Primaryo To evaluate the effects of oliceridine following IV bolus dose administration on neurocognitive functioning, when compared to morphine and placeboSecondaryo To evaluate the effects of oliceridine following IV bolus dose administration on…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Acute Pain
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
o Saccadic eye movement: peak velocity (°/s)
Secondary outcome
o Saccadic eye movement: reaction time (s), inaccuracy (%)
o Smooth pursuit eye movement: percentage of time the eyes of the subjects are
in smooth pursuit of the target (%)
o Pupillometry (pupil/iris ratio): pupil constriction compared to baseline (mm)
o Adaptive tracking: average performance (%)
o Body sway: antero-posterior sway (mm)
o Symbol-digit substitution test (SDST): total number of correct and incorrect
responses, average reaction time for 1st SDST trial until 36th SDST trial (s)
o Visual analogue scale (VAS) Bond & Lader (Alertness, mood, calmness) (mm)
o VAS Bowdle (internal perception, external perception, *feeling high*) (mm)
o Cold pressor test
* Pain Detection Threshold (PDT) (s)
* Pain Tolerance Threshold (PTT) (s)
* Area above the curve (AAC) (s*mm)
* Post-test VAS (mm)
o The maximum plasma concentration observed (Cmax)
o Time to reach Cmax (tmax)
o The area under the concentration*time curve from time zero to time of last
quantifiable concentration (AUClast)
o The area under the concentration*time curve from time zero to 12 hours
(AUC0-12)
o The area under the concentration*time curve from time zero and extrapolated
from the time of last quantifiable concentration to infinity (AUCinf)
o The half-life (t1/2)
o Other parameters, including volume of distribution (Vz), clearance (CL), and
other parameters as appropriate, as well as dose adjusted parameters, may be
determined
o EC50 and Emax for oliceridine and morphine effects on NeuroCart measurements
and the cold pressor test as determined by PK/PD models
o Treatment-emergent AEs (TEAEs)
o Clinical laboratory evaluations: haematology, biochemistry including glucose,
coagulation, and urinalysis
o Vital signs: systolic and diastolic blood pressure, pulse rate, respiratory
rate, and body temperature
o Safety 12-lead ECG: Heart rate (bpm), PR, RR, QRS, QT, QTcF
o Specific assessments for opioid effects:
* Pasero Opioid-Induced Sedation Scale (POSS)
* Pulse oximetry
Background summary
TRV130, registered as oliceridine injection or Olinvyk®, is a novel, small
molecule mu opioid receptor (MOR) agonist. In-vitro, oliceridine stimulates G
protein signaling with higher potency than morphine. In contrast, oliceridine
is markedly less effective than morphine, fentanyl, and hydromorphone in
stimulating recruitment of *-arrestin2 to the MOR. These findings define
oliceridine as a *G protein-biased ligand*, a novel class of G protein coupled
receptor (GPCR) ligands that stimulate only a subset of the normal repertoire
of receptor coupling mechanisms.
Twelve Phase 1 studies (nine in healthy subjects and three in special
populations), two Phase 2 studies, one pilot Phase 2 study, two Phase 3 pivotal
efficacy and safety studies, and a Phase 3 open-label safety study have been
completed. Oliceridine has been approved by the FDA for use in adults for the
management of acute pain severe enough to require an intravenous opioid
analgesic, and alternative treatments are inadequate or not expected to be
tolerated.
Clinicians have reported observing apparent better neurocognitive functioning
in patients who were administered oliceridine than in patients being treated
with classic opioids such as morphine. This study is designed to evaluate
neurocognitive functioning using the NeuroCart test battery at the Centre for
Human Drug Research in healthy subjects when administered an IV bolus dose of
oliceridine compared to IV doses of morphine or placebo.
Study objective
Primary
o To evaluate the effects of oliceridine following IV bolus dose administration
on neurocognitive functioning, when compared to morphine and placebo
Secondary
o To evaluate the effects of oliceridine following IV bolus dose administration
on neurocognitive functioning, when compared to morphine and placebo
o To evaluate the analgesic activity of oliceridine and morphine following IV
bolus dose administration
o To assess pharmacokinetics of oliceridine, morphine, and morphine*s
metabolite M6G after IV bolus dose administration
o To assess the pharmacokinetic/ pharmacodynamic (PK/PD) relationships of
oliceridine following IV bolus dose administration
o To assess the CNS effect:nociception ratio and compare between oliceridine
and morphine using utility functions
o To assess safety and tolerability to IV bolus dose administration of
oliceridine and morphine
Study design
This single-centre, randomised, double-blind, placebo-controlled, 3-way partial
crossover study will investigate the effects of IV oliceridine on CNS
functions, opioid related parameters, and evoked pain tests in approximately 20
healthy male and female volunteers, aged 18-55. Each subject will have 3 study
periods of 26 hours (evening Day -1 to evening Day 1) with treatment
administered on Day 1 and PD tests performed throughout the day.
Intervention
Oliceridine 1 mg
Oliceridine 3 mg
Morphine HCl 5 mg
Morphine HCl 10 mg
Matching placebo
Study burden and risks
Opioids are effective treatments commonly prescribed for pain. However, opioid
pain medications are associated with serious risks including overdose,
respiratory depression, constipation, sedation, and opioid use disorder. As
such, there is an unmet need for well-tolerated and effective therapies,
including opioids with improved safety characteristics, for the management of
pain
Commonly reported adverse events (AEs) for opioid agonists include
constipation, nausea, vomiting, sedation, headache, and pruritus. Molecules
with a preference toward G-protein coupled intracellular signalling with low
levels of *-arrestin recruitment, such as oliceridine, are thought to retain
analgesic efficacy and reduce the risk of key side effects of opioids.
Morphine, the drug used as reference therapy in this study, could elicit these
symptoms. The total maximum dose of 10 mg of morphine IV on one day was chosen
because it is expected to provide adequate analgesic properties and possibly
measurable effects on neurocognitive tests, while having manageable adverse
effects.
The clinical data available for oliceridine and morphine are considered in the
risk assessment of this study, including the study inclusion/exclusion
criteria, as well as planned safety monitoring of participating subjects. All
study drug administrations will be performed in the clinic under medical
supervision. The subjects receiving any study drug will remain in the clinic
for at least 12 hours after first administration of study drug on each day of
dosing and will be closely monitored by medically qualified staff for any
adverse events during the treatment period(s), with adequate rescue therapies
available (e.g., supplemental oxygen, naloxone as antidote). Medical monitoring
will include peripheral oxygen saturation (SpO2), respiratory rate, sedation,
and ECG. Subjects will be discharged by a physician only if their medical
condition allows. The assessment of alertness according to the Pasero Opioid
Sedation Scale (POSS), which is also be scheduled for the 12-hour post-dose
time point, will be documented, and taken into account when the decision is
made to discharge a subject. Therefore, careful observation and medical
management will minimize any associated risk in this study.
Chesterbrook Blvd., Suite 110 955
Chesterbrook PA 19087
US
Chesterbrook Blvd., Suite 110 955
Chesterbrook PA 19087
US
Listed location countries
Age
Inclusion criteria
Subjects must meet all the following criteria to be included in this study:
1. Signed informed consent prior to any study-mandated procedure.
2. Ability to communicate well with the Investigator in the Dutch language and
willing and able to follow the procedures and comply with study restrictions as
outlined in the protocol.
3. Healthy male and female volunteers aged *18 years and *55 years old at the
time of informed consent.
4. Body mass index (BMI) *18 and <32 kg/m2 at Screening.
5. Females of childbearing potential must agree to the use of the
double-barrier contraceptive method, meaning the use of a highly effective
method of contraception (e.g., intrauterine device (IUD), diaphragm with
spermicide, oral contraceptive, injectable progesterone, subdermal implant or a
tubal ligation) in combination with the use of a condom by a male partner of
the female subject, from screening through 5 half-lives or 90 days, whichever
is longer, after administration of the last dose of IP.
6. Males who are sexually active and whose partners are females of childbearing
potential must agree to use condoms from screening through 5 half-lives or 90
days, whichever is longer, after administration of the last dose of IP, and
their partners must be willing to use a highly effective method of
contraception (e.g., IUD, diaphragm with spermicide, oral contraceptive,
injectable progesterone, subdermal implant or a tubal ligation) from screening
through 5 half-lives or 90 days after administration of the last dose of IP.
Exclusion criteria
1. Poor metabolisers of CYP 2D6 substrates, as defined after genotyping
assessment at screening.
2. Use of prescription or OTC medications that are clinically relevant CYP P450
3A4 or CYP P450 2D6 inducers or inhibitors from 14 days prior to study drug
administration until follow up.
3. Any current, clinically significant, known medical condition that would
affect sensitivity to cold (such as atherosclerosis, Raynaud*s disease,
urticaria, hypothyroidism) or pain (including pain disorders, such as chronic
low back pain and osteoarthritis, or diseases or conditions that cause pain,
hypaesthesia, hyperalgesia, allodynia, paraesthesia, neuropathy, etc.), in the
opinion of the investigator.
4. Subjects indicating pain test intolerability at Screening or achieving pain
tolerance at >80% of maximum input intensity for the cold pressor pain test.
5. Clinically significant illness or disease (e.g., psychiatric disorders,
disorders of the gastrointestinal tract, liver [excluding Gilbert*s syndrome],
kidney [including nephrectomy], respiratory system, endocrine system,
haematological system, neurological system, or cardiovascular system,
dermatologic condition, clinically significant infection within 2 weeks of
dosing, or subjects who have a congenital abnormality in metabolism), or any
clinically significant abnormal symptom or organ impairment, as judged by the
Investigator, found by medical history, physical examinations, vital signs,
electrocardiogram (ECG) finding, or either abnormal laboratory values or
laboratory test results at Screening or Baseline.
6. Any finding that may compromise the safety of the subject or affect their
ability to adhere to the protocol requirements (e.g., difficulty with venous
access or fear of needles).
7. Presence of any condition in which an opioid is contraindicated (e.g.,
opioid intolerance, significant respiratory depression, acute or severe
bronchial asthma, gastrointestinal ileus, etc.).
8. A prolonged corrected QT interval (Fridericia-corrected QT interval [QTcF]
>450 ms in males and >470 in females) demonstrated on ECG at Screening or
Baseline.
9. A history of risk factors for torsade de pointes (e.g., heart failure,
hypokalaemia, family history of long QT syndrome). A history of myocardial
infarction, ischaemic heart disease, or cardiac failure at Screening. History
of clinically significant arrhythmia or uncontrolled arrhythmia as determined
by the Investigator at Screening.
10. Left bundle branch block at Screening or Baseline.
11. Systolic blood pressure (BP) >140 or <90 mmHg or diastolic BP >90 or <50
mmHg at Screening or Baseline, or history of clinically significant orthostatic
hypotension.
12. Heart rate (HR) <45 beats per minute (bpm) or >100 bpm at Screening or
Baseline.
13. Demonstrated allergic reactions (e.g., food, drug, atopic reactions, or
asthmatic episodes) which, in the opinion of the Investigator, interfere with
the subject*s ability to participate in the trial.
14. Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibodies
(Anti-HBc), hepatitis C antibodies (HCV Ab), or human immunodeficiency virus
antibody (HIV Ab) at Screening.
15. Use of nicotine-containing products within 4 weeks before the Screening
visit and not able to withhold from smoking during the study.
16. History of opioid use disorder per Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) classification, or other drug/substance
or alcohol dependency or abuse before Screening, or those who have a positive
drug test or alcohol test at Screening or Baseline.
17. Use of prescription, non-prescription medications or herbal preparations
containing St. John*s Wort, and nutritional supplements within 7 days or 5
half-lives prior to dosing, whichever is longer. An exception is made for
incidental use of paracetamol or ibuprofen, which is allowed up to 48 hours
before start of each visit. Other exceptions are allowed only when clearly
documented by the investigator.
18. Any clinically significant lifetime history of suicidal behaviour or
ideation and/or poses a current (within the past year) suicide risk, as
assessed by scores on the Columbia Suicide Severity Rating Scale (C-SSRS) at
Screening per Investigator judgment
19. Receipt of blood products within 4 weeks, blood donation or blood loss >250
mL within 8 weeks, or donation of plasma within 1 week of any Study Drug dose
administration.
20. Is employed by Trevena, the Centre for Human Drug Research (CHDR), or the
Investigator or study site (permanent, temporary contract worker, or designee
responsible for the conduct of the study), or is immediate family* of a
Trevena, CHDR, Investigator, or study site employee.
* Immediate family is defined as a spouse, parent, sibling, or child, whether
biological or
legally adopted
21. Is currently enrolled in another clinical study or used any investigational
drug or device within 3 months prior to dosing or has participated in more than
4 investigational drug studies within 1 year prior to Screening.
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 | EUCTR2021-006334-39-NL |
| CCMO | NL79823.056.21 |