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.

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).

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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

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.

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.

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.

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".

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.

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.

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.

DN4 (Douleur Neuropathique en 4 Questions) was used as a screening tool for neuropathic pain. The DN4 consists of a total of 10 questions and tests, including interview questions (DN4-interview) and physical tests. The DN4 test was considered "positive" if there was a score of 4 or more (the maximum score is 10) then the participant has a neuropathic pain component. If the DN4 is negative, i.e., a score 3 or less then the participant was considered not to have a neuropathic pain component.

For this assessment, each participant was asked "Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours" on an 11-point Numerical Rating Scale, where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The mean of the assessments of average pain intensity in the last 24 hours in the last 3 days prior to first intake of cebranopadol is reported.

For this assessment, each participant was asked "Please rate your pain by selecting the one number that best describes your pain at its worst during the last 24 hours" on an 11-point Numerical Rating Scale, where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The mean of the assessments of worst pain intensity in the last 24 hours in the last 3 days prior to first intake of cebranopadol is reported.

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.

Safety Set; event-based analysis

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.

Safety Set - participants with data available

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).

Safety Set; event-based analysis

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).

Safety Set; event-based analysis for 661 TEAEs.

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.

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

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.

Safety Set; event-based analysis on 661 TEAEs

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.

Safety Set; event-based analysis.

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.

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.

Safety Set

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).

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

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.

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 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.

Safety Set; 59 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.

Safety Set; 61 participants completed End of Treatment Visit

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).

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

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.

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.

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

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.

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".

Safety Set; 62 participants completed the End of Treatment 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.

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

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.

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

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.

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