Abuse, Drug
Conditions
Keywords
Cebranopadol, Hydromorphone, Drug liking
Brief summary
The primary objective of this study was to evaluate the abuse potential of single doses of cebranopadol (GRT6005) relative to hydromorphone (immediate-release formulation \[IR\] and placebo in 48 non-dependent recreational opioid users. Secondary objectives were to evaluate the abuse potential of hydromorphone IR compared to placebo (trial validation), to evaluate the safety and tolerability of single doses of cebranopadol (200, 400, and 800 micrograms), and to evaluate pharmacokinetics (PK) of cebranopadol and optionally some of its metabolites.
Detailed description
The study comprised an Enrollment Visit, a Qualification Phase, a Treatment Phase with 7 double-blind treatment periods for each participant, and a Final Examination. In the Qualification Phase, all participants completed a naloxone challenge test to confirm that they were not opioid-dependent. The Objective Opioid Withdrawal Scale was used to record the signs or symptoms of withdrawal observed during the naloxone challenge test. Following the naloxone challenge test, participants received a single oral dose of hydromorphone immediate-release (IR) 12 milligrams (mg) and placebo in a double-blinded, randomized crossover manner to ensure that they could discriminate between an active drug and placebo and could tolerate hydromorphone IR 12 mg. After a washout phase of at least 3 days, participants could continue with the Treatment Phase. In the Treatment Phase, each participant received single oral doses of the 7 different investigational medicinal products (IMPs) (Treatment A to Treatment G) in 7 sequential treatment periods. The treatment sequences per participant were randomly assigned, except for one administration of placebo (Treatment G) which always followed the highest dose of cebranopadol (Treatment C). Each IMP administration was given under fasted conditions and was separated by a washout period of at least 14 days. Participants were confined to the study site from Day -1 until 48 hours after the first IMP administration in the Qualification Phase and from Day -1 until 56 hours after the IMP administration in the treatment periods. Pharmacodynamic assessments and blood sampling for pharmacokinetics were performed from pre-dose until 56 hours post-dose in each treatment period. The Final Examination was conducted 5 days to 10 days after the discharge from the last treatment period or upon early discontinuation from the study.
Interventions
DRUGCebranopadol 100 micrograms
Tablets were taken under fasted conditions with non-carbonated water.
DRUGCebranopadol 400 micrograms
Tablets were taken under fasted conditions with non-carbonated water.
DRUGHydromorphone hydrochloride 4 milligrams
Over-encapsulated immediate-release tablets were taken under fasted conditions with non-carbonated water.
DRUGPlacebo matching hydromorphone
Placebo matching over-encapsulated hydromorphone tablets were taken under fasted conditions with non-carbonated water.
DRUGPlacebo matching cebranopadol
Placebo matching cebranopadol tablets were taken under fasted conditions with non-carbonated water.
Sponsors
Tris Pharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Nested-randomized, single site, double-blind, double-dummy, placebo- and active-controlled, crossover design with administration of a single oral dose. Based on the assigned treatment sequence, each participant was randomly allocated to receive a single oral dose of the investigational medicinal product (IMP) in each of 7 periods. One administration of placebo (Treatment G) always followed cebranopadol 800 micrograms (Treatment C). Each IMP administration was given under fasted conditions and was separated by a washout period of at least 14 days.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent signed. 2. Male and female, aged 18 years to 55 years, inclusive. 3. History of recreational opioid use (defined as non-therapeutic use at least 10 times in the participant's lifetime and at least once in the last 12 weeks prior to the Enrollment Visit). 4. Body mass index between 19 kilograms per square meter and 32 kilograms per square meter inclusive, with a body weight of not less than 50 kilograms at enrollment. 5. Participants must be in good health as determined by medical history, physical examination, 12-lead electrocardiogram (ECG), and vital signs (pulse rate, systolic blood pressure and diastolic blood pressure, respiratory rate, and oxygen saturation using pulse oximetry) at enrollment. 6. Adequate contraception is being used or women of non-childbearing potential may be enrolled if surgically sterile (i.e., after hysterectomy) or post-menopausal for at least 2 years (based on participant's report). * For women of childbearing potential: A medically acceptable and highly effective method of birth control is defined as any form of contraception with a low failure rate defined as less than 1 percent per year. For example: * Hormonal contraceptives for at least 8 weeks prior to the Enrollment Visit and at least until 4 weeks after the Final Examination. * An intra-uterine device. Additional barrier contraception should be used by the partner for the duration of the study, defined as from the time of the Enrollment Visit until 4 weeks after the Final Examination. A single barrier method alone is not acceptable. * For men: Participants must be willing to use medically acceptable and highly effective methods of birth control. Participants must be willing to use barrier contraception (condom) during sexual intercourse with females from the first administration of investigational medicinal product (IMP) until 4 weeks after the Final Examination. Participants must be willing to take care that their female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as less than 1 percent per year (e.g., hormonal contraceptives, diaphragm) during this time frame. A single barrier method alone is not acceptable.
Exclusion criteria
(at Enrollment): 1. Current substance dependence (except nicotine and caffeine dependence) as defined by the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). 2. Unwillingness or inability to abstain from recreational drug use for the duration of the study. 3. Positive or missing alcohol breath test at enrollment. 4. Participants attempting to discontinue their recreational drug use or who had been in a drug rehabilitation program in the 12 months prior to enrollment. 5. Current consumption of more than 20 cigarettes per day or inability to abstain from smoking (or use of any nicotine-containing substance) for at least 26 hours. 6. Participation in another clinical study within 30 days prior to enrollment that resulted in the administration of at least 1 dose of IMP. 7. Diseases or conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs. 8. Prolongation of corrected QT interval (Fridericia) (QTcF) (after repeated assessment) at enrollment, i.e., above 450 milliseconds, or presence of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia), or use of concomitant medications that prolong QT interval. 9. History of orthostatic hypotension or other cardiovascular diseases. 10. Any clinically significant disease that in the investigator's opinion may affect efficacy or safety assessments or may compromise the participant's safety during study participation, e.g., significant pulmonary, gastrointestinal, cardiac, endocrine, metabolic, neurological, or psychiatric disorders. 11. Definite or suspected history of drug allergy or hypersensitivity to opioids or naloxone. 12. Use of forbidden medication within 2 weeks prior to enrollment into this study. 13. Any contraindication for naloxone or hydromorphone immediate-release (IR) administration. 14. Not able to abstain from consumption of: * Beverages or food containing caffeine (tea, coffee, cola, chocolate, etc.) or alcohol from 2 days prior to each Day 1 until discharge from the ward. * Beverages or food containing quinine (e.g., bitter lemon, tonic water) from 1 week before Day 1 of the Qualification Phase until the Final Examination. * Grapefruit juice (sweet or sour) or Seville oranges from 1 week before Day 1 of the Qualification Phase until the Final Examination. 15. Pregnant or breastfeeding women, or missing pregnancy test. 16. Blood loss of 500 milliliters or more within 4 weeks before enrollment in this study, including blood donation. Planned blood donations during the study and up to 12 weeks after the Final Examination. 17. History of seizure disorder and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the Enrollment Visit at the discretion of the investigator. 18. Known or suspected of not being able to comply with the study protocol. 19. Not able to communicate meaningfully with the investigator or study site staff. 20. Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug Liking (at this moment) | At 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: At this moment, my liking for this drug is ...; Bipolar response anchors: 0 (Strong disliking), 50 (Neither like nor dislike), 100 (strong liking). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Floating | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: I feel as if I am floating; Unipolar response anchors: 0 (Not at all) to 100 (Very much). |
| Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) scale | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | The Addiction Research Center Inventory (ARCI) scale to assess sedation was presented to the participant on a computer screen as multiple choices. Participants were asked to select their responses by pointing to one of them with the mouse; the two responses are False or True. |
| Pupillometry | Pre-dose and at 9 distinct time points between 1 and 56 hours after drug intake | Pupil diameter was measured under mesopic lighting conditions. Data from a series of frames were used in the calculation, and the weighted average and standard deviation of the pupil size was calculated. |
| Divided Attention Test | Pre-dose and at 8 distinct time points between 1 and 56 hours after drug intake | Manual-tracking test with a simultaneous visual target detection component. Participant is provided with joystick and presented with the image of an airplane and a randomly curving road; participant has to position the airplane over the center of the road while being distracted repeatedly by visual targets they have to respond to. Time over the road (percentage), response latency of correct responses (milliseconds) and target hits (percentage) are recorded. |
| Any Drug Effects | At 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: I can feel any drug effect. Unipolar response anchors: 0 (Definitely not) to 100 (Definitely so). |
| Good Drug Effects | At 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: I can feel good drug effects; Unipolar response anchors: 0 (Definitely not) to 100 (Definitely so). |
| Bad Drug Effects | At 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: I can feel bad drug effects; Unipolar response anchors: 0 (Definitely not) to 100 (Definitely so). |
| High | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: I am feeling high; Unipolar response anchors: 0 (Definitely not) to 100 (Definitely so). |
| Take Drug Again | At 12, 24, and 56 hours aft drug intake | Visual analog scale (VAS) rating; Question text: I would take this drug again; Unipolar response anchors: 0 (Definitely not) to 100 (Definitely so). |
| Feeling Sick | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating: Question text: I am feeling sick; Unipolar response anchors: 0 (Definitely not) to 100 (Definitely so). |
| Alertness/Drowsiness | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: My mental state is...; Bipolar response anchors: 0 (Very drowsy), 50 (Neither drowsy nor alert), 100 (Very alert). |
| Detached | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | Visual analog scale (VAS) rating; Question text: I feel detached from my body; Unipolar response anchors: 0 (Not at all) to 100 (Very much). |
| Overall Drug Liking | At 12, 24, and 56 hours aft drug intake | Visual analog scale (VAS) rating; Question text: Overall, my liking for this drug is ...; Bipolar response anchors: 0 (Strong disliking), 50 (Neither like nor dislike), 100 (Strong liking) |
| Drug Similarity | At 12, 24, and 56 hours aft drug intake | Visual analog scale (VAS) rating; Questions 1-15: How similar is the drug you most recently received to...? with 15 drugs to be assessed and response anchors 0 (Not at all similar) to 100 (Very similar); Question 16: How familiar was the effect of the drug you most recently received? for an overall familiarity assessment with response anchors 0 (Very unfamiliar) to 100 (Very familiar). |
| Morphine-Benzedrine Group (MBG) scale | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | The Addiction Research Center Inventory (ARCI) scale to assess euphoria (MBG scale) was presented to the participant on a computer screen as multiple choices. Participants were asked to select their responses by pointing to one of them with the mouse; the two responses are False or True. |
| Benzedrine Group (BG) scale | Pre-dose and at 16 distinct time points between 30 minutes and 56 hours after drug intake | The Addiction Research Center Inventory (ARCI) scale to assess stimulant-like effects: amphetamine, A-scale and Benzedrine Group (BG scale) was presented to the participant on a computer screen as multiple choices. Participants were asked to select their responses by pointing to one of them with the mouse; the two responses are False or True. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed plasma concentration (Cmax) | From pre-dose until 56 hours post-dose in each treatment period (13 samples in total) | Plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry bioanalytical assays. Blood samples for pharmacokinetic analyses of cebranopadol and 3 of its metabolites were collected from pre-dose until 56 hours post-dose in each treatment period. Cmax was calculated based on plasma concentration-time data (using actual blood sampling times). |
| Time to attain maximum concentration (tmax) | From pre-dose until 56 hours post-dose in each treatment period (13 samples in total) | Plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry bioanalytical assays. Blood samples for pharmacokinetic analyses of cebranopadol and 3 of its metabolites were collected from pre-dose until 56 hours post-dose in each treatment period. Tmax was calculated based on plasma concentration-time data (using the actual blood sampling times). |
| Area under the concentration-time curve up to the sampling time t (AUC0-t) | From pre-dose until 56 hours post-dose in each treatment period (13 samples in total) | Plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry bioanalytical assays. Blood samples for pharmacokinetic analyses of cebranopadol and 3 of its metabolites were collected from pre-dose until 56 hours post-dose in each treatment period. The AUC0-t was calculated based on plasma concentration-time data (using the actual blood sampling times). |
Countries
Canada
Outcome results
None listed