Clinical trial NCT05480228: EPPIC-Net: Novaremed Painful Diabetic Peripheral Neuropathy ISA
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Painful Diabetic Neuropathy
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: New York University
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Icahn School of Medicine at Mount Sinai
First posted: 2022-07-29
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is an interventional, prospective, parallel-group, multicenter, randomized, double-blind, placebo-controlled, Phase 2 study.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 7.1 ISA-Specific Inclusion Criteria (To be used in conjunction with Platform Protocol criteria; note, some ISA criteria may be more stringent than Platform criteria; always follow the more stringent criteria when determining eligibility.)

1. Provides written consent for the EN21-01 ISA. Legally Authorized Representatives (LARs) are not allowed, but impartial witnesses may be utilized as needed for visually impaired participants.
2. 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. 7.2 ISA-Specific Exclusion Criteria (To be used in conjunction with Platform Protocol criteria; note, some ISA criteria may be more stringent than Platform criteria; always follow the more stringent criteria when determining eligibility.) Participants fulfilling any of the following criteria are not eligible for the study.

1. Diagnosis of alcohol or substance abuse or dependence (other than nicotine or caffeine) within the 2 years before the Screening visit. \*\*This criterion is more stringent than a related Platform Protocol criterion.\*\*
2. 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 during the screening process. \*\*This criterion is more stringent than a related Platform Protocol criterion.\*\*
3. Any of the following conditions related to corrected QT intervals using Fridericia's formula (QTcF):

   1. A QTcF \> 500 ms prior to starting IP, up to and including the V3 pre-dose ECG.
   2. A history of the following additional risk factors for torsade de pointes: heart failure, hypokalemia, history or family history of long QT syndrome.
4. History of myocardial infarction, other clinically active significant heart disease, or stroke. \*\*This criterion is more stringent than a related Platform Protocol criterion.\*\*
5. Participants known to have participated in four or more studies for investigational pain drugs.
6. 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.
7. Known hypersensitivity or contraindication to any excipients of the study drug formulation.
8. Taking prohibited medications as described in Appendix A, "Prohibited Medications."
9. 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:

   1. 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);
   2. 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;
   3. A lifetime history of suicide attempt (V1).
10. Previous known or possible exposure to NRD135S.E1.

Waivers to the exclusion criteria will not be allowed.

Primary outcomes:
measure: To demonstrate that NRD135S.E1 80 mg daily is superior to placebo in relieving neuropathic pain associated with PDPN, after 13 weeks' treatment.
timeFrame: 13 weeks
measure: 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.
timeFrame: 13 weeks
Secondary outcomes:
measure: Occurrence of 30% reduction of WAP from Baseline to Week 13.
timeFrame: 13 weeks
measure: Occurrence of 50% reduction of WAP from Baseline to Week 13.
timeFrame: 13 weeks
Other outcomes:
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to Pain Catastrophizing Scale - Short Form 6 (PCS-SF6)
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Pain, Enjoyment, and General activity scale (PEG).
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the PROMIS Physical Functioning Short-Form 6b
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Pain Health Questionnaire (PHQ-2).
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Generalized Anxiety Disorder - 2 item scale (GAD-2).
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Tobacco, Alcohol, Prescription medication, and other Substance use Tool (TAPS-1).
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the PROMIS Sleep Disturbance - 6A.
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Sleep Duration Scale.
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Opioid Use Questionnaire (OUQ).
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Patient Global Impression of Change (PGIC).
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN)
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the Neuropathy examination.
timeFrame: 13 weeks
measure: To assess the effect of NRD135S.E1 in comparison to placebo with respect to the actigraphy step count.
timeFrame: 13 weeks
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Clermont
country: United States
facility: South Lake Pain Institute
state: Florida
city: Gainesville
country: United States
facility: SIMEDHealth LLC
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern Department of Neurology
state: Illinois
city: Flossmoor
country: United States
facility: Healthcare Research Network (Flossmoor)
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland - Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: MGH Department of Anesthesia, Critical Care, and Pain
state: Massachusetts
city: Hazelwood
country: United States
facility: Healthcare Research Network (Hazelwood)
state: Missouri
city: New York
country: United States
facility: NYU Langone Manhattan
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University Medical Center/Neurological Institute
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Beavercreek
country: United States
facility: Clinical Inquest Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Orangeburg
country: United States
facility: Low Country Pain Center
state: South Carolina
city: Rapid City
country: United States
facility: American Indian Clinical Trials Research Network
state: South Dakota
city: Houston
country: United States
facility: Nerve and Muscle Center of Texas
state: Texas
city: Houston
country: United States
facility: Clinicore International
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Richmond
country: United States
facility: VCU Department of Neurology
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Jessica Robinson-Papp, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dworkin RH, Turk DC, Peirce-Sandner S, McDermott MP, Farrar JT, Hertz S, Katz NP, Raja SN, Rappaport BA. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain. 2010 Jul;150(1):12-16. doi: 10.1016/j.pain.2010.02.002. Epub 2010 Mar 3. No abstract available.
citation: Tarpey T, Petkova E, Ciarleglio A, Ogden RT. Extracting scalar measures from functional data with applications to placebo response. Stat Interface. 2021;14(3):255-265. doi: 10.4310/20-sii633.
citation: Tarpey T, Petkova E, Lu Y, Govindarajulu U. Optimal Partitioning for Linear Mixed Effects Models: Applications to Identifying Placebo Responders. J Am Stat Assoc. 2010 Jan 1;105(491):968-977. doi: 10.1198/jasa.2010.ap08713.
citation: Van Buuren, S., & Groothuis-Oudshoorn, K. (2011). Journal of Statistical Software mice: Multivariate Imputation by Chained Equations in R (Vol. 45). http://www.jstatsoft.org/