A Phase 1, Randomized, Double-Blind, Placebo- and Positive-Controlled, Parallel-Group Study to Evaluate the Effect of LMTM on the Response to an Oral Tyramine Challenge and to Determine the Multiple-Dose Pharmacokinetics of LMTM.

LMTM is a new compound that may potentially be used for the treatment of
Alzheimer*s disease. Alzheimer's disease is a slowly developing disease of the
brain that affects memory and other brain functions. It is a disease in which
misfolding of tau proteins occurs in the brain. Tau proteins are important for
maintaining stability of certain parts of brain cells. When they are misfolded
it causes damage to these brain cells. Therefore, treatment that helps to
prevent or decrease the misfolding of tau proteins is being tested as possible
treatment in Alzheimer*s disease. LMTM is thought to prevent the misfolding of
tau proteins and to dissolve already misfolded tau proteins.

Part 1:
The purpose of this study is to determine whether LMTM inhibits monoamine
oxidase (MAO). MAO is an enzyme (protein involved in reactions in the body)
which breaks down tyramine. By giving participants tyramine which raises the
blood pressure we can indirectly measure MAO. If LMTM inhibits MAO, less
tyramine is needed to reach a predefined rise in blood pressure, compared with
placebo.

Large amounts of tyramine can be found in some specific foods (especially found
in fermented food). The properties of some foods change through fermentation
(breakdown of biological products in the absence of oxygen by bacteria for
example) where tyramine is formed. This happens in particular in products such
as aged cheese, aged meat, and soy products (soy sauce). More examples of
tyramine rich foods and drinks are mentioned in Section 5 and Appendix E.

In this study we will also investigate how safe the new compound LMTM is and
how well it is tolerated when it is used by healthy participants.

We compare the effects of LMTM with the effects of a placebo. A placebo is a
compound without any active ingredient. We also compare the effects and safety
of LMTM to the effects and safety of similar compounds, selegiline and
phenelzine. Selegiline is already being used in the treatment of Parkinson*s
disease and phenelzine in the treatment of depression. Please note that when
the term *study compound* is used in this document, we mean LMTM, placebo,
selegiline or phenelzine.

LMTM has been used before by healthy volunteers and patients. In addition, it
has been extensively tested in the laboratory and on animals.


Part 2:
In this study we will investigate how safe the new compound LMTM is and how
well it is tolerated when it is used by healthy participants.
We also investigate how quickly and to what extent LMTM is absorbed,
transported, and eliminated from the body (this is called pharmacokinetics).

LMTM has been used before by healthy volunteers and patients. In addition, it
has been extensively tested in the laboratory and on animals.

Part 1:
For the research it is necessary that the volunteer stays in the research
center for a maximum of 1 period of 32 days (31 nights). After this there is
one more follow-up visit to the research center. This visit is between 6 and 8
days after leaving the research center.

Day 1 is the first day on which the volunteer receives tyramine. We expect the
volunteer at the research center on the day prior to the first tyramine
administration. The volunteer leaves the study center before or on Day 30 of
the study depending on the tyramine response. The volunteer will leave the
research center on Day 19 at the earliest.

Below is an overview of the days on which the volunteer stays in the research
center or on which the volunteer visits the research center for both Group 1
and Group 2.

Examination:
Day -28 to Day 2

Entry:
Day 1

In-house stay:
Day -1 to Day 31*

Departure:
Day 31*

Follow-up:
Between 6 and 8 days after leaving the research center

* The length of stay may be shorter based on the tyramine response. The
volunteer will leave the research center on Day 19 at the earliest.


In Group 1, the volunteer receives LMTM 60 mg/day, placebo or phenelzine 30
mg/day as capsules by mouth containing 240 milliliters (ml) of water.
In Group 2, the volunteer receives LMTM 16 mg/day, placebo or selegiline 10
mg/day as capsules by mouth containing 240 milliliters (ml) of water.

During the first 1.5 hours after taking the study drug, the volunteer should
not lie down (unless asked by one of the investigators), as this may affect the
absorption of the study drug.

Whether the volunteer receives LMTM, placebo, phenelzine (Group 1) or
selegiline (Group 2) is determined by lottery. Per treatment group, 6
participants received LMTM, 6 participants placebo and 6 participants
phenelzine (Group 1) or selegiline (Group 2). Neither the volunteer nor the
investigators know whether the volunteer is receiving LMTM, placebo,
selegiline, or phenelzine.

All volunteers also receive tyramine as capsules once daily in incremental
doses (6.25 to 600 mg/day, see table below). Tyramine is not a medicine, but a
substance that occurs naturally in several foods and drinks. This treatment
will last until a certain predetermined rise in blood pressure is reached. The
rise in blood pressure will probably occur between half an hour and 1 hour
after taking tyramine and return to normal values **2 hours after taking
tyramine. This will be closely monitored by the research team. You must lie
down for the first 0.5 hour before tyramine administration and approximately 2
hours after this (unless otherwise instructed by one of the investigators), as
this may affect the absorption of the study drug and the blood pressure being
measured.


Part 2:
Day 1 is the first day on which the volunteer receives the research drug. We
expect the volunteer at the study center on the day prior to the first
administration of the study drug. The volunteer will leave the study center on
Day 11 of the study.

Below is an overview of the days on which the volunteer stays in the research
center or on which the volunteer visits the research center:

Examination:
Day -28 to Day 1

Part 1:
For tyramine, the scheduled dosages are as follows:

- All treatment groups will receive Tyramine up to 100 mg to 600 mg once daily
as oral capsules from Days 1 to 6.
- All treatment groups will receive a single dose of tyramine between 150 and
550 mg given as oral capsules on day 7 after a pre-determined increase in blood
pressure has been achieved.
- The LMTM dose 1 and 2, placebo and selegiline group will receive Tyramine in
ascending order from 25 mg to 600 mg, once daily as oral capsules from days 18
to 30.
-The Phenelzine group receives Tyramine in ascending order of 6.25mg to 350mg,
once daily as oral capsules from day 18 to 30.
* The treatment stops when a predetermined increase in blood pressure is
reached. It is important to note that the volunteer will be excluded from the
study if they do not achieve the predetermined increase in blood pressure at
the minimum and maximum dose of tyramine between Day 1 and Day 7.


Below are the planned treatment groups in this study:

- LMTM dose 1 group will receive LMTM 16 mg/day, oral capsules twice daily from
day 8 to a maximum of 30.
- LMTM dose 2 group will receive LMTM 60 mg/day, oral capsules twice daily from
day 8 to a maximum of 30.
- Placebo group will receive Placebo, oral capsules twice daily from day 8 to a
maximum of 30.
- Selegiline will receive Selegiline 10 mg/day, oral capsules twice daily from
day 8 to a maximum of 30.
- Phenelzine group will receive Phenelzine 30 mg/day, oral capsules twice daily
from day 8 to a maximum of 30.
* The treatment stops when a predetermined increase in blood pressure is
reached.


Part 2:
The planned treatment for the study are as follows:

LMTM 8 mg oral tablets (two tablets of 4 mg)
Twice daily on day 1-9
Once daily on day 10

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 Part 1: 53 ml ; Part 2: 213 ml of blood from
screening to follow-up. This amount does not cause any problems in adults. To
compare: a blood donation involves 500 mL of blood being taken at once 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 may be more than the amount
indicated above.

Heart tracing:
To make a heart tracing, electrodes will be placed on arms, chest and legs.
Prolonged use of these electrodes can cause skin irritation.

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 gagging. When the sample is taken from the back of the
nose, The volunteer may experience a stinging sensation and eyes may become
watery.