A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass Balance, Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing Microtracer ([14C]-TAK-954)in Healthy Male Subjects

TAK-954 is being developed for the short-term treatment of critically ill
patients that have developed difficulty receiving feedings through a tube
leading into the stomach. TAK-954 activates the so-called 5-HT4 receptor. In
animal studies it has been shown, that it has a positive effect on the
gastrointestinal tract.

TAK-954 is an investigational drug which means that it has not yet been
approved for use. The main purpose of this study is to understand how the body
handles TAK-954 (how it is absorbed, processed by and removed from the body).
TAK-954 will be minutely radioactive labelled (with 14 Carbon [14C]) so that it
can be traced in blood, urine and feces. The radiation dose is considered to be
lower than that of background.

In addition, the safety and tolerability of TAK-954 will be investigated.

Participation in the entire study depends on the amount of radioactivity
measured in volunteers blood, feces and urine. The volunteer will stay in the
research center at least from Day -1 (the day before study compound is given)
until the afternoon of Day 8. If, from Day 8 onwards, the radioactivity levels
in urine and feces are below the pre-defined levels, the volunteer will be
allowed to leave the research center. At the latest the volunteer will be
allowed to leave the research center on the afternoon of Day 15.

A total of 0.5 mg TAK-954 with trace amount of radioactivity will be given as
an intravenous infusion over a 1-hour period during the morning of Day 1.

When TAK-954 is given, the volunteer should have fasted for at least 2 hours
(no eating and drinking). Water is permitted until 1 hour prior to the start of
dosing and may be consumed without restriction beginning 1 hour after the end
of dosing.

During the first 4 hours after starting the drug infusion, the volunteer has to
remain in a semi-recumbent (lying down with head of bed tilted up) position
(except when indicated as such by one of the investigators).

The study compound may cause side effects.

In general, doses up to 0.5 mg once daily for 5 consecutive days as IV
infusions, were well tolerated in healthy subjects.

Approximately 80 subjects have been exposed to different doses of TAK-954 in
clinical trials. Based on the results of those studies, the known side effects
that occurred for TAK-954 are as follows:
•headache (reported by 38% of the subjects)
•diarrhea (reported by 14% of the subjects)
•dizziness that may occur while standing or sitting up (reported by 10% of the
subjects)
•irregular heartbeat (reported by 10% of the subjects)
•low blood pressure when sitting or standing (reported by 7% of the subjects)

Other side effects observed when TAK-954 was taken by mouth were nausea
(reported by of the 56% subjects) and vomiting (reported by 29% of the
subjects).

Side effects that have occurred with other medications with in the same class
but were not reported with TAK-954 are as follows:
•abdominal pain with bloody diarrhea and increased size of abdomen
•heart attack or severe chest pain that may or may not spread into shoulders
and arms, and stroke or temporary stroke symptoms
•serious irregular heart rhythms

If the volunteer has a known hypersensitivity to TAK-954 or to any ingredient
in it, the volunteer will not be allowed to take part in the study.

The study compound can also have side effects that are not known yet.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.
In total, we will take about 400 mL of blood from the volunteer. This amount
does not cause any problems in adults. To compare: a blood donation involves
500 mL of blood being taken each time.

To make a heart tracing, electrodes (small, plastic patches) will be pasted at
specific locations on your arms and legs. Prolonged use of these electrodes can
cause skin irritation (rash and itching).

Exposure to radiation
This study involves using radioactive markers. The additional amount of
radiation the volunteer will be exposed to in this study is negligible (that
is, less than the natural background radiation in 1 month) compared to the
background radiation in the Netherlands, which is ~2.5 mSv per year. If the
volunteer participate in scientific research involving exposure to radiation
more often, the volunteer should discuss with the investigator whether
participation at this moment would be safe.

Procedures: pain, minor bleeding, bruising, possible infection.