EPPIC-Net: Novaremed Painful Diabetic Peripheral Neuropathy ISA

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety and efficacy of the current hard gelatin capsule formulation of NRD135S.E1 80 mg once daily in the treatment of PDPN when administered for 13 weeks.

Detailed Description
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This ISA describes a double-blind Phase II study of the PK/PD, safety, tolerability, and effect of 13 weeks of NRD135S.E1 (80mg/day) as an ISA within the context of the Platform Protocol to Assess Treatments for Painful Diabetic Peripheral Neuropathy, EN21-PP. The ISA is intended to be read and interpreted within the context of the Platform Protocol and focuses on the description of design features that are specific to NRD135S.E1.

Official Title
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EPPIC-Net EN21-01 A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of 80 mg Daily of NRD135S.E1 Versus Placebo in Adult and Elderly Participants With Painful Diabetic Peripheral Neuropathy.

Conditions
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Painful Diabetic Neuropathy

Intervention / Treatment
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* Drug: NRD135SE.1
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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ISA-Specific Inclusion Criteria (To be used in conjunction with Platform Protocol criteria.) At the time of screening (V1) at least 40 mm on a 100-mm visual analog scale (VAS) for average pain over the previous 24 hours. Patient-reported daily 11-point NRS (for average pain over the last 24 hours) meets the criteria specified in Appendix B: Blinded Information during both the 7-day screening and 7-day baseline periods. The algorithm will be assessed centrally. Waivers to the inclusion criteria will not be allowed. ISA-Specific Exclusion Criteria (To be used in conjunction with Platform Protocol criteria.) Participants fulfilling any of the following criteria are not eligible for the study. Diagnosis of alcohol or substance abuse or dependence (other than nicotine or caffeine) within the 2 years before the Screening visit. Moderate or severe renal impairment, known (documented) or defined as an estimated/calculated creatinine clearance/estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2, according to the Chronic Kidney Disease Epidemiology Collaboration formula. Any of the following conditions related to corrected QT intervals using Fridericia's formula (QTcF): A QTcF > 500 ms prior to starting IP. A history of the following additional risk factors for torsade de pointes: heart failure, hypokalemia, history or family history of long QT syndrome. History of myocardial infarction, other clinically active significant heart disease, or stroke. Participants known to have participated in four or more studies for investigational pain drugs. Participants known to be non-responders to more than three previous neuropathic pain medications at adequate doses over at least 4 weeks. Adequate doses (given as total daily doses) are defined as follows: 1,800 mg gabapentin; 300 mg pregabalin; opioid analgesics 60 mg oxycodone equivalent or 200 mg tramadol; 75 mg amitriptyline or equivalent tricyclic antidepressant; 60 mg duloxetine; 150 mg venlafaxine. Known hypersensitivity or contraindication to any excipients of the study drug formulation. Taking prohibited medications as described in Section 12, Concomitant Therapy, and Appendix A, Prohibited Medications. Major depressive episode within the 6 months before screening and/or a history of diagnosed recurrent major depressive disorder within two years. Any of the following conditions related to suicidality: Any suicidal ideation with intent, with or without a plan, at screening, i.e., answering yes to questions 4 or 5 on the Suicidal Ideation section of the Baseline/Screening version of the Columbia-Suicide Severity Rating Scale (C-SSRS); Answering yes on any item of the Suicidal Behavior Section (except for the non-suicidal self-injurious behavior) of the C-SSRS if this behavior occurred in the past 2 years; A lifetime history of suicide attempt (V1). Previous known or possible exposure to NRD135S.E1. Waivers to the exclusion criteria will not be allowed.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is an interventional, prospective, parallel-group, multicenter, randomized, double-blind, placebo-controlled, Phase 2 study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NRD135S.E1 80mg/day<br>NRD135S.E1 as a potential treatment for moderate to severe painful diabetic peripheral neuropathy (PDPN). While the activity of NRD135S.E1 has been extensively studied, its molecular target is not known, though it does not appear to work through any of the opioid receptors or molecular pathways currently targeted by available analgesics. The best evidence suggests it may act, at least in part, through modulating the Lyn kinase signaling pathway In clinical studies, NRD135S.E1 has been well tolerated at all dose levels tested in single-dose (up to 1,200 mg) and repeat-dose regimens (up to 300 mg/day over 5 days or 150 mg over 3 weeks), and it has been shown to have predictable pharmacokinetics with dose-dependent increases in exposure. | Drug: NRD135SE.1<br>* The double-blind treatment phase is up to 13 weeks.<br>* Other names: NRD135s.E1, a small chemical entity for treatment of neuropathic pain;|
| Placebo Comparator: Matching placebo<br>A matching placebo comparator will be used. | Other: Placebo<br>* A matching placebo will be taken for up to 13 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate that NRD135S.E1 80 mg daily is superior to placebo in relieving neuropathic pain associated with PDPN, after 13 weeks' treatment. | Change from Baseline to Week 13 in the weekly mean of the daily 24-hour average pain measured by Numeric Rating Scale (NRS) (abbreviated herein as WAP for weekly average pain). The NRS is a 0-10 scale, with 0 indicating no pain, and 10 being the worst possible pain. | 13 weeks | 
| The frequency (i.e. number of participants) with treatment emergent adverse events (TEAEs) reported in the time period defined by first administration of IP until 7 days after the last dose of IP. | A treatment-emergent adverse event (TEAE) is any AE temporally associated with the use of study treatment whether or not considered by the investigator as related to study treatment. | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of 30% reduction of WAP from Baseline to Week 13. | Weekly Average Pain is abbreviated as WAP. | 13 weeks | 
| Occurrence of 50% reduction of WAP from Baseline to Week 13. | Weekly Average Pain is abbreviated as WAP. | 13 weeks |