A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PHASE I STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SINGLE AND MULTIPLE ASCENDING DOSES OF THN391 IN HEALTHY SUBJECTS

THN391 is a new compound that may potentially be used for the treatment of
neurological diseases, such as dementia. THN391 is a monoclonal antibody and is
a *custom-made* protein that has been assembled in a laboratory. This can
attach to proteins that are on the surface of body cells or that move in the
blood. THN391 has been developed to block a specific part of the protein fibrin
that has an important role in several neurological diseases. It is expected
that THN391 does not reach the brain in healthy subjects, but it does in people
with neurologicaldisorders in which the so-called blood/brain barrier is
affected.

This study has been transitioned to CTIS with ID 2024-517955-10-00 check the CTIS register for the current data.

In this study we will investigate how safe the new compound THN391 is and how
well it is tolerated when it is used by healthy subjects.

We also investigate how quickly and to what extent THN391 is distributed, and
eliminated from the body. In addition, we look at the effect of THN391 on
specific proteins and RNA expression changes.

We compare the effects of THN391 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 THN391, placebo, or both.

THN391 has not been administered to humans before. It has been extensively
tested in the laboratory and on animals. THN391 will be tested at various dose
levels.

The study will take a maximum of approximately Part A: 16 weeks (Groups 1 and
2) or 30 weeks (Group 3 and higher), Part B: 20 weeks (Groups 1 to 2) or 24
weeks (Groups 3 to 4) from the screening until the follow-up visit.

Part A:
In total the volunteer will visit the research center 8 times if the volunteer
is in Groups 1 or 2 or 10 times if the volunteer is in Group 3 or higher:
- Once for the screening.
- Once for a stay in the research center. For the study it is necessary that
the volunteer stays in the research center for 1 period of 6 days (5 nights).
The volunteer will leave the research center on Day 4 of the study.
- After your stay in the research center there will be 6 short visits to the
research center if the volunteer is in Group 1 or 2 or 8 short visits if the
volunteer is in Group 3 or higher. For Groups 1 and 2, these short visits take
place on Days 8, 15, 29, 43, 57 and 85. For Groups 3 and above, these short
visits take place on Days 8, 15, 29, 43, 57, 85, 134 and 183.

Part B:
In total the volunteer will visit the research center 14 times if the volunteer
is in Group 1 or 2 or 16 times if the volunteer is in Group 3 or 4:
- Once for the screening.
- Three times for a stay in the research center. For the study it is necessary
that the volunteer stays in the research center for 1 period of 4 days (3
nights) and 32 periods of 3 days (2 nights). The volunteer will leave the
research center on Day 2 of the study. After the volunteers stay in the
research center, the volunteer will return to the research center for 2
additional stays. For Groups 1 to 2, these stays will take place from Day 14 to
Day 16 (2 nights), and from Day 28 to Day 30 (2 nights). For Groups 3 to 4,
these stays will take place from Day 28 to Day 30 (2 nights), and from Day 56
to Day 58 (2 nights).
- In between and after the volunteers stays in the research center there will
be 10 short visits to the research center if the volunteer is in Groups 1 to 2,
or 12 short visits to the research center if the volunteer is in Groups 3 to 4.
For Groups 1 to 2, these short visits will take place on Days 4, 8, 18, 22, 32,
36, 43, 57, 85, and 113. For Groups 3 to 4, these short visits will take place
on Days 4, 8, 15, 32, 36, 43, 60, 64, 71, 85, 113, and 141.

The volunteer will be given THN391 or placebo as an intravenous infusion
(solution of the compound that will be administered directly in a blood
vessel).

Part A:
Group Day Treatment How often How
1 1 THN391 0.3 mg/kg# or placebo once intravenous infusion
2 1 THN391 1 mg/kg* or placebo once intravenous infusion
3 1 THN391 3 mg/kg* or placebo once intravenous infusion
4 1 THN391 10 mg/kg* or placebo once intravenous infusion
5 1 THN391 20 mg/kg* or placebo once intravenous infusion
* In case the dose level will be lower or higher than planned, the volunteer
will be informed verbally.
# This means that 0.3 mg of THN391 will be administered per 1 kg of body weight.

Part B:
Group Days Treatment How often How
1 1, 15, 29 THN391 3 mg/kg# or placebo once every 2 weeks intravenous
infusion
2 1, 15, 29 THN391 10 mg/kg* or placebo once every 2 weeks intravenous infusion
3 1, 29, 57 THN391 20 mg/kg* or placebo once every 4 weeks intravenous infusion
4 1, 29, 57 THN391 40 mg/kg* or placebo once every 4 weeks intravenous infusion
* In case the dose level will be lower or higher than planned, the volunteer
will be informed verbally.
# This means that 3 mg of THN391 will be administered per 1 kg of body weight.

Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula (a tube in a vein in the arm) 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, sweating, low heart rate, or drop in blood
pressure with dizziness or fainting.

In total, we will take about Part A: 338.4 milliliters (mL) (Groups 1 and 2) or
396.4 mL (Groups 3 and higher) Part B: 364.4 milliliters (ml) (Groups 1 to 2)
or 400.2 milliliters (Groups 3 to 4) of blood from the volunteer 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 each time at once. If the
investigator thinks it is necessary for the safety of a subject, 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 (small, plastic patches) will be placed on
the volunteers arms, chest and legs. Prolonged use of these electrodes can
cause skin irritation (rash and itching).

Coronavirus test (if applicable)
Samples for the coronavirus test will be taken from the back of the volunteers
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 volunteers throat may cause the volunteer to gag. When the
sample is taken from the back of the volunteers nose, the volunteer may
experience a stinging sensation and the volunteers eyes may become watery.