A double-blind, placebo-controlled, dose escalation study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of KCP506 in healthy subjects

KCP506 is a new compound that is being research as a potential treatment for
chronic pain. The study compound is not registered in the Netherlands as a
medication. This means that the study compound is still in development and that
it is not known whether the study compound is safe and if it works. Current
treatment options for chronic pain include so-called
non-steroidal-anti-inflammatory drugs (NSAIDs) and opioid-based therapeutics.
Disadvantages of these treatment options are that NSAIDs are not always
effective in all patients and opioids are addictive and may have unwanted
effects on brain functioning. KCP506 has a different working mechanism and
works by inhibiting a protein called *α9α10 nicotinic acetylcholine receptor*.
This protein is important for pain perception. By inhibiting it, KCP506 aims to
reduce pain sensation.

The purpose of this study is to investigate how safe the new compound KCP506 is
and how well it is tolerated when it is administered to healthy volunteers. It
will also be investigated how quickly and to what extent KCP506 is absorbed and
eliminated from the body (this is called pharmacokinetics). KCP506 has not been
administered to humans before. It has been previously tested in the laboratory
and on animals. KCP506 will be tested at various dose levels.

KCP506 or placebo will be given as either an intravenous infusion (IV; solution
of the study compound that will be administered directly in a blood vessel) or
as an injection / infusion under the skin (SC; subcutaneous).

Part A:
Participation from screening until the follow-up visit will last about 5 weeks.
In total, the volunteer will come to the research center 4 times:
• 1 screening visit
• 1 stay in the research center of 5 days (4 nights)
• 2 visits to the research center on Day 8 and 15

Part B:
Participation from screening until the follow-up visit will last about 7 weeks.
In total, the volunteer will come to the research center 4 times:
• 1 screening visit
• 1 stay in the research center of 17 days (16 nights)
• 2 visits to the research center on Day 20 and 27

Part C:
participation from screening until the follow-up visit will last about 13 weeks
In total, the volunteer will come to the research center 8 times:
• 1 screening visit
• 2 stays in the research center of 3 days (2 nights)
• 4 visits to the research center on Day 4 and 8

Part A:
Group Study compound Dose* Route of administration
1 KCP506 or placebo 1.0 mg/kg In a vein
2 KCP506 or placebo 3.0 mg/kg In a vein
3 KCP506 or placebo 10 mg/kg In a vein
4 KCP506 or placebo 30 mg/kg In a vein
5 KCP506 or placebo 100 mg/kg In a vein
6 KCP506 or placebo 5.0 mg/kg Under the skin as 1 or 2
injections
7 KCP506 or placebo 50 mg/kg Under the skin as an infusion

Part B:

Group Day Study compound Dose Route of
administration
8 1, 4, 7, 10, and 13 KCP506 or placebo 50 mg/kg Under the skin
9 1, 4, 7, 10, and 13 KCP506 or placebo 30 mg/kg In a vein
10 1, 4, 7, 10, and 13 KCP506 or placebo 100 mg/kg In a vein
11** TBD KCP506 or placebo TBD TBD

Part C:
Group: Study period 1 Study period 2
1 KCP506 (100mg/kg) Placebo
2 Placebo KCP506 (100mg/kg)

As KCP506 will be administered to humans for the first time in this study, side
effects of KCP506 in humans have not been reported to date. However, KCP506 has
been studied extensively in the laboratory and in animals.

KCP506 was found to be well tolerated in an animal study where rats were given
repeat-doses of up to 1000 mg/kg KCP506. In humans, this is equal to a dose of
approximately 166 mg/kg compared to rats and 333 mg/kg compared to monkeys.

Possible discomforts due to procedures
Blood sampling
Blood is drawn using an indwelling venous cannula (tube in vein in forearm).
This might sometimes cause mild pain, inflammation, swelling, hardening of the
vein, blood clotting and bleeding into surrounding (bruising) at the insertion
site.

Part A:
In total, we will take about 120 milliliters (mL) of blood from the volunteer.
Part B:
In total, we will take about 190 milliliters (mL) of blood from the volunteer.
Part C:
In total, we will take about 100 milliliters (mL) of blood from the volunteer.

ECG
The volunteer will have small, soft pads (ECG electrodes), placed stuck
temporarily on different parts of his body. There is no pain or discomfort
during an ECG; however the area of skin in which the ECG pads will be stuck may
need to be shaved, and the pads may cause a skin reaction such as redness or
itching. Taking the pads off may cause localized irritation to the skin and/or
hair loss, similar to having a plaster taken off. To monitor the volunteers
heart rate (telemetry), electrodes will be pasted at specific locations on the
chest and abdomen.

Coronavirus test
A sample for the coronavirus test will be taken from the back of the volunteers
nose and throat using a swab. Taking the sample 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 you him gag. When the sample is
taken from the back of his nose, he may experience a stinging sensation and his
eyes may become watery

Different pain tests:
Flexible plastic skewer (Von Frey).
At the start of each examination day, we gently prick the skin of the forearm
with flexible plastic pricks. In this way we test what the volunteer's pain
threshold is. We poke around the area where capsaicin has been applied. When
the feeling of the injection changes from non-painful to painful, the volunteer
indicates this. For example, we test the sensitivity of the skin. During the
day we test this several times to determine the change in sensitivity (total
test time: ± 3 minutes).

Pressing pain test.
During this test, through a blood pressure band an increasing pressure is
exerted on the calf muscle of the volunteers right leg by means of a
computer-controlled pressure regulator. In this test you will also use the
electronic (*eVAS*) slider to indicate the volunteers pain threshold. By moving
the slider to the right, the volunteer indicate he starts to feel pain, and by
moving the slider all the way to the right the volunteer indicate that he has
reached his pain threshold, whereupon the test ends and the pressure band
immediately empties again. A safety maximum is set on the pressure band. The
test also ends when this maximum is reached. Duration ± 3-5 minutes.

Electric pain test.
During the electrical pain test, two electrodes are placed on the skin of the
shin with which electrical surges that increase in intensity are given. This
determines the volunteers tolerance for pain. Connecting the electrodes to the
power supply may cause a slight discharge of electricity. The pain test does
not cause damage, but it does increase pain sensation. The volunteer will be
asked to use an eVAS slider to indicate his pain threshold. By sliding the
slider to the right, the volunteer indicate that he starts to feel pain, and
moving the slider all the way to the right indicates that the volunteer has
reached his pain threshold, whereupon the electrical test is immediately
terminated. It might be necessary to shave a small area of the skin on the
volunteer his shin to place the electrodes. The entire procedure can cause some
skin irritation that will go away within a few days. Duration ± 2 minutes.

Application of capsaicin.
Capsaicin is a composite that is also present in red and green peppers. During
this study a small amount of 1% capsaicin on ethanol basis will be applied on
the volunteer his forearm. 30 minutes after application of the solution we will
determine if the site where the capsaicin was applied and the area around it
has become more sensitive for pain stimulation. The test with flexible plastic
sticks and a heat pain test will be performed to determine this. The capsaicin
may cause a transient warm or burning sensation on the skin.

Heat pain test with capsaicin.
During the study period, a heat pain test is performed on both forearms. So the
forearm where capsaicin has been applied, and the forearm where this has not
been done. For this, a small thermal block is placed on the skin. During the
test this block will gradually warm up. The volunteer will be asked to press a
button the moment the heat sensation becomes painful. Thereafter, the thermal
block quickly and automatically returns to a pleasant temperature. The test is
performed 3 times on the capsaicin treated skin and 3 times on the healthy
skin. Duration ± 5 minutes.

Cold pain test.
In this test, the volunteer first place his hand in a lukewarm water bath for
1 minute and 50 seconds. After this, the blood supply to the volunteers hand is
temporarily limited before the start of the measurement by slightly inflating a
blood pressure band around his arm. The volunteer will then place the same hand
in a tank of ice-cold water (~1.0 °C). In this way the volunteers hand is
exposed to a continuous cold stimulus for up to 2 min. This causes a pain
sensation. During the measurement, the blood supply to his hand is temporarily
limited by slightly inflating a blood pressure band. In this test the volunteer
will also use the eVAS slider to indicate his pain threshold and moving the
slider all the way to the right indicates that The volunteer has reached his
pain threshold. The test ends when the time limit of 2 minutes is reached or
when the volunteer indicate using the eVAS slider that the pain becomes
unbearable, after which the volunteer can remove his hand directly from the
cold-water bath. Duration 3-5 minutes.

Pain questionnaire.
Pain questionnaire. At the end of the pressure-, electrical-, heat and cold
pain tests the volunteer will be asked to give his pain a number between 0 and
10, in which 0 means no pain at all and 10 means the worst pain he can imagine.
Additionally, the volunteer will be asked to fill in a questionnaire about how
you experienced the test, e.g. was the sensation burning, stabbing, itching,
etc.