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

Efficacy, Safety and Tolerability of Multiple Doses of Oral Cebranopadol in Subjects With Moderate to Severe Chronic Pain Due to Diabetic Peripheral Neuropathy.

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Diabetic Neuropathies; Chronic Pain
• Intervention / Treatment: Drug: Cebranopadol 300 µg; Drug: Cebranopadol 600 µg; Drug: Pregabalin; Drug: Matching Placebo; Drug: Cebranopadol 100 µg

• Study Type: Interventional
• Enrollment (Actual): 699
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • AT007
  • Salzburg, Austria, 5020
    • AT005
  • Senftenberg, Austria, 3541
    • AT004
  • Vienna, Austria, 1090
    • AT001
  • Vienna, Austria, 1010
    • AT002
  • Vienna, Austria, 1060
    • AT003
  • Vienna, Austria, 1160
    • AT006
• Denmark
  • Aalborg, Denmark, 9100
    • DK005
  • Aarhus, Denmark, 8000
    • DK003
  • Copenhagen, Denmark, 2000
    • DK002
  • Odense, Denmark, 5000
    • DK001
• France
  • Corbeil Essonnes, France, 91100
    • FR008
  • Lille, France, 59037
    • FR001
  • Limoges cedex, France, 87042
    • FR007
  • Montauban cedex, France, 82013
    • FR005
  • Nantes, France, 44200
    • FR002
  • Orléans, France, 45000
    • FR004
  • Paris, France, 75004
    • FR006
• Germany
  • Aschaffenburg, Germany, 63739
    • DE018
  • Bad Oeynhausen, Germany, 32545
    • DE003
  • Berlin, Germany, 10115
    • DE005
  • Berlin, Germany, 10117
    • DE023
  • Berlin, Germany, 10787
    • DE031
  • Berlin, Germany, 12627
    • DE004
  • Berlin, Germany, 13125
    • DE025
  • Bochum, Germany, 44787
    • DE013
  • Dresden, Germany, 01069
    • DE033
  • Düsseldorf, Germany, 40210
    • DE017
  • Düsseldorf, Germany, 40212
    • DE012
  • Essen, Germany, 45136
    • DE010
  • Essen, Germany, 45277
    • DE034
  • Essen, Germany, 45355
    • DE022
  • Frankfurt, Germany, 60596
    • DE006
  • Görlitz, Germany, 02826
    • DE007
  • Hamburg, Germany, 20253
    • DE021
  • Hannover, Germany, 30159
    • DE020
  • Karlsruhe, Germany, 76199
    • DE016
  • Kiel, Germany, 24119
    • DE002
  • Künzing, Germany, 94550
    • DE030
  • Leipzig, Germany, 04103
    • DE008
  • Leipzig, Germany, 04109
    • DE009
  • Magdeburg, Germany, 39104
    • DE015
  • Magdeburg, Germany, 39112
    • DE032
  • Mainz, Germany, 55116
    • DE001
  • Mayen, Germany, 56727
    • DE028
  • München, Germany, 81477
    • DE027
  • Münster, Germany, 48145
    • DE014
  • Neuss, Germany, 41460
    • DE011
  • Schwerin, Germany, 19055
    • DE024
• Italy
  • Ancona, Italy, 60127
    • IT005
  • Milano, Italy, 20162
    • IT004
  • Rome, Italy, 00133
    • IT001
  • Turin, Italy, 10126
    • IT002
• Netherlands
  • Amsterdam, Netherlands, 1091 AC
    • NL007
  • Apeldoorn, Netherlands, 7334 DZ
    • NL004
  • Beek, Netherlands, 6191 JW
    • NL005
  • Eindhoven, Netherlands, 5623 EJ
    • NL001
  • Rotterdam, Netherlands, 3039 BD
    • NL002
  • Venlo, Netherlands, 5912 BL
    • NL006
  • Zwijndrecht, Netherlands, 3331 LZ
    • NL008
  • Zwolle, Netherlands, 8025 AB
    • NL003
• Spain
  • Cuenca, Spain, 16002
    • ES001
  • Madrid, Spain, 28041
    • ES009
  • Madrid, Spain, 28031
    • ES011
  • Madrid, Spain, 28040
    • ES010
  • Toledo, Spain, 45600
    • ES003
  • Valencia, Spain, 46010
    • ES006
• United States
  • Arizona
    • Mesa, Arizona, United States, 85215
      • US002
  • California
    • Garden Grove, California, United States, 92843
      • US001
    • Laguna Hills, California, United States, 92653
      • US019
    • National City, California, United States, 91950
      • US014
    • Orange, California, United States, 92868
      • US007
  • Florida
    • Hialeah, Florida, United States, 33012
      • US011
    • Miami, Florida, United States, 33135
      • US012
    • Orlando, Florida, United States, 32806
      • US009
  • Idaho
    • Blackfoot, Idaho, United States, 83221
      • US004
  • Illinois
    • Elgin, Illinois, United States, 60123
      • US006
  • New Jersey
    • West Long Branch, New Jersey, United States, 07764
      • US016
  • New York
    • Brooklyn, New York, United States, 11229
      • US008
    • Brooklyn, New York, United States, 11235
      • US005
    • New York, New York, United States, 10128
      • US021
  • Utah
    • West Jordan, Utah, United States, 84088
      • US003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Matching Placebo	Drug: Matching Placebo; Placebo will be matched to pregabalin and cebranopadol.
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®
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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Average Pain Intensity.	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.	Baseline; to End of Week 6 of the Maintenance Phase

Collaborators and Investigators

• Sponsor: Tris Pharma, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 27, 2013
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): January 28, 2015

Study Registration Dates

• First Submitted: September 6, 2013
• First Submitted That Met QC Criteria: September 6, 2013
• First Posted (ESTIMATE): September 11, 2013

Study Record Updates

• Last Update Posted (ACTUAL): July 15, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Painful Diabetic Peripheral Neuropathy
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Chronic Pain; Diabetic Neuropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anti-Anxiety Agents; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Pregabalin
• Other Study ID Numbers: KF6005/08; 2013-000473-68 (EUDRACT_NUMBER); U1111-1151-4331 (OTHER: WHO UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No