Een open label studie met een enkelvoudige dosering om de pharmacokinetiek te onderzoeken van CG5503 immediate release capsule in gezonde oudere en jongere vrijwilligers

The drug to be given, CG5503, is a new, investigational compound that may
eventually be used for the treatment of acute and chronic pain. CG5503 is a
centrally active analgesic and it partly works as the current marketed opium
like medicines.

The purpose of the study is to compare the single dose pharmacokinetics of
CG5503 between healthy elderly and young adult men and women (pharmacokinetics
means that will be studied how the body absorbs, distributes and eliminates the
investigated compound). In addition, the safety and tolerability of the
compound will be examined in healthy elderly and young adults.

Open-label, single-center study comparing the pharmacokinteics of CG5503 base
and its metabolite, CG5503-O-glucuronide, in healthy elderly and young adult
subjects

Screening and follow-up: clinical laboratory, full physical examination, ECG;
at eligibility screening: medical history, drug screen, HBsAg, anti HCV,
anti-HIV 1/2 and pregnancy test (females only); vital signs, pregnancy test and
drug and alcohol screen repeated upon admission

Observation period: one period in clinic from -17 h up to 48 h after drug
administration

Blood sampling: for pharmacokinetics: pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6,
9, 12, 16, 24, 36 and 48 h post-dose; for genotyping: pre-dose on day 1

Urine sampling: for pharmacokinetics: pre-dose and from 0-6, 6-12, 12-24, 24-48
h post-dose

Safety assessments: adverse events: throughout the study; vital signs: pre-dose
and at 24 h post-dose; ECG: pre-dose; clinical laboratory: pre-dose; creatinine
sample: at 12 h post-dose; pregnancy test: 48 h post-dose

Bioanalysis: by Sponsor

Study medication Active substance: CG5503 base Activity: morphine analogue Indication: pain relieve Strength: 80 mg Dosage form: oral capsule Treatments a single dose of 80 mg CG5503 base

Procedures: pain, light bleeding, haematoma, possibly an infection.

Medication: The safety of CG5503 has been determined in the 12 completed Phase
1 studies, in which 286 healthy subjects received either 2 minute or 15 minute
i.v. infusions of CG5503, single oral doses of the immediate release (IR)
capsule or the prolonged release (PR) tablet, or multiple oral doses (twice
daily) of the PR tablet, and in the seven completed Phase 2 studies, in which
1504 subjects with acute or chronic pain received single or multiple oral doses
of the CG5503 IR capsule or the PR tablet.
Single- and multiple dose administrations of the CG5503 IR capsule and the PR
tablet were well tolerated. The side effects profile was consistent with that
of a centrally acting analgesic (e.g. morphine). Most side effects were mild,
of short duration, and resolved spontaneously. Overall, when the dose of
medication was increased, there were more side effects.

Phase 1
In Phase 1 studies in healthy subjects, the most common side effects after
single dose administration (25 to 200 mg) of the CG5503 IR capsule were
fatigue, dizziness, sleepiness, headache, and dry mouth. At the same doses,
CG5503 has fewer side effects like nausea and vomiting, when compared to other
painkillers like tramadol and morphine. The most common adverse events after
single dose administration (100 and 200 mg) of the CG5503 PR tablet were
headache, fatigue, dizziness, and dry mouth, while the most common side effects
after multiple dose administration (100 and 200 mg twice daily) of the PR
tablet were fatigue, dizziness, headache and dry mouth. None of the treatments
had a considerable effect on vital signs, electrocardiograms (ECGs), or
laboratory parameters.
In one Phase 1 study, a 47-year-old man had an epileptic attack after receiving
multiple doses of 200 mg CG5503 PR tablets. He was hospitalized immediately
after the event and recovered without further consequences. The subject had a
history of seizure, which was not known at the time of commitment to the study,
and this volunteer was probably taking anti-epileptic drugs during the trial.

Phase 2 (patient studies)
In Phase 2a studies of single dose administration (25 to 200 mg) of the IR
capsule to subjects with postoperative pain, the most common side effects were
nausea, dizziness, vomiting, sleepiness and headache. At higher doses, several
subjects had light signs of respiratory depression, which were not considered
serious and were solved by speaking directly to the patient. In Phase 2a
studies of multiple dose (25 and 50 mg given 4 times daily) administration of
the IR capsule to subjects with postoperative or chronic pain, the most common
side effects were headache, nausea, dizziness, vomiting, sleepiness, and
constipation.
In Phase 2b studies of multiple dose administration (25, 50, and 100 mg twice
daily) of the CG5503 PR tablet to subjects with either chronic osteoarthritis
(OA) or chronic low back pain (LBP), the most common side effects were nausea,
headache, dizziness, vomiting, and sleepiness.

ICF amendement d.d. 22Dec06, additional to section above:
Dear volunteer,

The study for which you have shown interest has temporarily been paused
recently and PRA wants to inform you about the reason. For this, the following
amendment to the Informed Consent Form is made.

The conduct of the study was temporarily paused because an adverse event, which
had occurred in one subject after administration of the study medication, had
to be evaluated thoroughly. This adverse event comprised a short-lasting sudden
loss of consciousness interpreted as respiratory arrest by the investigator.
The subject recovered without any negative effects.
After thorough and intensive investigations, the assessment was made that this
case does not change the risk and safety profile of the study medication which
has been explained to you in the Informed Consent Form. Thus, the current study
will be continued under the same conditions as originally planned. Limited to
this particular study, telemetric ECG monitoring and pulse oximetry during 4
hours after drug administration will be performed. These non-invasive measures
mean that ECG electrodes will be applied on your skin for telemetric ECG
monitoring and a finger-clip device will be attached on one finger for pulse
oximetry. These measures would provide the medical investigator continuous
information about heart and lung function to optimize adequate diagnostics.

In case of questions we ask you to direct them to the medical investigator of
this study.