E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neuropathic pain associated with diabetic peripheral neuropathy |
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E.1.1.1 | Medical condition in easily understood language |
A condition called diabetic neuropathic pain (DNP). In DNP, long-term high blood sugar levels cause nerve damage in people with diabetes. People with DNP may have pain and numbness. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067547 |
E.1.2 | Term | Diabetic peripheral neuropathic pain |
E.1.2 | System Organ Class | 100000004852 |
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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 |
Part A: to evaluate the efficacy of BAY1817080 on the treatment of pain associated with DNP as compared with placebo
Part B: to describe the dose-response relationship and evaluate the efficacy of BAY1817080 on the treatment of pain associated with DNP as compared with placebo (and active comparator) |
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E.2.2 | Secondary objectives of the trial |
To further evaluate the efficacy of BAY1817080 on pain and associated symptoms
To evaluate the safety and tolerability of BAY1817080 on the treatment of pain associated with DNP as compared with placebo in Part A and placebo as well as active comparator in Part B |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adults ≥ 18 years of age at the time of signing the informed consent.
2. At the time of screening, have documented diagnosis of type 1 OR type 2 diabetes mellitus (DM) with painful distal symmetrical sensorimotor neuropathy of more than 6 months duration according to modified Toronto Clinical Neuropathy Score.
3. Weekly mean 24-hour average pain NRS ≥ 4 with adequate variability (not the same score on all daily pain ratings) and compliance (non-missing pain score on at least 6 out of 7 consecutive days) in daily pain recording during the 7 day NRS baseline period.
4. Neuropathic pain according to the DN4 questionnaire.
5. Women of childbearing potential must agree to use acceptable effective or highly effective birth control methods. |
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E.4 | Principal exclusion criteria |
1. Any differential diagnosis of peripheral diabetic neuropathy (PDN) including but not limited to other neuropathies (e.g. vitamin B12 deficiency, Chronic Inflammatory Demyelinating Polyneuropathy), polyradiculopathies, central disorders (e.g. demyelinating disease), or rheumatological disease (e.g. foot arthritis, plantar fasciitis).
2. Any other diseases or conditions that according to the investigator can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study intervention (e.g. chronic bowel disease, Crohn's disease and ulcerative colitis).
3. Any serious or unstable diseases or conditions including psychiatric disorders that might interfere with the conduct of the study or the interpretation of the results.
4. Major surgery or radiological procedures (e.g. PTA and stenting of peripheral vascular lesions in lower extremities) within 3 months before screening visit or scheduled during the study period, which might interfere pain response evaluation.
5. Symptomatic peripheral arterial disease in lower or upper extremities, including diabetic ulcers.
6. Previous use of strong opioids (e.g. oxymorphone, oxycodone) for neuropathic pain anytime, or topical use of capsaicin within 3 months prior to the screening visit.
7. History or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for study participants.
8. Moderate-to-severe hepatic impairment defined as Child-Pugh Class B or C.
9. Have platelets ≤ 100 x 109/L, or neutrophil count < 1.2 x 109/L (or equivalent), hemoglobin ≤ 100 g/L for women or hemoglobin ≤ 110 g/L for men at screening.
10. Glycemic control unstable (hemoglobin HbA1c ≥11%) within 3 months prior to screening (e.g. ketoacidosis requiring hospitalization, any recent episode of hypoglycemia requiring assistance through medical intervention, uncontrolled hyperglycemia).
11. ALT >2xULN, or AST >2xULN, or total bilirubin greater than ULN, or alkaline phosphatase (AP) >2x ULN, or INR greater than ULN (unless related to
anticoagulation treatment) at screening.
12. Positive hepatitis B virus surface antigen (HBsAg) or positive hepatitis C virus antibodies (anti-HCV) and detection of mRNA (HCV-mRNA tested only if hepatitis C virus antibodies detected).
13. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2 calculated by Modification of Diet in Renal Disease (MDRD) formula (local formulas will be used where applicable.
14. Uncontrolled hypertension despite optimal treatment with antihypertensive(s), indicated by a sitting systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg.
15. Any other disease or condition that, according to the investigator, can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study intervention (e.g., excessively low body weight, chronic bowel diseases, Crohn's disease and ulcerative colitis) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in weekly mean 24-hour average pain intensity score using the 11-point Numeric Rating Scale (NRS) from baseline to the end of intervention |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: from baseline to end of intervention (in total up to 9 weeks)
Part B: from baseline to end of intervention (in total up to 13 weeks) |
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E.5.2 | Secondary end point(s) |
- Change in Neuropathic Pain Symptom Inventory (NPSI) score from baseline to the end of intervention
- Patient Global Impression of Change (PGI-C) at the end of intervention
- The proportion of participants achieving a ≥30% and a ≥50% reduction in weekly mean 24-hour average pain intensity score (i.e. responder rates using NRS)
- Number of participants with treatment emergent adverse events (TEAE) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
NPSI:
Part A: at visit 2, visit 4 (day 15 +/- 2), visit 5 (day 29 +/-2) and visit 7 EOI (day 57 +/-2)
Part B: at visit 2, visit 4 (day 15 +/- 2), visit 5 (day 29 +/-2), visit 7 (day 57 +/-2) and visit 8 EOI (day 85 +/-2)
PGI-C:
Part A: at visit 5 (day 29 +/-2) and at end of intervention (day 57 +/- 2)
Part B: at visit 5 (day 29 +/-2), at visit 7 (day 57 +/- 2) and at end of intervention (day 85 +/-2)
Responder rates:
Part A: from baseline to end of intervention (in total up to 9 weeks)
Part B: from baseline to end of intervention (in total up to 13 weeks)
TEAE: start of intervention to 14 days after stop of treatment |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Phase 2b will use Pregabalin as comparator |
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E.8.2.4 | Number of treatment arms in the trial | 7 |
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 | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Japan |
United States |
Austria |
Denmark |
Finland |
France |
Germany |
Hungary |
Norway |
Poland |
Slovakia |
Sweden |
Czechia |
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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
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last visit of the last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |