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

NCT05491785 | Completed Phase 1 FDA Drug

• 1 other identifier: PARK-104-VRH
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Pain

Keywords

cebranopadol; pain; respiratory; hypercapnia

Outcome Measures

Primary Outcomes (1)

• Ventilatory response to hypercapnia (VRH) by maximum decrease in minute ventilation (L)

  Pre-dose to 24 h postdose

  24 hours

Secondary Outcomes (3)

• Pupil constriction compared to baseline (mm)

  24 hours

• Electrical and pressure pain tests

  24 hours

• Adverse event reporting

  24 hours

Study Arms (6)

Cebranopadol 600 µg

EXPERIMENTAL

3 x 200 µg cebranopadol tablets

Drug: Cebranopadol 600 µg

Cebranopadol 800 µg

EXPERIMENTAL

4 x 200 µg cebranopadol tablets

Drug: Cebranopadol 800 µg

Cebranopadol 1000 µg

EXPERIMENTAL

5 x 200 µg cebranopadol tablets

Drug: Cebranopadol 1000 µg

Oxycodone 30 mg

ACTIVE COMPARATOR

3 x 10 mg Oxycodone tablets

Drug: Oxycodone 30 mg

Oxycodone 60 mg

ACTIVE COMPARATOR

3 x 20 mg Oxycodone tablets

Drug: Oxycodone 60 mg

Cebranopadol placebo tablets/ Oxycodone placebo capsules

PLACEBO COMPARATOR

Cebranopadol placebo tablets/ Oxycodone placebo capsules

Drug: Placebo

Interventions

Cebranopadol 600 µg DRUG

Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone placebo capsules, 3 cebranopadol 200 µg tablets and 2 cebranopadol placebo tablets

Also known as: Experimental

Cebranopadol 600 µg

Cebranopadol 800 µg DRUG

Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone placebo capsules, 4 cebranopadol 200 µg tablets and 1 cebranopadol placebo tablet

Also known as: Experimental

Cebranopadol 800 µg

Cebranopadol 1000 µg DRUG

Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone placebo capsules, and 5 cebranopadol 200 µg tablets

Also known as: Experimental

Cebranopadol 1000 µg

Oxycodone 30 mg DRUG

Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone 10 mg capsules, and 5 cebranopadol placebo tablets

Also known as: Active Comparator

Oxycodone 30 mg

Oxycodone 60 mg DRUG

Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone 20 mg capsules, and 5 cebranopadol placebo tablets

Also known as: Active Comparator

Oxycodone 60 mg

Placebo DRUG

Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone placebo capsules, and 5 cebranopadol placebo tablets

Also known as: Placebo comparator

Cebranopadol placebo tablets/ Oxycodone placebo capsules

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent prior to any study-mandated procedure.
• Subject is able to speak, read, and understand Dutch and voluntarily provide written informed consent to participate in the study.
• Adult men or women aged 18 to 45 years, inclusive.
• Subjects are in good health as indicated by medical history, physical examination, vital signs, oxygen saturation, clinical laboratory tests, and 12-lead ECG.
• Body mass index between 18.0 kg/m2 and 32.0 kg/m2 and body weight greater than 50 kg, inclusive.
• 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).

You may not qualify if:

• 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.
• History of known difficult airway access or uncontrolled gastroesophageal reflux disease (GERD), gastric motility disorders, or delayed gastric emptying
• Has clinically significant abnormalities on ECG at screening or Day -1, as defined by the following:
• prolonged corrected QT interval (Fridericia-corrected QT interval \[QTcF\] \>450 ms in males and \>470 ms in females) demonstrated on ECG;
• Left bundle branch block at Screening or Baseline
• 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.
• Heart rate (HR) \<40 beats per minute (bpm) or \>100 bpm at Screening.
• 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.
• 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).
• 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.
• 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.
• 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.
• Use of nicotine-containing products within 4 weeks before the Screening visit and not able to withhold from smoking during the study.
• Pregnant or breastfeeding.
• Subjects indicating pain test intolerability at Screening or achieving pain tolerance at \>80% of maximum input intensity for the pain tests.

Sponsors & Collaborators

• Tris Pharma, Inc.: lead

Study Sites (2)

Centre for Human Drug Research (CHDR)

Leiden, Netherlands

Location

Leiden University Medical Centre (LUMC)

Leiden, Netherlands

Location

Related Publications (1)

• Dahan A, Boom M, Sarton E, Hay J, Groeneveld GJ, Neukirchen M, Bothmer J, Aarts L, Olofsen E. Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers. Anesthesiology. 2017 Apr;126(4):697-707. doi: 10.1097/ALN.0000000000001529.

  PMID: 28291085 BACKGROUND

MeSH Terms

Conditions

Pain; Hypercapnia

Interventions

6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro(cyclohexane-1,1'(3'H)-pyrano(3,4-b)indol)-4-amine; Oxycodone

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory

Intervention Hierarchy (Ancestors)

Codeine; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Albert Dahan, MD, PhD

  LUMC

  PRINCIPAL INVESTIGATOR

• Geert Jan Groeneveld, MD, PhD

  CHDR

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-dummy
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, double blind, four- period, six-treatment, double-dummy, placebo controlled, partial-crossover study

Study Record Dates

• First Submitted: July 27, 2022
• First Posted: August 8, 2022
• Study Start: July 29, 2022
• Primary Completion: March 30, 2023
• Study Completion: January 2, 2024
• Last Updated: May 9, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2)