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CORAL - Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer (CORAL)

This study has been terminated.
(low accrual that made the study no longer feasible/ decision not related to safety and efficacy)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01964378
First Posted: October 17, 2013
Last Update Posted: November 6, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Grünenthal GmbH
  Purpose
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.

Condition Intervention Phase
Pain Neoplasms Chronic Pain Drug: Cebranopadol Drug: Morphine Prolonged Release Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.

Resource links provided by NLM:


Further study details as provided by Grünenthal GmbH:

Primary Outcome Measures:
  • Average amount of daily rescue medication at the end of the maintenance period. [ Time Frame: The last two weeks of the expected 6 week treatment period. ]
    Morphine sulfate immediate release 10 mg tablets will be supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol will be allowed during the maintenance period. The daily use of morphine sulfate 10 mg immediate release tablets will be documented by each participant in the trial. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period. It will be analyzed by means of a mixed-effects model for repeated measures (MMRM).


Secondary Outcome Measures:
  • Proportion of participants with clinically relevant pain reduction at the end of the maintenance period. [ Time Frame: The last two weeks of the expected 6 week treatment period. ]
    For this assessment, each participant is to indicate the level of pain on an 11-point Numerical Rating Scale, where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The participants enter their pain intensity in their diary on a daily basis. The pain intensity score in the 14 days prior to the final evaluation in the maintenance period will be compared with the baseline, the baseline pain intensity will be calculated based on the 3 days prior to treatment allocation.


Other Outcome Measures:
  • Change in weekly mean of the daily Average Pain Intensity Score from Baseline [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    Participants will be asked: "Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours." every day in the morning. They will score their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The weekly mean value of the 24 h average pain intensity will be calculated as a mean score of these daily entries of average pain intensity for each trial week.

  • Response rate to treatment [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    Pain intensity will be recorded daily by each participant in the morning on an 11-point Numerical Rating Scale, ranging from 0 (no pain) to 10 (worst imaginable pain). From this the weekly average 24-hour pain intensity will be calculated. The number of participants with a 0, 10, 20, 30, up to a 100% reduction in weekly mean pain intensity will be reported over each week and over the last two weeks of the maintenance period.

  • Overall Score of the Neuropathic Pain Symptom Inventory (NPSI) [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    The participant with neuropathic pain (determined by the completion of the DN4 [Douleur Neuropathique] at enrollment) will rate their symptoms of neuropathic pain on Neuropathic Pain Symptom Inventory (NPSI). Ten out of 12 questions are answered on an 11-point scale 0 (no symptom present) to 10 (worst imaginable). Two out of 12 questions are answered by selecting one of 5 possible responses. Mean scores of NPSI will be calculated.

  • EuroQol-5 Dimension (EQ-5D) Health Questionnaire over time [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]

    The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. The participants will answer 5 questions on 5 dimensions of their health related quality of life: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each question has 3 possible answers reflecting 3 levels of impact on the quality of life.

    Participants will also rate their current health state on the visual analogue scale (VAS; 0 = worst imaginable health state and 100 = best imaginable health state). A positive change indicates an improvement.


  • Change in the Physical and Mental Component Scores from the Short Form 12® Health Survey (SF-12). [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    The Physical and Mental Component Scores are calculated from the responses by participants to 12 questions. These 12 questions cover 8 domains, (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role participation with emotional health problems, and mental health) that a participant was asked to rate over the last week. Questions are scored on a Likert-scale. An overall value for the physical and mental component summary is calculated. A positive change will indicate an improvement

  • Patient global impression of change (PGIC) [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period compared to his condition prior to the start of treatment. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.

  • Clinical global impression of change (CGIC) [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change in patient's condition over the treatment period as compared to patient's condition prior to the start of treatment. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.

  • Overall score of the Patient Assessment of Constipation Symptoms (PAC-SYM) [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assesses the severity of symptoms of constipation during past 2 weeks. There are 3 subscales with 4 items on Abdominal symptoms, 3 on rectal symptoms and 5 on stool symptoms. Each item is rated on a 5-point Likert scale, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe. If the changes in the overall or subscale scores are positive then there is a worsening in symptoms associated with constipation.

  • Change in weekly mean of the daily Worst Pain Intensity Score from Baseline [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]
    Participants will be asked: "Please rate your pain by selecting the one number that best describes your pain at its worst during the last 24 hours." every day in the morning. They will score their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The weekly mean value of the 24 h worst pain intensity will be calculated as a mean score of these daily entries of worst pain intensity for each trial week. A positive change will indicate an improvement, whilst a negative change will indicate a worsening of pain.


Enrollment: 200
Study Start Date: November 2013
Study Completion Date: October 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cebranopadol
Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day.
Drug: Cebranopadol
Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.
Other Name: GRT6005
Active Comparator: Morphine Prolonged Release
Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day.
Drug: Morphine Prolonged Release
Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.

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 for 44 days. Initially participants will be titrated after 2 and then every 4 days to a morphine or cebranopadol dose that provides adequate analgesia and is tolerated. The titration period is planned to last 16 days. Thereafter the dose of morphine prolonged release 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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 QTcF (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).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01964378


  Show 43 Study Locations
Sponsors and Collaborators
Grünenthal GmbH
Investigators
Study Director: Director Clinical Trials Grünenthal GmbH
  More Information

Responsible Party: Grünenthal GmbH
ClinicalTrials.gov Identifier: NCT01964378     History of Changes
Other Study ID Numbers: KF6005/07
2012‐001316‐35 ( EudraCT Number )
U1111-1143-1808 ( Other Identifier: World Health Organization )
First Submitted: October 7, 2013
First Posted: October 17, 2013
Last Update Posted: November 6, 2015
Last Verified: November 2015

Keywords provided by Grünenthal GmbH:
cancer-related pain
neuropathic related cancer pain
morphine
cebranopadol (GRT6005)
Numerical Rating Scale

Additional relevant MeSH terms:
Chronic Pain
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Morphine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents