Cebranopadol Efficacy and Safety in Diabetic Patients Suffering From Chronic Pain Caused by Damage to the Nerves

• Sponsor: Tris Pharma, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01939366
• Collaborator: (none)
• Enrollment: 699
• Locations: 82
• Arms: 5
• Actual Duration (Months): 16
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this trial is to evaluate if cebranopadol is safe and can decrease pain in patients when compared to placebo (a tablet that does not contain active product) and when compared to a marketed product containing pregabalin (Lyrica®). Furthermore, this trial will be undertaken to find out if the patient's general health and well-being improves under trial treatment.

The concentrations of cebranopadol in the blood will be investigated to get a better understanding of how it is absorbed from the gut, distributed and broken down in the body, and eliminated from the body.

Condition or Disease	Intervention/Treatment	Phase
Chronic Pain; Diabetic Neuropathies; Diabetes Mellitus	Drug: Cebranopadol 100 µg; Drug: Cebranopadol 300 µg; Drug: Cebranopadol 600 µg; Drug: Pregabalin; Drug: Matching Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 699 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 Multiple Doses of Oral Cebranopadol in Subjects With Moderate to Severe Chronic Pain Due to Diabetic Peripheral Neuropathy.
• Actual Study Start Date: Sep 27, 2013
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 28, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cebranopadol 300 µg	Drug: Cebranopadol 300 µg; Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day.
Experimental: Cebranopadol 600 µg	Drug: Cebranopadol 600 µg; Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day.
Active Comparator: Pregabalin	Drug: Pregabalin; Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.; Other Names: Lyrica®
Placebo Comparator: Matching Placebo	Drug: Matching Placebo; Placebo will be matched to pregabalin and cebranopadol.
Experimental: Cebranopadol 100 µg	Drug: Cebranopadol 100 µg; Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day.

Outcome Measures

Primary Outcome Measures

1. Change in Average Pain Intensity. [Baseline; to End of Week 6 of the Maintenance Phase]

   Participants will be asked to record their pain intensity in the evening. Participants are asked to rate how much pain they had on average in the past 24 hours. The participant scores 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". Baseline average pain scores are calculated from the averages of all scores recorded during the 3 days prior to randomization. The average pain at week 6 will be the average pain scores calculated from all pain scores measured during week 6.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• written signed informed consent

• type 1 or type 2 diabetes mellitus

• clinical diagnosis of painful Diabetic Polyneuropathic Neuropathy (DPN) with symptoms and signs for at least 3 months

• must require medication (e.g., non-opioids or opioids up to an equivalent dose of 160 mg oral morphine/day) for the treatment of pain due to DPN for at least 1 month prior to Visit 1 and must be dissatisfied with the current treatment (in terms of efficacy and/or tolerability). Medication for the treatment of pain due to DPN should be required on at least 4 of 7 consecutive days.

• blood glucose to be controlled by a diet, oral anti-hyperglycemic medication, and/or insulin for at least 3 months prior. Glycosylated hemoglobin (HbA1C) should not be greater than 11%

• baseline pain intensity score greater or equal to 5 on the 11-point Numerical Rating Scale (NRS) without intake of any analgesic at allocation. For each of the last 3 days prior to allocation of treatment, a 24 hour NRS score greater or equal to 4 is required

• women of childbearing potential must have a negative urine pregnancy test at enrollment

• using medically acceptable and highly effective methods of birth control (and willing to use them during the trial).

Exclusion Criteria:

• presence of other pain that could confound the painful Diabetic Polyneuropathy (DPN) assessments, e.g. pain due to nerve entrapment (tarsal tunnel syndrome, osteoarthritis of the knee etc), peripheral vascular disease, radiculopathy, plantar fasciitis, tendonitis, mononeuritis multiplex, postherpetic neuralgia, complex regional pain syndrome, or fibromyalgia.

• neuropathy due to etiologies other than diabetes, e.g. autoimmune disorders, inflammatory neuropathies (e.g. chronic inflammatory demyelinating polyneuropathy), thyroid disease or endocrine disorders (other than diabetes), heavy metal or toxic neuropathy, nutritional deficiency, metabolic disorders, vasculitis, infections, injury, or paraneoplastic syndromes.

• severe or extensive diabetic ulcers or amputations due to diabetes

• Charcot's joints due to diabetes.

• any clinically significant disease or laboratory findings, e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, metabolic, neurological, or psychiatric disorders.

• inability to comply with the protocol and with the intake of trial medication that, in the investigator's opinion, might indicate that the participant is unsuitable for the trial.

• conditions that require treatment with medication that is not allowed to be taken during the trial

• previous or current alcohol or drug abuse or opioid dependency.

• severe functional hepatic impairment corresponding to Child-Pugh classification C.

• history of acute hepatitis

• impaired renal function, a creatinine clearance less than 60 mL/min at the enrollment (Cockcroft-Gault calculated).

• history of any major gastrointestinal procedures (e.g., gastric bypass) or gastrointestinal conditions (e.g. acute diarrhea, blind loop syndrome, gastric dumping syndrome, Whipple's disease) that might affect the absorption or metabolism of cebranopadol or pregabalin.

• risk factors for or history of torsade de pointes and/or marked prolongation of the QT interval (e.g. heart failure, hypokalemia, or bradycardia).

• history of seizure disorder and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the discretion of the investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	US002	Mesa	Arizona	United States	85215
2	US001	Garden Grove	California	United States	92843
3	US019	Laguna Hills	California	United States	92653
4	US014	National City	California	United States	91950
5	US007	Orange	California	United States	92868
6	US011	Hialeah	Florida	United States	33012
7	US012	Miami	Florida	United States	33135
8	US009	Orlando	Florida	United States	32806
9	US004	Blackfoot	Idaho	United States	83221
10	US006	Elgin	Illinois	United States	60123
11	US016	West Long Branch	New Jersey	United States	07764
12	US008	Brooklyn	New York	United States	11229
13	US005	Brooklyn	New York	United States	11235
14	US021	New York	New York	United States	10128
15	US003	West Jordan	Utah	United States	84088
16	AT007	Graz		Austria	8036
17	AT005	Salzburg		Austria	5020
18	AT004	Senftenberg		Austria	3541
19	AT002	Vienna		Austria	1010
20	AT003	Vienna		Austria	1060
21	AT001	Vienna		Austria	1090
22	AT006	Vienna		Austria	1160
23	DK005	Aalborg		Denmark	9100
24	DK003	Aarhus		Denmark	8000
25	DK002	Copenhagen		Denmark	2000
26	DK001	Odense		Denmark	5000
27	FR008	Corbeil Essonnes		France	91100
28	FR001	Lille		France	59037
29	FR007	Limoges cedex		France	87042
30	FR005	Montauban cedex		France	82013
31	FR002	Nantes		France	44200
32	FR004	Orléans		France	45000
33	FR006	Paris		France	75004
34	DE018	Aschaffenburg		Germany	63739
35	DE003	Bad Oeynhausen		Germany	32545
36	DE005	Berlin		Germany	10115
37	DE023	Berlin		Germany	10117
38	DE031	Berlin		Germany	10787
39	DE004	Berlin		Germany	12627
40	DE025	Berlin		Germany	13125
41	DE013	Bochum		Germany	44787
42	DE033	Dresden		Germany	01069
43	DE017	Düsseldorf		Germany	40210
44	DE012	Düsseldorf		Germany	40212
45	DE010	Essen		Germany	45136
46	DE034	Essen		Germany	45277
47	DE022	Essen		Germany	45355
48	DE006	Frankfurt		Germany	60596
49	DE007	Görlitz		Germany	02826
50	DE021	Hamburg		Germany	20253
51	DE020	Hannover		Germany	30159
52	DE016	Karlsruhe		Germany	76199
53	DE002	Kiel		Germany	24119
54	DE030	Künzing		Germany	94550
55	DE008	Leipzig		Germany	04103
56	DE009	Leipzig		Germany	04109
57	DE015	Magdeburg		Germany	39104
58	DE032	Magdeburg		Germany	39112
59	DE001	Mainz		Germany	55116
60	DE028	Mayen		Germany	56727
61	DE027	München		Germany	81477
62	DE014	Münster		Germany	48145
63	DE011	Neuss		Germany	41460
64	DE024	Schwerin		Germany	19055
65	IT005	Ancona		Italy	60127
66	IT004	Milano		Italy	20162
67	IT001	Rome		Italy	00133
68	IT002	Turin		Italy	10126
69	NL007	Amsterdam		Netherlands	1091 AC
70	NL004	Apeldoorn		Netherlands	7334 DZ
71	NL005	Beek		Netherlands	6191 JW
72	NL001	Eindhoven		Netherlands	5623 EJ
73	NL002	Rotterdam		Netherlands	3039 BD
74	NL006	Venlo		Netherlands	5912 BL
75	NL008	Zwijndrecht		Netherlands	3331 LZ
76	NL003	Zwolle		Netherlands	8025 AB
77	ES001	Cuenca		Spain	16002
78	ES011	Madrid		Spain	28031
79	ES010	Madrid		Spain	28040
80	ES009	Madrid		Spain	28041
81	ES003	Toledo		Spain	45600
82	ES006	Valencia		Spain	46010

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: NCT01939366
• Other Study ID Numbers: KF6005/08; 2013-000473-68; U1111-1151-4331
• First Posted: Sep 11, 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: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tris Pharma, Inc.: Painful Diabetic Peripheral Neuropathy
• Additional relevant MeSH terms: Diabetic Neuropathies; Chronic Pain; Pregabalin

Study Results

Participant Flow

Recruitment Details	The trial started on 27 Sep 2013 with the enrollment of the first participants and was completed on 28 Jan 2015 when the last participant completed the last follow-up examination according to the protocol.
Pre-assignment Detail	Of the 699 participants enrolled 370 participants were not allocated (322 did not meet the eligibility criteria, 29 withdrew consent, 6 due to Adverse Events, 2 due to protocol deviations, 11 due to other reasons). 13 participants allocated to treatment were excluded from the PPS, FAS & SAF analyses populations due to GCP non-compliance at 2 sites.

Arm/Group Title	Cebranopadol 100 µg	Cebranopadol 300 µg	Cebranopadol 600 µg	Pregabalin	Matching Placebo
Arm/Group Description	Cebranopadol 100 µg: Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day.	Cebranopadol 300 µg: Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day.	Cebranopadol 600 µg: Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day.	Pregabalin: Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.	Matching Placebo: Placebo will be matched to pregabalin and cebranopadol.
Period Title: Overall Study
STARTED	66	64	65	68	66
Allocated Set Excl. Non-compliant Sites	64	61	63	65	63
Safety Set	64	61	62	65	62
Full Analysis Set	64	60	61	65	62
Per Protocol Set	58	55	50	51	49
COMPLETED	52	41	27	51	48
NOT COMPLETED	14	23	38	17	18

Baseline Characteristics

Arm/Group Title	Cebranopadol 100 µg	Cebranopadol 300 µg	Cebranopadol 600 µg	Pregabalin	Matching Placebo	Total
Arm/Group Description	Cebranopadol 100 µg: Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day.	Cebranopadol 300 µg: Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day.	Cebranopadol 600 µg: Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day.	Pregabalin: Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.	Matching Placebo: Placebo will be matched to pregabalin and cebranopadol.	Total of all reporting groups
Overall Participants	64	61	62	65	62	314
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.2 (8.6)	61.6 (8.7)	62.2 (8.1)	61.7 (9.9)	63.3 (10.3)	62.2 (9.1)
Sex: Female, Male (Count of Participants)
Female	20 31.3%	23 37.7%	22 35.5%	16 24.6%	13 21%	94 29.9%
Male	44 68.8%	38 62.3%	40 64.5%	49 75.4%	49 79%	220 70.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 10.9%	6 9.8%	6 9.7%	10 15.4%	5 8.1%	34 10.8%
Not Hispanic or Latino	57 89.1%	55 90.2%	56 90.3%	55 84.6%	57 91.9%	280 89.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 1.6%	2 3.3%	1 1.6%	0 0%	0 0%	4 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 3.1%	0 0%	2 3.2%	4 6.2%	1 1.6%	9 2.9%
White	61 95.3%	58 95.1%	57 91.9%	58 89.2%	61 98.4%	295 93.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.6%	2 3.2%	3 4.6%	0 0%	6 1.9%
Region of Enrollment (participants) [Number]
Austria	5 7.8%	6 9.8%	5 8.1%	6 9.2%	5 8.1%	27 8.6%
Netherlands	3 4.7%	3 4.9%	4 6.5%	2 3.1%	4 6.5%	16 5.1%
United States	13 20.3%	10 16.4%	9 14.5%	13 20%	10 16.1%	55 17.5%
Denmark	2 3.1%	2 3.3%	2 3.2%	1 1.5%	2 3.2%	9 2.9%
Italy	2 3.1%	2 3.3%	2 3.2%	2 3.1%	1 1.6%	9 2.9%
France	7 10.9%	7 11.5%	8 12.9%	8 12.3%	8 12.9%	38 12.1%
Germany	31 48.4%	30 49.2%	30 48.4%	32 49.2%	31 50%	154 49%
Spain	1 1.6%	1 1.6%	2 3.2%	1 1.5%	1 1.6%	6 1.9%
Height (meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meter]	1.721 (0.098)	1.736 (0.092)	1.717 (0.104)	1.736 (0.110)	1.736 (0.076)	1.729 (0.097)
Weight (kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram]	95.77 (15.62)	96.51 (18.12)	93.72 (16.05)	92.25 (17.28)	99.00 (15.99)	95.42 (16.69)
BMI (kilogram per square meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter]	32.30 (4.41)	31.87 (4.39)	31.70 (4.29)	30.66 (5.26)	32.80 (4.53)	31.86 (4.62)
Pain Assessment - Average 24-hour pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.92 (1.34)	6.80 (1.37)	6.80 (1.25)	6.78 (1.22)	6.84 (1.15)	6.83 (1.26)
Pain Assessment - Worst 24-hour pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.41 (1.36)	7.32 (1.28)	7.38 (1.21)	7.32 (1.16)	7.33 (1.14)	7.35 (1.23)
Pain Assessment - Current Morning Pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.60 (1.58)	6.58 (1.53)	6.44 (1.46)	6.61 (1.44)	6.58 (1.48)	6.56 (1.49)
Pain Assessment - Current Evening Pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.98 (1.50)	6.87 (1.46)	6.68 (1.33)	6.75 (1.36)	6.55 (1.34)	6.80 (1.40)

Outcome Measures

1. Primary Outcome

Title	Change in Average Pain Intensity.
Description	Participants will be asked to record their pain intensity in the evening. Participants are asked to rate how much pain they had on average in the past 24 hours. The participant scores 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". Baseline average pain scores are calculated from the averages of all scores recorded during the 3 days prior to randomization. The average pain at week 6 will be the average pain scores calculated from all pain scores measured during week 6.
Time Frame	Baseline; to End of Week 6 of the Maintenance Phase

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Mixed-effects model for repeated measures (MMRM).

Arm/Group Title	Cebranopadol 100 µg	Cebranopadol 300 µg	Cebranopadol 600 µg	Pregabalin	Matching Placebo
Arm/Group Description	Cebranopadol 100 µg: Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day.	Cebranopadol 300 µg: Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day.	Cebranopadol 600 µg: Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day.	Pregabalin: Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.	Matching Placebo: Placebo will be matched to pregabalin and cebranopadol.
Measure Participants	64	60	58	64	61
Least Squares Mean (95% Confidence Interval) [units on a scale]	-2.24	-2.28	-2.56	-2.79	-1.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cebranopadol 100 µg, Matching Placebo
	Comments	The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0621
	Comments	Due to the exploratory character of this trial, no multiple testing adjustment for control of the false positive rate was applied.
	Method	Mixed Models Analysis
	Comments	The analysis consisted of the contrasts (mixed model Wald tests) of individual cebranopadol doses versus placebo during Week 6 of Maintenance Phase.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 95%; -1.43 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.37
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cebranopadol 300 µg, Matching Placebo
	Comments	The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0564
	Comments	Due to the exploratory character of this trial, no multiple testing adjustment for control of the false positive rate was applied.
	Method	Mixed Models Analysis
	Comments	The analysis consisted of the contrasts (mixed model Wald tests) of individual cebranopadol doses versus placebo during Week 6 of Maintenance Phase.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.74
	Confidence Interval	(2-Sided) 95%; -1.50 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.39
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cebranopadol 600 µg, Matching Placebo
	Comments	The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0153
	Comments	Due to the exploratory character of this trial, no multiple testing adjustment for control of the false positive rate was applied.
	Method	Mixed Models Analysis
	Comments	The analysis consisted of the contrasts (mixed model Wald tests) of individual cebranopadol doses versus placebo during Week 6 of Maintenance Phase.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.01
	Confidence Interval	(2-Sided) 95%; -1.83 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.41
	Estimation Comments

Adverse Events

Time Frame	Safety Analysis Set Baseline Visit (Day 1) to End of Maintenance Phase (Day 57).
Arm/Group Title	Cebranopadol 100 µg		Cebranopadol 300 µg		Cebranopadol 600 µg		Pregabalin		Matching Placebo
Arm/Group Description	Cebranopadol 100 µg: Participants randomized to 100 μg cebranopadol will start with 100 μg per day and will remain on 100 µg per day.		Cebranopadol 300 µg: Participants randomized to 300 μg cebranopadol will start with 100 μg per day and increase to 300 µg per day on day 4 and will remain on 300 µg per day.		Cebranopadol 600 µg: Participants randomized to 600 μg cebranopadol will start with 200 μg per day and increase to 400 µg per day on day 4 and to 600 µg on day 7, thereafter they will remain on 600 µg per day.		Pregabalin: Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.		Matching Placebo: Placebo will be matched to pregabalin and cebranopadol.
All Cause Mortality
	Cebranopadol 100 µg		Cebranopadol 300 µg		Cebranopadol 600 µg		Pregabalin		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/61 (0%)		0/62 (0%)		0/65 (0%)		0/62 (0%)
Serious Adverse Events
	Cebranopadol 100 µg		Cebranopadol 300 µg		Cebranopadol 600 µg		Pregabalin		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/64 (1.6%)		2/61 (3.3%)		4/62 (6.5%)		1/65 (1.5%)		2/62 (3.2%)
Gastrointestinal disorders
Abdominal Pain	0/64 (0%)		0/61 (0%)		1/62 (1.6%)		0/65 (0%)		1/62 (1.6%)
Diverticulum Intestinal Haemorrhagic	0/64 (0%)		0/61 (0%)		0/62 (0%)		1/65 (1.5%)		0/62 (0%)
Gastrooesophageal Reflux Disease	0/64 (0%)		0/61 (0%)		1/62 (1.6%)		0/65 (0%)		0/62 (0%)
Vomiting	0/64 (0%)		0/61 (0%)		2/62 (3.2%)		0/65 (0%)		0/62 (0%)
General disorders
Peripheral Swelling	0/64 (0%)		0/61 (0%)		0/62 (0%)		0/65 (0%)		1/62 (1.6%)
Metabolism and nutrition disorders
Dehydration	0/64 (0%)		0/61 (0%)		1/62 (1.6%)		0/65 (0%)		0/62 (0%)
Diabetes Mellitus	0/64 (0%)		1/61 (1.6%)		0/62 (0%)		0/65 (0%)		0/62 (0%)
Nervous system disorders
Hypoglycaemic Coma	0/64 (0%)		0/61 (0%)		1/62 (1.6%)		0/65 (0%)		0/62 (0%)
Renal and urinary disorders
Renal Failure Acute	0/64 (0%)		1/61 (1.6%)		0/62 (0%)		0/65 (0%)		0/62 (0%)
Vascular disorders
Haematoma	1/64 (1.6%)		0/61 (0%)		0/62 (0%)		0/65 (0%)		0/62 (0%)
Other (Not Including Serious) Adverse Events
	Cebranopadol 100 µg		Cebranopadol 300 µg		Cebranopadol 600 µg		Pregabalin		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/64 (73.4%)		50/61 (82%)		53/62 (85.5%)		49/65 (75.4%)		43/62 (69.4%)
Gastrointestinal disorders
Abdominal pain upper	0/64 (0%)		6/61 (9.8%)		0/62 (0%)		0/65 (0%)		2/62 (3.2%)
Constipation	3/64 (4.7%)		6/61 (9.8%)		7/62 (11.3%)		6/65 (9.2%)		2/62 (3.2%)
Diarrhoea	4/64 (6.3%)		2/61 (3.3%)		3/62 (4.8%)		2/65 (3.1%)		5/62 (8.1%)
Dry mouth	1/64 (1.6%)		1/61 (1.6%)		8/62 (12.9%)		1/65 (1.5%)		1/62 (1.6%)
Nausea	6/64 (9.4%)		22/61 (36.1%)		16/62 (25.8%)		6/65 (9.2%)		6/62 (9.7%)
Vomiting	2/64 (3.1%)		10/61 (16.4%)		17/62 (27.4%)		1/65 (1.5%)		2/62 (3.2%)
General disorders
Fatigue	8/64 (12.5%)		11/61 (18%)		10/62 (16.1%)		5/65 (7.7%)		2/62 (3.2%)
Oedema peripheral	3/64 (4.7%)		3/61 (4.9%)		1/62 (1.6%)		6/65 (9.2%)		1/62 (1.6%)
Infections and infestations
Bacteriuria	5/64 (7.8%)		3/61 (4.9%)		3/62 (4.8%)		6/65 (9.2%)		6/62 (9.7%)
Nasopharyngitis	3/64 (4.7%)		1/61 (1.6%)		1/62 (1.6%)		5/65 (7.7%)		6/62 (9.7%)
Investigations
Weight increased	0/64 (0%)		0/61 (0%)		0/62 (0%)		5/65 (7.7%)		1/62 (1.6%)
Nervous system disorders
Dizziness	8/64 (12.5%)		10/61 (16.4%)		21/62 (33.9%)		12/65 (18.5%)		6/62 (9.7%)
Headache	3/64 (4.7%)		6/61 (9.8%)		3/62 (4.8%)		4/65 (6.2%)		2/62 (3.2%)
Somnolence	3/64 (4.7%)		8/61 (13.1%)		8/62 (12.9%)		3/65 (4.6%)		1/62 (1.6%)
Tremor	1/64 (1.6%)		1/61 (1.6%)		1/62 (1.6%)		4/65 (6.2%)		0/62 (0%)
Psychiatric disorders
Depressed mood	1/64 (1.6%)		1/61 (1.6%)		2/62 (3.2%)		0/65 (0%)		4/62 (6.5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/64 (4.7%)		8/61 (13.1%)		6/62 (9.7%)		1/65 (1.5%)		2/62 (3.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The sponsor reserves the right to review any proposed presentation of the results of this trial before they are submitted for publication or public disclosure. Neither party has the right to prohibit publication or public disclosure unless it can be shown to affect possible patent rights.