A randomized, double blind, four-period, six-treatment, double-dummy, placebo controlled, partial-crossover study to explore and compare the ventilatory response to hypercapnia (VRH) of cebranopadol, oxycodone, and placebo in healthy subjects

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:
o 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.
o 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:
o 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.
o 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.

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]
>450 ms in males and >470 in females) demonstrated on ECG;
b) Left bundle branch block at Screening or Baseline
4. Systolic blood pressure (BP) >150 or <90 mmHg or diastolic BP >95 or <50
mmHg at Screening or Baseline, or history of clinically significant orthostatic
hypotension.
5. Heart rate (HR) <40 beats per minute (bpm) 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 14days or 5 half-lives prior to dosing,
whichever is longer. An exception is made for contraceptives and 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.
17. No vitamin, mineral, herbal, and dietary supplements will be permitted
within 7 days prior to study drug administrations, or less than 5 half-lives
(whichever is longer, and during the course of the study.
18. Any clinically significant lifetime history of suicidal behaviour or
ideation and/or poses a current (within the past12 months) 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 Tris, Park, 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 Tris, Park, CHDR, Investigator, or study site employee. * Immediate family is
defined as a spouse, parent, sibling, or child, whether biological or legally
adopted