Cebranopadol Effects on Ventilatory Drive, Central Nervous System (CNS) and Pain.

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

Opioids are potent painkillers but come with serious adverse effects ranging from addiction to potentially lethal respiratory depression via activation of μ-opioid receptors (MOP) at specific sites in the central nervous system. Cebranopadol is a first-in-class investigational drug to treat patients with acute and chronic pain. The molecule dually activates the Nociceptin/Orphanin FQ peptide (NOP) receptor and the classical MOP receptor. This is a unique mechanism of action and has demonstrated efficacy in multiple Phase 2 and Phase 3 clinical studies across several nociceptive and neuropathic indications as well as a superior safety profile, low potential for abuse and minimal risk of physical dependence. In animal studies, cebranopadol produced considerably less respiratory depression at comparably analgesic doses of oxycodone and fentanyl and appeared to have a ceiling to its respiratory effects. Preliminary clinical trials have suggested that these results will be similar in humans.

The present study is designed to investigate if: 1) cebranopadol produces less respiratory depression than oxycodone 2) cebranopadol respiratory effects have a ceiling at very high doses and 3) cebranopadol does not produce significant respiratory depression, as measured in this study design with 30 subjects, at any dose in the VRH model.

This is a 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 hypercapnia (VRH), nociceptive thresholds and safety.

VRH testing is non-invasive and is an established technique to evaluate respiratory depression following the administration of opioids.

The test will be performed using a rebreathing setup with the subjects comfortably seated or semi-supine in a hospital bed and breathing through a facemask. VRH will be performed at several timepoints post-administration of cebranopadol, oxycodone or placebo in a randomized fashion. At each time point, subjects will be allowed an acclimation period of ambient air to establish regular breathing pattern; immediately followed by rebreathing a hypercapnic gas mixture (7%CO2, in oxygen (50%)), for at least 3 min. Between timepoints, subjects will remove their face masks and breathe ambient air.

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).

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:

   1. prolonged corrected QT interval (Fridericia-corrected QT interval [QTcF] >450 ms in males and >470 ms in females) demonstrated on ECG;
   2. Left bundle branch block at Screening or Baseline

4. Systolic blood pressure (BP) >150 or <90 mmHg or diastolic BP >90 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.

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 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 past 12 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.