Clinical trial NCT01964378: CORAL - Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer
Official title: Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pain
Neoplasms
Chronic Pain
Keywords: cancer pain
neuropathic related cancer pain
morphine
cebranopadol (GRT6005)
Numerical Rating Scale
Lead sponsor: Tris Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2013-10-17
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Pain is one of the most common symptoms associated with malignant tumor. The purpose of this trial is to determine whether cebranopadol is as effective in patients with cancer related pain as morphine sulfate prolonged release (PR).

Detailed description: The trial comprises an enrollment period, a treatment period (titration and maintenance), and a follow-up period. Participants will receive either cebranopadol or morphine PR for 44 days. Initially participants will be titrated after 2 and then every 4 days to a morphine PR or cebranopadol dose that provides adequate analgesia and is tolerated. The titration period is planned to last 16 days. Thereafter the dose of morphine PR or cebranopadol is to be kept stable for a further 28 days, i.e. no dose adjustments will be allowed during the maintenance period. This 28 day period is the maintenance period. The follow-up period is planned for up to 18 days after the end of last pain medication treatment intake.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent.
2. Negative pregnancy test before first dose.
3. Female and male participants willing to use acceptable and highly effective methods of birth control.
4. The following criteria must be fulfilled by participants:

   1. Require daily analgesia for their pain,
   2. Diagnosed with active cancer,
   3. Receiving daily opioid treatment at doses not higher than 90 mg oral morphine or its equivalent (World Health Organization Step II and Step III analgesics) for an appropriate length of time,
   4. Participants must be dissatisfied with their current pain treatment,
   5. Participants must be suffering from cancer-related but not cancer therapy-related chronic pain for a period of 4 weeks or more prior to enrollment.
5. Eastern Cooperation Oncology Group (ECOG) score 2 or below.
6. Average pain intensity over the last 24 hours of 5 or more calculated from the pain assessments recorded during the last 3 days prior to randomization.
7. Compliance with the use of the electronic diary defined as at least 3 out of 4 of the 24 hour Numerical Rating Scale entries available during the last 4 days prior to and including the day of allocation to treatment.

Exclusion Criteria:

1. Evidence of ongoing alcohol and or drug abuse and/or a history of alcohol and/or drug abuse within the last 2 years.
2. A clinically significant disease other than cancer which in the investigator's opinion may affect efficacy or safety assessments e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, infectious disease, psychiatric (resulting in disorientation, memory impairment or inability to report accurately) or metabolic disorders.
3. Any gastrointestinal disorder that could affect the absorption and/or elimination of Investigational Medicinal Product.
4. Any planned major surgery during the trial.
5. Known to or suspected of not being able to comply with the trial protocol and the use of Investigational Medicinal Product.
6. History of seizure disorder and/or epilepsy or any condition associated with a significant risk of seizure or epilepsy.
7. Known history and/or presence of cerebral tumor or cerebral metastases.
8. Moderate to severe hepatic impairment corresponding to Child-Pugh classification B and C. Impaired hepatic cellular integrity indicated by aspartate transaminase or alanine transaminase greater than 3 times the upper limit of normal at the Enrollment Visit.
9. Inadequate baseline bone marrow reserve with a white blood cell count below 2000/µL, a platelet count 100 000/µL or less, and a hemoglobin level below 8 g/dL at the Enrollment Visit.
10. Impaired renal function. Creatinine clearance less than 60 mL per minute(as per amendment 45 mL per minute) at the Enrollment Visit (calculated from the Cockcroft-Gault formula).
11. Forbidden concomitant medications
12. Uncontrolled hypertension
13. Clinically relevant history of hypersensitivity, allergy or contraindications to opioid medication or any of the excipients of morphine sulfate (Prolonged Released or Immediate Release), or cebranopadol film-coated tablets.
14. Chronic hepatitis B or C, or human immunodeficiency virus (HIV) known by history, or presence of active hepatitis B or C within the 3 months before the Enrollment Visit.
15. History of torsade de pointes and/or presence of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, or bradycardia).
16. Marked prolongation of corrected QT interval (Fridericia) (greater than 450 milliseconds) at the Enrollment Visit.
17. Employees of the sponsor, investigator, or trial site or family members of the employees, sponsor, or investigator.
18. Concurrent participation in another trial or planning to be enrolled in another clinical trial (i.e., administration of experimental treatment in another clinical trial) during the course of this trial.
19. Previous participation in this or other trials with cebranopadol with the following exceptions:

    * Participants who failed enrollment in this trial only because of exclusion criterion 10, and who may now be eligible can be re-enrolled.
    * Participants who failed enrollment due to technical failure of equipment (e.g., ECG machine and e-diary device).
20. Participant has received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment.
21. Currently not receiving opioid treatment for cancer-related pain at the enrollment visit (i.e., opioid naïve).

Primary outcomes:
measure: Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Per Protocol Set)
timeFrame: The last 2 weeks of the expected 6-week treatment period.
measure: Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Full Analysis Set)
timeFrame: The last 2 weeks of the expected 6-week treatment period.
Secondary outcomes:
measure: Proportion of Participants With Clinically Relevant Pain Reduction at the End of the Maintenance Period
timeFrame: The last 2 weeks of the expected 6-week treatment period.
Other outcomes:
measure: Change in Weekly Mean of the Daily Average Pain Intensity Score From Baseline
timeFrame: Baseline; last 2 weeks of the expected 6-week treatment period
measure: Response Rate to Treatment
timeFrame: Baseline; last 2 weeks of the expected 6-week treatment period
measure: Overall Score of the Neuropathic Pain Symptom Inventory (NPSI)
timeFrame: Baseline; End-of-Treatment Visit (Week 6)
measure: EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Weighted EQ-5D Health Status Index
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Visual Analog Scale (VAS) Score
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: Change in the Physical and Mental Component Scores From the Short Form 12® Health Survey (SF-12)
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: Patient Global Impression of Change (PGIC)
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: Clinical Global Impression of Change (CGIC)
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: Overall Score of the Patient Assessment of Constipation Symptoms (PAC-SYM)
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: Change in Weekly Mean of the Daily Worst Pain Intensity Score From Baseline
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
measure: Change From Baseline to End-of-Treatment Visit in Chronic Pain Sleep Inventory (CPSI) Scores
timeFrame: Baseline; End-of-Treatment Visit (6 weeks)
Locations:
city: Vienna
country: Austria
facility: AT004
city: Brussels
country: Belgium
facility: BE005
city: Ottignies
country: Belgium
facility: BE002
city: Sint-Niklaas
country: Belgium
facility: BE001
city: Shumen
country: Bulgaria
facility: BG001
city: Sofia
country: Bulgaria
facility: BG008
city: Sofia
country: Bulgaria
facility: BG003
city: Sofia
country: Bulgaria
facility: BG006
city: Sofia
country: Bulgaria
facility: BG007
city: Varna
country: Bulgaria
facility: BG004
city: Vratsa
country: Bulgaria
facility: BG005
city: Temuco
country: Chile
facility: CL005
city: Zagreb
country: Croatia
facility: HR001
city: Aalborg
country: Denmark
facility: DK006
city: Herlev
country: Denmark
facility: DK004
city: Böhlen
country: Germany
facility: DE008
city: München
country: Germany
facility: DE010
city: Gyula
country: Hungary
facility: HU004
city: Miskolc
country: Hungary
facility: HU002
city: Nyiregyhaza
country: Hungary
facility: HU011
city: Bydgoszcz
country: Poland
facility: PL008
city: Będzin
country: Poland
facility: PL012
city: Chorzów
country: Poland
facility: PL013
city: Dąbrowa Górnicza
country: Poland
facility: PL014
city: Gdansk
country: Poland
facility: PL003
city: Gliwice
country: Poland
facility: PL010
city: Warszawa
country: Poland
facility: PL015
city: Wloclawek
country: Poland
facility: PL002
city: Brasov
country: Romania
facility: RO001
city: Cluj-Napoca
country: Romania
facility: RO002
city: Constanta
country: Romania
facility: RO009
city: Craiova
country: Romania
facility: RO011
city: Belgrade
country: Serbia
facility: RS001
city: Belgrade
country: Serbia
facility: RS003
city: Sremska Kamenica
country: Serbia
facility: RS002
city: Zrenjanin
country: Serbia
facility: RS005
city: Bratislava
country: Slovakia
facility: SK007
city: Bratislava
country: Slovakia
facility: SK004
city: Prešov
country: Slovakia
facility: SK001
city: Pruské
country: Slovakia
facility: SK005
city: Barcelona
country: Spain
facility: ES012
city: Leeds
country: United Kingdom
facility: UK004
Study officials:
affiliation: Grünenthal GmbH
name: Director Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Eerdekens MH, Kapanadze S, Koch ED, Kralidis G, Volkers G, Ahmedzai SH, Meissner W. Cancer-related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial. Eur J Pain. 2019 Mar;23(3):577-588. doi: 10.1002/ejp.1331. Epub 2019 Jan 9.