| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Peripheral neuropathic pain |
|
| E.1.1.1 | Medical condition in easily understood language |
| Peripheral neuropathic pain |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10034606 |
| E.1.2 | Term | Peripheral neuropathies |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 evaluate the efficacy of once-daily PGB XR for the treatment of subjects with peripheral neuropathic pain. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess changes in physical functioning of subjects with peripheral neuropathic pain after initiating once-daily PGB XR.
• To assess changes in emotional functioning measures of subjects with peripheral neuropathic pain after initiating once-daily PGB XR.
• To evaluate the global improvement of subjects with peripheral neuropathic pain after initiating once-daily PGB XR.
• To evaluate the treatment response of subjects with peripheral neuropathic pain after initiating once-daily PGB XR. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must be willing and capable of giving signed informed consent.
2. Subject must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
3. Probable or definite NP diagnosis according to the IASP grading system.
4. Diagnosis of either painful diabetic neuropathy (PDN) or PHN.
5. Presence of chronic peripheral neuropathic pain for more than 3 months and less than 10 years prior to Screening.
6. Subjects with weekly average NPRS pain assessment score of ≥ 4 and ≤ 9 at Baseline (Visit 1).
7. Female subjects:
a) A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP).
OR
ii) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of study treatment.
8. Disease specific criteria
a) Painful Diabetic Neuropathy: PDN subjects with diagnosis of type 1 or type 2 diabetes mellitus with painful distal symmetrical sensorimotor neuropathy of more than 3 months duration with all of the following:
i) Neuropathic symptoms (e.g., numbness, nonpainful paresthesias or tingling, nonpainful sensory distortions or misinterpretations, etc).
ii) Decreased distal sensation (e.g., decreased vibration, pinprick sensation, light touch, etc).
iii) Glycosylated hemoglobin A1c (HbA1c) of ≤ 9.5%.
iv) Stable anti-diabetic treatment for at least 3 months prior to Screening.
v) No evidence of skin ulcers, advanced retinopathy (defined as greater than State 3 [moderate nonproliferative diabetic retinopathy]) severe nephropathy, or obstructive atherosclerotic disease resulting from their diabetes.
b) Postherpetic Neuralgia: PHN subjects with pain persisting for more than 3 months after onset of herpes zoster rash with lesions healed. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with evidence of a known etiology of peripheral neuropathy other than diabetes mellitus or postherpetic infection, including but not limited to hereditary (e.g., amyloidosis, Tangier disease, Fabry’s disease, hereditary sensory autonomic neuropathy), alcohol-related neuropathy, drug-induced neuropathy (chemotherapy, antibiotics, antiretrovirals, or other neurotoxic agents), or autoimmune disease.
2. Subjects with diagnosis of fibromyalgia.
3. Subjects with very severe pain likely to affect self-assessment of pain due to DPN or PHN.
4. Subjects with skin conditions likely to alter sensation.
5. History of alcohol or substance dependence or abuse within 1 year before the study initiation.
6. Previous failed PGB treatment due to lack of efficacy, experienced hypersensitivity, or intolerance to PGB or other α2-δ ligands.
7. History or presence of clinically significant or unstable cardiovascular, gastrointestinal, renal, or psychiatric disease or other condition that may indicate an increased risk of study participation or interfere with interpretation of the study results.
8. History or presence of any clinically significant abnormality in vital signs, electrocardiogram (ECG), or laboratory test results or has any medical or psychiatric condition that, in the opinion of the Investigator, may interfere with the study procedures or compromise subject safety.
9. History of suicide attempt within 6 months prior to Screening, or a positive response to item 4 or 5 of the Columbia Suicide Severity Rating Scale (CSSRS).
10. Episode of major depression within 6 months prior to Screening (clinically stable minor depression is not exclusionary).
11. Pregnant or breastfeeding women.
12. Subjects who have cognitive ability that makes it difficult to understand the nature, scope, and possible outcomes of the clinical study or who are not cooperative in the clinical study, as judged by the Investigator.
13. Subjects with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × the upper limit of normal (ULN) or bilirubin ≥ 1.5 × ULN (isolated increase of bilirubin in fasting condition, consistent with Gilbert’s syndrome, is acceptable) or clinically significant abnormalities in biochemistry and hematology at Screening.
14. Subjects with creatinine clearance (CrCl) ≤ 60 mL/minute.
15. Subjects with a history of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B infection within the past year, or history of Hepatitis C infection that has not been adequately treated.
16. Subjects that have initiated a chronic therapy with analgesics ≤ 14 days before the Screening phase.
Note: Subjects chronically using analgesics, for conditions other than NP, may continue but they should not change the pattern of use during the study.
17. Unable or unwilling to comply with the prohibited concomitant medication restrictions as detailed in the list of excluded medication.
18. Treatment with live attenuated vaccines (including live attenuated COVID-19 vaccines) within 2 weeks before the IMPs administration or during the study.
19. History of COVID-19 PCR positivity within 3 months before the IMPs administration, suspected COVID-19 based on clinical presentation within 3 months before the IMPs administration, COVID 19 requiring hospitalization, or presence of long-term sequelae of COVID-19 after discussion with medical monitor.
20. Use of capsaicin patch within 3 months prior to Screening.
21. Pregabalin use in the last 30 days. Subjects taking PGB in the last 30 days should be washed out of PGB for at least 30 days prior to Screening Visit. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change in average daily pain (ADP) score on the Numeric Pain Rating Scale (NPRS) from single-blind (SB) baseline to the end of the double-blind (DB) treatment period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Change in ADP score on the NPRS from DB baseline to the end of the DB treatment period.
• Change in the NPSI measure of chronic pain from DB baseline to the end of the DB treatment period.
• Change in the daily physical functioning according to the self-administered Brief Pain Inventory (BPI-SF) from SB baseline to the end of the DB treatment period. Change from DB baseline will be evaluated, also.
• Change in the health-related quality of life (HRQoL) measured with the 36-item Short-Form Health Survey (SF-36) from SB baseline to the end of the DB treatment period. Change from DB baseline will be evaluated, also.
• Change in the quality and quantity of sleep measured with the Medical Outcomes Study Sleep Scores (MOS-SS) from SB baseline to the end of the DB treatment period. Change from DB baseline will be evaluated, also.
• Change in the overall emotional functioning assessed with the Hospital Anxiety and Depression Scale (HADS) from SB baseline to the end of the DB treatment period. Change from DB baseline will be evaluated, also.
• Percentage of subjects reporting ≥ 30% decrease in mean pain score on the NPRS from SB baseline to the end of the DB treatment period. Percentage of responder subjects from DB baseline will be evaluated, also.
• Percentage of subjects reporting ≥ 50% decrease in mean pain score on the NPRS from SB baseline to the end of the DB treatment period. Percentage of responder subjects from DB baseline will be evaluated, also.
• Time to loss of therapeutic response (LTR), defined as a reduction < 30% pain response relative to SB baseline or discontinuation due to adverse event (AE) or due to lack of efficacy. Pain response relative to DB baseline will be evaluated, also.
• Time to LTR, defined as a reduction < 50% pain response relative to SB baseline or discontinuation due to AE or due to lack of efficacy. Pain response relative to DB baseline will be evaluated, also.
• Subject’s subjective overall health status and improvement assessed with the Patient Global Impression of Change (PGIC) at the end of the DB treatment period.
• Subject’s overall health status and improvement assessed with the Clinician Global Impression of Change (CGIC) by the Investigator at the end of the DB treatment period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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
|
| Last visit of the last subject |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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