To evaluate the effect of 12 weeks subcutaneous evolocumab (140 mg pre-filled pen every 2 weeks) compared to placebo on post fat load non-HDL-C levels in 30 subjects with FD, in a multicenter, randomized, placebo-controlled, double-blind, crossover…
ID
Source
Brief title
Condition
- Lipid metabolism disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is non-HDL-C AUC (area under the curve).
Secondary outcome
1. Fasting, post fat load AUC and iAUC of total cholesterol (TC), LDL-C
(directly measured), HDL-C, TG, ApoB and Lp(a); as well as fasting non-HDL-C
after 12 weeks treatment with subcutaneous evolocumab (140 mg pre-filled pen
every 2 weeks) compared to placebo in subjects with FD on standard
lipid-lowering therapy.
2. Percentage change and absolute change from baseline in fasting and post fat
load AUC and iAUC of non-HDL-c, TC, LDL-C (directly measured), HDL-C, TG, ApoB
and Lp(a) after 12 weeks treatment with subcutaneous evolocumab (140 mg
pre-filled pen every 2 weeks) compared to placebo in subjects with FD on
standard lipid-lowering therapy.
3. Fasting and post fat load AUC and iAUC of lipoprotein (CM, VLDL, IDL, LDL
and HDL) concentrations and composition (triglycerides, cholesterol, ApoB and
apolipoproteins) and metabolic parameters after 12 weeks treatment with
subcutaneous evolocumab (140 mg pre-filled pen every 2 weeks) compared to
placebo in patients with FD on standard lipid-lowering therapy.
4. Post fat load AUC and iAUC of ApoB48-containing lipoprotein concentrations
(chylomicrons, chylomicron remnants) after 12 weeks treatment with
subcutaneous evolocumab (140 mg pre-filled pen every 2 weeks) compared to
placebo in patients with FD on standard lipid-lowering therapy.
5. Occurrence of adverse events after 12 weeks treatment with subcutaneous
evolocumab (140 mg pre-filled pen every 2 weeks) compared to placbo in subjects
with FD on standard lipid-lowering therapy.
Background 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 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.
Study objective
To evaluate the effect of 12 weeks subcutaneous evolocumab (140 mg pre-filled
pen every 2 weeks) compared to placebo on post fat load non-HDL-C levels in 30
subjects with FD, in a multicenter, randomized, placebo-controlled,
double-blind, crossover study.
Study design
Multicenter, randomised, placebo-controlled, double-blind, crossover trial. It
consists of 2 treatment periods of 12 weeks in which patients receive
evolocumab and placebo in a randomised order. Between treatment periods is an 8
week cross-over period. Before and at the end of the 2 treatment periods
patients visit the hospital for an oral fat load. Before and after the oral fat
load blood samples are collected through an intravenous catheter. Patients have
to stay until 8 hours after the oral fat load and receive a meal at the end.
Before the visits to the hospital people have to fast for at least 12 hours
(meaning that they cannot eat or drink anything, except water). The study lasts
40 weeks excluding screening visit (-2 to -4 weeks prior to the first baseline
visit).
Intervention
Evolocumab 140 mg subcutaneous every 2 weeks
Study burden and risks
Risks: low but known and unknown side effects of evolocumab can occur. Minimal
risk concerning venapunctions are pain, hematoma or infection of injection site.
Burden: Patients are asked to keep a stable diet and alcohol consumption. They
have to visit the hospital 5 times in total. Prior to each visit, patients are
asked to fast for at least 12 hours and to fast 8 hours after the oral fat
load. Four of the five visits include ingestion of an oral fat load (sweetened
fresh cream). Patients might not like the taste of the cream. The four visit
can lasts up to 9 hours. The screening visit lasts 60 minutes.
Heidelberglaan 100
Utrecht 3508 GA
NL
Heidelberglaan 100
Utrecht 3508 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subjects diagnosed with Familial Dysbetalipoproteinemia; defined as;
*known *2*2 genotype or known dominant APOE mutation genotype (confirmed by
genotyping or isoelectric focusing) and a phenotype of familial
dysbetalipoproteinemia (defined as an ApoB/TC ratio < 0.15, TC > 5 mmol/L and
TG > 3 mmol/L or non-HDL-c/ApoB ratio > 6.55 mmol/g; with or without
medication.
2. If using any lipid lowering treatment: dose must be stable for at least
three months with non-HDL-C levels > 1.6 mmol/L.
3. >=18 or =< 80 years years old (on the day of signing informed consent).
4. Women are postmenopausal and not receiving systemic cyclic estrogen hormone
agonist/antagonist therapy to prevent external effects due to estrogen on
lipoprotein metabolism. 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).
5. Willingness to maintain a stable diet for the duration of the study.
6. 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
1. Intolerance, known allergy or hypersensitivity to evolocumab (or other
PCSK-9 monoclonal antibodies), latex or any of the components of the medication.
2. Current or prior exposure ((< 1 year before screening) and not discontinued
with PCSK9-inhibitor mAbs due to side effects) to evolocumab or another
PCSK9-inhibitor mAb.
3. Unable or unwilling to drink an oral fat load.
4. Premenopausal women.
5. Uncontrolled diabetes as defined by a HbA1c >69 mmol/mol.
6. BMI >40 kg/m2.
7. Uncontrolled blood pressure with systolic blood pressure >180 mmHg or
diastolic blood pressure >110 mmHg.
8. 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.
9. 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.
10. (Sub)clinical hypothyroidism defined as TSH >5.0 mcl/U/mL or (sub)clinical
hyperthyroidism defined as TSH < 0.35 mcl/U/ml.
11. Increased levels of creatinine kinase defined as >3 times the ULN.
12. Increased fasting levels of triglycerides defined as >10 mmol/L.
13. History of organ transplantation.
14. Current use or use in the past 3 months of immunosuppressive medication.
15. 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.
16. Active malignancy (<2 year prior to informed consent), except non-melanoma
skin cancer or carcinoma in situ of the cervix.
17. Known infection with Human Immunodeficiency Virus (HIV) or AIDS.
18. Known celiac disease or other disorder associated with significant
intestinal malabsorption, including short-bowel syndrome after intestinal
resection or gastric bypass.
19. Known galactose-intolerance, Lapp-lactase deficiency or glucose-galactose
malabsorption.
20. 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.
21. Current participation or participation in a study with an investigational
compound or device within 30 days of signing informed consent.
22. Any medical, social or physiological circumstance which interferes the
study, based on judgement by the principal investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003476-12-NL |
| ClinicalTrials.gov | NCT03811223 |
| CCMO | NL67476.041.19 |