In this study we will investigate how quickly and to what extend the approved compounds repaglinide, tolbutamide, midazolam or caffeine are absorbed and eliminated from the body when it is given together with PXL770. This study is a drug-drug…
ID
Source
Brief title
Condition
- Other condition
- Hepatic and hepatobiliary disorders
Synonym
Health condition
NASH
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the effect of repeated doses of PXL770 on the primary
pharmacokinetics (PK) parameters of repaglinide, tolbutamide, midazolam, and
caffeine in healthy subjects.
Secondary outcome
To assess the safety and tolerability of PXL770 with and without
coadministration of repaglinide, tolbutamide, midazolam, and caffeine in
healthy subjects.
To assess the effect of repeated doses of PXL770 on the secondary PK parameters
of repaglinide, tolbutamide, midazolam, and caffeine in healthy subjects.
To assess PK parameters of PXL770 after repeated dosing.
To assess the effect of repeated doses of PXL770 on the PK parameters of
midazolam*s metabolite 1* hydroxymidazolam in healthy subjects.
To assess the effect of repeated doses of PXL770 on the PK parameters of
caffeine*s metabolite paraxanthine in healthy subjects.
Background summary
Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat in the
liver which is not caused by excessive alcohol consumption. Some NAFLD patients
also develop inflammation in the liver, this is called non-alcoholic
steatohepatitis (NASH). The inflammation leads to damage and scar tissue
(fibrosis) in the liver. This can lead to liver cirrhosis, cancer and
eventually liver failure. PXL770 is a new compound that may eventually be used
for the treatment of NASH. PXL770 works by activating a protein (AMPK) that
results, among other things, in a decrease in the uptake of fat by the liver,
which can be beneficial for patients that suffer from NASH.
The study compound will be administered in combination with the compounds
repaglinide, tolbutamide, midazolam, or caffeine. Repaglinide, tolbutamide,
midazolam and caffeine are approved drugs and available in the Netherlands
under several dosages and formulations. Which compound subjects will receive
depends on the group in which they will participate. Repaglinide is a drug that
lowers the blood glucose levels and is being used in the treatment of diabetes
mellitus type 2. Tolbutamide is a medication used for the treatment of diabetes
type 2 because it stimulates the release of insulin. Midazolam is a short
acting sedative used prior to invasive diagnostic or surgical procedures.
Caffeine is a stimulant and is given in combination with pain medication (such
as paracetamol) for the treatment of headache and migraine.
Study objective
In this study we will investigate how quickly and to what extend the approved
compounds repaglinide, tolbutamide, midazolam or caffeine are absorbed and
eliminated from the body when it is given together with PXL770. This study is a
drug-drug interaction study.
Repaglinide, tolbutamide, midazolam and caffeine have been chosen because they
are known to be broken down by certain enzymes in the liver. By looking at the
effect of PXL770 on these compounds, something can also be said about whether
PXL770 has an influence on these enzymes. This is important to know when PXL770
is given in the future along with compounds that are also broken down by these
enzymes.
We also investigate how safe the new compound PXL770 is and how well it is
tolerated when it is administered to healthy volunteers. In addition, we also
investigate the pharmacokinetics of PXL770 itself.
PXL770 has been administered to humans before. It has previously also
extensively been tested in the laboratory and on animals. PXL770 will be tested
at a fixed dose of 500 mg. Repaglinide, tolbutamide, midazolam and caffeine are
no new compounds; they are already available on the market in several dosages
and formulations.
Study design
The study will take a maximum of 6 weeks (Groups 1, 2 and 3) or 7 weeks (Group
4) from the screening until the follow-up visit.
Group 1, 2 and 3:
For the study it is necessary that you stay in the research center for 1 period
of 12 days (11 nights). Day 1 is the first day when subjects receive the study
compound. Subjects will leave the research center on Day 11 of the study.
Screening Between Day -21 and Day -2
Entry Day -1
Stay Day -1 to 11
Leave Day 11
Follow-up Day 17 ± 1
Group 4
For the study it is necessary that you stay in the research center for 1 period
of 20 days (19 nights). Day 1 is the first day when subjects receive the study
compound. Subjects will leave the research center on Day 19 of the study.
Screening Between Day -21 and Day -2
Entry Day -1
Stay Day -1 to 19
Leave Day 19
Follow-up Day 25 ± 1
Intervention
Subjects will be given PXL770 and repaglinide (Group 1), PXL770 and tolbutamide
(Group 2), PXL770 and midazolam (Group 3), or PXL770 and caffeine (Group 4). On
the day that both PXL770 and repaglinide, tolbutamide, midazolam or caffeine
will be administered (Day 9 or Day 17), subjects will be given PXL770 first,
followed within 10 minutes by the second study compound.
Group 1
PXL770 will be given as 2 oral tablets (2x 250 mg) and repaglinide will be
given as 1 oral tablet (0.5mg). These will be given with 240 milliliters (mL)
of (tap) water. Subject will be given PXL770 once daily for 8 days on Day 3 to
Day 10, and repaglinide on Day 1 and Day 9 (once each day).
Group 2
PXL770 will be given as 2 oral tablets (2x 250 mg) and tolbutamide will be
given as an oral tablet (500mg). These will be given with 240 mL of (tap)
water. Subjects will be given PXL770 once daily for 8 days on Day 3 to Day 10,
and tolbutamide on Day 1 and Day 9 (once each day).
Group 3
PXL770 will be given as 2 oral tablets (2x 250 mg) with 240 milliliters (mL)
of (tap) water, and midazolam will be given as an oral solution (2mg). Because
of the small volume of the oral solution, this will be squirted in the mouth
using a syringe (without a needle). Subjects will be given PXL770 once daily
for 8 days on Day 3 to Day 10, and midazolam on Day 1 and Day 9 (once each day).
Group 4
PXL770 will be given as 2 oral tablets (2x 250mg), and caffeine will be given
as 4 oral tablets (200 mg). These will be given with 240 milliliters (mL) of
(tap) water. Subjects will be given PXL770 once daily for 16 days on Day 3 to
Day 18, and caffeine on Day 1 and Day 17 (once each day).
After intake of the study compounds one of the investigators will inspect hands
and mouth. This it to check if subjects have taken the study compound.
Study burden and risks
Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
canula can sometimes lead to inflammation, swelling, hardening of the vein,
blood clotting, and bleeding in the environment (bruising) of the puncture
site. In some individuals, a blood draw can sometimes cause pallor, nausea,
seating, low heart rate, or drop in blood pressure with dizziness or fainting.
In total, we will take less than 500 milliliters (mL) of blood. This amount
does not cause any problems in adults. To compare: a blood donation involves
500 mL of blood being taken each time. If the investigator thinks it is
necessary for the safety of a participant, extra samples might be taken for
possible additional testing. If this happens, the total amount of blood drawn
will be more than the amount indicated above.
Heart tracing
To make a heart tracing, electrodes will be placed at specific locations on
arms, chest and legs. Prolonged use of these electrodes can cause skin
irritation.
Finger prick
For measuring the blood sugar levels, we will take blood samples on multiple
days via finger prick.
Coronavirus test
A sample for the coronavirus test will be taken from the back of the nose and
throat using a swab. Taking the sample only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
the throat may cause subjects to gag. When the sample is taken from the back of
the nose, subjects may experience a stinging sensation and the eyes may become
watery.
Avenue Jean Jaurès 259-261
Lyon 69007
FR
Avenue Jean Jaurès 259-261
Lyon 69007
FR
Listed location countries
Age
Inclusion criteria
1. Gender: male or female.
2. Age: 18 to 55 years, inclusive, at screening.
3. Body mass index (BMI): 18.0 to 30.0 kg/m2, inclusive. at screening.
4. Weight: >=50 kg at screening.
5. Status: healthy subjects.
6. Race: Caucasian.
Exclusion criteria
1. Previous participation in any clinical study with PXL770 (only if subject
received study drug).
2. Employee of PRA or the Sponsor.
3. Mental handicap, legal incapacity, or any history of clinically important
emotional and/or psychiatric illness.
4. Vulnerable subjects (eg, persons kept in detention).
5. History of relevant drug and/or food allergies.
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 | EUCTR2019-004915-30-NL |
| CCMO | NL76722.056.21 |