSH >5.0 mcl/U/mL or (sub)clinical hyperthyroidism defined as TSH < 0.35 mcl/U/ml.
- Increased levels of creatinine kinase defined as >3 times the ULN.
- Increased fasting levels of triglycerides defined as >10 mmol/L.
- History of organ transplantation and/or use of immunosuppressive medication.
- Use of fish oil or red yeast rice, bempedoic acid, niacin, CETP inhibitors, lomitapide, mipomersen < 6 weeks prior to the study or the use of siRNA targeting PCSK9 inhibitors < 36 weeks prior to the study.
- Active malignancy (<2 year prior to informed consent), except non-melanoma skin cancer or carcinoma in situ of the cervix.
- Known infection with Human Immunodeficiency Virus (HIV) or AIDS.
- Known celiac disease or other disorder associated with significant intestinal malabsorption.
- Known galactose-intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.
- 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.
- Current participation or participation in a study with an investigational compound or device within 30 days of signing informed consent.
- Any medical, social or physiological circumstance which interferes the study, based on judgement by the principal investigator.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Evolocumab
Placebo
Arm Description
Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Placebo injection once every 2 weeks for 12 weeks
Outcomes
Primary Outcome Measures
AUC (area under the curve) non-HDL-cholesterol
Secondary Outcome Measures
Fasting levels, AUC and iAUC of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB, as well as fasting non-HDL-cholesterol.
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.
Fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL, HDL) concentrations and composition (triglycerides, cholesterol, ApoB and apolipoproteins).
Post fat load ApoB 48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) and proteins involved in postprandial lipid metabolism.
Full Information
NCT ID
NCT03811223
First Posted
January 17, 2019
Last Updated
January 17, 2019
Sponsor
UMC Utrecht
Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Erasmus Medical Center, University Medical Center Nijmegen
1. Study Identification
Unique Protocol Identification Number
NCT03811223
Brief Title
Effects of Evolocumab Versus Placebo Added to Standard Lipid-lowering Therapy on Fasting and Post Fat Load Lipids in Patients With Familial Dysbetalipoproteinemia
Acronym
EVOLVE-FD
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2019
Overall Recruitment Status
Unknown status
Study Start Date
August 2019 (Anticipated)
Primary Completion Date
January 2021 (Anticipated)
Study Completion Date
March 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UMC Utrecht
Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Erasmus Medical Center, University Medical Center Nijmegen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Patients with familial dysbetalipoproteinemia (FD) have increased triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), beta VLDL, premature atherosclerosis and cardiovascular disease. They also have a delayed postprandial triglyceride and chylomicron (CM) remnant clearance. Postprandial hypertriglyceridemia is associated with increased vascular risk. Although combination therapy with statin and fibrate is recommended in the treatment of patients with FD, there is still a substantial amount of patient who do not reach their treatment target with this medication. Furthermore no information is available about the postprandial effects of adding evocolumab to standard lipid lowering therapy in FD patients.
Detailed Description
See brief summary
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Dysbetalipoproteinemia, Hyperlipoproteinemia Type III
Keywords
Postprandial hyperlipidemia, Evolocumab, PCSK9 monoclonal antibody
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Evolocumab
Arm Type
Experimental
Arm Description
Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo injection once every 2 weeks for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Evolocumab Auto-Injector [Repatha]
Intervention Description
Evolocumab 140 mg every 2 weeks for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebos
Other Intervention Name(s)
Placebo
Intervention Description
Placebo subcutaneous injection every 2 weeks for 12 weeks
Primary Outcome Measure Information:
Title
AUC (area under the curve) non-HDL-cholesterol
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Fasting levels, AUC and iAUC of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB, as well as fasting non-HDL-cholesterol.
Time Frame
12 weeks
Title
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.
Time Frame
12 weeks
Title
Fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL, HDL) concentrations and composition (triglycerides, cholesterol, ApoB and apolipoproteins).
Time Frame
12 weeks
Title
Post fat load ApoB 48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) and proteins involved in postprandial lipid metabolism.
Time Frame
12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria:
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.
>18 years old (on the day of signing informed consent).
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).
Willingness to maintain a stable diet for the duration of the study.
Understanding of the study procedures, alternative treatments available, and risks involved with the study and voluntarily agreement to participate by giving written informed consent.
Exclusion criteria:
Intolerance, known allergy or hypersensitivity to evolocumab (or other PCSK-9 monoclonal antibodies), latex or any of the components of the medication.
Current or prior exposure to evolocumab or another PCSK9-inhibitor mAb in the past 12 weeks.
Unable or unwilling to drink an oral fat load.
Premenopausal women.
Uncontrolled diabetes as defined by a HbA1c >69 mmol/mol.
BMI >40 kg/m2.
Uncontrolled blood pressure with systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg.
Increased hepatic enzymes, defined as alanine transaminase (ALAT) or aspartate transaminase (ASAT) >3 times the ULN, or active liver disease defined as non alcoholic steatohepatitis (NASH), cirrhosis or Child Pugh B and C, or history of chronic active hepatitis B or C; subjects with documented resolution after treatment are permitted.
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.
(Sub)clinical hypothyroidism defined as TSH >5.0 mcl/U/mL or (sub)clinical hyperthyroidism defined as TSH < 0.35 mcl/U/ml.
Increased levels of creatinine kinase defined as >3 times the ULN.
Increased fasting levels of triglycerides defined as >10 mmol/L.
History of organ transplantation and/or use of immunosuppressive medication.
Use of fish oil or red yeast rice, bempedoic acid, niacin, CETP inhibitors, lomitapide, mipomersen < 6 weeks prior to the study or the use of siRNA targeting PCSK9 inhibitors < 36 weeks prior to the study.
Active malignancy (<2 year prior to informed consent), except non-melanoma skin cancer or carcinoma in situ of the cervix.
Known infection with Human Immunodeficiency Virus (HIV) or AIDS.
Known celiac disease or other disorder associated with significant intestinal malabsorption.
Known galactose-intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.
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.
Current participation or participation in a study with an investigational compound or device within 30 days of signing informed consent.
Any medical, social or physiological circumstance which interferes the study, based on judgement by the principal investigator.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Frank LJ Visseren, prof
Phone
+31 88 7557324
Email
f.l.j.visseren@umcutrecht.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Britt E Heidemann, MD
Phone
+31 88 75 579 94
Email
b.e.heidemann@umcutrecht.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Frank LJ Visseren, prof
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Currently, there is no plan to make individual participant data available to other researchers, but this is possible in the future.
Learn more about this trial
Effects of Evolocumab Versus Placebo Added to Standard Lipid-lowering Therapy on Fasting and Post Fat Load Lipids in Patients With Familial Dysbetalipoproteinemia
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