Multiple dose safety, tolerability, plasma and cerebrospinal-fluid pharmacokinetic study of oral doses of CORT113176

CORT113176 is a new compound that may potentially be used for the treatment of
amyotrophic lateral sclerosis (ALS). In ALS, nerve cells involved in movements
degenerate. This results in decreasing control over muscles and ends in
paralysis. One of the possible mechanisms causing ALS is an increased level of
cortisol in the brain. CORT113176 inhibits the activity of cortisol and thus
may help to improve the mobility of the patients.

In this study we will investigate how safe the new compound CORT113176 is and
how well it is tolerated when it is used by healthy participants.

We also investigate how quickly and to what extent CORT113176 is absorbed,
transported, eliminated from the body and to what extent it enters the CNS.

We compare the effects of CORT113176 with the effects of a placebo. A placebo
is a compound without any active ingredient.

CORT113176 has been used by humans before. In addition, it has been extensively
tested in the laboratory and on animals. CORT113176 will be tested at various
dose levels.

For the study it is necessary that the volunteers stay in the research center
for 1 period of 18 days (17 nights).

Day 1 is the first day when the volunteer will receive the study compound. He
is expected at the research center the day before the day of first
administration of the study compound. The volunteer has to be at the research
center at 14:00 hrs in the afternoon. The time of entry may be changed. The
volunteer will leave the research center on Day 17 of the study.

The planned dose levels for the study are as follows:

Group 1 - Day 1 to 14 - Treatment: CORT113176 150 mg or placebo - How often:
once daily (14 times in total)
Group 2 - Day 1 to 14 - Treatment: CORT113176 300 mg or placebo - How often:
once daily (14 times in total)
Group 3 - Day 1 to 14 - Treatment: CORT113176 450 mg or placebo - How often:
once daily (14 times in total)

Group 3 is optional.

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 210 milliliters of blood from the volunteer.

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

Sampling of cerebrospinal fluid
Insertion of the needle for the collection of cerebrospinal fluid may be
painful. Removing the needle is painless. Usually no complications occur during
a lumbar puncture. Sometimes, during the puncture, a nerve can be hit. Then the
volunteer will feel an electric pulse or a shooting pain in their leg. This can
be painful, but is not harmful.

This method has been performed with humans before and was generally well
tolerated. A number of complaints and complications related to the procedure
are already known from previous studies:
• headache
• back pain and neck pain
• discomfort during the procedure
• hypersensitivity reaction to the lidocaine, the risk is very small
• pain at the location of the spinal catheter
• dizziness
• fainting
• inflammation or infection (1% of the cases with multiple cerebrospinal fluid
sampling via a catheter); in rare cases this may result in meningitis
• bleeding and nerve damage; this risk is very small

The risks of abovementioned complaints are limited, but the volunteers may
suffer from these or other, still unknown, complications. To keep the risks as
low as possible, their health will be monitored continuously during the study.

Post-lumbar puncture headache is the most frequently occurring side effect and
can occur sometimes up to 5 days later. The headache is characterized by the
fact that it worsens with sitting and standing up or walking and improves when
lying down. It can also be associated with severe nausea, double or blurry
vision and disturbances in hearing. Post-lumbar puncture headaches are caused
by leakage of cerebrospinal fluid through the puncture hole in the tough
membrane (dura mater) that surrounds the spinal cord. This leakage decreases
the pressure exerted by the spinal fluid on the brain and spinal cord, which
leads to headache. The chance of a post-lumbar puncture headache developing
depends on different factors such as age, weight and size of the needle used
for sampling the CSF. Usually, the headache goes away by itself with resting on
the bed and drinking plenty of fluids, including coffee containing caffeine.
Therefore, if needed, as judged by the responsible doctor, the volunteers are
allowed to drink coffee containing caffeine and/or will receive caffeine
tablets.

If the volunteer do not respond to the standard *treatment* of bed rest, fluid
intake and time, the responsible doctor may decide to perform an *epidural
blood patch*. During this procedure a small volume of the volunteer own blood
(approximately 15-20 mL that will be drawn from a vein in the arm) will be
injected in the epidural space of the spinal cord (space just outside the
meninges around the spinal cord) using an epidural needle. This will be
performed by an anesthesiologist under sterile conditions. The volunteer will
have to be in a sitting position with the legs held against each other. Relief
of headache usually occurs swiftly after this procedure, sometimes directly
after administration of the blood patch. In some instances more than 1 attempt
may be required for relief of headache.

After the procedure the volunteers have to lie down on their back for 1.5 - 2
hours, this is to decrease the risk of leakage of cerebrospinal fluid.
To limit the chance of headaches it is important that the volunteers drinks
plenty of liquids (minimal 1.5 liters a day, from 1 day prior to the puncture
[Day 6] until 1 day thereafter [Day 8]). During the lumbar puncture and the 1.5
to 2 hours thereafter fluid will be administered using an intravenous infusion.

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 their eyes may
become watery.