CORAL XT - Open-label Extension Trial of the CORAL Trial

• Sponsor: Tris Pharma, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02031432
• Collaborator: (none)
• Enrollment: 76
• Locations: 22
• Arm: 1
• Actual Duration (Months): 28.5
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial was to find out how well cebranopadol is tolerated and how often, and which, adverse reactions occur when it is taken every day for a longer period of time. In addition, information was collected how cebranopadol affects pain and well-being in patients suffering from cancer-related pain.

Condition or Disease	Intervention/Treatment	Phase
Pain; Neoplasms; Chronic Pain	Drug: Cebranopadol	Phase 3

Detailed Description

The trial consisted of 3 phases: Titration Phase, Maintenance Phase, and Follow-Up. The total duration of the trial was approximately 28 weeks for each individual participant, including the Follow-up. The participants received cebranopadol for a maximum of approximately 26 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multi-site Trial to Describe the Safety and Tolerability of Oral Cebranopadol Administered for 26 Weeks in Subjects With Cancer-related Pain Who Have Completed Treatment in the KF6005/07 Trial
• Actual Study Start Date: Dec 18, 2013
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: May 3, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cebranopadol Cebranopadol 200 µg to 1000 µg per taken taken once a day in the morning. Allowed dose levels in the Maintenance Phase were 200, 400, 600, 800, or 1000 µg per day.	Drug: Cebranopadol; Film-coated tablet; strengths: 200, 400, or 600 µg; Other Names: GRT6005

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Event (TEAEs) [Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow up after the last dose)]

   The safety of cebranopadol was assessed by the number of participants with treatment emergent adverse events (TEAEs). A TEAE was any adverse event that occurred after the first administration of investigational medicinal product (IMP), i.e., cebranopadol in this study. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs.

Secondary Outcome Measures

1. Intensity of Treatment Emergent Adverse Events [Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow-up after the last dose)]

   A Treatment Emergent Adverse Event (TEAE) was defined as any Adverse Event (AE) that occurred on or after the first intake of cebranopadol or a pretreatment AE which worsened during the treatment period. TEAEs were classified by the investigator as falling into 1 of 3 categories: Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the participant is distracted. Moderate: Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration. Severe: Symptoms which affect usual daily activity. For TEAE where the intensity changed over time, the maximum intensity observed during the whole duration of the adverse event was documented.

2. Changes From Baseline in the Average Pain Intensity in the Last Week During the Treatment Period [Baseline Visit (Day 1) to End of Treatment Visit (up to 26 weeks).]

   Participants were asked "Please rate your pain by selecting the one number that best describes your pain on average during the last week." and scored their average pain intensity during the last week of the treatment period 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 absolute change from baseline for the average pain intensity during the last week was determined for all participants that scored their pain intensities. A mean value for all participants was calculated.

Other Outcome Measures

1. Outcome of Treatment Emergent Adverse Events (TEAE) [Baseline (Day 2) to End of trial (i.e., up to Week 28)]

   The outcome of a TEAE was classified into 1 of the following 6 categories by the investigator, i.e. Recovered/Resolved. Recovered/Resolved with sequelae. Fatal Recovering/Resolving. Not recovered/Not resolved. Unknown (e.g., because the participant is lost to follow up).

2. Time to Onset of Treatment Emergent Adverse Events (TEAEs) [Baseline (Day 2) to End of trial (up to Week 28)]

   The median time, in days, from the start of the open-label cebranopadol treatment to the start day of the treatment emergent adverse event (TEAE).

3. Duration of Treatment Emergent Adverse Events (TEAEs) [Baseline (Day 2) to End of trial (up to Week 28)]

   An adverse event is any untoward medical occurrence attributed to cebranopadol. Duration of Adverse Event was calculated as stop date minus start date plus 1 for non-missing and partial dates.

4. Causal Relationship of Treatment Emergent Adverse Events (TEAEs) [Baseline (Day 2) to End of trial (up to Week 28)]

   The causality of TEAEs was assessed by the investigator as falling into 1 of the following 7 categories: Conditional/Unclassified, Unassessable/Unclassifiable, Not related, Unlikely, Possible, Probable/likely, or Certain. The numbers of TEAEs per category are presented.

5. Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) [Baseline (Day 2) to End of trial (up to Week 28)]

   The countermeasure of a Treatment Emergent Adverse Event (TEAE) was classified by the investigator as being a study medication-related countermeasure and based on non-study medication countermeasures. Non-study medication related countermeasures were categorized as being one of the following: No countermeasure given; A newly started medication or change in dose or route of application of a concomitant medication due to the AE; Other countermeasures, e.g., physical therapy, surgery. Study medication-related countermeasures were categorized as being one of the following: Dose not changed; Dose reduced; Drug interrupted; Trial discontinuation. Absolute numbers are per category reported.

6. Number of Participants With Treatment Emergent Adverse Events (TEAEs) Related to Cebranopadol [Baseline (Day 2) to End of trial (up to Week 28)]

   Only participants with TEAEs which were assessed by the investigator as falling into one of the 3 categories of causality (Possible, Probable/likely, or Certain) were summarized. The initial breakdown planned based on intensity, outcome, time to onset, duration, and countermeasures was not performed and is therefore not reported.

7. Columbia-Suicide Severity Rating Scale (C-SSRS) Scores [Baseline (Day 1) to End of trial (up to Week 28)]

   The C-SSRS was administered by a clinician who had been certified to administer the C-SSRS at each visit. Suicidal ideation is classified on a 5-item scale (where 1 = Wish to be dead, 2 = Non-specific active suicidal thoughts, 3 = Active Suicidal Ideation with any methods (not plan) without intent to act, 4 = Active Suicidal Ideation with some intent to act, without specific plan, 5 = Active suicidal ideation with a specific plan and intent). The number of participants with suicidal ideation at baseline is presented below for categories with at least 1 participant.

8. Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline [Baseline (Day 1); End of Treatment (up to Week 26)]

   The CPSI was completed by the participants. It measures 5 items, all on a 100-mm visual analog scale: Participant's assessment of Sleep Problem Index subscores and need for sleep medication (the lower the score the better): (1) Trouble falling asleep (0 = never; 100 = always); (2) Needing sleep medication to help fall asleep (0 = never, 100 = always); (3) Awakened by pain during the night (0 = never, 100 = always); and (4) Awakened by pain in the morning (0 = never, 100 = always). The Sleep Problem Index is the sum of items (1), (3), and (4) with a maximum score of 100 indicating maximum sleep problems. Participant's assessment of the Overall Quality of Sleep (the higher the score the better): (5) Overall quality of sleep (0 = very poor, 100 = excellent).

9. Weekly Means of Daily Average Pain Intensity During the First Month of Treatment [Baseline (Day 1); Titration Weeks 1 and 2; Maintenance Weeks 1 and 2]

   Participants were 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 during the first month of treatment (comprising Titration Weeks 1 and 2 and Maintenance Weeks 1 and 2). They scored 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-hour average pain intensity was calculated as a mean score of these daily entries of average pain intensity for each week.

10. Worst Pain Intensity in the Last Week of Treatment (Week 26) [Baseline (Day 1); End of Treatment (Week 26)]

    Participants were asked: "Please rate your pain by selecting the one number that best describes your pain at its worst during the last week." at some of the visits during the treatment period. They scored 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 mean scores of the worst pain intensity were calculated for all participants. Results for baseline and Week 26 are presented.

11. Weekly Average Number of Breakthrough Pain Episodes [Baseline (Day 1); End of Treatment (Week 26)]

    The number of episodes of breakthrough pain during the past week was planned to be collected. However, for some participants, the intensity of breakthrough pain for the past week has been collected instead of the incidence of breakthrough pain events. Since the values of the intensity of breakthrough pain were much higher (maximum of up to 99) than the frequency of pain events, the mean is skewed and cannot be interpreted. The median for the weekly average number of breakthrough pain episodes is less influenced by these values and is reported below.

12. Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) [Baseline (Day 1); Weeks 2, 6, 14, 18; End of Treatment (up to Week 26)]

    Participants with neuropathic pain (determined by the completion of the DN4 [Douleur Neuropathique] questionnaire at enrollment) rated their symptoms of neuropathic pain using the NPSI. Ten out of 12 questions (Q1-3, 5, 6, 8-12) are answered on an 11-point numerical scale (NRS) ranging from 0 (no symptom present) to 10 (worst imaginable). The NPSI Total Score was calculated as the sum of the 10 single items scored on the 11-point NRS divided by 100. The mean score is reported on a scale of 0 (no neuropathic pain components present) to 1 (all neuropathic pain components have the maximum imaginable intensity).

13. EuroQol-5 Dimension (EQ-5D) Health Status Index Outcome [Baseline (Day 1); End of Treatment (up to Week 26)]

    Participants answered 5 questions on the 5 dimensions of the EuroQol-5 Dimension Health Questionnaire: 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. Each dimension was assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the 5 EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D Health Status Index score between 0 to 1 (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.

14. EuroQol-5 Dimension (EQ-5D) Health Questionnaire - Visual Analog Scale (VAS) [Baseline (Day 1); End of Treatment (up to Week 26)]

    The EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant-rated scale where a single value is ticked for "Your own health state today" on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.

15. Patient Global Impression of Change (PGIC) [Baseline (Day 1); End of Treatment (up to Week 26)]

    In the PGIC, participants indicates the perceived change over the treatment period compared to their condition prior to the start of treatment. Participants are requested to choose 1 of 7 categories. Scores range from "very much improved" to "very much worse". The frequency of responses per category are provided.

16. Clinical Global Impression of Change (CGIC) [Baseline (Day 1); End of Treatment Visit (up to Week 26)]

    For the CGIC assessment, the clinician indicates the perceived change in the patient's condition over the treatment period as compared to the patient's condition prior to the start of treatment. The clinician is requested to choose 1 of 7 categories. Categories range from "very much improved" to "very much worse".

17. Use of On-demand Opioid Analgesic Medication [From Day 3 to End of Treatment (up to Week 26) (13 time points)]

    Participants reported the opioid type and amount of an opioid in mg/day used to relieve their breakthrough pain over the time period in the study. The average number of units of on-demand opioid medication administered during the previous day (reported on Day 3) and during the last 3 days (reported at all other visits) were documented. The number of units of on-demand opioid medication administered during the Treatment Period is summarized descriptively over the treatment period.

18. Mean Equipotency Ratio of Morphine Sulfate Prolonged Release Compared to Cebranopadol. [Baseline (Day 1); End of first month of treatment]

    For those participants, who received morphine prolonged release in the CORAL trial (KF6005/07, NCT01964378) and were, thus, switched from morphine prolonged release to cebranopadol in the CORAL XT trial, the equianalgesic doses of morphine prolonged release and cebranopadol was identified.

19. Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores [From Baseline (Day 1) through to End of treatment (up to Week 26) (9 time points)]

    The investigator scores the ECOG performance status for a participant on a 6-point categorical scale as follows: 0 indicates that a participant is "fully active, able to carry on all pre-disease performance without restriction." 1 indicates that a participant is "restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work." 2 indicates that a participant is "ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours." 3 indicates that a participant is "capable of only limited selfcare, confined to bed or chair more than 50% of waking hours." 4 indicates that a participant is "completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair." 5 indicates that a participant is "dead". Mean ECOG performance status scores are calculated for the number of participants with data available.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent signed indicating that the participant understands the purpose of and procedures required for the trial and is willing to participate in the trial.

• Participants must be at least 18 years of age at the Enrollment Visit.

• Women of childbearing potential must have a negative pregnancy test at enrollment and must not be lactating at the Enrollment Visit.

• Participants must be willing to use medically acceptable and highly effective methods of birth control.

• Participants who have completed treatment in KF6005/07 and are still in need of around-the-clock pain analgesia with strong opioids.

Exclusion Criteria:

• The participant has a clinically significant disease or condition other than cancer which in the investigator's opinion may affect efficacy or safety assessments.

• Known to or suspected of not being able to comply with the protocol and the use of cebranopadol.

• Participants taking forbidden concomitant medications or not being able to follow the rules of use of concomitant treatment.

• History of torsade de pointes and/or presence of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, bradycardia).

• Concurrent participation in another trial (except participation in KF6005/07) 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, or previous participation in this trial.

• Employees of the sponsor, investigator, or trial site or family members of the employees, sponsor, or investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AT004	Vienna		Austria	1090
2	BE001	Sint-Niklaas		Belgium	9100
3	BG001	Shumen		Bulgaria	9700
4	BG008	Sofia		Bulgaria	1330
5	BG003	Sofia		Bulgaria	1407
6	BG004	Sofia		Bulgaria	1407
7	DK006	Aalborg		Denmark	9000
8	DK004	Herlev		Denmark	2730
9	DE008	Böhlen		Germany	4564
10	DE010	Munich		Germany	81377
11	HU011	Nyiregyhaza		Hungary	4400
12	PL012	Będzin		Poland	42-500
13	PL014	Dąbrowa Górnicza		Poland	41-300
14	PL003	Gdansk		Poland	80-208
15	PL010	Gliwice		Poland	44-100
16	RO002	Cluj-Napoca		Romania	400015
17	RS003	Belgrade		Serbia	11000
18	RS002	Sremska Kamenica		Serbia	21204
19	RS005	Zrenjanin		Serbia	23000
20	SK004	Bratislava		Slovakia	851 07
21	SK001	Presov		Slovakia	08001
22	SK005	Pruské		Slovakia	018 52

Sponsors and Collaborators

• Tris Pharma, Inc.

Investigators

• Study Director: Director Clinical Trials, Grünenthal GmbH

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tris Pharma, Inc.
• ClinicalTrials.gov Identifier: NCT02031432
• Other Study ID Numbers: KF6005/09; 2013-001877-26; U1111-1144-0778
• First Posted: Jan 9, 2014
• Last Update Posted: Jul 15, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tris Pharma, Inc.: cancer-related pain; cebranopadol
• Additional relevant MeSH terms: Chronic Pain

Study Results

Participant Flow

Recruitment Details	The first participant was enrolled on the 18 Dec 2013 (first dose taken on the 19 Dec 2013 received) and the last participant completed the trial on the 03 May 2016 (last dose taken on the 12 Apr 2016). All participants in this trial completed the maintenance period in the KF6005/07 (NCT01964378) trial.
Pre-assignment Detail	Participants who completed treatment in KF6005/07 and who were still in need of around-the-clock pain analgesia with strong opioids directly entered the KF6005/09 trial from the KF6005/07 trial. Seventy-six participants (37 previously on cebranopadol and 39 subjects previously on morphine treatment) were enrolled in this trial.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol: Cebranopadol 200 µg to 1000 µg per day taken once a day in the morning.
Period Title: Overall Study
STARTED	76
Completing the Titration Phase	67
Completing the Treatment	39
COMPLETED	38
NOT COMPLETED	38

Baseline Characteristics

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol: Cebranopadol 200 µg to 1000 µg per day taken once a day in the morning.
Overall Participants	76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (9.81)
Age, Customized (Count of Participants)
Below 18 years	0 0%
From 18 to less than 65 years	43 56.6%
From 65 to less than 85 years	33 43.4%
Above 85 years	0 0%
Sex: Female, Male (Count of Participants)
Female	32 42.1%
Male	44 57.9%
Race/Ethnicity, Customized (Count of Participants)
White	76 100%
Region of Enrollment (participants) [Number]
Romania	2 2.6%
Hungary	2 2.6%
Austria	3 3.9%
Belgium	1 1.3%
Denmark	2 2.6%
Poland	17 22.4%
Slovakia	21 27.6%
Bulgaria	4 5.3%
Serbia	4 5.3%
Germany	20 26.3%
DN4 Neuropathic Pain at start of KF6005/07 (participants) [Number]
DN4 positive	21 27.6%
DN4 negative	55 72.4%
Height (meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meter]	1.684 (0.0844)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	72 (14.04)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.36 (4.5)
Weekly means of average daily pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.96 (1.89)
Weekly means of worst daily pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.95 (2.447)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Event (TEAEs)
Description	The safety of cebranopadol was assessed by the number of participants with treatment emergent adverse events (TEAEs). A TEAE was any adverse event that occurred after the first administration of investigational medicinal product (IMP), i.e., cebranopadol in this study. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs.
Time Frame	Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow up after the last dose)

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Count of Participants [Participants]	64 84.2%

2. Secondary Outcome

Title	Intensity of Treatment Emergent Adverse Events
Description	A Treatment Emergent Adverse Event (TEAE) was defined as any Adverse Event (AE) that occurred on or after the first intake of cebranopadol or a pretreatment AE which worsened during the treatment period. TEAEs were classified by the investigator as falling into 1 of 3 categories: Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the participant is distracted. Moderate: Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration. Severe: Symptoms which affect usual daily activity. For TEAE where the intensity changed over time, the maximum intensity observed during the whole duration of the adverse event was documented.
Time Frame	Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow-up after the last dose)

Outcome Measure Data

Analysis Population Description

Safety Set; event-based analysis

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Measure Number of TEAEs	661
Mild intensity	242
Moderate intensity	300
Severe intensity	119

3. Secondary Outcome

Title	Changes From Baseline in the Average Pain Intensity in the Last Week During the Treatment Period
Description	Participants were asked "Please rate your pain by selecting the one number that best describes your pain on average during the last week." and scored their average pain intensity during the last week of the treatment period 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 absolute change from baseline for the average pain intensity during the last week was determined for all participants that scored their pain intensities. A mean value for all participants was calculated.
Time Frame	Baseline Visit (Day 1) to End of Treatment Visit (up to 26 weeks).

Outcome Measure Data

Analysis Population Description

Safety Set - participants with data available

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	59
Mean (Standard Deviation) [units on a scale]	0.8 (2.14)

4. Other Pre-specified Outcome

Title	Outcome of Treatment Emergent Adverse Events (TEAE)
Description	The outcome of a TEAE was classified into 1 of the following 6 categories by the investigator, i.e. Recovered/Resolved. Recovered/Resolved with sequelae. Fatal Recovering/Resolving. Not recovered/Not resolved. Unknown (e.g., because the participant is lost to follow up).
Time Frame	Baseline (Day 2) to End of trial (i.e., up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set; event-based analysis

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Measure Number of TEAEs	661
Recovered/resolved	349
Recovered/resolved with sequelae	11
Not recovered/not resolved	260
Recovering/resolving	14
Fatal	11
Unknown	16

5. Other Pre-specified Outcome

Title	Time to Onset of Treatment Emergent Adverse Events (TEAEs)
Description	The median time, in days, from the start of the open-label cebranopadol treatment to the start day of the treatment emergent adverse event (TEAE).
Time Frame	Baseline (Day 2) to End of trial (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set; event-based analysis for 661 TEAEs.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Measure Number of TEAEs	661
Median (Inter-Quartile Range) [days]	53.0

6. Other Pre-specified Outcome

Title	Duration of Treatment Emergent Adverse Events (TEAEs)
Description	An adverse event is any untoward medical occurrence attributed to cebranopadol. Duration of Adverse Event was calculated as stop date minus start date plus 1 for non-missing and partial dates.
Time Frame	Baseline (Day 2) to End of trial (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set; data available for 373 TEAEs (duration data for 288 of 661 TEAEs were not available)

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Measure Number of TEAEs	373
Median (Inter-Quartile Range) [days]	9.0

7. Other Pre-specified Outcome

Title	Causal Relationship of Treatment Emergent Adverse Events (TEAEs)
Description	The causality of TEAEs was assessed by the investigator as falling into 1 of the following 7 categories: Conditional/Unclassified, Unassessable/Unclassifiable, Not related, Unlikely, Possible, Probable/likely, or Certain. The numbers of TEAEs per category are presented.
Time Frame	Baseline (Day 2) to End of trial (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set; event-based analysis on 661 TEAEs

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Measure Number of TEAEs	661
Certainly Related	0
Possibly Related	42
Probably/Likely Related	7
Unlikely Related	37
Not Related	574
Unassessable/Unclassifiable	1
Conditional/Unclassifiable	0

8. Other Pre-specified Outcome

Title	Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs)
Description	The countermeasure of a Treatment Emergent Adverse Event (TEAE) was classified by the investigator as being a study medication-related countermeasure and based on non-study medication countermeasures. Non-study medication related countermeasures were categorized as being one of the following: No countermeasure given; A newly started medication or change in dose or route of application of a concomitant medication due to the AE; Other countermeasures, e.g., physical therapy, surgery. Study medication-related countermeasures were categorized as being one of the following: Dose not changed; Dose reduced; Drug interrupted; Trial discontinuation. Absolute numbers are per category reported.
Time Frame	Baseline (Day 2) to End of trial (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set; event-based analysis.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Measure Number of TEAEs	661
No countermeasure	361
Newly started medication	281
Other	19
Cebranopadol dose not changed as countermeasure	595
Cebranopadol dose reduced	5
Cebranopadol treatment interrupted	14
Cebranopadol withdrawn	23
Cebranopadol to dosing missing	24

9. Other Pre-specified Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) Related to Cebranopadol
Description	Only participants with TEAEs which were assessed by the investigator as falling into one of the 3 categories of causality (Possible, Probable/likely, or Certain) were summarized. The initial breakdown planned based on intensity, outcome, time to onset, duration, and countermeasures was not performed and is therefore not reported.
Time Frame	Baseline (Day 2) to End of trial (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Participants with related TEAEs	20 26.3%
Participants with related serious TEAEs	1 1.3%
Participants without related TEAEs	55 72.4%

10. Other Pre-specified Outcome

Title	Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
Description	The C-SSRS was administered by a clinician who had been certified to administer the C-SSRS at each visit. Suicidal ideation is classified on a 5-item scale (where 1 = Wish to be dead, 2 = Non-specific active suicidal thoughts, 3 = Active Suicidal Ideation with any methods (not plan) without intent to act, 4 = Active Suicidal Ideation with some intent to act, without specific plan, 5 = Active suicidal ideation with a specific plan and intent). The number of participants with suicidal ideation at baseline is presented below for categories with at least 1 participant.
Time Frame	Baseline (Day 1) to End of trial (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
No suicidal ideation or behaviour	74 97.4%
Wish to be dead	1 1.3%
Non-specific active suicidal thoughts	1 1.3%

11. Other Pre-specified Outcome

Title	Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline
Description	The CPSI was completed by the participants. It measures 5 items, all on a 100-mm visual analog scale: Participant's assessment of Sleep Problem Index subscores and need for sleep medication (the lower the score the better): (1) Trouble falling asleep (0 = never; 100 = always); (2) Needing sleep medication to help fall asleep (0 = never, 100 = always); (3) Awakened by pain during the night (0 = never, 100 = always); and (4) Awakened by pain in the morning (0 = never, 100 = always). The Sleep Problem Index is the sum of items (1), (3), and (4) with a maximum score of 100 indicating maximum sleep problems. Participant's assessment of the Overall Quality of Sleep (the higher the score the better): (5) Overall quality of sleep (0 = very poor, 100 = excellent).
Time Frame	Baseline (Day 1); End of Treatment (up to Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; participants with data available at respective time point.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline - Trouble falling asleep	10.0 (18.00)
End of Treatment - Trouble falling asleep	11.7 (22.91)
Baseline - Need for sleep medication	9.2 (24.93)
End of Treatment - Need for sleep medication	10.7 (28.53)
Baseline - Woken up by pain during night	12.5 (21.02)
End of Treatment - Woken up by pain during night	15.3 (26.36)
Baseline - Woken by pain in the morning	12.6 (20.71)
End of Treatment - Woken by pain in the morning	17.5 (28.21)
Baseline - Overall quality of sleep	74.0 (27.91)
End of Treatment - Overall quality of sleep	71.3 (30.97)
Baseline - Sleep Problem Index	35.0 (54.03)
End of Treatment - Sleep Problem Index	44.5 (71.10)

12. Other Pre-specified Outcome

Title	Weekly Means of Daily Average Pain Intensity During the First Month of Treatment
Description	Participants were 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 during the first month of treatment (comprising Titration Weeks 1 and 2 and Maintenance Weeks 1 and 2). They scored 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-hour average pain intensity was calculated as a mean score of these daily entries of average pain intensity for each week.
Time Frame	Baseline (Day 1); Titration Weeks 1 and 2; Maintenance Weeks 1 and 2

Outcome Measure Data

Analysis Population Description

Safety Set; data for participants who completed respective visit.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline	2.96 (1.890)
Titration Week 1	3.18 (1.795)
Titration Week 2	2.90 (1.838)
Maintenance Week 1	2.73 (1.848)
Maintenance Week 2	2.69 (1.843)

13. Other Pre-specified Outcome

Title	Worst Pain Intensity in the Last Week of Treatment (Week 26)
Description	Participants were asked: "Please rate your pain by selecting the one number that best describes your pain at its worst during the last week." at some of the visits during the treatment period. They scored 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 mean scores of the worst pain intensity were calculated for all participants. Results for baseline and Week 26 are presented.
Time Frame	Baseline (Day 1); End of Treatment (Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; 59 participants completed End of Treatment Visit

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline	4.3 (2.52)
End of Treatment (Week 26)	5.1 (2.89)

14. Other Pre-specified Outcome

Title	Weekly Average Number of Breakthrough Pain Episodes
Description	The number of episodes of breakthrough pain during the past week was planned to be collected. However, for some participants, the intensity of breakthrough pain for the past week has been collected instead of the incidence of breakthrough pain events. Since the values of the intensity of breakthrough pain were much higher (maximum of up to 99) than the frequency of pain events, the mean is skewed and cannot be interpreted. The median for the weekly average number of breakthrough pain episodes is less influenced by these values and is reported below.
Time Frame	Baseline (Day 1); End of Treatment (Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; 61 participants completed End of Treatment Visit

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline	1.00
End of Treatment (Week 26)	1.00

15. Other Pre-specified Outcome

Title	Mean Scores of Neuropathic Pain Symptom Inventory (NPSI)
Description	Participants with neuropathic pain (determined by the completion of the DN4 [Douleur Neuropathique] questionnaire at enrollment) rated their symptoms of neuropathic pain using the NPSI. Ten out of 12 questions (Q1-3, 5, 6, 8-12) are answered on an 11-point numerical scale (NRS) ranging from 0 (no symptom present) to 10 (worst imaginable). The NPSI Total Score was calculated as the sum of the 10 single items scored on the 11-point NRS divided by 100. The mean score is reported on a scale of 0 (no neuropathic pain components present) to 1 (all neuropathic pain components have the maximum imaginable intensity).
Time Frame	Baseline (Day 1); Weeks 2, 6, 14, 18; End of Treatment (up to Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set (21 participants with neuropathic pain of 76 participants enrolled)

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	21
Baseline	0.243 (0.1677)
Week 2	0.200 (0.2006)
Week 6	0.146 (0.1397)
Week 14	0.150 (0.1564)
Week 18	0.117 (0.1529)
Final Visit (Week 26)	0.236 (0.2183)

16. Other Pre-specified Outcome

Title	EuroQol-5 Dimension (EQ-5D) Health Status Index Outcome
Description	Participants answered 5 questions on the 5 dimensions of the EuroQol-5 Dimension Health Questionnaire: 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. Each dimension was assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the 5 EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D Health Status Index score between 0 to 1 (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.
Time Frame	Baseline (Day 1); End of Treatment (up to Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; participants with data available at respective time point.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline	0.687 (0.2111)
Final Visit (Week 26)	0.606 (0.3214)

17. Other Pre-specified Outcome

Title	EuroQol-5 Dimension (EQ-5D) Health Questionnaire - Visual Analog Scale (VAS)
Description	The EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant-rated scale where a single value is ticked for "Your own health state today" on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
Time Frame	Baseline (Day 1); End of Treatment (up to Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; participants with data available at respective time point.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline	61.9 (20.62)
Final Visit (Week 26)	56.6 (21.94)

18. Other Pre-specified Outcome

Title	Patient Global Impression of Change (PGIC)
Description	In the PGIC, participants indicates the perceived change over the treatment period compared to their condition prior to the start of treatment. Participants are requested to choose 1 of 7 categories. Scores range from "very much improved" to "very much worse". The frequency of responses per category are provided.
Time Frame	Baseline (Day 1); End of Treatment (up to Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; 62 participants completed the End of Treatment Visit.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	62
Very much improved	5 6.6%
Much improved	17 22.4%
Minimally improved	15 19.7%
No change	9 11.8%
Minimally worse	8 10.5%
Much worse	3 3.9%
Very much worse	1 1.3%
Missing	4 5.3%

19. Other Pre-specified Outcome

Title	Clinical Global Impression of Change (CGIC)
Description	For the CGIC assessment, the clinician indicates the perceived change in the patient's condition over the treatment period as compared to the patient's condition prior to the start of treatment. The clinician is requested to choose 1 of 7 categories. Categories range from "very much improved" to "very much worse".
Time Frame	Baseline (Day 1); End of Treatment Visit (up to Week 26)

Outcome Measure Data

Analysis Population Description

Safety Set; 62 participants completed the End of Treatment Visit.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	62
Very much improved	9 11.8%
Much improved	25 32.9%
Minimally improved	10 13.2%
No change	5 6.6%
Minimally worse	4 5.3%
Much worse	3 3.9%
Very much worse	3 3.9%
Missing	3 3.9%

20. Other Pre-specified Outcome

Title	Use of On-demand Opioid Analgesic Medication
Description	Participants reported the opioid type and amount of an opioid in mg/day used to relieve their breakthrough pain over the time period in the study. The average number of units of on-demand opioid medication administered during the previous day (reported on Day 3) and during the last 3 days (reported at all other visits) were documented. The number of units of on-demand opioid medication administered during the Treatment Period is summarized descriptively over the treatment period.
Time Frame	From Day 3 to End of Treatment (up to Week 26) (13 time points)

Outcome Measure Data

Analysis Population Description

Safety Set; participants with data available at the respective visit.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Day 3	1.08 (1.772)
Week 1	1.45 (2.396)
Day 11	1.29 (2.280)
Week 2	0.96 (1.817)
Day 17	0.64 (1.218)
Week 3	0.78 (2.126)
Week 4	0.72 (1.380)
Week 6	0.59 (1.252)
Week 10	0.51 (1.044)
Week 14	0.47 (1.174)
Week 18	0.55 (1.250)
Week 22	0.77 (1.641)
End of Treatment (up to Week 26)	1.06 (2.397)

21. Other Pre-specified Outcome

Title	Mean Equipotency Ratio of Morphine Sulfate Prolonged Release Compared to Cebranopadol.
Description	For those participants, who received morphine prolonged release in the CORAL trial (KF6005/07, NCT01964378) and were, thus, switched from morphine prolonged release to cebranopadol in the CORAL XT trial, the equianalgesic doses of morphine prolonged release and cebranopadol was identified.
Time Frame	Baseline (Day 1); End of first month of treatment

Outcome Measure Data

Analysis Population Description

Safety Set; the Conversion Ratio of Morphine Prolonged Release to Cebranopadol was available for 32 of 76 participants.

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	32
Mean (Standard Deviation) [Ratio]	156.8 (58.2)

22. Other Pre-specified Outcome

Title	Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores
Description	The investigator scores the ECOG performance status for a participant on a 6-point categorical scale as follows: 0 indicates that a participant is "fully active, able to carry on all pre-disease performance without restriction." 1 indicates that a participant is "restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work." 2 indicates that a participant is "ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours." 3 indicates that a participant is "capable of only limited selfcare, confined to bed or chair more than 50% of waking hours." 4 indicates that a participant is "completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair." 5 indicates that a participant is "dead". Mean ECOG performance status scores are calculated for the number of participants with data available.
Time Frame	From Baseline (Day 1) through to End of treatment (up to Week 26) (9 time points)

Outcome Measure Data

Analysis Population Description

Safety Set; number of participants with data available at the respective visit

Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Measure Participants	76
Baseline	1.1 (0.75)
Week 2	1.1 (0.76)
Week 4	1.1 (0.78)
Week 6	1.2 (0.74)
Week 10	1.1 (0.77)
Week 14	1.1 (0.73)
Week 18	1.2 (0.91)
Week 22	1.4 (0.82)
Final Visit (up to Week 26)	1.6 (1.10)

Adverse Events

Time Frame	All AEs were documented from the time of enrollment (i.e., the time the informed consent form was signed) up to the time of the last protocol scheduled contact occurred, i.e., date of last visit/contact (a telephone call in the case of discontinuation). Treatment emergent adverse events (TEAEs) were reported for up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow-up after the last dose).
Adverse Event Reporting Description	Tables below present TEAEs reported in participants who took at least 1 dose of cebranopadol (Safety Set). Ten participants died during the trial; 5 further deaths occurred after the participants were discontinued from the trial and were reported spontaneously by the investigators.
Arm/Group Title	Cebranopadol
Arm/Group Description	Cebranopadol: Cebranopadol 200 µg to 1000 µg per day taken once a day in the morning. Subjects who completed the treatment in KF6005/07 and were willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects.
All Cause Mortality
	Cebranopadol
	Affected / at Risk (%)	# Events
Total	10/76 (13.2%)
Serious Adverse Events
	Cebranopadol
	Affected / at Risk (%)	# Events
Total	32/76 (42.1%)
Blood and lymphatic system disorders
Anaemia	3/76 (3.9%)	3
Anaemia of malignant disease	2/76 (2.6%)	2
Cardiac disorders
Myocardial infarction	1/76 (1.3%)	1
Cardiac failure	1/76 (1.3%)	1
Gastrointestinal disorders
Colitis	1/76 (1.3%)	1
Ileus paralytic	1/76 (1.3%)	1
General disorders
Asthenia	2/76 (2.6%)	2
Pain	1/76 (1.3%)	1
Infections and infestations
Epididymitis	1/76 (1.3%)	1
Erysipelas	1/76 (1.3%)	1
Gastroenteritis	1/76 (1.3%)	1
Lung abscess	1/76 (1.3%)	1
Pneumonia	1/76 (1.3%)	1
Injury, poisoning and procedural complications
Concussion	2/76 (2.6%)	2
Facial bone fracture	1/76 (1.3%)	2
Subdural haemorrhage	1/76 (1.3%)	1
Metabolism and nutrition disorders
Dehydration	1/76 (1.3%)	1
Musculoskeletal and connective tissue disorders
Osteonecrosis of jaw	1/76 (1.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	19/76 (25%)	26
Metastases to liver	2/76 (2.6%)	2
Malignant melanoma	1/76 (1.3%)	1
Tumour haemorrhage	1/76 (1.3%)	1
Nervous system disorders
Subarachnoid haemorrhage	1/76 (1.3%)	1
Cerebral infarction	1/76 (1.3%)	1
Coma	1/76 (1.3%)	1
Epilespsy	1/76 (1.3%)	1
Psychiatric disorders
Adjustment disorder with depressed mood	1/76 (1.3%)	1
Alcohol abuse	1/76 (1.3%)	1
Confusional state	1/76 (1.3%)	1
Depression	1/76 (1.3%)	1
Renal and urinary disorders
Acute kidney injury	1/76 (1.3%)	1
Hydronephrosis	1/76 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
Haemoptysis	2/76 (2.6%)	4
Skin and subcutaneous tissue disorders
Skin lesion	1/76 (1.3%)	1
Vascular disorders
Superior vena cava syndrome	1/76 (1.3%)	1
Aortic thrombosis	1/76 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Cebranopadol
	Affected / at Risk (%)	# Events
Total	63/76 (82.9%)
Blood and lymphatic system disorders
Anaemia	6/76 (7.9%)	7
Leukocytosis	5/76 (6.6%)	5
Leukopenia	6/76 (7.9%)	7
Thrombocytopenia	6/76 (7.9%)	6
Thrombocytosis	7/76 (9.2%)	10
Gastrointestinal disorders
Abdominal pain	4/76 (5.3%)	5
Abdominal pain upper	5/76 (6.6%)	6
Constipation	11/76 (14.5%)	13
Diarrhoea	4/76 (5.3%)	4
Nausea	15/76 (19.7%)	18
Vomiting	8/76 (10.5%)	11
General disorders
Asthenia	19/76 (25%)	21
Fatigue	9/76 (11.8%)	10
Feeling drunk	4/76 (5.3%)	4
Oedema peripheral	9/76 (11.8%)	9
Pyrexia	9/76 (11.8%)	10
Infections and infestations
Bacteriuria	5/76 (6.6%)	5
Upper respiratory tract infection	4/76 (5.3%)	4
Urinary tract infection	6/76 (7.9%)	7
Investigations
Gamma-glutamyltransferase increased	4/76 (5.3%)	4
Metabolism and nutrition disorders
Decreased appetite	17/76 (22.4%)	21
Musculoskeletal and connective tissue disorders
Back pain	8/76 (10.5%)	11
Arthralgia	8/76 (10.5%)	8
Musculoskeletal pain	7/76 (9.2%)	10
Pain in extremity	4/76 (5.3%)	5
Nervous system disorders
Headache	8/76 (10.5%)	8
Somnolence	8/76 (10.5%)	9
Dizziness	5/76 (6.6%)	6
Psychiatric disorders
Depressed mood	4/76 (5.3%)	4
Insomnia	5/76 (6.6%)	5
Anxiety	4/76 (5.3%)	7
Nervousness	4/76 (5.3%)	4
Respiratory, thoracic and mediastinal disorders
Dyspnoea	7/76 (9.2%)	8

Limitations/Caveats

A limitation is the open-label design of the study. An extrapolation to a population not suffering from cancer-related pain is limited due to the nature of the underlying disorder.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor reserves the right to review any publication pertaining to the trial before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.