| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066714 |
| E.1.2 | Term | Acute pain |
| E.1.2 | System Organ Class | 100000004867 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| o To evaluate the effects of oliceridine following IV bolus dose administration on neurocognitive functioning, when compared to morphine and placebo |
|
| E.2.2 | Secondary objectives of the trial |
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 showing the difference in probability of analgesia and probability of CNS effects, as a function of the biophase oliceridine or morphine concentration
o To assess safety and tolerability to IV bolus dose administration of oliceridine and morphine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ≤55years 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 use condoms from screening through 5 half lives or 90 days, whichever is longer, after administration of the last dose of IP, and must be willing to use a highly effective method of contraception (e.g. intrauterine device (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.
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.
|
|
| E.4 | Principal 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 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.
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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
o Saccadic eye movement: reaction time (s), peak velocity (°/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)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
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 apparent half-life (t1/2)
o The area under the concentration–time curve from time zero and extrapolated from the time of last quantifiable concentration to infinity (AUCinf)
o Other parameters for oliceridine and morphine, 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
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
Print
