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

Pain Clinical Trial

— CORAL  

Official title:

Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01964378
• Other study ID #: KF6005/07
• Secondary ID: 2012-001316-35U1
• Status: Terminated
• Phase: Phase 3
• Start date: October 29, 2013
• Est. completion date: October 16, 2015

Study information

• Verified date: July 2021
• Source: Tris Pharma, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 200
• Est. completion date: October 16, 2015
• Est. primary completion date: October 16, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Chronic Pain
• Neoplasms
• Pain

Intervention

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.
• 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.

Locations

Country	Name	City	State
Austria	AT004	Vienna
Belgium	BE005	Brussels
Belgium	BE002	Ottignies
Belgium	BE001	Sint-Niklaas
Bulgaria	BG001	Shumen
Bulgaria	BG003	Sofia
Bulgaria	BG006	Sofia
Bulgaria	BG007	Sofia
Bulgaria	BG008	Sofia
Bulgaria	BG004	Varna
Bulgaria	BG005	Vratsa
Chile	CL005	Temuco
Croatia	HR001	Zagreb
Denmark	DK006	Aalborg
Denmark	DK004	Herlev
Germany	DE008	Böhlen
Germany	DE010	München
Hungary	HU004	Gyula
Hungary	HU002	Miskolc
Hungary	HU011	Nyiregyhaza
Poland	PL012	Bedzin
Poland	PL008	Bydgoszcz
Poland	PL013	Chorzów
Poland	PL014	Dabrowa Górnicza
Poland	PL003	Gdansk
Poland	PL010	Gliwice
Poland	PL015	Warszawa
Poland	PL002	Wloclawek
Romania	RO001	Brasov
Romania	RO002	Cluj-Napoca
Romania	RO009	Constanta
Romania	RO011	Craiova
Serbia	RS001	Belgrade
Serbia	RS003	Belgrade
Serbia	RS002	Sremska Kamenica
Serbia	RS005	Zrenjanin
Slovakia	SK004	Bratislava
Slovakia	SK007	Bratislava
Slovakia	SK001	Prešov
Slovakia	SK005	Pruské
Spain	ES012	Barcelona
United Kingdom	UK004	Leeds

Sponsors (1)

Lead Sponsor	Collaborator
Tris Pharma, Inc.

Countries where clinical trial is conducted

Austria,  Belgium,  Bulgaria,  Chile,  Croatia,  Denmark,  Germany,  Hungary,  Poland,  Romania,  Serbia,  Slovakia,  Spain,  United Kingdom, 

References & Publications (1)

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( — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Weekly Mean of the Daily Average Pain Intensity Score From Baseline	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.	Baseline; last 2 weeks of the expected 6-week treatment period
Other	Response Rate to Treatment	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 2 weeks of the maintenance period.	Baseline; last 2 weeks of the expected 6-week treatment period
Other	Overall Score of the Neuropathic Pain Symptom Inventory (NPSI)	Participants with neuropathic pain (determined by the completion of the Douleur Neuropathique En 4 Questions [DN4] questionnaire at allocation) rated their symptoms of neuropathic pain on the Neuropathic Pain Symptom Inventory (NPSI). Ten out of 12 questions were answered on an 11-point scale 0 (no symptom present) to 10 (worst imaginable); 2 out of 12 questions assessed the duration of spontaneous pain and the number of pain attacks and were answered by selecting 1 of 5 possible responses.; Mean scores of NPSI were calculated. The overall NPSI score was calculated by the summation of all responses in the ranges between 0 (all symptoms absent) and 1 (all symptoms present and at the worst intensity). A negative change indicates that the intensity of all the neuropathic symptom components have decreased since the start of treatment.	Baseline; End-of-Treatment Visit (Week 6)
Other	EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Weighted EQ-5D Health Status Index	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. The weighted EQ-5D health status index values are derived and reported as change from baseline. The responses to the 5 EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score (with 1 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group.; A positive change indicates an improvement.	Baseline; End-of-Treatment Visit (6 weeks)
Other	EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Visual Analog Scale (VAS) Score	The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.	Baseline; End-of-Treatment Visit (6 weeks)
Other	Change in the Physical and Mental Component Scores From the Short Form 12® Health Survey (SF-12)	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.; The Physical and Mental Component Scores were not derived as the trial was terminated.; Changes in the individual item scores are therefore reported. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state.; If the values are positive there was an improvement. The higher the value the greater the improvement.	Baseline; End-of-Treatment Visit (6 weeks)
Other	Patient Global Impression of Change (PGIC)	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.	Baseline; End-of-Treatment Visit (6 weeks)
Other	Clinical Global Impression of Change (CGIC)	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.	Baseline; End-of-Treatment Visit (6 weeks)
Other	Overall Score of the Patient Assessment of Constipation Symptoms (PAC-SYM)	The PAC-SYM is a 12-item self-administered questionnaire that assesses the severity of constipation-related symptoms during past 2 weeks. Items are rated on a 5-point Likert scale, where 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.The PAC-SYM contains 3 subscales: stool symptoms (5 items), abdominal symptoms (4 items), rectal symptoms (3 items). If at least 6 items are assessed, the PAC-SYM overall score is calculated as the sum of the scores of all non-missing items divided by number of non-missing items. The minimum overall score is 0, the maximum overall score is 4. If more than 6 items are missing, no overall score is calculated. Changes from baseline for the overall score are presented. If the changes in the overall (or subscale) scores are positive then there is a worsening in symptoms associated with constipation.	Baseline; End-of-Treatment Visit (6 weeks)
Other	Change in Weekly Mean of the Daily Worst Pain Intensity Score From Baseline	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 from baseline will indicate a worsening, whilst a negative change will indicate an improvement of pain.	Baseline; End-of-Treatment Visit (6 weeks)
Other	Change From Baseline to End-of-Treatment Visit in Chronic Pain Sleep Inventory (CPSI) Scores	The CPSI measures 5 items on 100-mm visual analog scales: trouble falling asleep (CPSI1), needing sleep medication (CPSI2), awakened by pain during the night (CPSI3) and in the morning (CPSI4) [all with anchors for 0 = never and 100 = always], and overall quality of sleep (CPSI5) [with anchors of 0 = very poor and 100 = excellent]. The sleep problem index is the sum of items CPSI1, CPSI3 and CPSI4. The minimum sleep problem index is 0 mm, the maximum 300 mm, the higher the worse. For the overall quality of sleep, minimum and maximum are 0 and 100 mm, the higher the better. A decrease in the sleep problem index indicates an improvement as does an increase in the overall quality of sleep. Changes from baseline to the End-of-Treatment Visit of the Maintenance Phase (scheduled for Week 6) were calculated.	Baseline; End-of-Treatment Visit (6 weeks)
Primary	Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Per Protocol Set)	Morphine sulfate immediate release (IR) 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.	The last 2 weeks of the expected 6-week treatment period.
Primary	Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Full Analysis Set)	Morphine sulfate IR 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.	The last 2 weeks of the expected 6-week treatment period.
Secondary	Proportion of Participants With Clinically Relevant Pain Reduction at the End of the Maintenance Period	Each participant indicated the level of pain 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 participants entered their pain intensity in their diary on a daily basis. The pain intensity score in the 2 weeks prior to the final evaluation in the maintenance period was compared with the baseline, the baseline pain intensity was calculated based on the 3 days prior to treatment allocation.; The definition of a clinically relevant pain reduction (yes/no) was the presence of at least 1 of the 3 following conditions: Average pain intensity (i.e., average of the 24-hour pain intensities over the last 2 weeks of the Maintenance Phase) of less than 4 points on the 11-point NRS, or; Reduction in average pain intensity by at least 30% (compared to the baseline assessment), or; Reduction in average pain intensity by at least 2 points (compared to the baseline assessment).	The last 2 weeks of the expected 6-week treatment period.