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

Primary Purpose

Pain

Status
Recruiting
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Cebranopadol 600 µg
Cebranopadol 800 µg
Cebranopadol 1000 µg
Oxycodone 30 mg
Oxycodone 60 mg
Placebo
Sponsored by
Tris Pharma, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pain focused on measuring cebranopadol, pain, respiratory, hypercapnia

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Centre for Human Drug Research (CHDR)Recruiting
  • Leiden University Medical Centre (LUMC)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Cebranopadol 600 µg

Cebranopadol 800 µg

Cebranopadol 1000 µg

Oxycodone 30 mg

Oxycodone 60 mg

Cebranopadol placebo tablets/ Oxycodone placebo capsules

Arm Description

3 x 200 µg cebranopadol tablets

4 x 200 µg cebranopadol tablets

5 x 200 µg cebranopadol tablets

3 x 10 mg Oxycodone tablets

3 x 20 mg Oxycodone tablets

Cebranopadol placebo tablets/ Oxycodone placebo capsules

Outcomes

Primary Outcome Measures

Ventilatory response to hypercapnia (VRH) by maximum decrease in minute ventilation (L)
Pre-dose to 24 h postdose

Secondary Outcome Measures

Pupil constriction compared to baseline (mm)
Pre-dose to 24 h postdose
Electrical and pressure pain tests
Pre-dose to 24 h postdose
Adverse event reporting
Pre-dose to 24 h postdose

Full Information

First Posted
July 27, 2022
Last Updated
August 4, 2022
Sponsor
Tris Pharma, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT05491785
Brief Title
Cebranopadol Effects on Ventilatory Drive, Central Nervous System (CNS) and Pain.
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 29, 2022 (Actual)
Primary Completion Date
March 30, 2023 (Anticipated)
Study Completion Date
March 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tris Pharma, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pain
Keywords
cebranopadol, pain, respiratory, hypercapnia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
Randomized, double blind, four- period, six-treatment, double-dummy, placebo controlled, partial-crossover study
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-dummy
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cebranopadol 600 µg
Arm Type
Experimental
Arm Description
3 x 200 µg cebranopadol tablets
Arm Title
Cebranopadol 800 µg
Arm Type
Experimental
Arm Description
4 x 200 µg cebranopadol tablets
Arm Title
Cebranopadol 1000 µg
Arm Type
Experimental
Arm Description
5 x 200 µg cebranopadol tablets
Arm Title
Oxycodone 30 mg
Arm Type
Active Comparator
Arm Description
3 x 10 mg Oxycodone tablets
Arm Title
Oxycodone 60 mg
Arm Type
Active Comparator
Arm Description
3 x 20 mg Oxycodone tablets
Arm Title
Cebranopadol placebo tablets/ Oxycodone placebo capsules
Arm Type
Placebo Comparator
Arm Description
Cebranopadol placebo tablets/ Oxycodone placebo capsules
Intervention Type
Drug
Intervention Name(s)
Cebranopadol 600 µg
Other Intervention Name(s)
Experimental
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Cebranopadol 800 µg
Other Intervention Name(s)
Experimental
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Cebranopadol 1000 µg
Other Intervention Name(s)
Experimental
Intervention Description
Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone placebo capsules, and 5 cebranopadol 200 µg tablets
Intervention Type
Drug
Intervention Name(s)
Oxycodone 30 mg
Other Intervention Name(s)
Active Comparator
Intervention Description
Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone 10 mg capsules, and 5 cebranopadol placebo tablets
Intervention Type
Drug
Intervention Name(s)
Oxycodone 60 mg
Other Intervention Name(s)
Active Comparator
Intervention Description
Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone 20 mg capsules, and 5 cebranopadol placebo tablets
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo comparator
Intervention Description
Participants will be administered a single dose of 8 identically appearing capsules containing: 3 oxycodone placebo capsules, and 5 cebranopadol placebo tablets
Primary Outcome Measure Information:
Title
Ventilatory response to hypercapnia (VRH) by maximum decrease in minute ventilation (L)
Description
Pre-dose to 24 h postdose
Time Frame
24 hours
Secondary Outcome Measure Information:
Title
Pupil constriction compared to baseline (mm)
Description
Pre-dose to 24 h postdose
Time Frame
24 hours
Title
Electrical and pressure pain tests
Description
Pre-dose to 24 h postdose
Time Frame
24 hours
Title
Adverse event reporting
Description
Pre-dose to 24 h postdose
Time Frame
24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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). Exclusion Criteria: 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. 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. 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. 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. 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. 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 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Antonio Pardo, MD
Phone
732-823-4755
Email
clinicalaffairs@trispharma.com
First Name & Middle Initial & Last Name or Official Title & Degree
Simone Hansen, MD
Email
clintrials@chdr.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Albert Dahan, MD, PhD
Organizational Affiliation
LUMC
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Geert Jan Groeneveld, MD, PhD
Organizational Affiliation
CHDR
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre for Human Drug Research (CHDR)
City
Leiden
Country
Netherlands
Individual Site Status
Recruiting
Facility Name
Leiden University Medical Centre (LUMC)
City
Leiden
Country
Netherlands
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28291085
Citation
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.
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Cebranopadol Effects on Ventilatory Drive, Central Nervous System (CNS) and Pain.

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