Ventilatory drive, central nervous system and pain in healthy subjects Other
Conditions
Interventions
This randomized, double blind, four- period, six-treatment, double-dummy, placebo controlled, partial-crossover study will investigate the effects of cebranopadol on the ventilatory response to hyperc
single oral doses of 600 µg, 800 µg, and 1000 µg
• Oxycodone IR capsules (strengths: 10 mg and 20 mg)
single oral doses of 30 mg and 60 mg
• Matching placebo for cebranopadol and oxycodone
Sponsors
Park Therapeutics Inc
Eligibility
Sex/Gender
All
Age
18 Years to 45 Years
Inclusion criteria
Inclusion criteria: 1. Signed informed consent prior to any study-mandated procedure. 2. Subject is able to speak, read, and understand Dutch and voluntarily provide written informed consent to participate in the study. 3. Adult men or women aged 18 to 45 years, inclusive. 4. Subjects are in good health as indicated by medical history, physical examination, vital signs, oxygen saturation, clinical laboratory tests, and 12-lead ECG. 5. Body mass index between 18.0 kg/m2 and 32.0 kg/m2 and body weight greater than 50 kg, inclusive. 6. Adequate contraception is being used or women of nonchildbearing potential may be enrolled if surgically sterile (i.e., after hysterectomy) or postmenopausal for at least 2 years (based on subject’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 <1% per year. - For example: • Hormonal contraceptives for at least 8 weeks prior to screening and at least until 4 weeks after the Follow-up visit. • An intra-uterine device. • Additional barrier contraception should be used by the partner for the duration of the trial, defined as from the time of screening until 4 weeks after the follow-up visit. A single barrier method alone is not acceptable. • For men: - Subjects must be willing to use medically acceptable and highly effective methods of birth control. Subjects must be willing to use barrier contraception (condom) during sexual intercourse with females from the first administration of IMP until 4 weeks after the Follow-up visit. - Subjects 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 <1% per year (e.g., hormonal contraceptives, diaphragm) during this time
Exclusion criteria
Exclusion criteria: 1. History or presence of clinically significant cardiovascular (incl. a history of risk factors for torsade de pointes e.g., heart failure, hypokalaemia, family history of long QT syndrome, history of myocardial infarction, ischaemic heart disease, clinically significant arrhythmia or uncontrolled arrhythmia or cardiac failure), pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease(e.g., anxiety); or any other condition (e.g., hyperventilation disorder), which, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results. 2. History of known difficult airway access or uncontrolled gastroesophageal reflux disease (GERD), gastric motility disorders, or delayed gastric emptying 3. Has clinically significant abnormalities on ECG at screening or Day -1, as defined by the following: a. prolonged corrected QT interval (Fridericia-corrected QT interval [QTcF] > 450ms in males and >470 ms in females) demonstrated on ECG; b. Left bundle branch block at Screening or Baseline 4. Systolic blood pressure (BP) >150 or 95 or 100 bpm at Screening. 6. 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. 7. Has any condition in which an opioid is contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, or has or is suspected of having paralytic ileus). 8. Have a history of chronic obstructive pulmonary disease or any other lung disease (e.g., asthma, bronchitis, obstructive sleep apnoea, exercise-induced asthma) that would cause CO2 retention. 9. 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 (excluding nicotine and caffeine) within the last 5 years before Screening, which, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results 10. Has a positive alcohol test or urine drug screen for drugs of abuse (amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine and opioids) at Screening or Day -1. 11. Use of nicotine-containing products within 4 weeks before the Screening visit and not able to withhold from smoking during the study. 12. Pregnant or breastfeeding. 13. Subjects indicating pain test intolerability at Screening or achieving pain tolerance at >80% of maximum input intensity for the pain tests. 14. 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. 15. 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. 16. Use of prescription, non-prescription medications or herbal preparations containing St. John’s Wort, within 14 days or 5 half-lives prior to dosing, whichever is longer. An exception is made for contraceptives
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Respiratory drive measured by the VRH by maximum decrease in minute ventilation (L) after administration of cebranopadol, oxycodone, and placebo. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Pupil diameter (mm) measured by pupillometry predose and at multiple time points after administration of cebranopadol, oxycodone, and placebo 2. Sensitivity of the ventilatory response to hypercapnia after single oral administration of cebranopadol, oxycodone, and placebo by measuring: 2.1. Minute ventilation (expired minute volume; L) 2.2. Respiratory rate (breaths/min) 2.3. Flow rates (peak expired flow; L/min) 2.4. Tidal volume (expired tidal volume; mL) 2.5. End tidal CO2 (partial pressure) 2.6. O2 Saturation peripheral (%) 3. Analgesic activity of cebranopadol and oxycodone, compared to each other and placebo, following single oral administration, on the electrical and pressure pain tests by measuring the mean: 3.1. Pain Detection Threshold (PDT) 3.2. Pain Tolerance Threshold (PTT – electrical pain only) 4. Clinical safety data from adverse event (AE) reporting, clinical observations, 12-lead electrocardiograms (ECGs) (Heart rate (bpm), PR, RR, QRS, QT, QTcF), vital signs (blood pressure, heart rate, respiratory rate, body temperature, oxygen saturation, and safety laboratory tests following administration of cebranopadol, oxycodone, and placebo. 5. Blood samples will be collected to evaluate pharmacokinetics (PK) of cebranopadol (and its metabolites) and oxycodone by determining the following parameters 5.1. The maximum plasma concentration observed (Cmax) 5.2. Time to reach Cmax (tmax) 5.3. The area under the concentration–time curve from time zero to time of last quantifiable concentration (AUClast) 5.4. The area under the concentration–time curve from time zero to 24 hours (AUC0-24) 5.5. Other parameters as appropriate, as well as dose adjusted parameters, may be determined 6. Pharmacokinetic-pharmacodynamic (PK/PD) analysis will be conducted | — |
Countries
Netherlands
Contacts
Public ContactSimone Jansen
Outcome results
None listed