Trial Outcomes & Findings for CORAL XT - Open-label Extension Trial of the CORAL Trial (NCT NCT02031432)

NCT ID: NCT02031432

Last Updated: 2021-07-15

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 76 participants
• Primary outcome timeframe: Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow up after the last dose)
• Results posted on: 2021-07-15

Participant Flow

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.

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.

Participant milestones

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

Reasons for withdrawal

Measure	Cebranopadol Cebranopadol: Cebranopadol 200 µg to 1000 µg per day taken once a day in the morning.
Overall Study Protocol Violation	1
Overall Study Lack of Efficacy	5
Overall Study Cancer Progression	2
Overall Study Withdrawn as forbidden meds required	1
Overall Study Adverse Event	8
Overall Study Withdrawal by Subject	5
Overall Study Lost to Follow-up	1
Overall Study Inclusion/Exclusion criteria not met	5
Overall Study Death	10

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Cebranopadol n=76 Participants Cebranopadol: Cebranopadol 200 µg to 1000 µg per day taken once a day in the morning.
Age, Continuous	61.7 years STANDARD_DEVIATION 9.81 • n=5 Participants
Age, Customized Below 18 years	0 Participants n=5 Participants
Age, Customized From 18 to less than 65 years	43 Participants n=5 Participants
Age, Customized From 65 to less than 85 years	33 Participants n=5 Participants
Age, Customized Above 85 years	0 Participants n=5 Participants
Sex: Female, Male Female	32 Participants n=5 Participants
Sex: Female, Male Male	44 Participants n=5 Participants
Race/Ethnicity, Customized White	76 Participants n=5 Participants
Region of Enrollment Romania	2 participants n=5 Participants
Region of Enrollment Hungary	2 participants n=5 Participants
Region of Enrollment Austria	3 participants n=5 Participants
Region of Enrollment Belgium	1 participants n=5 Participants
Region of Enrollment Denmark	2 participants n=5 Participants
Region of Enrollment Poland	17 participants n=5 Participants
Region of Enrollment Slovakia	21 participants n=5 Participants
Region of Enrollment Bulgaria	4 participants n=5 Participants
Region of Enrollment Serbia	4 participants n=5 Participants
Region of Enrollment Germany	20 participants n=5 Participants
DN4 Neuropathic Pain at start of KF6005/07 DN4 positive	21 participants n=5 Participants
DN4 Neuropathic Pain at start of KF6005/07 DN4 negative	55 participants n=5 Participants
Height	1.684 meter STANDARD_DEVIATION 0.0844 • n=5 Participants
Weight	72 kilograms STANDARD_DEVIATION 14.04 • n=5 Participants
Body Mass Index (BMI)	25.36 kg/m^2 STANDARD_DEVIATION 4.5 • n=5 Participants
Weekly means of average daily pain	2.96 units on a scale STANDARD_DEVIATION 1.89 • n=5 Participants
Weekly means of worst daily pain	3.95 units on a scale STANDARD_DEVIATION 2.447 • n=5 Participants

PRIMARY outcome

Timeframe: Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow up after the last dose)

Population: Safety Set

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Number of Participants With Treatment Emergent Adverse Event (TEAEs)	64 Participants

SECONDARY outcome

Timeframe: Up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow-up after the last dose)

Population: Safety Set; event-based analysis

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.

Outcome measures

Measure	Cebranopadol n=661 Number of TEAEs Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Intensity of Treatment Emergent Adverse Events Mild intensity	242 Number of TEAEs
Intensity of Treatment Emergent Adverse Events Moderate intensity	300 Number of TEAEs
Intensity of Treatment Emergent Adverse Events Severe intensity	119 Number of TEAEs

SECONDARY outcome

Timeframe: Baseline Visit (Day 1) to End of Treatment Visit (up to 26 weeks).

Population: Safety Set - participants with data available

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.

Outcome measures

Measure	Cebranopadol n=59 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Changes From Baseline in the Average Pain Intensity in the Last Week During the Treatment Period	0.8 units on a scale Standard Deviation 2.14

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 2) to End of trial (i.e., up to Week 28)

Population: Safety Set; event-based analysis

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).

Outcome measures

Measure	Cebranopadol n=661 Number of TEAEs Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Outcome of Treatment Emergent Adverse Events (TEAE) Recovered/resolved with sequelae	11 Number of TEAEs
Outcome of Treatment Emergent Adverse Events (TEAE) Recovered/resolved	349 Number of TEAEs
Outcome of Treatment Emergent Adverse Events (TEAE) Not recovered/not resolved	260 Number of TEAEs
Outcome of Treatment Emergent Adverse Events (TEAE) Recovering/resolving	14 Number of TEAEs
Outcome of Treatment Emergent Adverse Events (TEAE) Fatal	11 Number of TEAEs
Outcome of Treatment Emergent Adverse Events (TEAE) Unknown	16 Number of TEAEs

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 2) to End of trial (up to Week 28)

Population: Safety Set; event-based analysis for 661 TEAEs.

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).

Outcome measures

Measure	Cebranopadol n=661 Number of TEAEs Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Time to Onset of Treatment Emergent Adverse Events (TEAEs)	53.0 days Interval 19.0 to 106.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 2) to End of trial (up to Week 28)

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

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.

Outcome measures

Measure	Cebranopadol n=373 Number of TEAEs Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Duration of Treatment Emergent Adverse Events (TEAEs)	9.0 days Interval 3.0 to 27.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 2) to End of trial (up to Week 28)

Population: Safety Set; event-based analysis on 661 TEAEs

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.

Outcome measures

Measure	Cebranopadol n=661 Number of TEAEs Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Certainly Related	0 Number of TEAEs
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Possibly Related	42 Number of TEAEs
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Probably/Likely Related	7 Number of TEAEs
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Unlikely Related	37 Number of TEAEs
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Not Related	574 Number of TEAEs
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Unassessable/Unclassifiable	1 Number of TEAEs
Causal Relationship of Treatment Emergent Adverse Events (TEAEs) Conditional/Unclassifiable	0 Number of TEAEs

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 2) to End of trial (up to Week 28)

Population: Safety Set; event-based analysis.

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.

Outcome measures

Measure	Cebranopadol n=661 Number of TEAEs Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) No countermeasure	361 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Newly started medication	281 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Other	19 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Cebranopadol dose not changed as countermeasure	595 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Cebranopadol dose reduced	5 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Cebranopadol treatment interrupted	14 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Cebranopadol withdrawn	23 Number of TEAEs
Countermeasures Taken for Treatment Emergent Adverse Events (TEAEs) Cebranopadol to dosing missing	24 Number of TEAEs

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 2) to End of trial (up to Week 28)

Population: Safety Set

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Related to Cebranopadol Participants with related TEAEs	20 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Related to Cebranopadol Participants with related serious TEAEs	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Related to Cebranopadol Participants without related TEAEs	55 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1) to End of trial (up to Week 28)

Population: Safety Set

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores No suicidal ideation or behaviour	74 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores Wish to be dead	1 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores Non-specific active suicidal thoughts	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment (up to Week 26)

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

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).

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline Baseline - Trouble falling asleep	10.0 units on a scale Standard Deviation 18.00
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline End of Treatment - Trouble falling asleep	11.7 units on a scale Standard Deviation 22.91
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline Baseline - Need for sleep medication	9.2 units on a scale Standard Deviation 24.93
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline End of Treatment - Need for sleep medication	10.7 units on a scale Standard Deviation 28.53
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline Baseline - Woken up by pain during night	12.5 units on a scale Standard Deviation 21.02
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline End of Treatment - Woken up by pain during night	15.3 units on a scale Standard Deviation 26.36
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline Baseline - Woken by pain in the morning	12.6 units on a scale Standard Deviation 20.71
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline End of Treatment - Woken by pain in the morning	17.5 units on a scale Standard Deviation 28.21
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline Baseline - Overall quality of sleep	74.0 units on a scale Standard Deviation 27.91
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline End of Treatment - Overall quality of sleep	71.3 units on a scale Standard Deviation 30.97
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline Baseline - Sleep Problem Index	35.0 units on a scale Standard Deviation 54.03
Mean Scores of Chronic Pain Sleep Inventory (CPSI) and Changes From Baseline End of Treatment - Sleep Problem Index	44.5 units on a scale Standard Deviation 71.10

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); Titration Weeks 1 and 2; Maintenance Weeks 1 and 2

Population: Safety Set; data for participants who completed respective visit.

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Weekly Means of Daily Average Pain Intensity During the First Month of Treatment Baseline	2.96 units on a scale Standard Deviation 1.890
Weekly Means of Daily Average Pain Intensity During the First Month of Treatment Titration Week 1	3.18 units on a scale Standard Deviation 1.795
Weekly Means of Daily Average Pain Intensity During the First Month of Treatment Titration Week 2	2.90 units on a scale Standard Deviation 1.838
Weekly Means of Daily Average Pain Intensity During the First Month of Treatment Maintenance Week 1	2.73 units on a scale Standard Deviation 1.848
Weekly Means of Daily Average Pain Intensity During the First Month of Treatment Maintenance Week 2	2.69 units on a scale Standard Deviation 1.843

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment (Week 26)

Population: Safety Set; 59 participants completed End of Treatment Visit

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Worst Pain Intensity in the Last Week of Treatment (Week 26) Baseline	4.3 units on a scale Standard Deviation 2.52
Worst Pain Intensity in the Last Week of Treatment (Week 26) End of Treatment (Week 26)	5.1 units on a scale Standard Deviation 2.89

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment (Week 26)

Population: Safety Set; 61 participants completed End of Treatment Visit

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Weekly Average Number of Breakthrough Pain Episodes Baseline	1.00 Weekly average number of episodes Interval 0.0 to 66.0
Weekly Average Number of Breakthrough Pain Episodes End of Treatment (Week 26)	1.00 Weekly average number of episodes Interval 0.0 to 99.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); Weeks 2, 6, 14, 18; End of Treatment (up to Week 26)

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

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).

Outcome measures

Measure	Cebranopadol n=21 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) Baseline	0.243 units on a scale Standard Deviation 0.1677
Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) Week 2	0.200 units on a scale Standard Deviation 0.2006
Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) Week 6	0.146 units on a scale Standard Deviation 0.1397
Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) Week 14	0.150 units on a scale Standard Deviation 0.1564
Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) Week 18	0.117 units on a scale Standard Deviation 0.1529
Mean Scores of Neuropathic Pain Symptom Inventory (NPSI) Final Visit (Week 26)	0.236 units on a scale Standard Deviation 0.2183

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment (up to Week 26)

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

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
EuroQol-5 Dimension (EQ-5D) Health Status Index Outcome Baseline	0.687 units on a scale Standard Deviation 0.2111
EuroQol-5 Dimension (EQ-5D) Health Status Index Outcome Final Visit (Week 26)	0.606 units on a scale Standard Deviation 0.3214

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment (up to Week 26)

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

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
EuroQol-5 Dimension (EQ-5D) Health Questionnaire - Visual Analog Scale (VAS) Baseline	61.9 units on a scale Standard Deviation 20.62
EuroQol-5 Dimension (EQ-5D) Health Questionnaire - Visual Analog Scale (VAS) Final Visit (Week 26)	56.6 units on a scale Standard Deviation 21.94

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment (up to Week 26)

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

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.

Outcome measures

Measure	Cebranopadol n=62 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Patient Global Impression of Change (PGIC) Very much improved	5 Participants
Patient Global Impression of Change (PGIC) Much improved	17 Participants
Patient Global Impression of Change (PGIC) Minimally improved	15 Participants
Patient Global Impression of Change (PGIC) No change	9 Participants
Patient Global Impression of Change (PGIC) Minimally worse	8 Participants
Patient Global Impression of Change (PGIC) Much worse	3 Participants
Patient Global Impression of Change (PGIC) Very much worse	1 Participants
Patient Global Impression of Change (PGIC) Missing	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of Treatment Visit (up to Week 26)

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

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".

Outcome measures

Measure	Cebranopadol n=62 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Clinical Global Impression of Change (CGIC) Very much improved	9 Participants
Clinical Global Impression of Change (CGIC) Much improved	25 Participants
Clinical Global Impression of Change (CGIC) Minimally improved	10 Participants
Clinical Global Impression of Change (CGIC) No change	5 Participants
Clinical Global Impression of Change (CGIC) Minimally worse	4 Participants
Clinical Global Impression of Change (CGIC) Much worse	3 Participants
Clinical Global Impression of Change (CGIC) Very much worse	3 Participants
Clinical Global Impression of Change (CGIC) Missing	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 3 to End of Treatment (up to Week 26) (13 time points)

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

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Use of On-demand Opioid Analgesic Medication Week 10	0.51 units Standard Deviation 1.044
Use of On-demand Opioid Analgesic Medication Day 3	1.08 units Standard Deviation 1.772
Use of On-demand Opioid Analgesic Medication Week 1	1.45 units Standard Deviation 2.396
Use of On-demand Opioid Analgesic Medication Day 11	1.29 units Standard Deviation 2.280
Use of On-demand Opioid Analgesic Medication Week 2	0.96 units Standard Deviation 1.817
Use of On-demand Opioid Analgesic Medication Day 17	0.64 units Standard Deviation 1.218
Use of On-demand Opioid Analgesic Medication Week 3	0.78 units Standard Deviation 2.126
Use of On-demand Opioid Analgesic Medication Week 4	0.72 units Standard Deviation 1.380
Use of On-demand Opioid Analgesic Medication Week 6	0.59 units Standard Deviation 1.252
Use of On-demand Opioid Analgesic Medication Week 14	0.47 units Standard Deviation 1.174
Use of On-demand Opioid Analgesic Medication Week 18	0.55 units Standard Deviation 1.250
Use of On-demand Opioid Analgesic Medication Week 22	0.77 units Standard Deviation 1.641
Use of On-demand Opioid Analgesic Medication End of Treatment (up to Week 26)	1.06 units Standard Deviation 2.397

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); End of first month of treatment

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

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.

Outcome measures

Measure	Cebranopadol n=32 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Mean Equipotency Ratio of Morphine Sulfate Prolonged Release Compared to Cebranopadol.	156.8 Ratio Standard Deviation 58.2

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline (Day 1) through to End of treatment (up to Week 26) (9 time points)

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

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.

Outcome measures

Measure	Cebranopadol n=76 Participants Cebranopadol (GRT6005) 200 µg to 1000 µg per day taken once a day in the morning.
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Baseline	1.1 units on a scale Standard Deviation 0.75
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 2	1.1 units on a scale Standard Deviation 0.76
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 4	1.1 units on a scale Standard Deviation 0.78
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 6	1.2 units on a scale Standard Deviation 0.74
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 10	1.1 units on a scale Standard Deviation 0.77
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 14	1.1 units on a scale Standard Deviation 0.73
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 18	1.2 units on a scale Standard Deviation 0.91
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Week 22	1.4 units on a scale Standard Deviation 0.82
Mean Eastern Cooperative Oncology Group Performance Status (ECOG) Scores Final Visit (up to Week 26)	1.6 units on a scale Standard Deviation 1.10

Adverse Events

Cebranopadol

Serious events: 32 serious events

Other events: 63 other events

Deaths: 10 deaths

Serious adverse events

Measure	Cebranopadol n=76 participants at risk 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.
Vascular disorders Superior vena cava syndrome	1.3% 1/76 • Number of events 1 • 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). 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.
Vascular disorders Aortic thrombosis	1.3% 1/76 • Number of events 1 • 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). 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	25.0% 19/76 • Number of events 26 • 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). 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	2.6% 2/76 • Number of events 2 • 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). 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	1.3% 1/76 • Number of events 1 • 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). 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	1.3% 1/76 • Number of events 1 • 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). 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.
General disorders Asthenia	2.6% 2/76 • Number of events 2 • 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). 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.
General disorders Pain	1.3% 1/76 • Number of events 1 • 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). 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.
Psychiatric disorders Adjustment disorder with depressed mood	1.3% 1/76 • Number of events 1 • 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). 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.
Psychiatric disorders Alcohol abuse	1.3% 1/76 • Number of events 1 • 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). 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.
Psychiatric disorders Confusional state	1.3% 1/76 • Number of events 1 • 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). 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.
Psychiatric disorders Depression	1.3% 1/76 • Number of events 1 • 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). 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.
Injury, poisoning and procedural complications Concussion	2.6% 2/76 • Number of events 2 • 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). 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.
Injury, poisoning and procedural complications Facial bone fracture	1.3% 1/76 • Number of events 2 • 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). 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.
Injury, poisoning and procedural complications Subdural haemorrhage	1.3% 1/76 • Number of events 1 • 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). 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.
Cardiac disorders Myocardial infarction	1.3% 1/76 • Number of events 1 • 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). 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.
Cardiac disorders Cardiac failure	1.3% 1/76 • Number of events 1 • 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). 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.
Respiratory, thoracic and mediastinal disorders Haemoptysis	2.6% 2/76 • Number of events 4 • 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). 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.
Blood and lymphatic system disorders Anaemia	3.9% 3/76 • Number of events 3 • 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). 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.
Blood and lymphatic system disorders Anaemia of malignant disease	2.6% 2/76 • Number of events 2 • 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). 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.
Nervous system disorders Subarachnoid haemorrhage	1.3% 1/76 • Number of events 1 • 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). 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.
Nervous system disorders Cerebral infarction	1.3% 1/76 • Number of events 1 • 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). 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.
Nervous system disorders Coma	1.3% 1/76 • Number of events 1 • 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). 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.
Nervous system disorders Epilespsy	1.3% 1/76 • Number of events 1 • 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). 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.
Gastrointestinal disorders Colitis	1.3% 1/76 • Number of events 1 • 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). 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.
Gastrointestinal disorders Ileus paralytic	1.3% 1/76 • Number of events 1 • 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). 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.
Renal and urinary disorders Acute kidney injury	1.3% 1/76 • Number of events 1 • 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). 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.
Renal and urinary disorders Hydronephrosis	1.3% 1/76 • Number of events 1 • 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). 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.
Skin and subcutaneous tissue disorders Skin lesion	1.3% 1/76 • Number of events 1 • 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). 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.
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	1.3% 1/76 • Number of events 1 • 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). 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.
Metabolism and nutrition disorders Dehydration	1.3% 1/76 • Number of events 1 • 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). 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.
Infections and infestations Epididymitis	1.3% 1/76 • Number of events 1 • 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). 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.
Infections and infestations Erysipelas	1.3% 1/76 • Number of events 1 • 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). 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.
Infections and infestations Gastroenteritis	1.3% 1/76 • Number of events 1 • 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). 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.
Infections and infestations Lung abscess	1.3% 1/76 • Number of events 1 • 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). 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.
Infections and infestations Pneumonia	1.3% 1/76 • Number of events 1 • 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). 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.

Other adverse events

Measure	Cebranopadol n=76 participants at risk 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.
Investigations Gamma-glutamyltransferase increased	5.3% 4/76 • Number of events 4 • 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). 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.2% 7/76 • Number of events 8 • 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). 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.
Blood and lymphatic system disorders Anaemia	7.9% 6/76 • Number of events 7 • 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). 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.
Blood and lymphatic system disorders Leukocytosis	6.6% 5/76 • Number of events 5 • 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). 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.
Blood and lymphatic system disorders Leukopenia	7.9% 6/76 • Number of events 7 • 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). 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.
Blood and lymphatic system disorders Thrombocytopenia	7.9% 6/76 • Number of events 6 • 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). 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.
Blood and lymphatic system disorders Thrombocytosis	9.2% 7/76 • Number of events 10 • 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). 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.
Nervous system disorders Headache	10.5% 8/76 • Number of events 8 • 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). 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.
Nervous system disorders Somnolence	10.5% 8/76 • Number of events 9 • 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). 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.
Nervous system disorders Dizziness	6.6% 5/76 • Number of events 6 • 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). 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.
General disorders Asthenia	25.0% 19/76 • Number of events 21 • 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). 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.
General disorders Fatigue	11.8% 9/76 • Number of events 10 • 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). 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.
General disorders Feeling drunk	5.3% 4/76 • Number of events 4 • 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). 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.
General disorders Oedema peripheral	11.8% 9/76 • Number of events 9 • 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). 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.
General disorders Pyrexia	11.8% 9/76 • Number of events 10 • 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). 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.
Psychiatric disorders Depressed mood	5.3% 4/76 • Number of events 4 • 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). 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.
Psychiatric disorders Insomnia	6.6% 5/76 • Number of events 5 • 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). 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.
Psychiatric disorders Anxiety	5.3% 4/76 • Number of events 7 • 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). 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.
Psychiatric disorders Nervousness	5.3% 4/76 • Number of events 4 • 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). 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.
Gastrointestinal disorders Abdominal pain	5.3% 4/76 • Number of events 5 • 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). 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.
Gastrointestinal disorders Abdominal pain upper	6.6% 5/76 • Number of events 6 • 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). 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.
Gastrointestinal disorders Constipation	14.5% 11/76 • Number of events 13 • 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). 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.
Gastrointestinal disorders Diarrhoea	5.3% 4/76 • Number of events 4 • 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). 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.
Musculoskeletal and connective tissue disorders Back pain	10.5% 8/76 • Number of events 11 • 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). 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.
Musculoskeletal and connective tissue disorders Arthralgia	10.5% 8/76 • Number of events 8 • 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). 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.2% 7/76 • Number of events 10 • 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). 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.
Musculoskeletal and connective tissue disorders Pain in extremity	5.3% 4/76 • Number of events 5 • 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). 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.
Metabolism and nutrition disorders Decreased appetite	22.4% 17/76 • Number of events 21 • 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). 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.
Infections and infestations Bacteriuria	6.6% 5/76 • Number of events 5 • 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). 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.
Infections and infestations Upper respiratory tract infection	5.3% 4/76 • Number of events 4 • 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). 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.
Infections and infestations Urinary tract infection	7.9% 6/76 • Number of events 7 • 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). 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.
Gastrointestinal disorders Nausea	19.7% 15/76 • Number of events 18 • 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). 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.
Gastrointestinal disorders Vomiting	10.5% 8/76 • Number of events 11 • 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). 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.

Additional Information

Director of Clinical Trials

Grünenthal GmbH

Phone: +49 241 569 3223

Email: Clinical-Trials@grunenthal.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER