Painful Diabetic Peripheral Neuropathy
Conditions
Keywords
Diabetic Neuropathic Pain, Neuropathic Pain, HDAC6, ricolinostat, Painful Diabetic Peripheral Neuropathy, DPN
Brief summary
This is a randomized, double-blind, 2-arm, parallel group study of up to 274 evaluable patients designed to evaluate the safety and efficacy of the histone deacetylase 6 (HDAC6) inhibitor ricolinostat for painful DPN.
Detailed description
The study includes an approximately 12 week randomized, double-blind, placebo controlled Treatment period in which patients will receive either ricolinostat or placebo, followed by an approximately 12 week open label Safety Extension period during which all patients will receive ricolinostat 120 mg daily. Prior to randomization, patients will be enrolled in a baseline Pain Observation period from Day -14 to Day -1, during which the NRS (average and worst pain) will be recorded daily using an electronic daily diary that will be completed by patients to allow patients to familiarize themselves with the pain rating procedures, and to establish a baseline and confirm eligibility to participate. Patients will also initiate daily dosing during this time to evaluate compliance eligibility for participation. A daily diary will be used by the patient to record the pain assessments and rescue medication use. A follow-up phone contact will be conducted at Day -7 to Day -5 to review diary and dosing compliance. Following the baseline Pain Observation period, patients who meet entry criteria will be randomized in a 1:1 ratio to receive either ricolinostat or placebo. During the 12-week double-blind, placebo-controlled Treatment period, patients will return for assessments in accordance with the schedule of assessments. At the conclusion of the approximately 12 week open label Safety Extension period, patients will enter a Follow-up safety washout and assessment period, which will incorporate 2 visits at approximately 2 and 4 weeks following the final Safety Extension visit, with assessments performed as outlined in the schedule of assessments.
Interventions
DRUGricolinostat
120 mg per dose in 12 mL liquid formulation
DRUGPlacebo
12 mL liquid formulation placebo
Sponsors
Regenacy Pharmaceuticals LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double-blind
Intervention model description
Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 or Type 2 diabetes of at least 6 months with optimized and stable glycemic control during the 3 months prior to Screening * Painful distal symmetric sensorimotor polyneuropathy due to diabetes * Douleur Neuropathique 4 (DN4) score of ≥4 * Satisfactory diary data during the 14-day Pain Observation period determined by an algorithm that includes diary compliance, overall level of pain and day-to-day variability in pain
Exclusion criteria
* Pregnant or lactating * Body Mass Index (BMI) \>40 kg/m2 * Presence of any neuropathy other than DPN and/or significant risk factors for neuropathy other than diabetes * Other pain conditions that could confound the results of this study, or other chronic pain condition(s) that could affect compliance with pain medication restrictions or confound pain assessments * Painful DPN patients who have undergone lower limb amputations, are non-ambulatory, or whose walking is so impaired as to require a walker or other assistance for ambulation * Have met Diagnostic and Statistical Manual of Mental Disorders V (DSM V) criteria for opioid use disorder or alcohol use disorder * Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days a week during the month prior to Screening * Suicidal ideation/behavior as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) * The use of marijuana or cannabidiol (CBD) during the 30 days prior to starting study drug * Chronic use of over-the-counter capsaicin on extremities within 3 months of Screening and/or prescription Qutenza use within 6 months of Screening * Corrected QT interval at Screening using QTcF of ≥450 msec (male) or ≥460 msec (female) * Hemoglobin \< 11.5 g/dL (female) or \< 13 g/dL (male), total white blood cell count \< 2500/mm3, neutrophil count \< 1250/mm3, lymphocyte count \< 1000/mm3, or platelet count \< 100,000/mm3 * HIV positive and/or active hepatitis virus (A, B, or C) infection * Current or previous (≤1 month of Screening) enrollment in a clinical trial involving treatment with an investigational product * Any known recent exposure within the 14 days prior to initial Screening to coronavirus disease 2019 (COVID-19) or symptoms of COVID-19 infection or other reason to suspect COVID-19 infection as assessed by the Investigator at the time of initial Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Average Pain Intensity (NRS) | Baseline week [Day-7 to Day 1] compared to Final week [12 Weeks] | Difference between mean average pain intensity using the 11-point numerical pain rating scale (NRS) consisting of pain measurement from 0-10 with 10 being the worst pain and 0 being no pain at all. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Non-pain Neuropathic Signs (UENS) | Baseline week [Day-7 to Day 1] compared to Week 12 | Change in non-pain neuropathic signs utilizing the Utah Early Neuropathy Score (UENS) which is a physical examination-based scale designed to assess early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. The UENS utilizes a numeric scale from 0-42, with higher scores indicating greater disease severity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ricolinostat Ricolinostat 120 mg, taken once daily (QD) by mouth; each dose in 12 mL liquid formulation (10 mg ricolinostat per mL)
ricolinostat: 120 mg per dose in 12 mL liquid formulation | 142 |
| Placebo Placebo, 12 mL of liquid formulation with no active ingredient (i.e., ricolinostat), taken once daily (QD) by mouth
Placebo: 12 mL liquid formulation placebo | 140 |
| Total | 282 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment Period | Adverse Event | 0 | 5 |
| Double Blind Treatment Period | Lost to Follow-up | 3 | 0 |
| Double Blind Treatment Period | Not Provided | 1 | 0 |
| Double Blind Treatment Period | Physician Decision | 0 | 1 |
| Double Blind Treatment Period | Protocol Violation | 1 | 0 |
| Double Blind Treatment Period | Withdrawal by Subject | 5 | 10 |
| Open Label Extension | Adverse Event | 2 | 4 |
| Open Label Extension | Lost to Follow-up | 1 | 2 |
| Open Label Extension | Not Provided | 2 | 1 |
| Open Label Extension | Protocol Violation | 0 | 1 |
| Open Label Extension | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Ricolinostat | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 9.64 | 60.9 years STANDARD_DEVIATION 7.81 | 60.2 years STANDARD_DEVIATION 8.79 |
| Body Mass Index (BMI) | 31.31 kg/m^2 STANDARD_DEVIATION 4.91 | 32.21 kg/m^2 STANDARD_DEVIATION 4.17 | 31.75 kg/m^2 STANDARD_DEVIATION 4.57 |
| Height | 172.7 centimeters STANDARD_DEVIATION 9.82 | 173.1 centimeters STANDARD_DEVIATION 9.91 | 172.9 centimeters STANDARD_DEVIATION 9.85 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 37 Participants | 39 Participants | 76 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) White | 93 Participants | 95 Participants | 188 Participants |
| Sex: Female, Male Female | 86 Participants | 83 Participants | 169 Participants |
| Sex: Female, Male Male | 56 Participants | 57 Participants | 113 Participants |
| Weight | 93.7 Kg STANDARD_DEVIATION 18.29 | 96.76 Kg STANDARD_DEVIATION 16.5 | 95.22 Kg STANDARD_DEVIATION 17.46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 142 | 0 / 140 | 0 / 252 |
| other Total, other adverse events | 17 / 142 | 21 / 140 | 20 / 252 |
| serious Total, serious adverse events | 6 / 142 | 2 / 140 | 4 / 252 |
Outcome results
Primary
Change in Mean Average Pain Intensity (NRS)
Difference between mean average pain intensity using the 11-point numerical pain rating scale (NRS) consisting of pain measurement from 0-10 with 10 being the worst pain and 0 being no pain at all.
Time frame: Baseline week [Day-7 to Day 1] compared to Final week [12 Weeks]
Population: The number of subjects with non-missing values at both Baseline and specified visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ricolinostat | Change in Mean Average Pain Intensity (NRS) | -1.21 units on a scale | Standard Deviation 1.4 |
| Placebo | Change in Mean Average Pain Intensity (NRS) | -1.03 units on a scale | Standard Deviation 1.4 |
Secondary
Change in Non-pain Neuropathic Signs (UENS)
Change in non-pain neuropathic signs utilizing the Utah Early Neuropathy Score (UENS) which is a physical examination-based scale designed to assess early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. The UENS utilizes a numeric scale from 0-42, with higher scores indicating greater disease severity.
Time frame: Baseline week [Day-7 to Day 1] compared to Week 12
Population: The number of subjects with non-missing values at both Baseline and specified visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ricolinostat | Change in Non-pain Neuropathic Signs (UENS) | -1.51 units on a scale | Standard Deviation 0.39 |
| Placebo | Change in Non-pain Neuropathic Signs (UENS) | -1.84 units on a scale | Standard Deviation 0.4 |