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

• Sponsor: Tris Pharma, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01964378
• Collaborator: (none)
• Enrollment: 200
• Locations: 42
• Arms: 2
• Actual Duration (Months): 23.6
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Pain is one of the most common symptoms associated with malignant tumor. The purpose of this trial is to determine whether cebranopadol is as effective in patients with cancer related pain as morphine sulfate prolonged release (PR).

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

Detailed Description

The trial comprises an enrollment period, a treatment period (titration and maintenance), and a follow-up period. Participants will receive either cebranopadol or morphine PR for 44 days. Initially participants will be titrated after 2 and then every 4 days to a morphine PR or cebranopadol dose that provides adequate analgesia and is tolerated. The titration period is planned to last 16 days. Thereafter the dose of morphine PR or cebranopadol is to be kept stable for a further 28 days, i.e. no dose adjustments will be allowed during the maintenance period. This 28 day period is the maintenance period. The follow-up period is planned for up to 18 days after the end of last pain medication treatment intake.

Study Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.
• Actual Study Start Date: Oct 29, 2013
• Actual Primary Completion Date: Oct 16, 2015
• Actual Study Completion Date: Oct 16, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cebranopadol Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day.	Drug: Cebranopadol; Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.; Other Names: GRT6005
Active Comparator: Morphine Prolonged Release Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day.	Drug: Morphine Prolonged Release; Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.

Outcome Measures

Primary Outcome Measures

1. Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Per Protocol Set) [The last 2 weeks of the expected 6-week treatment period.]

   Morphine sulfate immediate release (IR) 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.

2. Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Full Analysis Set) [The last 2 weeks of the expected 6-week treatment period.]

   Morphine sulfate IR 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.

Secondary Outcome Measures

1. Proportion of Participants With Clinically Relevant Pain Reduction at the End of the Maintenance Period [The last 2 weeks of the expected 6-week treatment period.]

   Each participant indicated the level of pain on an 11-point numerical rating scale (NRS), where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The participants entered their pain intensity in their diary on a daily basis. The pain intensity score in the 2 weeks prior to the final evaluation in the maintenance period was compared with the baseline, the baseline pain intensity was calculated based on the 3 days prior to treatment allocation. The definition of a clinically relevant pain reduction (yes/no) was the presence of at least 1 of the 3 following conditions: Average pain intensity (i.e., average of the 24-hour pain intensities over the last 2 weeks of the Maintenance Phase) of less than 4 points on the 11-point NRS, or Reduction in average pain intensity by at least 30% (compared to the baseline assessment), or Reduction in average pain intensity by at least 2 points (compared to the baseline assessment).

Other Outcome Measures

1. Change in Weekly Mean of the Daily Average Pain Intensity Score From Baseline [Baseline; last 2 weeks of the expected 6-week treatment period]

   Participants will be asked: "Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours." every day in the morning. They will score their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The weekly mean value of the 24-h average pain intensity will be calculated as a mean score of these daily entries of average pain intensity for each trial week.

2. Response Rate to Treatment [Baseline; last 2 weeks of the expected 6-week treatment period]

   Pain intensity will be recorded daily by each participant in the morning on an 11-point Numerical Rating Scale, ranging from 0 (no pain) to 10 (worst imaginable pain). From this, the weekly average 24-hour pain intensity will be calculated. The number of participants with a 0, 10, 20, 30, up to a 100% reduction in weekly mean pain intensity will be reported over each week and over the last 2 weeks of the maintenance period.

3. Overall Score of the Neuropathic Pain Symptom Inventory (NPSI) [Baseline; End-of-Treatment Visit (Week 6)]

   Participants with neuropathic pain (determined by the completion of the Douleur Neuropathique En 4 Questions [DN4] questionnaire at allocation) rated their symptoms of neuropathic pain on the Neuropathic Pain Symptom Inventory (NPSI). Ten out of 12 questions were answered on an 11-point scale 0 (no symptom present) to 10 (worst imaginable); 2 out of 12 questions assessed the duration of spontaneous pain and the number of pain attacks and were answered by selecting 1 of 5 possible responses. Mean scores of NPSI were calculated. The overall NPSI score was calculated by the summation of all responses in the ranges between 0 (all symptoms absent) and 1 (all symptoms present and at the worst intensity). A negative change indicates that the intensity of all the neuropathic symptom components have decreased since the start of treatment.

4. EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Weighted EQ-5D Health Status Index [Baseline; End-of-Treatment Visit (6 weeks)]

   The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. The participants will answer 5 questions on 5 dimensions of their health related quality of life: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each question has 3 possible answers reflecting 3 levels of impact on the quality of life. The weighted EQ-5D health status index values are derived and reported as change from baseline. The responses to the 5 EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score (with 1 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group. A positive change indicates an improvement.

5. EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Visual Analog Scale (VAS) Score [Baseline; End-of-Treatment Visit (6 weeks)]

   The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.

6. Change in the Physical and Mental Component Scores From the Short Form 12® Health Survey (SF-12) [Baseline; End-of-Treatment Visit (6 weeks)]

   The Physical and Mental Component Scores are calculated from the responses by participants to 12 questions. These 12 questions cover 8 domains, (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role participation with emotional health problems, and mental health) that a participant was asked to rate over the last week. Questions are scored on a Likert-scale. The Physical and Mental Component Scores were not derived as the trial was terminated. Changes in the individual item scores are therefore reported. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state. If the values are positive there was an improvement. The higher the value the greater the improvement.

7. Patient Global Impression of Change (PGIC) [Baseline; End-of-Treatment Visit (6 weeks)]

   In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period compared to his condition prior to the start of treatment. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.

8. Clinical Global Impression of Change (CGIC) [Baseline; End-of-Treatment Visit (6 weeks)]

   In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change in patient's condition over the treatment period as compared to patient's condition prior to the start of treatment. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.

9. Overall Score of the Patient Assessment of Constipation Symptoms (PAC-SYM) [Baseline; End-of-Treatment Visit (6 weeks)]

   The PAC-SYM is a 12-item self-administered questionnaire that assesses the severity of constipation-related symptoms during past 2 weeks. Items are rated on a 5-point Likert scale, where 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.The PAC-SYM contains 3 subscales: stool symptoms (5 items), abdominal symptoms (4 items), rectal symptoms (3 items). If at least 6 items are assessed, the PAC-SYM overall score is calculated as the sum of the scores of all non-missing items divided by number of non-missing items. The minimum overall score is 0, the maximum overall score is 4. If more than 6 items are missing, no overall score is calculated. Changes from baseline for the overall score are presented. If the changes in the overall (or subscale) scores are positive then there is a worsening in symptoms associated with constipation.

10. Change in Weekly Mean of the Daily Worst Pain Intensity Score From Baseline [Baseline; End-of-Treatment Visit (6 weeks)]

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

11. Change From Baseline to End-of-Treatment Visit in Chronic Pain Sleep Inventory (CPSI) Scores [Baseline; End-of-Treatment Visit (6 weeks)]

    The CPSI measures 5 items on 100-mm visual analog scales: trouble falling asleep (CPSI1), needing sleep medication (CPSI2), awakened by pain during the night (CPSI3) and in the morning (CPSI4) [all with anchors for 0 = never and 100 = always], and overall quality of sleep (CPSI5) [with anchors of 0 = very poor and 100 = excellent]. The sleep problem index is the sum of items CPSI1, CPSI3 and CPSI4. The minimum sleep problem index is 0 mm, the maximum 300 mm, the higher the worse. For the overall quality of sleep, minimum and maximum are 0 and 100 mm, the higher the better. A decrease in the sleep problem index indicates an improvement as does an increase in the overall quality of sleep. Changes from baseline to the End-of-Treatment Visit of the Maintenance Phase (scheduled for Week 6) were calculated.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Signed informed consent.

2. Negative pregnancy test before first dose.

3. Female and male participants willing to use acceptable and highly effective methods of birth control.

4. The following criteria must be fulfilled by participants:

5. Require daily analgesia for their pain,

6. Diagnosed with active cancer,

7. Receiving daily opioid treatment at doses not higher than 90 mg oral morphine or its equivalent (World Health Organization Step II and Step III analgesics) for an appropriate length of time,

8. Participants must be dissatisfied with their current pain treatment,

9. Participants must be suffering from cancer-related but not cancer therapy-related chronic pain for a period of 4 weeks or more prior to enrollment.

10. Eastern Cooperation Oncology Group (ECOG) score 2 or below.

11. Average pain intensity over the last 24 hours of 5 or more calculated from the pain assessments recorded during the last 3 days prior to randomization.

12. Compliance with the use of the electronic diary defined as at least 3 out of 4 of the 24 hour Numerical Rating Scale entries available during the last 4 days prior to and including the day of allocation to treatment.

Exclusion Criteria:

1. Evidence of ongoing alcohol and or drug abuse and/or a history of alcohol and/or drug abuse within the last 2 years.

2. A clinically significant disease other than cancer which in the investigator's opinion may affect efficacy or safety assessments e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, infectious disease, psychiatric (resulting in disorientation, memory impairment or inability to report accurately) or metabolic disorders.

3. Any gastrointestinal disorder that could affect the absorption and/or elimination of Investigational Medicinal Product.

4. Any planned major surgery during the trial.

5. Known to or suspected of not being able to comply with the trial protocol and the use of Investigational Medicinal Product.

6. History of seizure disorder and/or epilepsy or any condition associated with a significant risk of seizure or epilepsy.

7. Known history and/or presence of cerebral tumor or cerebral metastases.

8. Moderate to severe hepatic impairment corresponding to Child-Pugh classification B and

1. Impaired hepatic cellular integrity indicated by aspartate transaminase or alanine transaminase greater than 3 times the upper limit of normal at the Enrollment Visit.

1. Inadequate baseline bone marrow reserve with a white blood cell count below 2000/µL, a platelet count 100 000/µL or less, and a hemoglobin level below 8 g/dL at the Enrollment Visit.

2. Impaired renal function. Creatinine clearance less than 60 mL per minute(as per amendment 45 mL per minute) at the Enrollment Visit (calculated from the Cockcroft-Gault formula).

3. Forbidden concomitant medications

4. Uncontrolled hypertension

5. Clinically relevant history of hypersensitivity, allergy or contraindications to opioid medication or any of the excipients of morphine sulfate (Prolonged Released or Immediate Release), or cebranopadol film-coated tablets.

6. Chronic hepatitis B or C, or human immunodeficiency virus (HIV) known by history, or presence of active hepatitis B or C within the 3 months before the Enrollment Visit.

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

8. Marked prolongation of corrected QT interval (Fridericia) (greater than 450 milliseconds) at the Enrollment Visit.

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

10. Concurrent participation in another trial or planning to be enrolled in another clinical trial (i.e., administration of experimental treatment in another clinical trial) during the course of this trial.

11. Previous participation in this or other trials with cebranopadol with the following exceptions:

• Participants who failed enrollment in this trial only because of exclusion criterion 10, and who may now be eligible can be re-enrolled.

• Participants who failed enrollment due to technical failure of equipment (e.g., ECG machine and e-diary device).

1. Participant has received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment.

2. Currently not receiving opioid treatment for cancer-related pain at the enrollment visit (i.e., opioid naïve).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AT004	Vienna		Austria	1090
2	BE005	Brussels		Belgium	1020
3	BE002	Ottignies		Belgium	1340
4	BE001	Sint-Niklaas		Belgium	9100
5	BG001	Shumen		Bulgaria	9700
6	BG008	Sofia		Bulgaria	1330
7	BG003	Sofia		Bulgaria	1407
8	BG006	Sofia		Bulgaria	1756
9	BG007	Sofia		Bulgaria	1784
10	BG004	Varna		Bulgaria	9003
11	BG005	Vratsa		Bulgaria	3000
12	CL005	Temuco		Chile	4810469
13	HR001	Zagreb		Croatia	10000
14	DK006	Aalborg		Denmark	9000
15	DK004	Herlev		Denmark	2730
16	DE008	Böhlen		Germany	4564
17	DE010	München		Germany	81377
18	HU004	Gyula		Hungary	5700
19	HU002	Miskolc		Hungary	3526
20	HU011	Nyiregyhaza		Hungary	4400
21	PL008	Bydgoszcz		Poland	85-796
22	PL012	Będzin		Poland	42 - 500
23	PL013	Chorzów		Poland	41-506
24	PL014	Dąbrowa Górnicza		Poland	41-300
25	PL003	Gdansk		Poland	80-208
26	PL010	Gliwice		Poland	44-100
27	PL015	Warszawa		Poland	01-231
28	PL002	Wloclawek		Poland	87-800
29	RO001	Brasov		Romania	500019
30	RO002	Cluj-Napoca		Romania	400015
31	RO009	Constanta		Romania	900591
32	RO011	Craiova		Romania	200347
33	RS001	Belgrade		Serbia	11000
34	RS003	Belgrade		Serbia	11000
35	RS002	Sremska Kamenica		Serbia	21204
36	RS005	Zrenjanin		Serbia	23000
37	SK007	Bratislava		Slovakia	81107
38	SK004	Bratislava		Slovakia	851 07
39	SK001	Prešov		Slovakia	080 01
40	SK005	Pruské		Slovakia	018 52
41	ES012	Barcelona		Spain	8022
42	UK004	Leeds		United Kingdom	LS14 6UH

Sponsors and Collaborators

• Tris Pharma, Inc.

Investigators

• Study Director: Director Clinical Trials, Grünenthal GmbH

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tris Pharma, Inc.
• ClinicalTrials.gov Identifier: NCT01964378
• Other Study ID Numbers: KF6005/07; 2012-001316-35; U1111-1143-1808
• First Posted: Oct 17, 2013
• Last Update Posted: Jul 15, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tris Pharma, Inc.: cancer pain; neuropathic related cancer pain; morphine; cebranopadol (GRT6005); Numerical Rating Scale
• Additional relevant MeSH terms: Chronic Pain; Morphine

Study Results

Participant Flow

Recruitment Details	The trial started on 29 Oct 2013 with the enrollment of the first subject and was completed on 16 Oct 2015 when the last subject completed the last follow-up examination.
Pre-assignment Detail	200 Participants were enrolled (signed consent): enrollment failures did not meet inclusion or met exclusion criteria (62 participants), died (1), withdrew consent (4), or met other reasons (1). 132 Participants were allocated to treatment and 126 were dosed (Safety Set).

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Period Title: Overall Study
STARTED	66	66
Participants Treated (Safety Set)	65	61
COMPLETED	41	45
NOT COMPLETED	25	21

Baseline Characteristics

Arm/Group Title	Cebranopadol	Morphine Prolonged Release	Total
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.	Total of all reporting groups
Overall Participants	65	61	126
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	36 55.4%	35 57.4%	71 56.3%
>=65 years	29 44.6%	26 42.6%	55 43.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.8 (9.18)	61 (10.64)	62.4 (9.98)
Sex: Female, Male (Count of Participants)
Female	27 41.5%	22 36.1%	49 38.9%
Male	38 58.5%	39 63.9%	77 61.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.1%	0 0%	2 1.6%
Not Hispanic or Latino	58 89.2%	60 98.4%	118 93.7%
Unknown or Not Reported	5 7.7%	1 1.6%	6 4.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	65 100%	61 100%	126 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Romania	2 3.1%	1 1.6%	3 2.4%
Hungary	4 6.2%	5 8.2%	9 7.1%
Spain	1 1.5%	0 0%	1 0.8%
Austria	2 3.1%	2 3.3%	4 3.2%
Belgium	0 0%	1 1.6%	1 0.8%
Denmark	1 1.5%	2 3.3%	3 2.4%
Poland	16 24.6%	16 26.2%	32 25.4%
Slovakia	13 20%	13 21.3%	26 20.6%
Bulgaria	7 10.8%	4 6.6%	11 8.7%
Chile	2 3.1%	0 0%	2 1.6%
Serbia	3 4.6%	3 4.9%	6 4.8%
Germany	13 20%	14 23%	27 21.4%
Croatia	1 1.5%	0 0%	1 0.8%
Prior opioid treatment (Count of Participants)
WHO Step II analgesic	27 41.5%	28 45.9%	55 43.7%
WHO Step III analgesic excluding morphine	22 33.8%	21 34.4%	43 34.1%
Morphine	16 24.6%	12 19.7%	28 22.2%
ECOG Status (Count of Participants)
Status 0	17 26.2%	13 21.3%	30 23.8%
Status 1	30 46.2%	30 49.2%	60 47.6%
Status 2	18 27.7%	18 29.5%	36 28.6%
Status 3	0 0%	0 0%	0 0%
Status 4	0 0%	0 0%	0 0%
Status 5	0 0%	0 0%	0 0%
Cancer history - Stage IV (Count of Participants)
Stage IV	52 80%	45 73.8%	97 77%
Other	13 20%	16 26.2%	29 23%
Participants with a neuropathic pain component (Count of Participants)
Neuropathic component present	28 43.1%	24 39.3%	52 41.3%
No neuropathic component present	37 56.9%	37 60.7%	74 58.7%
Participants with a visceral pain component (Count of Participants)
Visceral pain present	31 47.7%	28 45.9%	59 46.8%
No visceral pain present	34 52.3%	33 54.1%	67 53.2%
Participants with a somatic pain component (Count of Participants)
Somatic pain component present	39 60%	34 55.7%	73 57.9%
No somatic pain component present	26 40%	27 44.3%	53 42.1%
Height (meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meter]	1.6889 (0.09097)	1.692 (0.07952)	1.6904 (0.08529)
Weight (kilogram(s)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram(s)]	73.52 (14.126)	71.23 (12.807)	72.41 (13.499)
Body Mass Index (BMI) (kilogram(s)/square meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram(s)/square meter]	25.74 (4.39)	24.84 (4.022)	25.31 (4.223)
Baseline pain intensity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.23 (1.000)	6.30 (1.230)	6.26 (1.114)
Worst daily pain intensity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.27 (1.222)	7.29 (1.117)	7.28 (1.168)
Time since cancer pain onset (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	62.25 (111.915)	60.22 (79.792)	61.27 (97.313)

Outcome Measures

1. Primary Outcome

Title	Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Per Protocol Set)
Description	Morphine sulfate immediate release (IR) 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.
Time Frame	The last 2 weeks of the expected 6-week treatment period.

Outcome Measure Data

Analysis Population Description

The Per Protocol Set (PPS) describes a subset of subjects in the Full Analysis Set (FAS). The PPS included all allocated participants who completed at least 2 weeks of treatment in the maintenance phase and had no major protocol deviations relevant for efficacy evaluations.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	43	45
Least Squares Mean (Standard Error) [milligram(s)/24 hours]	4.25 (1.7)	8.92 (1.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cebranopadol, Morphine Prolonged Release
	Comments	The MMRM (mixed model repeated measurement) model includes fixed effects of pooled country, treatment, week, treatment-by-week interaction, history of opioid intake, baseline pain intensity as covariate & subject-specific random effects. Dependent variable being the weekly average rescue medication intake.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin of 8 mg. Assuming equal mean values in both the cebranopadol and morphine groups, it was calculated that for the final analysis of the primary endpoint 170 subjects would have been required per treatment arm in the Per Protocol Set using a 2 sample-t-test for 90% power and a 1-sided significance level of α = 0.025.
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	point-estimate
	Estimated Value	-7.48
	Confidence Interval	(2-Sided) 95%; -12.05 to -2.918
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.3
	Estimation Comments

2. Primary Outcome

Title	Average Amount of Daily Rescue Medication at the End of the Maintenance Period (Full Analysis Set)
Description	Morphine sulfate IR 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.
Time Frame	The last 2 weeks of the expected 6-week treatment period.

Outcome Measure Data

Analysis Population Description

The Full Analysis Set includes all allocated participants who took at least 1 dose of the investigational medicinal product (IMP) and had at least 1 day with information for the amount of rescue medication intake after the first intake of double-blind IMP (study drug).

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Least Squares Mean (Standard Error) [milligram(s)/24 hours]	3.46 (1.71)	10.94 (1.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cebranopadol, Morphine Prolonged Release
	Comments	The primary endpoint will be analyzed by means of a mixed-effects model for repeated measures (MMRM), based on observed case weekly averages. Under the assumption of a missing-at-random missing data mechanism, an MMRM does not require an imputation of missing data and can obtain an improved estimate of variance.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin of 8 mg. Assuming that 65% of the participants are available for the Per Protocol Set, a total of 524 participant would have to be allocated (randomized) to IMP. With 262 participants per group in the Full Analysis Set, the non-inferiority of cebranopadol as compared to morphine sulfate prolonged release could have been demonstrated with at least 98% power and a 1-sided significance level of α = 0.025.
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	MMRM model: fixed effects of pooled country, treatment, week, treatment-by-week interaction, opioid intake history, baseline pain intensity as covariate & subject-specific random effects. Dependent variable: weekly average rescue medication intake.
	Method	MMRM (mixed model repeated measurement)
	Comments	For participants with no data in the Maintenance Phase, the average amount of rescue medication over the last 3 days of titration was imputed.
Method of Estimation	Estimation Parameter	point-estimate
	Estimated Value	-4.67
	Confidence Interval	(2-Sided) 95%; -9.245 to -0.099
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.3
	Estimation Comments	Non-inferiority of cebranopadol compared with morphine will be established if the upper bound of the resulting 95% confidence interval for the average treatment difference is below the non-inferiority margin of 8mg.

3. Secondary Outcome

Title	Proportion of Participants With Clinically Relevant Pain Reduction at the End of the Maintenance Period
Description	Each participant indicated the level of pain on an 11-point numerical rating scale (NRS), where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The participants entered their pain intensity in their diary on a daily basis. The pain intensity score in the 2 weeks prior to the final evaluation in the maintenance period was compared with the baseline, the baseline pain intensity was calculated based on the 3 days prior to treatment allocation. The definition of a clinically relevant pain reduction (yes/no) was the presence of at least 1 of the 3 following conditions: Average pain intensity (i.e., average of the 24-hour pain intensities over the last 2 weeks of the Maintenance Phase) of less than 4 points on the 11-point NRS, or Reduction in average pain intensity by at least 30% (compared to the baseline assessment), or Reduction in average pain intensity by at least 2 points (compared to the baseline assessment).
Time Frame	The last 2 weeks of the expected 6-week treatment period.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Clinically relevant pain reduction (Yes/No) in Maintenance Week 3 and Week 4. Missing data were imputed using a multiple imputation on the weekly average pain intensity. Participants that discontinued from the trial due to a lack of efficacy were classified as non-responders.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Clinically relevant pain reduction (Yes)	48 73.8%	51 83.6%
Clinically relevant pain reduction (No)	16 24.6%	10 16.4%

4. Other Pre-specified Outcome

Title	Change in Weekly Mean of the Daily Average Pain Intensity Score From Baseline
Description	Participants will be asked: "Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours." every day in the morning. They will score their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The weekly mean value of the 24-h average pain intensity will be calculated as a mean score of these daily entries of average pain intensity for each trial week.
Time Frame	Baseline; last 2 weeks of the expected 6-week treatment period

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Mean (Standard Deviation) [units on a scale]	-3.4 (2.11)	-3.2 (1.60)

5. Other Pre-specified Outcome

Title	Response Rate to Treatment
Description	Pain intensity will be recorded daily by each participant in the morning on an 11-point Numerical Rating Scale, ranging from 0 (no pain) to 10 (worst imaginable pain). From this, the weekly average 24-hour pain intensity will be calculated. The number of participants with a 0, 10, 20, 30, up to a 100% reduction in weekly mean pain intensity will be reported over each week and over the last 2 weeks of the maintenance period.
Time Frame	Baseline; last 2 weeks of the expected 6-week treatment period

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Worsening in 24-hour pain or premature discontinuation due to lack of efficacy or Adverse Event was regarded a non-response, other missing data is imputed using last observation carried forward (LOCF).

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Non-responder	13 20%	9 14.8%
>= 0% pain reduction	51 78.5%	52 85.2%
>= 10% pain reduction	50 76.9%	52 85.2%
>= 20% pain reduction	44 67.7%	50 82%
>= 30% pain reduction	39 60%	42 68.9%
>= 40% pain reduction	31 47.7%	37 60.7%
>= 50% pain reduction	26 40%	27 44.3%
>= 60% pain reduction	19 29.2%	18 29.5%
>= 70% pain reduction	13 20%	11 18%
>= 80% pain reduction	10 15.4%	8 13.1%
>= 90% pain reduction	5 7.7%	2 3.3%
100% pain reduction	3 4.6%	2 3.3%

6. Other Pre-specified Outcome

Title	Overall Score of the Neuropathic Pain Symptom Inventory (NPSI)
Description	Participants with neuropathic pain (determined by the completion of the Douleur Neuropathique En 4 Questions [DN4] questionnaire at allocation) rated their symptoms of neuropathic pain on the Neuropathic Pain Symptom Inventory (NPSI). Ten out of 12 questions were answered on an 11-point scale 0 (no symptom present) to 10 (worst imaginable); 2 out of 12 questions assessed the duration of spontaneous pain and the number of pain attacks and were answered by selecting 1 of 5 possible responses. Mean scores of NPSI were calculated. The overall NPSI score was calculated by the summation of all responses in the ranges between 0 (all symptoms absent) and 1 (all symptoms present and at the worst intensity). A negative change indicates that the intensity of all the neuropathic symptom components have decreased since the start of treatment.
Time Frame	Baseline; End-of-Treatment Visit (Week 6)

Outcome Measure Data

Analysis Population Description

Subset of participants that were assessed to have Neuropathic Pain (using the DN4 questionnaire) at baseline.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	11	17
Mean (Standard Deviation) [units on a scale]	-0.15 (0.126)	-0.10 (0.129)

7. Other Pre-specified Outcome

Title	EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Weighted EQ-5D Health Status Index
Description	The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. The participants will answer 5 questions on 5 dimensions of their health related quality of life: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each question has 3 possible answers reflecting 3 levels of impact on the quality of life. The weighted EQ-5D health status index values are derived and reported as change from baseline. The responses to the 5 EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score (with 1 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group. A positive change indicates an improvement.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set; means (standard deviations) are presented for the number of participants at the End-of-Treatment Visit with respective data available.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	49	52
Mean (Standard Deviation) [units on a scale]	0.1 (0.331)	0.2 (0.287)

8. Other Pre-specified Outcome

Title	EuroQol-5 Dimension (EQ-5D) Health Questionnaire: Visual Analog Scale (VAS) Score
Description	The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set; means (standard deviations) are presented for the number of participants at the End-of-Treatment Visit with respective data available.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	47	52
Mean (Standard Deviation) [units on a scale]	-0.1 (22.983)	15.1 (24.305)

9. Other Pre-specified Outcome

Title	Change in the Physical and Mental Component Scores From the Short Form 12® Health Survey (SF-12)
Description	The Physical and Mental Component Scores are calculated from the responses by participants to 12 questions. These 12 questions cover 8 domains, (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role participation with emotional health problems, and mental health) that a participant was asked to rate over the last week. Questions are scored on a Likert-scale. The Physical and Mental Component Scores were not derived as the trial was terminated. Changes in the individual item scores are therefore reported. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state. If the values are positive there was an improvement. The higher the value the greater the improvement.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). End of Treatment (End of Maintenance Period Visit).

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Physical function	7.1 (31.04)	9.9 (24.68)
Role physical	5.1 (27.23)	6.4 (24.10)
Bodily pain	10.2 (29.28)	9.0 (31.43)
General health	5.4 (20.13)	9.2 (27.38)
Vitality	0.0 (25.00)	10.4 (28.77)
Social function	7.1 (28.87)	5.2 (33.38)
Role emotional	3.3 (28.39)	0.2 (27.57)
Mental health	3.1 (20.18)	6.1 (21.32)

10. Other Pre-specified Outcome

Title	Patient Global Impression of Change (PGIC)
Description	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period compared to his condition prior to the start of treatment. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). End of Treatment (End of Maintenance Period Visit). Participants with data available.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	56	56
Very much improved	5 7.7%	3 4.9%
Much improved	18 27.7%	17 27.9%
Minimally improved	17 26.2%	17 27.9%
No change	4 6.2%	10 16.4%
Minimally worse	4 6.2%	4 6.6%
Much worse	2 3.1%	2 3.3%
Very much worse	0 0%	0 0%
Missing	6 9.2%	3 4.9%

11. Other Pre-specified Outcome

Title	Clinical Global Impression of Change (CGIC)
Description	In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change in patient's condition over the treatment period as compared to patient's condition prior to the start of treatment. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). End of Treatment (End of Maintenance Period Visit). Participants with data available.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	56	56
Very much improved	8 12.3%	4 6.6%
Much improved	20 30.8%	26 42.6%
Minimally improved	10 15.4%	9 14.8%
No change	7 10.8%	5 8.2%
Minimally worse	3 4.6%	6 9.8%
Much worse	2 3.1%	1 1.6%
Very much worse	0 0%	2 3.3%
Missing	6 9.2%	3 4.9%

12. Other Pre-specified Outcome

Title	Overall Score of the Patient Assessment of Constipation Symptoms (PAC-SYM)
Description	The PAC-SYM is a 12-item self-administered questionnaire that assesses the severity of constipation-related symptoms during past 2 weeks. Items are rated on a 5-point Likert scale, where 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.The PAC-SYM contains 3 subscales: stool symptoms (5 items), abdominal symptoms (4 items), rectal symptoms (3 items). If at least 6 items are assessed, the PAC-SYM overall score is calculated as the sum of the scores of all non-missing items divided by number of non-missing items. The minimum overall score is 0, the maximum overall score is 4. If more than 6 items are missing, no overall score is calculated. Changes from baseline for the overall score are presented. If the changes in the overall (or subscale) scores are positive then there is a worsening in symptoms associated with constipation.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Safety Set; number of participants with data available.

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	49	53
Mean (Standard Deviation) [units on a scale]	0.07 (0.536)	0.07 (0.632)

13. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS)

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Mean (Standard Deviation) [units on a scale]	-3.3 (2.68)	-3.3 (2.11)

14. Other Pre-specified Outcome

Title	Change From Baseline to End-of-Treatment Visit in Chronic Pain Sleep Inventory (CPSI) Scores
Description	The CPSI measures 5 items on 100-mm visual analog scales: trouble falling asleep (CPSI1), needing sleep medication (CPSI2), awakened by pain during the night (CPSI3) and in the morning (CPSI4) [all with anchors for 0 = never and 100 = always], and overall quality of sleep (CPSI5) [with anchors of 0 = very poor and 100 = excellent]. The sleep problem index is the sum of items CPSI1, CPSI3 and CPSI4. The minimum sleep problem index is 0 mm, the maximum 300 mm, the higher the worse. For the overall quality of sleep, minimum and maximum are 0 and 100 mm, the higher the better. A decrease in the sleep problem index indicates an improvement as does an increase in the overall quality of sleep. Changes from baseline to the End-of-Treatment Visit of the Maintenance Phase (scheduled for Week 6) were calculated.
Time Frame	Baseline; End-of-Treatment Visit (6 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cebranopadol	Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.	Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
Measure Participants	64	61
Sleep Problem Index	-62.7 (77.91)	-53.7 (77.71)
Overall Quality of Sleep	20.5 (36.11)	8.1 (30.4)

Adverse Events

Time Frame	From first IMP intake up to day of last IMP in Week 6 + 3 weeks follow-up (max. 9 weeks in total). The All-Cause Mortality is reported for the Allocated Set. Serious and non-serious treatment emergent adverse events (i.e. events documented after the first dose of study medication and events which started before treatment and worsened after first dose of study medication) are reported for the Safety Set (all participants with at least one dose of study medication).
Arm/Group Title	Cebranopadol		Morphine Prolonged Release
Arm/Group Description	Once daily oral administration. 200, 400 or 600 µg film coated tablets. Dosage 200 µg to 1000 µg per day. Cebranopadol: Participant will take one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.		Twice daily oral administration. 15, 30 or 45 mg morphine sulfate capsules. Dosage 30 to 150 mg per day. Morphine Prolonged Release: Participant will take one or two morphine capsule(s) in the morning and in the evening and one or two placebo double-dummy cebranopadol-like tablet(s) in the morning.
All Cause Mortality
	Cebranopadol		Morphine Prolonged Release
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/66 (4.5%)		5/66 (7.6%)
Serious Adverse Events
	Cebranopadol		Morphine Prolonged Release
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/65 (21.5%)		11/61 (18%)
Blood and lymphatic system disorders
Anaemia	0/65 (0%)	0	1/61 (1.6%)	1
Cardiac disorders
Cardiac failure	0/65 (0%)	0	1/61 (1.6%)	1
Myocardial infarction	1/65 (1.5%)	1	0/61 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/65 (0%)	0	1/61 (1.6%)	1
Small intestinal obstruction	0/65 (0%)	0	1/61 (1.6%)	1
Vomiting	1/65 (1.5%)	1	1/61 (1.6%)	1
General disorders
Asthenia	0/65 (0%)	0	1/61 (1.6%)	1
Infections and infestations
Fungal infection	0/65 (0%)	0	1/61 (1.6%)	1
Infected skin ulcer	1/65 (1.5%)	1	0/61 (0%)	0
Pneumonia	1/65 (1.5%)	1	0/61 (0%)	0
Wound infection	0/65 (0%)	0	1/61 (1.6%)	1
Metabolism and nutrition disorders
Cachexia	0/65 (0%)	0	1/61 (1.6%)	1
Dehydration	1/65 (1.5%)	1	2/61 (3.3%)	2
Musculoskeletal and connective tissue disorders
Pathological fracture	1/65 (1.5%)	1	0/61 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	5/65 (7.7%)	5	7/61 (11.5%)	7
Metastases to central nervous system	1/65 (1.5%)	1	0/61 (0%)	0
Renal cancer	1/65 (1.5%)	1	0/61 (0%)	0
Nervous system disorders
Hemiparesis	1/65 (1.5%)	1	0/61 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/65 (0%)	0	1/61 (1.6%)	1
Respiratory tract haemorrhage	1/65 (1.5%)	1	0/61 (0%)	0
Other (Not Including Serious) Adverse Events
	Cebranopadol		Morphine Prolonged Release
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/65 (80%)		48/61 (78.7%)
Blood and lymphatic system disorders
Anaemia	3/65 (4.6%)	3	5/61 (8.2%)	5
Ear and labyrinth disorders
Vertigo	2/65 (3.1%)	2	4/61 (6.6%)	4
Gastrointestinal disorders
Constipation	8/65 (12.3%)	11	15/61 (24.6%)	15
Nausea	8/65 (12.3%)	11	10/61 (16.4%)	12
Vomiting	8/65 (12.3%)	13	5/61 (8.2%)	6
Diarrhoea	4/65 (6.2%)	4	5/61 (8.2%)	8
General disorders
Fatigue	7/65 (10.8%)	7	10/61 (16.4%)	10
Oedema peripheral	7/65 (10.8%)	8	0/61 (0%)	0
Asthenia	6/65 (9.2%)	6	8/61 (13.1%)	9
Pyrexia	4/65 (6.2%)	6	4/61 (6.6%)	5
Infections and infestations
Urinary tract infection	2/65 (3.1%)	2	6/61 (9.8%)	6
Metabolism and nutrition disorders
Decreased appetite	5/65 (7.7%)	5	9/61 (14.8%)	10
Nervous system disorders
Somnolence	6/65 (9.2%)	7	5/61 (8.2%)	5
Paraesthesia	4/65 (6.2%)	4	1/61 (1.6%)	1
Dizziness	2/65 (3.1%)	2	6/61 (9.8%)	6
Psychiatric disorders
Anxiety	4/65 (6.2%)	4	1/61 (1.6%)	1

Limitations/Caveats

As the enrollment was stopped for business reasons, only a fraction of the planned number of participants was enrolled; however, the trial still has a larger participant number per treatment than a majority of trials in cancer pain so far.

More Information

Certain Agreements

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

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