A randomized, single-center, double-blind, placebo-controlled, 2-way cross-over, single oral administration trial to evaluate blood-borne biomarker candidates to predict NOP receptor activation using GRT6010 as NOP receptor agonist in healthy human subjects.

GRT6010 is a new investigational compound that may eventually be used for the
treatment of neuropathic pain, chronic pain resulting from an injury to the
nervous system. GRT6010 activates a signaling structure (receptor) called *NOP
receptor*, which is related to but different from opioid receptors (e.g., the
receptor for morphine). Receptors are proteins found on the surface of a cell
with the ability to react on body or foreign signaling molecules. GRT6010
activates opioid receptors as well, but to a lesser extent. GRT6010 is not
registered as a drug but has been given to humans before.

Primair:
To assess the change in the CD11b expression in leukocytes and in plasma
concentrations of nociceptin after oral single dose administration of 12 mg
GRT6010 compared to placebo

Secundair:
To assess the difference in area of the capsaicin-induced flare and in the skin
blood flow within that area between treatments with GRT6010 or placebo.
To assess the difference in pain assessments (brush-induced allodynia,
mechanical pain threshold, heat pain threshold, and current pain) between
treatments with GRT6010 or placebo after generating a sort of neuropathic pain
by an intradermal capsaicin injection.
To assess the safety and tolerability of GRT6010.
To assess the pharmacokinetics of GRT6010 (including the influence of human AGP
levels on the pharmacokinetics of GRT6010).
To assess the change in expression levels of selected genes from whole-blood
mRNA after oral single dose administration of 12 mg GRT6010 compared to placebo

This is a randomized, single-center, double-blind, placebo-controlled,
2-period, cross-over, single oral administration, Phase I translational trial
in 24 healthy male subjects.

The study will consist of 2 periods, during each period subjects will receive
GRT6010 or inactive formulation (placebo) as a single dose of 12 mg in the form
of an oral solution of 2 mL. During the study subjects will once receive GRT
6010 and once placebo.

Procedures and assessments during the study:
Screening , follow-up and during study: demographics, body weight and height
(including body mass index calculation),
medical history, drug and alcohol screen, cotinine test, blood sampling for
serology (HBsAg, anti HCV and anti-HIV 1/2),
DNA test (CYP2D6 genotyping) clinical chemistry, hematology, clotting,
assessment biomarkers (mRNA, plasma nociceptin concentrations and leukocyte
CD11b expression levels), alpha-1 acid glycoprotein, and pharmacokinetics,
Heart trace (ECG*s), assessment of pain after capsaicin administration; adverse
events

The study will consist of 6 groups, each group will stay in the clinical
research centre for 2 periods of 5 days (4 nights) each (Day -1 to 4 and Day 28
to 32).

During the study subjects will receive GRT6010 or inactive formulation
(placebo) after a fasting period (no food or drinks) of at least 10 hours.
Subjects will receive the study medication as an oral solution in a syringe
which will be emptied in their mouth; after this they will have to drink 240 mL
of water. One (1) hour after the intake of the study medication they will
receive an additional 240 mL of water. During the study they will receive GRT
6010 once and placebo once. Whether a subject will receive GRT6010 or placebo
in Period 1 or 2 will be determined by chance.
The subject, nor the investigator knows when GRT6010 and placebo will be dosed;
we call this *the study is blinded*. However, information on the administration
of study medication will be present in the clinical research facility, in
sealed envelopes, which can be opened in case of emergency.
For each period fasting will continue until 4 hours after drug administration.
Then subjects will receive a lunch. During fasting and after intake of the
study medication subjects are allowed to drink water with the exception of 1
hour prior to until 1 hour after drug administration.

During the study subject will undergo a pain test for 3 times. This pain test
will be performed by generating a sort of neuropathic pain by an intradermal
capsaicin injection (100ug/10ul), the hot substance in chili peppers, into the
skin of the anterior side of one of their forearms. At several timepoints after
the injection the extent to which this pain stimulus leads to increased pain
sensation will be assessed.

During the study several assessments will be conducted differing in extent and
the nature of burden:

Blood draws via direct puncture or an indwelling canula: It is anticipated that
for each period 1 time an indwelling canula will be used besides blood will be
drawn by direct puncture of the vein. Possible side effects of an indwelling
canula are pain, light bleeding, heamatoma, possibly an infection.

Heart trace (ECG's): During the entire investigation ECG*s will be made
regularly.

Pain test: During the study 3 times a pain test will be performed by
generating a sort of neuropathic pain by injecting capsaicin (10ug/100ul). Soon
after the injection, an area with increased pain/flare sensation (an intense,
burning pain) and allodynia (a painful response to a usually non-painful
stimulus) will develop around the injection site, in addition, there will be
redness of the skin. These symptoms may last for 12-24 hours.

Telemetry: heart trace (ECG), rhythm and oxygen in blood will be monitored
continuously from 0.5 hours before dosing until 24 hours after dosing.

In a previous study with healthy volunteers GR6010 was considered safe and well
tolerated and no serious adverse effects have been observed.