A MR30365/07 dose-ascending, cohort group, single-blind pilot phase followed by a randomised, double-blind, placebo controlled parallel group study to compare the effect of intravenous MR30365/07 and intravenous fentanyl on respiration and analgesic responses, in healthy volunteers.

MR30365/07 and fentanyl are opioid analgesics.
Respiratory depression is a common side effect with opioids. This study is to
assess the effect of MR30365/07 on ventilation and antinociception compared to
fentanyl and placebo.

The aim of the main study is to compare the effects of MR30365/07 and fentanyl
on ventilation and analgesic responses to noxious electrical and heat
stimulation in healthy volunteers, by performing pharmacokinetic /
pharmacodynamics (PK/PD) modeling.

A pilot phase will be performed prior to the main study In order to determine
the MR30365/07 doses, based on respiratory responses and safety data, to be
used In the main study. In the main the subjects were randomised into 2 groups,
the respiratory group to assess the effects on ventilation and the analgesia
group to assess the effects on anti-nociception. A single 10 minute infusion of
study medication was administered to each subject in a semi-supine position.
Safety assessments and respiratory measurements were recorded following each
study medication administration.

Pilot Phase (9 subjects - respiratory measurements and safety assessments):
After screening the subjects were allocated into 3 cohort groups. Each subject
received a single infusion of MR30365/07 on 3 occasions in dose-ascending
order, and a single infusion of placebo. Therefore, subjects received 4 doses
of study medication in total. Respiratory and safety assessments were
performed. The MR30365/07 doses tested in the pilot phase were 0.0125 µg/kg,
0.025 µg/kg, 0.05 µg/kg, 0.075 µg/kg, 0.1 µg/kg, 0.125 µg/kg and 0.15 µg/kg.
There was a minimum of 7 day wash out period between the study drug dosing.
Safety measurements were performed up to 24 hours post-dose and the subjects
returned for a post-medical visit 4-7 days after the last dose of the study
drug in case of completion/discontinuation from the study.

Main Phase (Respiratory and Analgesia Groups - 46 subjects per group):
Based on the data from the pilot phase the optimal concentrations of MR30365/07
to administer in the main phase were 0.0125, 0.075, 0.125 and 0.15 µg/kg
MR30365/07. After screening the subjects were allocated to a respiratory (n=46
subjects) or analgesia group (n=46 subjects) to receive a single 10 minute
infusion of MR30365/07, fentanyl or placebo on one occasion according to a
RAS. The appropriate PK, PD and safety assessments were performed for each
subject.


Concentration (ug/kg) Number of
Subjects (Respiratory) Number of Subjects (Analgesia)
Fentanyl 0.5 4 4

1
6
6

2 6
6 3 4 4
MR30365/07 0.0125
4 4
0.075
6
6
0.125
6 6
0.15
4 4

Placebo

0 6 6


Predefined stopping rules were applied in the pilot and the main phase:
• Apnoea, defined as discontinuation of rhythmic breathing for 1 minute
• pCO2 > 9 KPa
• O2 saturation 85% or less
• Increase in QTc of more than 60 msec above pre-dose values of each study
period or
QTc greater than 500 msec
• Serious adverse drug reaction.
If a subject experienced any of the above they were discontinued from the
study. If 2 subjects experienced any of the above the cohort was not further
dosed and the next cohort was not proceeded.

All subjects will have a screening visit and a post-study medical visit to
confirm healthy status before entering the study and after receiving study
treatment. Subjects in the pilot phase will have 4 treatment visits (placebo on
one occasion and MR30365/07 on 3 occasions). Subjects in the main study will
have one treatment visit (MR30365/07, fentanyl, or placebo). Subjects will
remain in the clinic for 24 hours after receiving a 10 minute infusion. In the
pilot phase there will be a 7-day washout before receiving their next dose.
While in the clinic subjects will have regular measurements of vital signs,
ECG, pulse oximetry and complete questionnaires. Respiratory tests involving
wearing breathing apparatus or analgesic tests (heat or electrical pain) will
be performed up to 8 hours post-dose. Headache may be experienced during or
after the respiratory test. In the main study, an arterial line will be used to
collect blood samples over 24 hours for pharmacokinetic analysis.
Typical opioid side effects would be expected such as nausea, feeling of
heaviness, itching/skin rush at infusion site. One of the side effects that may
occur is respiratory depression. If unexpected severe respiratory depression
occurs, the experiment will be stopped. Naloxone may be administered, which
reverses the effect of MR30365/07. Extra oxygen may also then be administered
to help breathing.
After the infusion into the vein has been removed a bruise may appear, which
usually disappears by itself after a few days. This may also occur after blood
sampling via the arterial line. There is no intended clinical benefit to the
subject from taking part in the study.