| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe chronic pain due to diabetic peripheral neuropathy (DPN) requiring analgesia in subjects with well-controlled and stable type 1 or type 2 diabetes mellitus. |
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| E.1.1.1 | Medical condition in easily understood language |
| Pain due to nerve damage caused by diabetes mellitus type 1 or type 2 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012680 |
| E.1.2 | Term | Diabetic neuropathy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the analgesic efficacy, safety, and tolerability of once daily orally administered cebranopadol in a total of 3 fixed doses (100 µg, 300 µg, and 600 µg cebranopadol) compared to placebo in subjects with moderate to severe chronic pain due to DPN. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 (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 analgesic 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).
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| E.4 | Principal exclusion criteria |
1. 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, 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, thyroid disease or endocrine disorders, 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 that, in the investigator’s opinion, might indicate that the subject is unsuitable for the trial.
6. Conditions that require treatment with forbidden medication.
7. Use of forbidden concomitant medication.
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 forbidden concomitant treatments.
9. Subjects with severe functional hepatic impairment corresponding to Child-Pugh classification C. Subjects with impaired hepatic cellular integrity indicated by aspartate transaminase (AST) or alanine transaminase (ALT) greater than 3 x the upper limit of normal (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 or gastrointestinal conditions that might affect the absorption or metabolism of cebranopadol.
13. Presence of risk factors for 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.
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.
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.
27. Previous or current alcohol or drug abuse or opioid dependency (investigator’s judgment).
28. The subject’s participation in the trial must be terminated if the subject takes 3000 mg or more of paracetamol per day for more than 3 consecutive days. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the change from baseline pain to the average 24 hour pain during Week 6 of the Maintenance Phase. The 24 hour pain will be assessed once daily (evening) using an 11 point numeric rating scale (NRS) and a 24 hour recall period |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 6 of the maintenance phase |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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