A RANDOMIZED, DOUBLE-BLINDED, DOUBLE-DUMMY, PLACEBO-CONTROLLED THOROUGH QTC STUDY WITH SINGLE ORAL DOSES OF CEDAZURIDINE IN HEALTHY SUBJECTS

Cedazuridine is a compound that could possibly be used in combination with
other agents to enable their oral administration. These agents include
hypomethylating agents (HMAs, a type of anticancer agent), such as decitabine,
for the treatment of a number of cancers, including acute myeloid leukemia
(AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia
(CMML). In these cancers, white blood cells in the bone marrow do not mature
and therefore do not become healthy blood cells.
When HMAs are administered orally, they do not work because HMAs are broken
down in the gut and liver, specifically by the enzyme called cytidine deaminase
(CDA). Cedazuridine is a new compound which slows down how fast HMAs disappear
in the body, especially in the stomach, intestine and the liver, which could
help HMAs be better absorbed in the body. At this moment, one of the
combinations with cedazuridine (INQOVI® [decitabine and cedazuridine] tablets)
has been approved for the treatment of MDS and CMML in the United States,
Canada, and Australia.

The purpose of the study is to investigate the effect of cedazuridine on the
values of specific electrocardiogram (ECG) parameters. One of these parameters
is the QT -interval. The QT -interval indicates the recovery time of the heart
muscle cells after they have been electrically stimulated. Importantly, the
study will assess whether there is a prolongation of the QT interval following
cedazuridine treatment. When the QT interval is prolonged, repolarization
(return to resting state) of the heart is delayed. This means that cardiac
(heart) cells need more time to prepare for the next beat. When a new heartbeat
is about to start and not all cardiac cells are ready for repolarization,
arrhythmias (abnormal heartbeat) could develop. For this study the expected
small changes to your ECG recordings are considered to be relatively safe.

In this study we will also investigate how safe the compound cedazuridine is
and how well it is tolerated when it is used by healthy participants. We also
investigate how quickly and to what extent cedazuridine is absorbed,
transported, and eliminated from the body (this is called pharmacokinetics).

Moxifloxacin is used as a control during this study. Moxifloxacin is known to
prolong the QT- interval and is therefore a suitable compound to monitor the
proper conduct of the study. In addition, moxifloxacine has a favorable safety
profile. Therefore, it is often used as a positive control in similar QT-
interval studies. Moxifloxacin is on the market as an antibiotic and has been
available in the European Union for more than 10 years. You will receive a
patient information leaflet for more information on this compound
.
We compare the effects of cedazuridine and moxifloxacin also with the effects
of a placebo. A placebo is a compound without any active ingredient. Please
note that when the term *study compound* is used in this document, we mean
cedazuridine, moxifloxacin, or placebo.
Cedazuridine has been used by humans before. In addition, it has been
extensively tested in the laboratory and on animals.

The study requires that the volunteers stay in the study center for 4
consecutive periods of 5 days (a total of 21 days and 20 nights).

Day 1 is the first day on which the research drug is given. Volunteers are
expected the day prior to the first study drug administration at the study
center. In that case, one must report at 14:00 o'clock in the afternoon. The
entry time can be adjusted. Leave the study center on Day 5 of study treatment
period 4 (19 days after the first study drug administration).

One receives cedazuridine, moxifloxacin, or placebo after an overnight fast (at
least 10 hours without food and drink) as oral capsules with 240 milliliters
(mL) of tap water.

After taking the research drug, one of the researchers will inspect the hands
and mouth. This is to check whether the study drug has been taken.

During each treatment period, fasting is continued for up to 4 hours after
study drug administration. Then they get lunch. During the fast one may drink
water with the exception of 2 hours before to 2 hours after administration of
the study drug.

Treatment A: once 100 mg cedazuridine
Treatment B: once 400 mg cedazuridine
Treatment C: once placebo
Treatment D: once 400 mg moxifloxacin

Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula can sometimes lead to inflammation, swelling, hardening of the vein,
blood clotting, and bleeding in the environment of the puncture site. In some
individuals, a blood draw can sometimes cause pallor, nausea, sweating, low
heart rate, or drop in blood pressure with dizziness or fainting.
In total, we will take about 130 mL of blood. This amount does not cause any
problems in adults.

Heart tracing (ECG)
To make a heart tracing, electrodes will be placed at specific locations on the
arms, chest and legs. To monitor the heart rate, electrodes will be placed on
the chest and abdomen. Prolonged use of these electrodes can cause skin
irritation.

Holter (monitoring heart rate)
The heart rate will be monitored continuously from 1 hour before administration
of the study compound until 24 hours thereafter. As long as the volunteers are
connected to the device they cannot take a shower, they have to behave as
relaxed as possible and prevent from sweating. As soon as hey are connected,
they cannot use electric devices (razor, electric toothbrush, hairdryer)
anymore. They may not wear jewelry or a watch. At certain time-points they will
be asked to remain lying down for 15 minutes without moving, talking or
sleeping. During these moments they may not listen to music, watch television
or use a laptop, media player or phone.

Fasting
If the volunteer has to fast for a prolonged time during the study, this may
lead to symptoms such as dizziness, headache, stomach upset, or fainting.

Coronavirus test
Samples for the coronavirus test will be taken from the back of the nose and
throat using swabs. Taking the samples 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 the volunteer to gag. When the sample is taken from the
back of the nose, they may experience a stinging sensation and the eyes may
become watery.