The primary objective is to evaluate the effect of UDCA and ezetimibe on cholesterol elimination assessed as total faecal sterol concentration. Secondary objective is to assess the effect of UDCA and ezetimibe on plasma lipid profile/composition.
ID
Source
Brief title
Condition
- Hepatobiliary disorders congenital
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main endpoint is the total faecal sterol concentration (faecal neutral sterol
concentration (FNS) + faecal bile acid concentration).
Secondary outcome
Secondary endpoint is plasma lipid profile/composition: LDL-c, HDL-c, TG, apoB,
apoA1.
Background summary
Atherosclerosis is the main underlying cause of cardiovascular disease (CVD).
Increasing cholesterol elimination is a widely used strategy to reduce CVD.
Intestinal cholesterol secretion is mediated via the ATP binding cassette (ABC)
half transporters G5 and G8 (ABCG5/G8) while cholesterol absorption is mediated
by the Niemann-Pick C1 Like (NPC1L1) protein, which is inhibited by ezetimibe.
There is growing evidence that hydrophilic bile acids like ursochol
(ursodeoxycholic acid, UDCA) promote ABCG5/G8 activity in mice. We hypothesize
that UDCA on top of ezetimibe leads to an increased cholesterol excretion via
the feces by stimulating ABCG5/8 and preventing absorption of cholesterol due
to blocking NPC1L1 and therefore promoting elimination of cholesterol from the
body.
Study objective
The primary objective is to evaluate the effect of UDCA and ezetimibe on
cholesterol elimination assessed as total faecal sterol concentration.
Secondary objective is to assess the effect of UDCA and ezetimibe on plasma
lipid profile/composition.
Study design
The current study is an investigator initiated, single-centre, randomized,
double blind, placebo-controlled , cross-over, proof of concept study, to
explore the translational relevance of UDCA on top of ezetimibe on cholesterol
elimination.
Intervention
One group will receive UDCA 600 mg orally once a day, the other group will
receive a matching placebo. This will be on the background of 20 mg/day
ezetimibe.
Study burden and risks
There will be five study visits with a questionnaire and physical examination.
Also, there will be five times blood sampling with a total amount of blood of
60 ml. In addition, they are subjected to behavioral changes, such as a
dietary registration, ingestion of D4-sitostanol and the collection of 5 fecal
stool samples of 5 mg per sample. D4-sitostanol does not confer any health
risks.
UDCA is a registered medicinal product for a number of indications and
considered safe. Most prevalent side effect of UDCA is diarrhea, a risk of
1-10% exists for this. Ezetimibe is a registered medicinal product for
hypercholesterolemia and considered safe. Most important side effect of
ezetimibe is elevated liver enzymes and rhabdomyolysis, most prevalent when
given in combination with statin therapy. The risk of developing these adverse
events is considered to be very low in our study population (0.1% - 1%)
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
Hypercholesterolemia
Aged 18 years or older
LDL > 2.6 mmol/L
Exclusion criteria
* Medical, surgical, laboratory or other conditions, which in the judgment of
the Physician Investigator would make the subject unsuitable for enrollment, or
potentially interfere with subject participation or completion of the study, *
Suffering from an inflammatory bowel disease, e.g. Crohn*s disease or
ulcerative colitis., * Suffering from gall stones or another biliary disease.,
* Suffering diabetes mellitus (type I or II)., * Recent history of, or current
drug or alcohol abuse, * AST or ALT levels > 2 x ULN, * Unable or unwilling to
comply with the protocol requirements or deemed by the investigator to be unfit
for the study., * Presence of contra indications for the use of UDCA and
ezetimibe (see SPC), * Use of lipid lowering drugs such as the following:, o
Statins and fibrates unless on a stable dose for at least 3 months prior to
screening, o Use of nicotinic acid or derivates of nicotinic acid within 4
weeks prior to screening, o Use of cholestyramine or colestipol, * Use of other
drugs such as the following:, o Ciclosporine, o Antacids containing aluminium
hydroxide or aluminium oxide, * Likely to leave the study before its completion
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003281-84-NL |
| CCMO | NL56321.018.16 |
| OMON | NL-OMON19907 |