Efficacy, safety and tolerability of multiple doses of oral cebranopadol in subjects with moderate to severe chronic pain due to diabetic peripheral neuropathy

1. Informed consent signed (Visit 1).
2. Male or female subjects aged 18 years to 80 years inclusive at the
Enrollment Visit (Visit 1).
3. All subjects must have type 1 or type 2 diabetes mellitus and must
have a documented clinical diagnosis of painful DPN with
symptoms and signs for at least 3 months and pain present at the
Enrollment Visit (Visit 1).
4. The investigator considers the subject*s blood glucose to be
controlled by a diet, oral anti-hyperglycemic medication, and/or insulin for at least 3 months prior to Enrollment Visit. This control should be documented. Hemoglobin (HbA1C) should not be greater than 11% at the Enrollment Visit (Visit 1).
5. Subject 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.
6. Subjects must be using medically acceptable and highly effective methods of birth control (and willing to use them during the trial):
For women of childbearing potential: A medically acceptable and highly effective method of birth control is defined as any form of contraception with a low failure rate defined as <1% per year. For example:
• Hormonal contraceptives for at least 2 months prior to the
Enrollment Visit and until at least 4 weeks after Visit 7.
• An intra-uterine device.
Additional barrier contraception must be used by the partner for the duration of the trial. A double-barrier method should be supplemented by the use of spermicidal agents.
Women of non-childbearing potential may be included if surgically sterile (i.e., after hysterectomy) or post-menopausal for at least
2 years.
For men: Men have to use barrier contraception (condom) during sexual intercourse for the duration of the trial. The male subject has to take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as <1% per year (e.g., oral contraceptives) during this time frame.
7. Women of childbearing potential must have a negative urine
β-human chorionic gonadotropin (β-hCG) pregnancy test at the
Enrollment Visit (Visit 1) and at the Baseline Visit (Visit 3).
8. A baseline pain intensity score >=5 on the 11-point NRS without
intake of any analgesic (including rescue medication) at Visit 3. For each of the last 3 days prior to Visit 3, a 24-hour NRS score >=4 is required.
The baseline pain will be calculated as the average over the three
24-hour pain assessments of the last 3 days prior to the Baseline
Visit (Visit 3).

Presence of other pain that could confound the assessment of, or
contribute to, painful DPN. Such pain could include, but is not
limited to, pain due to nerve entrapment (e.g., tarsal tunnel syndrome, osteoarthritis of the knee), peripheral vascular disease, radiculopathy, plantar fasciitis, tendonitis, mononeuritis multiplex, postherpetic neuralgia, complex regional pain syndrome, or fibromyalgia.
2. Neuropathy due to etiologies other than diabetes. These
neuropathies include, but are not limited to, those associated with
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.
3. Severe or extensive diabetic ulcers or amputations of the limbs (i.e.,
more than 2 toes) or Charcot*s joints due to diabetes. Subjects who
have had an amputation for a reason other than diabetes (e.g., injury) may be eligible for this trial.
4. Any clinically significant disease or laboratory findings that in the investigator*s opinion may affect efficacy or safety assessments or
may compromise the subject*s safety during trial participation, e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, metabolic, neurological, or psychiatric disorders.
5. Any medical or other reason (e.g., known or suspected inability of
the subject to comply with the protocol and with the use of the
IMP) that, in the investigator*s opinion, might indicate that the subject is unsuitable for the trial.
6. Conditions that require treatment with forbidden medication (see
Section 10.6.2).
7. Use of forbidden concomitant medication as specified in
Section 10.6.2.
8. Previous or current alcohol or drug abuse or opioid dependency,
according to the investigator*s judgment, based on the subject*s
history, examination, and the result of the drugs of abuse test. Subjects with positive urine drug test explained by a medically indicated treatment are allowed to participate in the trial as long as not specified otherwise in Section 10.6.2.
9. Subjects with severe functional hepatic impairment corresponding
to Child-Pugh classification C. Subjects with impaired hepatic cellular integrity indicated by AST or ALT greater than 3 x ULN.
10. History of acute hepatitis within 3 months of Visit 1 or chronic
hepatitis or a positive result on anti-hepatitis A IgM antibody within the past 6 months, hepatitis B surface antigen, or anti-hepatitis C antibody.
11. Subjects with impaired renal function with a creatinine clearance
less than 60 mL/min at the Enrollment Visit (Visit 1) (calculated from the Cockcroft-Gault [1976] formula).
12. History of any major gastrointestinal prior 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.
13. Presence of risk factors for (e.g., heart failure, hypokalemia, or
bradycardia), or history of, torsade de pointes and/or marked prolongation of the corrected QT (Fridericia) (QTcF >450 ms).
14. 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.
15. History or presence of malignancy with the exception of curative
treated subjects or subjects being in remission of cancer for at least
2 years and not requiring treatment.
16. Any scheduled surgery or painful procedure during the course of the trial.
17. Clinically relevant history of hypersensitivity, allergy, or
contraindications to any of the IMP*s excipients as well as to opioids, pregabalin or paracetamol.
18. Significant vascular disease (e.g., peripheral occlusive arterial
disease, Fontaine Class III-IV; post-thrombotic syndrome, venous insufficiency Stage III/IV).
19. Subjects whose BMI is lower than 18 kg/m2 or greater than
40 kg/m2.
20. History of human immunodeficiency virus (HIV) infection.
21. Severe signs of suicidal behavior and/or suicidal ideation within the
past 3 months based on the results of the C-SSRS (suicidal ideation rating of 4 or 5 or any suicidal behavior) a.
22. Female subjects who are pregnant or breastfeeding.
23. Concurrent participation in another trial, or within 30 days before the Enrollment Visit of this trial.
24. Previous participation in this trial (unless enrollment failure due to
technical reason or in- and exclusion criteria that were changed in
Amendment 03) or participation in another trial with cebranopadol
(unless enrollment failures, i.e., not allocated to IMP).
25. Employees of the investigator, trial site, or sponsor with direct involvement in the proposed trial or other trials under the direction
of that investigator, trial site, or sponsor, as well as family members of employees or the investigator.
26. Failure to complete the required medication washout by Baseline
Visit (Visit 3) or use of forbidden concomitant medications as specified in Section 10.6.2.
27. Previous or current alcohol or drug abuse or opioid dependency,
according to the investigator*s judgment, based on the subject*s history, examination, or the result of the drugs of abuse test. Subjects with positive urine drug test explained by a medically indicated treatment are allowed to participate in the trial as long as not specified otherwise in Section 10.6.2.