Clinical trial NCT03958123: Evaluation of the Effects of Multiple Doses of Cebranopadol on the Electrical Activity of the Heart in Healthy Subjects
Official title: Evaluation of the Effects of Multiple Therapeutic and Supratherapeutic Doses of Cebranopadol on Cardiac Repolarization in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Prolonged QTc Interval
Pharmacokinetic
Keywords: QT/QTc Interval
Lead sponsor: Tris Pharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Forest Laboratories
First posted: 2019-05-21
Enrollment: 171
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants were randomized to 1 of 4 treatment groups on Day -3: The study included a nested cross-over design for participants in treatment group 3 (A, B).
Primary purpose: TREATMENT

Brief summary: The objective of this study was to evaluate the effects of cebranopadol (GRT6005) on the electrical activity of the heart in healthy participants.

The study consisted of a screening period within 21 days before the first dose of investigational medicinal product (IMP) (between Day -25 and Day -4) during which informed consent was obtained and the general suitability of the participants for the trial was assessed according to the inclusion/exclusion criteria.

Participants were confined to the trial site from 4 days before first IMP dosing on Day 1 to 4 days after last IMP dosing on Day 30. During this period, multiple-doses of cebranopadol or matching placebo and a single-dose of moxifloxacin or matching placebo were administered. Moxifloxacin was used as a positive control. It has consistently shown that it has an effect on the heart rhythm. Continuous 12-lead ECGs were recorded at defined time points. Multiple blood and urine samples were drawn for pharmacokinetic evaluations and safety laboratory monitoring (hematology, chemistry, and urinalysis). Additional safety evaluations included recording of adverse events, vital signs (systolic and diastolic blood pressure, pulse rate, respiration rate, body temperature, and weight), oxygen saturation, standard 12-lead ECG, Clinical Opiate Withdrawal Scale (COWS) assessment, and Columbia-Suicide Severity Rating Scale (C-SSRS) assessment.

An End-of-Trial Visit was performed on Day 34, or within 7 days after the last pharmacokinetic sample on Day 34, or at early withdrawal.


Eligibility criteria: Inclusion Criteria:

* Sign the informed consent form (ICF) and have the mental capability to understand it.
* Be a healthy male or female, aged 18 through 45 years, inclusive.
* If female, have a negative result from a serum pregnancy test at screening and a negative result from a serum or urine pregnancy test on Day -4.
* If male, agree to use an effective method of contraception (ie, condom plus diaphragm with spermicide or condom plus spermicide) and not have their partners become pregnant throughout the study, or have been sterilized for at least 1 year (with supporting documentation of the absence of sperm in the ejaculate postvasectomy).
* If female of childbearing potential, agree to use an effective method of contraception (ie, condom plus diaphragm with spermicide, condom plus spermicide, or nonhormonal intrauterine device) and not become pregnant throughout the study. Females who are at least 2-years postmenopausal (with supporting documentation from an obstetrician/gynecologist) or who have had tubal ligation or hysterectomy (with supporting documentation from the physician who performed the surgery) will not be considered to be of childbearing potential.
* Be nonsmoking (never smoked or have not smoked within the previous 2 years).
* Have a body mass index (BMI) greater than or equal to 18 kilograms per square meter and less than or equal to 30 kilograms per square meter.
* Have a sitting pulse rate greater than or equal to 50 beats per minute (bpm) and less than or equal to 100 bpm during the vital sign assessment at screening.

Exclusion Criteria:

* Known hypersensitivity to cebranopadol, other opioids, or moxifloxacin or other fluoroquinolone antibiotics.
* Clinically significant disease state, in the opinion of the examining physician, in any body system.
* Sitting systolic blood pressure (BP) greater than or equal to 140 millimeters mercury (mm Hg) or less than or equal to 90 mm Hg or sitting diastolic BP greater than or equal to 90 mm Hg or less than or equal to 50 mm Hg at screening.
* Abnormal electrocardiogram (ECG) results thought to be potentially clinically significant (PCS), or QT prolongation (QTcF greater than or equal to 450 milliseconds (msec) or uncorrected QT greater than or equal to 500 msec) according to the Investigator.
* History of cardiovascular disease including but not limited to long QT syndrome (or family history of long QT syndrome), cardiac arrhythmia, orthostatic hypotension, and coronary artery or valvular disease.
* Positive test results for anti-human immunodeficiency virus type 1, hepatitis B surface antigen, hepatitis B core antibodies, or anti-hepatitis C virus at screening.
* Abnormal and clinically significant results on medical history, physical examination, serum chemistry, hematology, or urinalysis.
* History of alcohol or other substance abuse within the previous 5 years.
* Positive urine drug screen test results for benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, phencyclidine, or cotinine at screening or Day -4.
* Have taken opioids within the past 1 month.
* Participation in any other clinical investigation using an experimental drug requiring repeated blood or plasma draws within 60 days of investigational product administration.
* Participation in a blood or plasma donation program within 60 or 30 days, respectively, of investigational product administration.
* Consumption of caffeine products within 48 hours or any grapefruit-containing products or Seville oranges within 14 days or consumption of alcohol or poppy seeds within 72 hours before administration of investigational product.
* Consumption of beverages or food containing quinine (bitter lemon, tonic water) within 14 days before administration of investigational product until discharge from the study center.
* Have any clinical condition that might affect the absorption, distribution, biotransformation, or excretion of cebranopadol or moxifloxacin.
* Employee, or immediate relative of an employee, of Forest Laboratories, Inc. or Grünenthal GmbH, any of its affiliates or partners, or the study center.
* Taken any concomitant medications (including over-the-counter medications) within 14 days or hormonal drug products within 30 days before administration of investigational product.
* Previously taken cebranopadol or previously participated in an investigational study of cebranopadol.
* Breastfeeding.
* Responses to the Columbia-Suicide Severity Rating Scale (C-SSRS) that indicate any current suicidal ideation or a history of active suicidal ideation or suicide attempts.
* Suicidal risk based on the opinion of the principal investigator (or appropriately trained designee).

Primary outcomes:
measure: QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supported sitting position
timeFrame: Day -1 up to Day 29
Secondary outcomes:
measure: QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supine position
timeFrame: Day -1 up to Day 29
measure: QTcF change from time-matched baseline measurement on Day -1 to Day 29 - sitting position
timeFrame: Day -1 up to Day 29
measure: QTcF change from time-matched baseline measurement on Day -1 to Day 29 - supine position
timeFrame: Day -1 up to Day 29
measure: Pharmacokinetic parameter: AUC0-tau,ss of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-tau,ss of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-tau,ss of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-tau,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-t of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-t of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-t of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-t of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cav,ss of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cav,ss of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cav,ss of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cav,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmax,ss of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmax,ss of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmax,ss of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmax,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmin,ss of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmin,ss of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmin,ss of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmin,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Fluctuation of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Fluctuation of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Fluctuation of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Fluctuation of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Swing of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Swing of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Swing of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Swing of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: tmax of cebranopadol
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: tmax of M2 (7-hydroxy-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: tmax of M3 (N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: tmax of M6 (7-hydroxy N-desmethyl-GRT6005)
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-inf of moxifloxacin
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: AUC0-t of moxifloxacin
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: Cmax of moxifloxacin
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: t1/2 of moxifloxacin
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
measure: Pharmacokinetic parameter: tmax of moxifloxacin
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Other outcomes:
Locations:
city: West Bend
country: United States
facility: US001 Contract research organization
state: Wisconsin
Study officials:
affiliation: Grünenthal GmbH
name: Study Director Grünenthal
role: STUDY_DIRECTOR
References: