This study is intended to establish a dose response rate of MR30507/09 with respect to respiratory effects compared to MR30365/07, fentanyl and placebo..
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
ademhaling
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• To determine the effect of MR30507/09 on ventilation in healthy subjects
using the dynamic end-tidal forcing technique. • To obtain a dose-response
relationship for the respiratory response effects of MR30507/09 and to compare
this relationship with that of MR30365/07. • To assess MR30507/09 and
MR30365/07 induced respiratory depression reversibility using naloxone IV
injection.
Secondary outcome
• To assess the safety and tolerability of MR30507/09 and MR30365/07. • To
assess the PK of MR30507/09 and MR30365/07. • To assess arterial vs venous
blood sampling in the concentration effect model.
Background summary
The characteristics of MR30507/09 as an opioid analgesic will be investigated
in an extensive clinical study programme by Mundipharma Research Ltd. The
initial clinical studies will be performed in healthy volunteers with low
intravenous doses.
Study objective
This study is intended to establish a dose response rate of MR30507/09 with
respect to respiratory effects compared to MR30365/07, fentanyl and placebo..
Study design
A dose-ascending, parallel group, randomised, double-blind, placebo-controlled
pilot phase followed by a parallel group, randomised, double-blind,
placebo-controlled main phase. A separate single-dose, two-part, randomised,
double-blind crossover phase will assess the ability of intravenous (IV)
naloxone to reverse respiratory depression induced by MR30365/07 and MR30507/09
given as a 10 minute IV infusion. Subjects are not allowed to participate in
more than one study phase. There will be a minimum 7-day washout between study
drug doses in the naloxone phase. Subjects will be confined to the study unit
from the morning of study drug administration (Day 1) until post-dose
assessments are completed in each study period (24 hours post-dose). Subjects
will be discharged from the study unit after clinical assessment by the
investigator; this post dose observation period may be extended up to 48 hours
or longer when necessary. Subjects will return to the study unit for a
post-study medical 4-7 days after receiving their last dose of study drug.
Intervention
A single 10 minute infusion of study drug will be administered to each subject.
Each dose of study drug will be given to subjects in a semi-supine position.
Pilot phase: Each subject in each cohort will receive a single infusion of
MR30507/09 (µg/kg) or placebo.In each cohort 4 subjects will be dosed (ug/kg).
MR30507/09Cohort 1 MR30507/090.2 ug/kg (n=3) placebo (n=1) Cohort 2
MR30507/090.5 ug/kg (n=3) placebo (n=1) Cohort 3 MR30507/091.0 ug/kg (n=3)
placebo (n=1) Cohort 4 MR30507/092.0 (n=3) placebo (n=1) Cohort 5 MR30507/094.0
ug/kg (n=3) placebo (n=1) Cohort 6 MR30507/096.0 ug/kg (n=3) placebo (n=1)
Possibility to add extra dose groups if needed until irregular breathing
observed (e.g. 9.0 and 12.0 µg/kg) Data from each cohort will be assessed prior
to commencing dosing in the next cohort. There will be a minimum of 48 hours
between completion of dosing a cohort at one dose level and the start of dosing
the next cohort at the next dose level. A further cohort(s) of 4 subjects may
be added at a dose(s) falling between doses previously assessed, or at a higher
dose(s) than previously assessed. If a higher dose(s) is to be assessed, dosing
may continue until such time as irregular breathing is observed or any other
safety signals are observed that meet individual stopping criteria. Dose levels
will be determined based on review of safety and PD data from the pilot phase.
Safety data will be reviewed on an ongoing basis by a Safety Data Review
Committee (SDRC) comprising Investigator or Co-investigator and Sponsor
personnel (to include Clinical Leader and/or additional medical designee,
Clinical Operations representative, and Drug Safety representative). Data for a
subject(s) meeting the individual stopping rules, will be reviewed by the SDRC
before proceeding to dosing at the next dose level.The following stopping rules
apply: • Apnoea defined as discontinuation of rhythmic breathing for > 90
seconds • 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 • Liver function tests (ALT, AST, ALP) - discontinue subject if SAE
criteria reached • Investigator*s judgement of AEs/SAEs (e.g. severe nausea and
vomiting, and non-related SAEs) • Serious adverse drug reaction. The following
cohort stopping criteria also apply: • Severe respiratory depression, defined
as in need of naloxone administration. • Serious adverse drug reaction. If two
subjects in a cohort meet either of the above stopping rules, further dosing in
the cohort and further dose escalation will be stopped. The SDRC may also
revise the planned dose levels following a Cohort safety review. If a
subject(s) meets the individual stopping rules, further subjects may continue
to be dosed at the same dose level, based on SDRC review. SDRC review must take
place prior to further dose escalation. If a subject(s) meets the individual
stopping rules, up to two additional subjects may be randomised to expand the
cohort. If two subjects in a cohort meet the cohort stopping rules, further
dosing in the cohort and further dose escalation will be stopped. Safety data
will be reviewed by the SDRC before proceeding to the next cohort and before
proceeding to, and to select doses for, the main phase. Main phase: Subjects in
each group will receive a single 10-minute infusion of MR30507/09MR30365/07,
placebo or fentanyl according to a random allocation schedule. The starting
dose of MR30507/09 (A, B,C and D; µg/kg) will be determined from the pilot
phase. Group Dose (µg/kg) Group 1 (n=11) MR30507/09(A) (n=3); MR30365/07 0.2
(n=6); placebo (n=1); fentanyl 2.0 (n=1) Group 2 (n=11) MR30507/09 (B) (n=3);
MR30365/07 0.25 (n=6); placebo (n=1); fentanyl 2.0 (n=1) Group 3 (n=11)
MR30507/09(C) (n=3); MR30365/07 0.3 (n=6); placebo (n=1); fentanyl 2.0 (n=1)
Group 4 (n=11) MR30507/09 (D) (n=3; MR30365/07 0.4 (n=6, if no safety stopping
criteria met at 0.3 dose);placebo (n=1), fentanyl 2.0 (n=1) Group 5 (n=5)
Additional group if required: MR30507/09 (dose to be determined, n=3); placebo
(n=1); fentanyl 2.0 (n=1) As the main phase is double-blind, and contains
multiple active treatments, an Independent Safety Data Monitoring Committee
(ISDMC) will be set up before the main phase is initiated. The ISDMC will
consist of at least 3 independent persons (i.e. independent from the study and
Sponsor). When cohort stopping criteria are met, the ISDMC members will be
un-blinded to study treatments and doses to assist with safety data monitoring.
Safety data (AE listings) will be provided to the ISDMC and ISDMC meetings
scheduled depending on subject recruitment. Ad hoc committee meetings will be
called depending on severity and frequency of AEs and where unblinding is
necessary. The same individual and cohort stopping rules apply as for the pilot
phase. If cohort stopping rules are met in the main phase, the ISDMC may advise
to stop further dosing of the treatment that resulted in meeting the stopping
criteria, the treatment(s) not involved in reaching the stopping criteria may
continue in the next cohort(s) . Naloxone phase: Subjects will receive a single
10-minute infusion of MR30507/09 or MR30365/07 in Study Period 1 according to
the random allocation schedule. Subjects will receive the alternate treatment
in Study Period 2. Naloxone IV injection or placebo will be administered 5
minutes after the end of MR30365/07 infusion according to the random allocation
schedule. The timing of naloxone or placebo administration for MR30507/09 will
be determined from the pilot phase PD data. Reversal effects will be monitored
and naloxone administration repeated at 0.4 mg at 4 minute intervals, as
necessary up to a maximum of 4 doses. Reversal will be deemed to have been
effective when ventilation levels return to baseline (+/- 10%). All treatments
will be administered in a semi-supine position and will be followed by the
appropriate measurements and safety assessments. The same individual and cohort
stopping rules apply as for the pilot phase. Naloxone administration in this
phase will not be considered an SAE as it is a scheduled study procedure.
Study burden and risks
Available non-clinical data on safety and efficacy of MR30507/09 demonstrates
that MR30507/09 may be a potent analgesic with a similar adverse event (AE)
profile to other mu-opioid receptor agonists. Therefore similar precautions
apply to MR30507/09 as to other analgesics in this class. Preliminary clinical
studies must be performed to evaluate the potential analgesic efficacy and
adverse effects MR30507/09 may have in humans. Based on non-clinical data
comparing MR30507/09 to MR30365/07 and fentanyl, it is expected that typical
opioid effects will be observed after administering MR30507/09 to humans. A low
starting dose (0.2µg/kg) will be selected based on non-clinical data, before
dose escalating, to establish the MR30507/09 therapeutic range based on
pharmacodynamic responses. Each dose level will be completed and safety and
pharmacodynamic data assessed by a Safety Data Review Committee (SDRC), before
dose escalation can occur. Individual subject and cohort stopping criteria also
apply. In order to ensure the safety of all volunteers enrolled into the study,
stringent cardiovascular assessments (12 lead ECGs) will be performed at
regular intervals up to 24 hours post-dose to enable thorough assessment of QTc
changes. In addition, a central ECG provider will be employed to review all
ECGs. Rigorous stopping rules have been defined within this protocol and any
observable cardiovascular events will be thoroughly documented and regularly
reviewed by a SDRC comprising Sponsor and Investigator site personnel. The
study will be performed in the anaesthesiology department of a hospital, with
all appropriate emergency procedures in place and by investigators experienced
in managing respiratory depression. Naloxone injection will be available for
emergency use for severe respiratory depression. Other supportive measures to
assist respiration and hemodynamics will also be available e.g. maintenance of
fluid and electrolyte levels (100 mL/h of 2.5% glucose infusion for up to 24
hours), oxygen, and vasopressors. Subjects will be monitored overnight in an
observation ward by an on duty physician and nursing staff. Extra blankets or
Bair® hugger therapy will be used, in case of low body temperature, as
appropriate to prevent hypothermia. Cardiovascular emergency measures such as
defibrillation, magnesium sulfate (infusion), and antiarrhythmic drugs, will
also be available. The overall risk/benefit assessment is considered
acceptable, under the conditions described above.
Cambridge Science Park, Milton Road 194
Cambridge CB4 0GW
GB
Cambridge Science Park, Milton Road 194
Cambridge CB4 0GW
GB
Listed location countries
Age
Inclusion criteria
1. Written informed consent obtained.
2. Healthy male subjects aged 18 to 45 years inclusive.
3. Body weight ranging from 60 to 100 kg and a BMI >= 18 and <= 30
4. Healthy and free of significant abnormal findings as determined by medical history, physical examination, vital signs, laboratory tests and ECG.
5. Male subjects must be willing to use contraception with their partners throughout the study and for 30 days after completion of the study and agree to inform the Investigator if their partner becomes pregnant during this time
6. Subject is deemed suitable by the Investigator for inclusion in the study.
Exclusion criteria
1. Any history of drug or alcohol abuse, or recreational drug use within 30 days prior to study drug administration.
2. Any history of conditions that might interfere with drug absorption, distribution, metabolism or excretion.
3. Use of opioid or opioid antagonist-containing medication in the past 90 days.
4. Any history of frequent nausea or vomiting regardless of etiology.
5. Any history of seizures or symptomatic head trauma.
6. Participation in a clinical drug study during the 90 days preceding the initial dose in this study.
7. In the Investigator*s opinion a clinically significant upper or lower respiratory infection within 4 weeks prior to the screening visit.
8. History of asthma, COPD, or other bronchial or lung diseases.
9. History of regurgitation or difficulty of intubation.
10. A history of additional risk factors for Torsades de Pointes (e.g. heart failure, hypokalaemia, personal or family history of long QT syndrome, syncope, or family history of sudden death).
11. Abnormal cardiac conditions including QTc interval greater than 450 msec at screening or pre-dose.
12. Use of medication within five times the half-life or minimum 14 days for prescription medication or 7 days for over-the-counter preparations (including vitamins, herbal and/or mineral supplements), whichever is longer, before the first dose of study treatment and during the study.
13. Refusal to abstain from food 6 hours preceding and 8 hours following study drug administration and to abstain from caffeine or xanthine containing beverages entirely during each confinement.
14. Weekly alcohol intake exceeding the equivalent of 21 units/week.
15. Consumption of alcoholic beverages within 24 hours before study drug administration, and refusal to abstain from alcohol for at least 48 hours after study drug administration.
16. History of heavy smoking (more than 20 cigarettes a day) within 45 days of study drug administration and refusal to abstain from smoking while in the study unit.
17. Blood or blood products donated within 90 days prior to study drug administration or any time during the study, except as required by this protocol.
18. Abnormal result obtained from Allen*s circulation test.
19. Positive results of urine drug screen, alcohol test, HBsAg, Hepatitis C antibody, or HIV tests.
20. Known sensitivity to fentanyl, opioids, naloxone, natrexone, or related compounds.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002229-31-NL |
| CCMO | NL42507.058.12 |