Clinical trial NCT03176472
Conditions: Painful Diabetic Peripheral Neuropathy
Keywords: Diabetic Neuropathic Pain Neuropathic Pain HDAC6 ricolinostat Painful Diabetic Peripheral Neuropathy DPN
Sponsor: Regenacy Pharmaceuticals LLC
Start date: 2020-12-07; Completion date: 2023-04-28
Enrollment: 282 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Ricolinostat 120 mg, taken once daily (QD) by mouth; each dose in 12 mL liquid formulation (10 mg ricolinostat per mL) arm 2: Placebo, 12 mL of liquid formulation with no active ingredient (i.e., ricolinostat), taken once daily (QD) by mouth
Interventions: intervention 1: ricolinostat intervention 2: Placebo
Intervention descriptions: intervention 1: 120 mg per dose in 12 mL liquid formulation intervention 2: 12 mL liquid formulation placebo

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL REGY-DN-201 
Study Title: 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY OF 
RICOLINOSTAT IN PATIENTS WITH PAINFUL DIABETIC 
PERIPHERAL NEUROP A THY 
Investigational Ricolinostat (ACY-1215) 
Product: 
Protocol 
Number: 
REGY-DN-201 
Study Phase: 
2 
IND Number: 
130871 
Sponsor: 
Regenacy Pharmaceuticals, INC 
303 Wyman Street, Suite 300 
Waltham, MA 02451 
VERSION HISTORY 
Version Number 
Version Date 
1.0 
30 May 201 7 
2.0 
03 August 2020 
3.0 
11 overnber 2020 
4.0 
16June2021 
5.0 
24 September 2021 
SPONSOR APPROVAL 
lsponsoc's Signature~~vJl.=: 
CONFIDENTIAL AND PROPRIETARY 
Status 
Final 
Final 
Final 
Final 
Final 
This document contains information that is confidential and proprietary to Regenacy 
Pharmaceuticals, INC and is being provided for the purpose of conducting a clinical trial. The 
contents may be disclosed to personnel involved in the conduct of the study an to applicable 
committees involved with the review and oversight of research at your institution. No other 
parties should have access to this information without the written consent ofRegenacy 
Pharmaceuticals, INC. The information in this protocol is from both public and non-public 
sources and should not be used for any purpose other than guidance in the conduct of the study. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
1.0 
INVESTIGATOR AGREEMENT ...................................................................................6 
2.0 
LIST OF ABBREVIATIONS ...........................................................................................7 
3.0 
SYNOPSIS ..........................................................................................................................9 
4.0 
ETHICAL CONSIDERATIONS ....................................................................................20 
4.1 
Independent Review Board ....................................................................................20 
4.2 
Ethical Conduct of the Study .................................................................................20 
4.3 
Patient Information and Consent ...........................................................................20 
5.0 
INTRODUCTION............................................................................................................21 
5.1 
Diabetic Neuropathic Pain .....................................................................................21 
5.2 
Medical Need .........................................................................................................21 
5.3 
HDAC6 Inhibition and Ricolinostat ......................................................................21 
5.4 
Dose Justification and Clinical Experience ...........................................................22 
5.5 
Study Design Rationale..........................................................................................26 
6.0 
STUDY OBJECTIVES ....................................................................................................27 
6.1 
Primary and Key Secondary Objectives ................................................................27 
6.2 
Secondary Objective ..............................................................................................27 
6.3 
Exploratory Objectives ..........................................................................................27 
7.0 
INVESTIGATIONAL PLAN .........................................................................................27 
7.1 
Overall Study Design and Plan Description ..........................................................27 
7.2 
Discussion of Study Design, Including the Choice of Control Groups .................30 
7.3 
Selection of Study Population ................................................................................31 
7.3.1 
Inclusion Criteria ...................................................................................31 
7.3.2 
Exclusion Criteria..................................................................................32 
7.4 
Randomization and Blinding .................................................................................35 
7.4.1 
Patient Identification .............................................................................35 
7.4.2 
Randomization ......................................................................................35 
7.4.3 
Blinding .................................................................................................35 
7.5 
Study Duration .......................................................................................................35 
7.6 
Study Discontinuation ............................................................................................36 
7.7 
Patient Discontinuation ..........................................................................................36 
8.0 
STUDY TREATMENTS .................................................................................................36 
8.1 
Study Drug Characteristics ....................................................................................36 
8.1.1 
Formulation ...........................................................................................36 
8.1.2 
Container, Closure, Packaging, and Labeling .......................................37 


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8.2 
Study Drug Dose and Regimen..............................................................................37 
8.2.1 
Active Arm ............................................................................................37 
8.2.2 
Placebo Arm ..........................................................................................38 
8.3 
Study Drug Handling and Management ................................................................38 
8.3.1 
Storage and Stability .............................................................................38 
8.3.2 
Study Drug Ordering, Shipment, Dispensing, and Accountability .......38 
8.4 
Concomitant Medications ......................................................................................39 
8.4.1 
Concomitant Pain Medications and Therapies ......................................39 
8.4.2 
Allowed Medications and Therapies .....................................................40 
8.4.3 
Prohibited Medications .........................................................................40 
9.0 
STUDY VISITS AND PROCEDURES ..........................................................................41 
9.1 
Schedule of Study Procedures ...............................................................................41 
9.2 
Screening and Washout Period (Day -45 to Day -14) ...........................................41 
9.2.1 
Screening Evaluation ............................................................................41 
9.3 
Pain Observation Period (Day -14 to Day -1/Pre-Treatment) ...............................42 
9.3.1 
Day -14 Training Visit ..........................................................................42 
9.3.2 
Follow-Up Phone Contact (Day -7 to Day -5) ......................................43 
9.4 
Pre-Treatment/Baseline Visit (Day 1) ...................................................................43 
9.5 
Treatment Period (Week 1 to Week 12) ................................................................44 
9.5.1 
Week 1 ..................................................................................................45 
9.5.2 
Week 2 ..................................................................................................45 
9.5.3 
Week 4 ..................................................................................................46 
9.5.4 
Week 8 ..................................................................................................46 
9.6 
Safety Extension (Week 12 to Week 24) ...............................................................47 
9.6.1 
Week 12 ................................................................................................47 
9.6.2 
Week 14 ................................................................................................48 
9.6.3 
Week 18 ................................................................................................49 
9.6.4 
Week 24 ................................................................................................49 
9.7 
Follow-Up Period (Week 26 and Week 28) ..........................................................50 
9.7.1 
Week 26 ................................................................................................50 
9.7.2 
Week 28 ................................................................................................51 
9.8 
Premature Discontinuation.....................................................................................51 
10.0 
EVALUATIONS AND STATISTICAL ANALYSES ..................................................52 
10.1 
Data Management and Quality Assurance .............................................................52 
10.2 
Efficacy and Safety Evaluations ............................................................................52 
10.2.1 
Efficacy Assessments ............................................................................52 


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10.2.1.1 
Primary Efficacy Assessment ........................................................52 
10.2.1.1.1 
Numerical Pain Rating Scale .........................................................53 
10.2.1.2 
Secondary Endpoints .....................................................................53 
10.2.1.2.1 
Brief Pain Inventory Questionnaire – Short Form .........................53 
10.2.1.2.2 
Patient Global Impression of Change ............................................54 
10.2.1.2.3 
Neuropathy Total Symptom Score – 6...........................................54 
10.2.1.2.4 
Utah Early Neuropathy Scale.........................................................54 
10.2.1.2.5 
Norfolk Diabetic Quality of Life-Diabetic Neuropathy .................54 
10.2.1.2.6 
Use of Rescue Medication .............................................................55 
10.2.1.3 
Intraepidermal Nerve Fiber Density Determination ......................55 
10.2.1.4 
Masquerading Disorders Tool........................................................55 
10.2.2 
Safety Assessments ...............................................................................56 
10.3 
Statistical Methods .................................................................................................56 
10.3.1 
Sample Size and Power .........................................................................56 
10.3.2 
Analysis Approach ................................................................................56 
10.3.3 
Primary Efficacy Outcome Measures ...................................................57 
10.3.4 
Key Secondary Outcome Measures ......................................................58 
10.3.5 
Secondary Outcome Measures ..............................................................59 
10.3.6 
Exploratory Efficacy Outcome Measures .............................................59 
10.3.7 
Safety Analyses .....................................................................................59 
10.3.8 
Interim Analysis and Data Monitoring Committee ...............................60 
11.0 
SAFETY MONITORING AND RISK MANAGEMENT ...........................................61 
11.1 
Safety Events and Reporting ..................................................................................61 
11.1.1 
Definitions .............................................................................................61 
11.1.2 
Documenting and Reporting Adverse Events .......................................62 
11.1.2.1 
Assessment of Intensity (or Severity) ............................................63 
11.1.2.2 
Assessment of Relationship to Study Treatment ...........................63 
11.1.3 
Special Procedures for Reporting Serious Adverse Events ..................64 
11.2 
Pregnancy Reporting ..............................................................................................65 
11.3 
Expedited Reporting ..............................................................................................66 
11.4 
Clinical Laboratory Evaluations ............................................................................66 
11.5 
Vital Signs ..............................................................................................................66 
11.6 
Electrocardiograms ................................................................................................67 
11.7 
Physical Examinations ...........................................................................................67 
11.8 
Height and Weight .................................................................................................68 
11.9 
Safety Data and Potential Risks .............................................................................68 


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11.10 Risk Mitigation ......................................................................................................69 
11.10.1 
Study Level Risk Mitigation .................................................................69 
11.10.1.1 
Training and Data Management .....................................................69 
11.10.1.2 
Data Monitoring Committee ..........................................................70 
11.10.2 
Patient Level Risk Mitigation ...............................................................70 
11.10.2.1 
Patient Exclusion ...........................................................................70 
11.10.2.2 
Adverse Events of Special Interest and Monitoring Procedure .....71 
11.10.2.2.1 Hematological Adverse Events of Special Interest 
Confirmatory Monitoring ..............................................................72 
12.0 
ADMINISTRATIVE AND REGULATORY OBLIGATIONS ...................................73 
12.1 
Confidentiality .......................................................................................................73 
12.1.1 
Confidential and Proprietary Information .............................................73 
12.1.2 
Publication and Media Inquiries ...........................................................73 
12.1.3 
Patient Identity and Protected Health Information................................73 
12.2 
Independent Review Board ....................................................................................74 
12.3 
Patient Recruitment and Informed Consent ...........................................................74 
12.3.1 
Patient Referrals ....................................................................................74 
12.3.2 
Informed Consent and Other Written Information for Patients ............74 
12.4 
Study Documentation.............................................................................................75 
12.5 
Protocol Compliance ..............................................................................................75 
12.6 
Investigational Drug Accountability ......................................................................76 
12.7 
Study Monitoring ...................................................................................................76 
12.8 
Reports ...................................................................................................................76 
13.0 
COVID-19 RISK MITIGATION ...................................................................................77 
13.1 
Risk/Benefit Assessment in the Context of COVID-19 ........................................77 
13.2 
Remote Visits .........................................................................................................77 
13.3 
Patient Disposition in the Context of COVID-19 ..................................................79 
13.4 
Regulatory and Oversight Considerations in the Context of COVID-19 ..............79 
14.0 
REFERENCES .................................................................................................................80 
15.0 
APPENDICES ..................................................................................................................84 
15.1 
APPENDIX I – Clinical Laboratory Evaluations ..................................................84 
15.2 
APPENDIX II – Suicidal Ideation/Behavior Screening ........................................85 
 


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1.0 
INVESTIGATOR AGREEMENT 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees that 
any changes to the protocol, except to eliminate an immediate patient risk, must be approved by 
the Sponsor and the Institutional Review Board prior to implementation. The Investigator will 
delegate study-related responsibilities only to individuals with proper experience, training, and 
credentials, and will fully review all aspects of the protocol with study personnel prior to their 
involvement. This study will be conducted in accordance with International Conference on 
Harmonization Good Clinical Practice (ICH E6 GCP) guidelines, the Declaration of Helsinki, 
and all other applicable ethical and legal requirements. 
The Investigator understands that the study may be terminated or enrollment suspended at any 
time by the Sponsor, with or without cause. The Investigator may also choose to stop enrollment 
and study treatment if it becomes necessary to protect the best interests of the study patients. 
However, it is understood that study patients should be followed, as agreed with the Sponsor, for 
final evaluations of safety. 
 
 
 
Investigator’s Signature 
 
Date 
 
 
Investigator’s Printed Name 


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2.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
% 
percent 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration curve 
BMI 
body mass index 
BPI-SF 
brief pain inventory – short form 
CBD 
marijuana or cannabidiol 
CFR 
US Code of Federal Regulations 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
DN4 
Douleur Neuropathique 4 
DPN 
diabetic peripheral neuropathy 
DSM 
Diagnostic and Statistical Manual of Mental Disorders V 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EIU 
Exposure In Utero 
FDA 
Food and Drug Administration 
FOCBP 
female of childbearing potential 
FSH 
follicle-stimulating hormone 
g/dL 
gram per deciliter 
GCP 
Good Clinical Practice 
HbA1c 
glycated hemoglobin 
HDAC 
histone deacetylases 
HDAC6 
histone deacetylase 6 
HEENT 
head, eyes, ears, nose, and throat 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IENFD 
intraepidermal nerve fiber density 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU/L 
international units per liter 
kg/m2 
kilogram per square meter 
MAR 
Medical Administration Record 
MDT  
Masquerading Disorders Tool  
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
Mg 
milligram 
Mm 
millimeter 
mm3 
cubic millimeter 
MMRM 
mixed model repeated measures 
mmHg 
millimeters of mercury 
Msms 
milliseconds 
ng*hr/mL 
nanogram per milliliter per hour 
NOAEL 
no observed adverse effect level 
NRS 
numerical rating scale (or numerical pain rating scale) 
NSAID 
non-steroidal anti-inflammatory drugs 
NTSS-6 
Neuropathy Total Symptom Score – 6 
PBMC 
peripheral blood monocytes 
PCR 
polymerase chain reaction  
pg/mL 
picogram per milliliter 
PGIC 
Patient Global Impression of Change 
PT 
preferred term 
QD 
once daily 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class  
STZ 
streptozotocin 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
UENS 
Utah Early Neuropathy Scale 
ULN 
upper limit of normal 
 
 


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3.0 
SYNOPSIS 
Protocol Number: 
REGY-DN-201 
Title of Study: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group 
Study of Ricolinostat in Patients with Painful Diabetic Peripheral Neuropathy 
Study Phase: 
Phase 2 
Number of Study Sites: Approximately 50 investigative sites in the US 
Study Objectives: 
The primary objective of this study is to evaluate the safety and efficacy of 
ricolinostat compared with placebo for painful diabetic peripheral neuropathy 
(DPN) as measured by an 11-point numerical pain rating scale (NRS) after 
12 weeks. 
Methodology/  
Study Design: 
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. 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 with placebo (single-blind) 
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 described in Table 1. 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 (Table 1).  
Study Population: 
Patients with Type 1 or Type 2 diabetes suffering from painful distal 
symmetric sensorimotor polyneuropathy (painful DPN) present for 
≥ 6 months who meet all inclusion and exclusion criteria are eligible to 
participate.  
Sample Size: 
The sample size for this study is planned to be approximately 274 evaluable 
patients, which provides a power of 0.8 for detecting a treatment difference of 
0.8 points on the NRS. Assuming a pooled standard deviation of 2.35, this 
corresponds to a standardized effect size of approximately 0.34, an effect size 


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comparable to effect sizes observed in recent diabetic neuropathic pain studies 
using efficacious agents such as duloxetine and pregabalin (Smith et al, 
2018). An effect size of this magnitude or greater, if observed in this study, 
would support the further investigation of ricolinostat as a potential treatment 
for painful DPN.  
Study Eligibility: 
Inclusion Criteria 
Eligible patients will meet the following criteria: 
1. 
Able to understand the study’s purpose and requirements, and able to 
voluntarily provide informed consent to participate. 
2. 
Age ≥ 18 years and < 80 years at the time of signing the informed 
consent form (ICF). 
3. 
Females of childbearing potential (FOCBP) must agree to use reliable 
contraceptive methods for the duration of the study and for at least 
3 months after completing treatment with study drug. For the 
purposes of this study, reliable methods of contraception include 
abstinence, oral contraceptives, hormonal contraceptive implants such 
as Nexplanon, hormonal vaginal ring such as NuvaRing, intrauterine 
devices in place for at least 3 months, or barrier methods used in 
conjunction with spermicide. To be considered post-menopausal and 
of non-child-bearing potential, women less than 60 years with less 
than 2 years since their last period must have follicle-stimulating 
hormone (FSH) > 40 IU/L and estradiol < 20 pg/mL unless on 
hormone replacement.  
Male patients participating in the study must also agree to use these 
reliable contraceptive methods if sexually active with a FOCBP 
partner and also agree to abstain from sperm donation from Day 1 
through 3 months after completing treatment with study drug. 
4. 
Type 1 or Type 2 diabetes of at least 6 months duration that meets 
American Diabetes Association criteria (American Diabetes 
Association, 2020) with a glycated hemoglobin (HbA1c) > 6.5% at 
the time of Screening. If the HbA1c at the time of Screening is less 
than 6.5%, evidence that the patient meets American Diabetes 
Association criteria for diabetes must be documented and reviewed 
with the Sponsor prior to entering the patient in the study. 
Additionally, the diabetes should be adequately controlled, with an 
HbA1c < 11% and no evidence of severe hypoglycemia requiring 
hospitalization within the past 6 months, and in the Investigator’s 
judgment sufficiently stable to allow participation in the study.  


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5. 
Painful distal symmetric sensorimotor polyneuropathy due to diabetes 
as defined by having 1 or more relatively symmetric, distally 
accentuated (stocking or stocking-glove) neuropathic symptom(s) and 
1 or more relatively symmetric, distally accentuated (stocking or 
stocking-glove) neuropathic sign(s), except that diminished reflexes 
are not, in the absence of at least 1 other neuropathic sign, sufficient 
to make the diagnosis. Neuropathic symptoms can include pain, 
numbness, tingling, or weakness in a distal to proximal (stocking and 
glove) distribution; signs can include impaired pinprick, light touch, 
vibration, or position sense. The neuropathy must have been present 
(by history) for at least 6 months and must be confirmed and 
documented by the Investigator based on clinical history and physical 
examination. 
6. 
Douleur Neuropathique 4 (DN4) score ≥ 4. 
7. 
Meets initial diary criteria during the 14 days in the Pain Observation 
period as determined by an algorithm that includes diary compliance, 
overall level of pain, and day-to-day variability in pain, including at 
least 5 of 7 daily entries completed the 7 days prior to Day 1, and a 
mean intensity and standard deviation within a pre-specified bound 
(the precise bounds are held as double-blind to avoid introducing bias 
into the ratings). Additionally, at least 5 of 7 doses of placebo must be 
taken the 7 days prior to Day 1 as prescribed during the Pain 
Observation period for patients to be eligible to continue in the study. 
8. 
Able to adhere to the study visit schedule and other protocol 
requirements. 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. 
Females who are pregnant or lactating.  
2. 
Extremely overweight, defined as body mass index (BMI) 
> 40 kg/m2. 
3. 
Difficulty understanding instructions for diary use as determined by 
the Investigator or other issues that are likely to make compliance 
with study requirements difficult. 


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4. 
Presence of any neuropathy other than DPN and/or significant risk 
factors for neuropathy other than diabetes, including Charcot Marie 
Tooth disease; alcohol abuse; B12 deficiency not adequately treated; 
uncontrolled hypothyroidism; evidence of paraproteins by serum 
immunofixation; history of chemotherapy with neurotoxic agents 
such as platinum analogs, taxanes, vinca alkaloids, eribulin, 
bortezomib and other proteasome inhibitors; or immunomodulatory 
agents such as thalidomide, lenalidomide, pomalidomide, neurotoxic 
check-point inhibitors, or any other chemotherapy known to have 
neurotoxic effects.  
5. 
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. In addition to a 
general history and clinical examination, this will be assessed using 
the Masquerading Disorders Tool (MDT). Patients who screen 
positive on this tool for a potentially confounding disorder must be 
discussed with and approved by the Sponsor’s Medical Monitor prior 
to being randomized into the study. 
6. 
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. Individuals whose 
neuropathy is so severely advanced as to create a significant risk that 
the neuropathy will be poorly responsive to treatment as defined by a 
Utah Early Neuropathy Scale (UENS) score > 24 at the time of 
Screening are also excluded from participation. 
7. 
Have met Diagnostic and Statistical Manual of Mental Disorders V 
(DSM V) criteria for opioid use disorder or DSM V criteria for 
alcohol use disorder (moderate or severe) within the past 2 years. 
8. 
Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or 
more days a week during the month prior to Screening. 
9. 
Active suicidal ideation or suicidal behavior as assessed by the 
Investigator and/or by a rating of 3 or greater on the Columbia 
Suicide Severity Rating Scale (C-SSRS; see Appendix II).  
10. 
The use of marijuana or cannabidiol (CBD) during the 30 days prior 
to starting study drug.   
11. 
A positive urine screen for illicit or non-prescribed controlled 
substances at baseline. 


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12. 
Have been using non-drug interventions for pain (eg, acupuncture, 
mindfulness therapy, etc) for at least 3 months prior to starting study 
drug may continue these interventions, however such treatments may 
not be initiated during the study, and any patients who plan to initiate 
such treatment during the study are excluded from participation. 
13. 
Repeated use (greater than 3 occasions) of over-the-counter capsaicin 
on extremities within 3 months of Screening or prescription Qutenza 
use within 6 months of Screening.  
14. 
Implanted medical device (eg, spinal cord stimulator, intrathecal 
pump, or peripheral nerve stimulator) for the treatment of pain. 
15. 
Has a QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 450 msec (male) or > 460 msec (female) or > 480 msec 
with right bundle branch block on 12 lead ECG at Screening, or 
requires treatment with drugs known to prolong the QT interval 
(including azithromycin, chloriquine/melfiloquine, clarithromycin, 
droperidol, erythromycin, moxifloxacin and sevoflurane), or has a 
known history of torsade de pointes or congenital long QT syndrome. 
16. 
Family or personal history of long QT syndrome or ventricular 
arrhythmias including ventricular bigeminy, previous history of QT 
prolongation not attributable to an identified and transient cause, or 
need for treatment with medications associated with QT prolongation. 
17. 
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. 
18. 
eGFR of < 45 mL/min/1.73 m2 (ie, patients with stage 3b or more 
severe renal disease are excluded). 
19. 
Serum bilirubin values > 2.0 mg/dL. Individuals with known 
hereditary benign hyperbilirubinemia (Gilberts’ syndrome) and a 
bilirubin < 3.0 may participate in the study after discussion and 
agreement with the Sponsor’s Medical Monitor. 
20. 
Serum alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) values > 1.5 x the upper limit of normal 
(ULN).  
21. 
Known human immunodeficiency virus (HIV) positive or active 
hepatitis virus (A, B, or C) infection. 


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22. 
Participation within 1 month of Screening in a clinical trial involving 
treatment with an investigational product. Concurrent participation in 
an observational study (ie, no investigational treatment being used) is 
allowed provided it does not interfere with the procedures and 
conduct of this protocol. 
23. 
Any serious medical condition or comorbidity, laboratory 
abnormality, or psychiatric illness not otherwise specified that could 
place the patient at undue risk during trial participation, that could 
confound the results of the study, or that could reasonably be 
expected to affect patient compliance with study requirements for 
treatment and evaluation, as judged by the Investigator. 
24. 
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. 
Note: Abnormal Screening laboratory values that appear to be spurious 
(eg, laboratory error), or that are the result of an identified transient 
event that if resolved is unlikely to recur, may be repeated once. Should 
this occur, the Investigator should document the reason for repeating the 
test, and if the repeat examination is within the acceptable range, the 
patient may participate. 
Study Treatments: 
Active Arm 
Ricolinostat 120 mg, taken once daily (QD) by mouth in the morning at least 
30 minutes prior to eating and at least 2 hours after the last meal; each dose in 
12 mL liquid formulation (10 mg ricolinostat per mL). 
Placebo Arm 
Placebo, 12 mL of liquid formulation with no active ingredient (i.e., 
ricolinostat), taken QD by mouth at least 30 minutes prior to eating and at 
least 2 hours after the last meal. 
Duration of Study 
Treatment and Patient 
Participation: 
Following the initial Screening and the 14 day placebo lead-in Pain 
Observation period, study treatment will be taken QD for approximately 
24 weeks, which includes an approximately 12-week double-blind, 
placebo-controlled Treatment period and an approximately 12-week open 
label Safety Extension period, and will be followed by an approximately 
4-week washout and Safety Observation period. 
Efficacy Evaluation: 
Primary Endpoint 
The primary endpoint is the change from baseline in mean average pain 
intensity following 12 weeks of treatment as measured by the NRS. 
Key Secondary Endpoints 
• 
Change in mean average pain intensity from baseline to Week 4 as 
measured by the NRS. 


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• 
Change in non-pain neuropathic signs after 12 weeks in patients as 
assessed by change in the UENS.  
Secondary Endpoints 
• 
Change in weekly mean worst pain from baseline to week12 and week 4 
as measured by the NRS. 
• 
Proportion of patients achieving ≥ 30% and ≥ 50% improvement in mean 
NRS score from baseline to Week 4 and to Week 12. 
• 
Change in mean brief pain inventory – short form (BPI-SF) pain 
interference score from Pre-Treatment/Day 1 to Week 12. 
• 
Change in mean BPI-SF pain interference score from Pre-Treatment/Day 
1 to Week 4. 
• 
Change from baseline to Week 12 in the Neuropathy Total Symptom 
Score – 6 (NTSS-6). 
• 
Change from baseline to Week 12 in Norfolk Diabetic Quality of 
Life-Diabetic Neuropathy (QOL-DN).  
• 
Patient global impression of change (PGIC) at Week 4 and Week 12. 
• 
Rescue medication (acetaminophen) use.  
Exploratory Endpoints 
• 
Change in epidermal nerve fiber density in a subset of patients with 
painful DPN and reduced intraepidermal nerve fiber density (IENFD) at 
baseline after 24 weeks of treatment with ricolinostat.  
• 
Other exploratory endpoints may be identified at the time of analysis of 
the study data. 
Safety Evaluations: 
Safety evaluations will include assessment of adverse events (AEs), vital 
signs, physical examination, 12-lead electrocardiogram (ECG), and laboratory 
measures. An independent Data Monitoring Committee (DMC) will review 
safety after a vanguard cohort of at least 30 patients has had the opportunity to 
complete 4 weeks of treatment, and again after this cohort has had the 
opportunity to complete 12 weeks of treatment. The DMC will have another 
planned meeting to review safety when approximately 50% of the planned 
number of patients have been enrolled. The DMC may also meet for 
unplanned meetings should safety observations during the study warrant such 
meetings. 
Statistical Methods: 
Primary Analysis 
The primary analysis will be based on a mixed model repeated measures 
(MMRM) analysis to estimate the difference in change from baseline to Week 
12 in mean average pain score in patients receiving ricolinostat versus those 
receiving placebo. The outcome will include the weekly mean change from 
baseline in the daily average pain scores computed each week during Week 1 
through Week 12. The baseline average pain score will be computed as the 
mean of the average daily pain scores during the 7 days prior to 
randomization. The following covariates will be included in the model: 
baseline value of the pain score, visit, treatment group, use of concomitant 
medication for painful DPN (yes vs. no), a treatment group by visit interaction 
term, and a baseline pain score by visit interaction term. The model will first 


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be fit with an unstructured covariance matrix. If this model does not converge, 
then additional structures will be considered as outlined in the protocol and 
Statistical Analysis Plan (SAP). 
Key Secondary Analysis  
The key secondary endpoint of the change from baseline in the average pain 
at Week 4 using the 11-point NRS will be assessed using a MMRM. The 
model will be fit with the average change from baseline in the NRS from 
Weeks 1 through 4 as the outcome and the baseline pain score, visit, treatment 
group, use of concomitant medication for painful DPN (yes vs. no), a 
treatment group by visit interaction term, and a baseline score by visit 
interaction term. The second key secondary endpoint of change in non-pain 
neuropathic signs after 12 weeks in patients as assessed by change in the 
UENS will be analyzed using an analysis of covariance (ANCOVA) model 
with the change from baseline as the outcome, and baseline UENS score, 
treatment group, and use of concomitant medication for painful DPN (yes vs. 
no) as covariates. 
The fixed-sequence method will be used to control the overall significance 
level at 0.05. The first key secondary endpoint of change from baseline in the 
average NRS score at Week 4 will only be tested if the primary endpoint of 
change from baseline in the average NRS score at Week 12 is statistically 
significant at 0.05. The UENS endpoint will only be tested if the key 
secondary endpoint of change from baseline in the average NRS score at 
Week 4 are statistically significant. 
Secondary Analyses  
The BPI-SF, NTSS-6, the Norfolk Diabetic QOL-DN will be analyzed using 
an ANCOVA model with the change from baseline at Week 4 or Week 12 for 
the given outcome and baseline value of the outcome, treatment group, and 
use of concomitant medication for painful DPN (yes vs. no) as covariates.  
The PGIC at Week 4 and Week 12 will be analyzed using a two-sample t-test. 
The proportion of patients achieving ≥ 30% and ≥ 50% improvement in mean 
NRS score from baseline to Week 4 and Week 12 will be summarized 
descriptively with chi-square tests used to test for differences between groups. 
Use of rescue medication (acetaminophen) will be analyzed using a 
chi-square test. 
Exploratory Analyses  
The change in IENFD at baseline and after 24 weeks of treatment with 
ricolinostat will be summarized descriptively. An ANCOVA model will be 
used to assess the change from baseline and differences between groups. 
References: 
American Diabetes Association. 2. Classification and diagnosis of diabetes: 
standards of medical care in diabetes- 2020. Diabetes Care. 2020;43(Suppl 
1):S14-S31.  
 
Smith SM, Jensen MP, He H, et al. A comparison of the assay sensitivity of 
average and worst pain intensity in pharmacologic trials: an ACTTION 
systematic review and meta-analysis. J Pain. 2018;19(9):953-960.  
 
 


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Table 1: 
Schedule of Assessments 
Screening 
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
Screening 
Evaluation1 
Washout  
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
DAY 
-45 to -14 
-14 to -7 
-7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
Informed consent 
X 
Eligibility 
evaluation1 
X 
X 
Demographics 
X 
Medical history 
X 
X 
X 
C-SSRS3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diabetes & 
painful DPN 
history 
X 
Masquerading 
disorders tool 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and 
weight 
X 
Physical 
examination5
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin integrity 
and wound 
healing6
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG7 
X 
X 
X 
X 
X 
Chemistry 8 
X 
X 
X 
X 
X 
X 
X 
Hematology 
(CBC with 
differential) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
Vitamin B12 and 
serum 
paraproteins 
X 
Urine pregnancy 
test (if FOCBP)9
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH and 
estradiol10 
X 
SARS-CoV-2 
(COVID-19) 
Qualitative 
PCR11 
X 
Urine drug 
screen12 
X 
X12 
X12 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X12 
X12 
X12 


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Screening 
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
Screening 
Evaluation1 
Washout  
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
DAY 
-45 to -14 
-14 to -7 
-7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
Urinalysis 
X 
X 
X 
X 
HIV, HBsAg, 
HCV screen 
X 
DN4 
X 
Intraepidermal 
nerve biopsy 
(eligible patients 
at selected sites 
only) 
X 
X15 
Numerical Pain 
Rating Scale 
-------------------------------------------COLLECTED DAILY VIA DIARY------------------------------------------- 
Brief Pain 
Inventory Short 
Form (pain 
interference 
section only)  
X 
X 
X 
X 
X 
Neuropathy 
Total Symptom 
Score – 6 
X 
X 
X 
X 
UENS 
X 
X 
X 
X 
X 
Norfolk Diabetic 
QOL-DN 
X 
X 
X 
X 
Patient Global 
Impression of 
Change 
X 
X 
X 
X 
Patient training 
X13 
X13 
X 
X13 
X13 
X 
X 
X13 
X13 
X13 
X13 
X13 
Randomization14 
X 
Dispense, collect 
and perform 
study drug 
accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record study 
drug 
-------------------------------------------COLLECTED DAILY VIA DIARY------------------------------------------- 
Prior & 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule 
observation 
period 
X 
Review 
prohibited 
X 


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Screening  
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
 
Screening 
Evaluation1 
Washout  
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
DAY 
-45 to -14 
-14 to -7 
 -7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
medications and 
rescue 
medication 
guidelines 
Phone contact 
and diary review 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
Note: If a patient is discontinued early from the study for any reason, the Investigator should make every effort to ensure that the final assessments at Week 24 are completed as 
outlined in the schedule of events. The reason for discontinuation will be recorded in the patient’s record and the study database. 
1. 
Screening evaluations for patients on pain medication that is not permitted should be scheduled so as to allow for a minimum washout of 7 days prior to the start of the Pain 
Observation period. Patients who are not taking pain medication and do not require washout can be scheduled for Screening evaluations at any time during the period with the 
understanding that it may take several days before laboratory results are available. 
2. 
All patients are required to complete the Pain Observation period from Day -14 to Day -1. During the Pain Observation Period, on Day -7 to -5, a phone contact to the patient 
will be conducted to review diary and dosing compliance and provide re-training as necessary. The Day 1 clinic visit will be scheduled during this call. A patient may be 
randomized after 10-14 days in the Pain Observation period if all eligibility requirements have been met. An algorithm comprised of several aspects of the diary data will 
determine final eligibility prior to randomization.  
3. 
C-SSRS Screening version used for Screening. Subsequent visits will use the Since Last Visit version. 
4. 
Vital signs include temperature, respiration rate, pulse, and blood pressure while patient is sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be 
obtained following sitting vital signs.  
5. 
A comprehensive physical examination will be performed at Screening; subsequent physical examinations will be directed exams to assess changes from the prior visit or new 
concerns. 
6. 
Skin breaches and wounds will be examined and the following parameters recorded: location, size, depth, and evidence of erythema, edema, warmth, odor, or drainage. 
7. 
12-lead ECG after the patient has been resting in the supine position. On Day 1, an additional 12-lead ECG will be obtained 1 hour (+/- 10 minutes) post-dose.  
8. 
Chemistry will be collected in a fasting state (8 to 10 hours fasting). 
9. 
A urine pregnancy test is required at Screening and Day 1 (prior to randomization) for females of child-bearing potential, and must be negative for treatment to proceed. 
10. Only for females less than 60 years of age with less than 2 years since last period. 
11. Only required if any recent exposure within past 14 days prior to screening to COVID-19 and/or symptoms of COVID-19 along with reason to suspect COVID-19. 
12. Urine drug screen is required at Screening and Week 8, and may be performed at any other visit at the discretion of the Investigator. 
13. Patient training is required at Day-14, Day 1, Week 4 and Week 8. Patient training may be repeated, as applicable, at other visits during the study at the discretion of the 
Investigator. Day-14 training is conducted in the WCG aLearn Learning Management System platform. The following training modules are to be completed: Accurate Pain 
Reporting, Placebo Response Reduction and Research Subject Responsibility.   
14. On Day 1, all assessments are to be performed prior to randomization. Once randomized, patients will be given the first dose of study drug in the clinic and an ECG will be 
performed 1 hour post-dose. 
15. If visit is being conducted as an early termination visit and the timing is during the Safety Extension (Week 12 to Week 24), collection of the intraepidermal nerve biopsy 
should occur if patient previously provided consent and intraepidermal nerve biopsy collection occurred at Day 1. 
 
COVID-19 = coronavirus disease 2019; C-SSRS = Columbia-Suicide Severity Scale; DN4 = Douleur Neuropathique 4 Score; DPN = diabetic peripheral neuropathy; 
ECG = electrocardiogram; FOCBP = female of childbearing potential; HbA1c = glycated hemoglobin; HbsAg = hepatitis B virus surface antigen; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; PCR = polymerase chain reaction; QOL-DN = Quality of Life-Diabetic Neuropathy; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; UENS = Utah Early Neuropathy Scale.  
 
 


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4.0 
ETHICAL CONSIDERATIONS 
4.1 
Independent Review Board 
In accordance with the US Code of Federal Regulations (CFR) 21 CFR 56, the protocol, ICF, 
any additional information for patients, and patient recruitment materials will be submitted to a 
properly constituted Institutional Review Board (IRB) prior to commencing the study. 
Verification of the IRB’s review and approval of the protocol, ICF, and other materials will be 
required before investigational product is shipped to the study sites and study enrollment begins. 
All subsequent protocol amendments or changes to the ICF, information for patients, and/or 
recruitment materials will be submitted to the IRB for review and approval prior to 
implementation. The IRB will be informed of any new information that becomes available 
during the study that could impact patient health and safety, including the occurrence of 
Suspected Unexpected Serious Adverse Reactions (SUSARs). 
Periodic and final progress reports will be submitted to the IRB at appropriate intervals not to 
exceed 1 year. 
4.2 
Ethical Conduct of the Study 
The study procedures outlined in this protocol will be conducted in accordance with the CFR 
governing Protection of Human Patients (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), Institutional Review Boards (21 CFR 56), Investigational New Drug 
Application (21 CFR 312), and with the International Conference on Harmonisation Good 
Clinical Practice (ICH E6 GCP) guidelines, as appropriate. As such, this study will be conducted 
in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
4.3 
Patient Information and Consent 
Each study patient, upon deciding to participate, will sign the IRB-approved ICF before any 
study-related procedures are performed. The Investigator will ensure that each patient being 
considered for inclusion in this study is given a full explanation of the procedures and 
expectations for study participation. Study personnel will adhere to the requirements of 21 CFR 
50 when obtaining consent from any potential study candidate, including explaining the rationale 
for and the details of the study, the risks and benefits of alternative treatments, and the extent of 
involvement. Once the essential information has been provided to the patient and fully explained 
by the Investigator (or a qualified designee) and it is felt the patient understands the implications 
and risks of participating in the study, the IRB-approved ICF will be signed and dated. 
The patient will be given a copy of the signed consent, and the original will be maintained with 
the patient’s records. 


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5.0 
INTRODUCTION 
5.1 
Diabetic Neuropathic Pain 
According to recent estimates, more than 400 million people worldwide and more than 
30 million in the United States suffer from diabetes mellitus, while an additional 80 million 
people in the United States are prediabetic and at increased risk for progression to frank diabetes 
within 5 years (World Health Organization, 2016; Centers for Disease Control and Prevention, 
2014). This constitutes a major health problem, as diabetes is associated with a number of 
complications that lead to significant morbidity and disability. Among the most common 
complications are diabetic neuropathies, which occur in up to 50% of patients and are 
characterized by loss of sensation, paresthesias, and, in approximately 10% to 20% of patients, 
pain (Pop-Busui R et al, 2017; Barrett, 2007; Veves, 2008). Patients with diabetic peripheral 
neuropathy (DPN) and diabetic neuropathic pain experience functional impairments as well as 
reduced quality of life, with negative effects on physical, emotional, social functioning, and sleep 
(Davies, 2006; Pop-Busui R et al, 2017). 
5.2 
Medical Need  
Pharmacologic treatments for diabetic neuropathy have been shown to be efficacious for diabetic 
neuropathic pain, and not for other aspects of diabetic neuropathy. Multiple drugs including 
tricyclic antidepressants (eg, amitriptyline), selective serotonin-norepinephrine reuptake 
inhibitors (SSNRIs) (eg, duloxetine), anticonvulsants (eg, gabapentin, pregabalin), and opiates 
(eg, oxycodone, tramadol) are used, but only pregabalin (Lyrica®), duloxetine (Cymbalta®), and 
the opioid tapentadol-ER (Nucynta) are approved by the US Food and Drug Administration 
(FDA) for the treatment of diabetic neuropathic pain. Unfortunately, many patients’ symptoms 
fail to respond to these drugs, and among responders, few patients experience complete symptom 
control and remission of pain. Additionally, the available medications are associated with 
unwanted effects, and many patients tolerate them poorly. There thus remains a large, unmet 
medical need for new treatments that are efficacious and well-tolerated in patients with diabetic 
neuropathic pain, as well as more broadly for the treatment of diabetic neuropathy.  
5.3 
HDAC6 Inhibition and Ricolinostat 
Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from lysine 
residues on substrate proteins. The function of most HDACs is associated with gene transcription 
through modification of histone tail acetylation and regulation of chromatin dynamics. However, 
it has become apparent that some HDACs play a critical role in the regulation and function of 
lysine acetylation of non-histone proteins in most, if not all, major cellular functions 
(Choudhary, 2009). In particular, HDAC6 is localized predominantly in the cytoplasm of cells 
where it is crucial in regulating the stability and function of microtubules (Matsuyama, 2002; 
Zhang, 2003; Zilberman, 2009; Tapia, 2010; Badding, 2013). Microtubule transport is a crucial 
component of neuronal survival (Sudo, 2010; Tapia, 2010; Morfini, 2009). HDAC6 activity has 
been associated with a loss in fast axonal transport, which requires stable microtubules 


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(d’Ydewalle, 2011; Xu, 2014; Xiong, 2013; Govindarajan, 2013; Dompierre, 2007), and 
inhibition of HDAC6 with the selective inhibitor Tubastatin A reverses motor neuropathy in a 
mouse model of type 2 Charcot-Marie-Tooth disease (d’Ydewalle, 2011). These data suggest 
that inhibition of HDAC6 in peripheral neurons may preserve neuron function and reverse or 
ameliorate the axonal degeneration observed in peripheral neuropathies such as those common in 
patients with diabetes. 
Ricolinostat is a potent inhibitor of HDAC6 activity (enzymatic IC50 value of 4.7 nM), is 10- to 
12-fold less active against Class I HDAC enzymes (HDAC1, 2, 3, and 8), and has minimal 
activity against Class IIa HDAC enzymes (HDAC4, 5, 7, and 9). HDAC6 is the primary 
deacetylase enzyme for alpha tubulin (Matsuyama, 2002). Ricolinostat treatment increased the 
level of acetylated α-tubulin in primary rat dorsal root ganglion neurons. In a human 
neuroblastoma cell line, ricolinostat increased the level of acetylated α-tubulin in a 
dose-dependent manner.  
Neurons are particularly sensitive to disruptions in intracellular transport via the microtubule 
network. Transport of mitochondria from the cell body to the nerve terminal through the axon 
(anteriograde transport), as well as transport back to the cell body (retrograde transport), are 
disrupted in many neurological conditions. Treatment of cultured dorsal root ganglion neurons 
with high glucose decreases transport in both directions. Pre-Treatment of the cells with 
ricolinostat prevents the disruption in mitochondrial transport. 
Diabetic neuropathic pain is modelled in rats using the streptozotocin (STZ) rat model of tactile 
allodynia. Rats rendered diabetic by an injection of streptozotocin develop increased sensitivity 
to otherwise non-painful stimuli (tactile allodynia). Rats with established STZ induced tactile 
allodynia, as measured by von Frey filament paw withdrawal threshold, treated with ricolinostat 
showed an immediate restoration of normal paw sensitivity after the first dose. The effect 
persisted for several days following withdrawal of ricolinostat. The persistence of effect is in 
contrast with standard of care comparator gabapentin, which reversed tactile allodynia only in 
the hours following drug administration.  
Current treatments for diabetic neuropathic pain are ineffective for the non-painful 
manifestations of DPN such as numbness and tingling. Mechanism of action studies with 
HDAC6 inhibitors in chemotherapy-induced neuropathy indicate that ricolinostat has the 
potential to treat these other symptoms in addition to neuropathic pain. In a mouse model of 
cisplatin-induced neuropathy, HDAC6 inhibition increased IENFD, reversed numbness, and 
restored mitochondrial function in peripheral nerves (Krukowski, 2016).  
5.4 
Dose Justification and Clinical Experience 
As described below, a dose of 120 mg ricolinostat administered QD while fasted using a 
10 mg/mL oral solution formulation is most likely to demonstrate a treatment benefit vs. placebo 
in this Phase 2 proof-of-concept study. This dose and dosing regimen selection is based on 


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pharmacokinetic, pharmacodynamic, and safety data from previous clinical studies, while 
maintaining appropriate safety margins to exposures achieved in long-term non-clinical 
toxicology studies. 
The pharmacodynamic effects of ricolinostat treatment in humans have been assessed by 
measurement of concentrations of acetylated α-tubulin and acetylated histones in circulating 
peripheral blood monocytes (PBMCs) collected from clinical study patients. α-tubulin is a 
substrate for HDAC6 (Matsuyama, 2002) and ricolinostat increases concentrations of acetylated 
α-tubulin in PBMCs, multiple myeloma and neuroblastoma cell lines, and dorsal root ganglion 
neurons in a concentration-dependent manner in vitro. Accumulation of acetylated α-tubulin in 
PBMCs is therefore considered a proximal marker of intracellular HDAC6 target engagement by 
ricolinostat (Chang et al, 2007). Histone acetylation is catalyzed by Class 1 HDAC enzymes (eg, 
HDAC1, 2, 3, and 8) and hence accumulation of acetylated histone represents a marker of 
off-target pharmacological effects. Data from the 4 completed or ongoing studies in oncology 
patients demonstrate increases in levels of both acetylated α-tubulin and acetylated histone 
following ricolinostat dosing either alone or in combination with other oncology treatments. 
However, consistent with the selectivity of ricolinostat for HDAC6 over HDAC1, increases in 
acetylated α-tubulin are more robust and larger than changes in acetylated histone (Figure 1), 
suggesting that desired effects on -tubulin can be achieved while limiting unwanted effects of 
histone acetylation. Additionally, the time-course profile of α-tubulin acetylation mirrors the 
ricolinostat plasma concentration vs. time profile (Figure 1), suggesting a direct relationship 
between ricolinostat exposure and its pharmacodynamic effect. 
Figure 1: 
Ricolinostat Plasma Concentration and Pharmacodynamic Effect vs. Time 
Profiles Following Ricolinostat Treatment in Combination With 
Pomalidomide/Dexamethasone 
 
Source: Study ACE-MM-102 


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Ricolinostat exposures from dosing with the previous 20 mg/mL oral solution formulation show 
dose-proportionality up to 160 mg, with an exposure plateau at dose levels ≥ 160 mg (Figure 2). 
Comparative bioavailability data demonstrate that a 120 mg dose of ricolinostat administered 
using the current 10 mg/mL oral solution formulation provides similar exposures to a 160 mg 
dose using the previous 12 or 20 mg/mL oral solution formulations (Study ACE-HV-100 and 
ACE-MM-104). Based on these data, a 120 mg ricolinostat dose has been selected for this study 
as most likely to provide the highest practically achievable ricolinostat exposure and the 
maximal achievable pharmacodynamic effect. 
Figure 2: 
Maximum Observed Plasma Concentrations of Ricolinostat in Patients With 
Relapsed or Refractory Multiple Myeloma Dosed With Previous 20 mg/ml Oral Solution 
Formulation 
 
Ricolinostat alone (open markers) or combination with bortezomib (closed markers). Circles denote first dose 
(Day 1) and squares repeat dosing (Day 11). Markers represent individual patients and the horizontal bars the 
geometric mean of the data for each group.  
Source: Vogl et al, 2017 (Study ACY-100)  
Selection of a once daily dosing regimen and the recommendation to dose while fasted are also 
based on pharmacodynamic considerations. Ricolinostat is a reversible inhibitor of HDAC6, and 
the proximal pharmacodynamic effect of acetylation of -tubulin in peripheral neurons is 
expected to correlate with intracellular ricolinostat concentrations. By contrast, downstream 
pharmacological effects are anticipated to be more long-lived, as the overall acetylation status of 
α-tubulin reflects the sum of opposing tubulin acetyl transferase activities: HDAC6-mediated 
deacetylation is counterbalanced by the acetylation of assembled microtubules by α-tubulin 


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N-acetyltransferase 1 (Skultetyova et al, 2017). Even a short-lived decrease in HDAC6 activity is 
therefore expected to shift the acetylation equilibrium of stable microtubules over a longer 
time-scale. This is consistent with the results of in vivo pharmacology studies (eg, reversal of 
paclitaxel-induced neuropathy in rats) where the functional effects of the HDAC6 inhibitors were 
similar between once- and twice-daily dosing regimens and persisted beyond the end of dosing. 
On this basis, a QD dosing regimen has been chosen in preference to a twice-daily dosing 
regimen. With respect to food, although dosing with food appears to have no clinically relevant 
effect on ricolinostat bioavailability (Study ACE-HV-100), absorption is delayed and peak 
concentrations are lower. To the degree that pharmacodynamic effects are mediated by 
maximum plasma concentration (Cmax) as well as area under the concentration curve (AUC), 
such effects might be smaller if dosed under fed conditions, and therefore ricolinostat will be 
dosed while fasted. 
Clinical safety data from patients with multiple myeloma and healthy volunteers support 
selection of a 120 mg QD dosing regimen. Clinical data in patients are available from treatment 
studies of 229 patients assessing ricolinostat’s efficacy in multiple myeloma. These data include 
15 patients treated with ricolinostat monotherapy at doses up to 360 mg and 214 patients treated 
with ricolinostat at doses up to 360 mg in combination with several different anti-neoplastic 
agents. An additional 19 healthy volunteers received up to 3 doses of ricolinostat monotherapy 
using 2 different formulations in a relative bioavailability/food effect study. The median duration 
of ricolinostat monotherapy in oncology studies ranged from 1.7 weeks to 12.3 weeks across 
different dose cohorts, with a maximum duration of therapy of 29.5 weeks in a patient treated 
with up to 360 mg of ricolinostat daily. Treatment durations in studies of ricolinostat 
administered in combination with other chemotherapeutic agents have been longer, the longest 
being 174 weeks in combination with lenalidomide and dexamethasone.  
Reviewing the safety data from the monotherapy studies, there did not appear to be a pattern of 
AEs or laboratory changes attributable to ricolinostat either acutely or during chronic treatment, 
as the observed AEs and changes in laboratory measures were generally those expected in a 
population of patients with hematologic malignancies and/or those seen with the oncolytic agents 
administered in combination with ricolinostat. Similarly, the safety findings in the combination 
studies did not demonstrate a pattern of AE or laboratory changes suggestive of a 
ricolinostat-specific serious safety concern. Specifically, there were few AEs among 19 healthy 
volunteers who received single doses of ricolinostat, while among the 15 patients who received 
ricolinostat monotherapy at doses up to 360 mg QD, many of the observed AEs were attributed 
to the underlying disease or intercurrent illness, and there was no clear relationship with dose 
(Vogl et al, 2017; Study ACY-100). Similarly, safety data from 214 patients who received 
ricolinostat in combination with other oncology treatments showed no clear dose-related trends 
in the pattern or incidence of AEs, except that twice daily ricolinostat dosing in combination with 
bortezomib and dexamethasone was associated with a higher incidence of nausea, vomiting, and 
diarrhea compared with a QD dosing regimen. The design and results of clinical trials of 
ricolinostat in combination with anti-neoplastic agents are detailed in the Investigator’s 


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Brochure. Further safety information about ricolinostat is presented in the Investigator’s 
Brochure. Overall the results of these studies do not suggest new concerns or a tolerability 
profile that would be specific or unsafe in patients with DPN.  
The plasma pharmacokinetics of ricolinostat monotherapy are detailed in the Investigator’s 
Brochure. Briefly, ricolinostat is rapidly absorbed (time to maximum plasma concentration 
~1 hour) from the gastrointestinal tract, with an apparent plasma elimination half-life of 
approximately 3 hours. Ricolinostat has been studied in 2 oral formulations, 20 mg/mL and 
10 mg/ml. For this study, the 10 mg/mL formulation has been selected for use. With this 
formulation, ricolinostat plasma exposures plateau at doses above 120 mg, a dose for which 
exposure (Cmax and AUC) is similar to that observed with 160 mg in the previous 20 mg/mL 
formulation. Ricolinostat exposures at the proposed 120 mg clinical dosing regimen using the 
10 mg/mL formulation are comparable to exposures associated with efficacy in non-clinical 
pharmacology studies. Peak plasma exposures from 120 mg QD dosing while fasted are expected 
to be approximately 600 ng/mL, corresponding to unbound exposures of approximately 150 nM. 
By comparison, ricolinostat inhibits HDAC6 in vitro with an IC50 of 5.7 nM and average peak 
exposures from 30 mg/kg dosing in rats were <500 ng/mL.    
Table 2: 
Exposures in Humans Relative to Highest Exposures Observed in Rat and 
Dog Chronic Toxicology Studies 
 
Cmax (mean [RSD] ng/mL) 
AUC-infinity (mean [RSD] 
hr*ng/mL) 
Human exposure (120 mg) 
609 (38%) 
962 (30%) 
Rat (Day 180) (60 mg/kg) 
Male 
Female 
Male 
Female 
662 (+) 
1069 (+) 
2693 (+) 
1736 (+) 
Dog (Day 271) (30 mg/kg) 
Male  
Female  
Male 
Female  
7155 (40%) 
4873 (33%) 
18839 (34%) 13459 (33%) 
+ 
RSD not calculated. 
Source: Ricolinostat (ACY-1215) Investigator’s Brochure, section 3.3.2.2 for chronic toxicology study details 
Taken together, the available evidence suggests that a 120 mg dose will provide sufficient 
exposure to allow an informative test of the hypothesis that HDAC6 inhibition can ameliorate the 
symptoms of painful DPN while maintaining a favorable safety and tolerability profile based on 
acute and chronic non-clinical toxicology studies and previous human experience. 
5.5 
Study Design Rationale  
The study described here is a Phase 2 proof-of-concept investigation of the efficacy of 
ricolinostat for the treatment of diabetic neuropathic pain. As noted above, ricolinostat is a potent 
inhibitor of HDAC6 enzyme activity and represents a promising novel approach to the treatment 
of diabetic neuropathic pain. As described above and in the Investigator’s Brochure, preclinical 
data from animal models suggest that ricolinostat may offer advantages over currently available 


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therapies with respect to magnitude of effect, duration of effect, and/or tolerability. Because pain 
is measured subjectively, it can be subject to expectation bias or other non-specific effects, and 
in order to accurately assess the efficacy of interventions, it is important to control for this. For 
this reason, this study is designed as double-blind and placebo-controlled. The use of placebo 
rather than active comparator is required to provide a definitive understanding of whether 
observed improvement is or is not treatment-specific, and is justified on scientific and ethical 
grounds, as 1) there is no convincing evidence that the active treatments currently available to 
patients change the course of the disease, and thus patients are not put at risk for disease 
worsening or long-term harm by not administering currently available active treatments for 
limited periods; 2) rescue medication for acute episodes of pain is permitted in this protocol to 
ensure that patients are not at risk for excessive discomfort; and 3) per protocol, one medication 
that patients have been taking to treat their pain for at least 3 months at the time of Screening can 
be continued during the study provided the regimen has been stable and is expected to remain 
stable during the study.  
6.0 
STUDY OBJECTIVES 
6.1 
Primary and Key Secondary Objectives 
• The primary objective of this study is to evaluate the safety and efficacy of ricolinostat 
compared with placebo for painful DPN as measured by an 11-point NRS after 12 weeks. 
• Key secondary objectives include 1) evaluating the efficacy of ricolinostat at 4 weeks as 
assessed by NRS and 2) evaluating the efficacy of ricolinostat in improving non-pain 
neuropathic signs after 12 weeks as assessed by change in the UENS. 
6.2 
Secondary Objective 
The secondary objective of this study are to assess the efficacy of ricolinostat for non-pain 
diabetic peripheral neuropathic signs and to further assess efficacy in painful DPN.  
6.3 
Exploratory Objectives 
The exploratory objectives of this study are to assess the effects of ricolinostat on IENFD, a 
potential biomarker for efficacy, at 24 weeks in a subset of patients with painful DPN who have 
reduced IENFD at baseline. 
7.0 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan Description 
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 ricolinostat for painful DPN.  


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After signing the ICF and agreeing to participate, initial eligibility assessments will be completed 
during a Screening visit scheduled between 45 and 14 days prior to planned randomization. 
Patients may continue one permitted medication for painful DPN if they have been taking it for 
at least 3 months prior to Screening, provided that the regimen and dose have been stable for at 
least 3 months prior to Screening and are expected to remain unchanged for the duration of the 
study. If any pain medication is stopped during the Screening period, then prior to proceeding to 
the Pain Observation Period:  
1. The Investigator must document that there has not been a ‘rebound flare,’ or that if such a 
flare has occurred, it has resolved.  
2. The Investigator must document that a steady state pain baseline is present.  
3. A minimum period of time equal to at least 5 half-lives of the drug in question must pass. 
Prior to randomization, patients will participate 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 along with initiation of daily placebo dosing. During 
the Pain Observation period and thereafter during the study, patients will be allowed to use 
acetaminophen as rescue pain medication at a maximum dose of 500 mg at 6-hour intervals up to 
4 times in any given 24-hour period. Patients will record the pain assessments and any rescue 
medication use. A follow-up phone contact will be conducted at Day -7 to Day -5 to review diary 
and dosing compliance. 
At the end of the Pain Observation period, patients whose diary compliance, overall level of 
pain, and pain variability, along with placebo dosing meet entry criteria, will be randomized in a 
1:1 ratio to receive either ricolinostat or placebo.  
Pre-Treatment assessments will be completed as outlined in Table 1. The first dose of study drug 
will be given in the clinic and a 12-lead ECG will be performed 1-hour post-dose. 
During the 12-week randomized, double-blind, placebo-controlled Treatment period, patients 
will return for assessments as per the schedule of assessments shown in Table 1. An electronic 
daily diary will be completed by patients to record study and rescue medication (acetaminophen) 
use, as well as NRS pain assessments. Rescue medication (as needed) and one permitted 
medication that has been used at a stable dose for at least 3 months prior to starting the Pain 
Observation period may be used during the study. Other pain medications are prohibited during 
the Treatment period. Diary data will be reviewed with the patient at each study visit to 
determine if further instruction is required and to document any discrepancies with study drug or 
rescue medication dosing. 


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At the conclusion of the approximately 12-week double-blind, placebo-controlled Treatment 
period, patients will enter an approximately 12-week open label Safety Extension period during 
which all patients will receive ricolinostat 120 mg daily and complete evaluations and clinic 
visits as per the schedule of events. At the conclusion of the Safety Extension, there will be an 
approximately 4-week washout and Safety Follow-up 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 (Table 1). 
IENFD will be studied in approximately 120 patients at a selected subgroup of investigational 
centers by skin biopsy during the baseline observation period and again at the end of the 
approximately 24 week treatment period. At each timepoint, two samples will be taken from 
each patient: one proximally on the lateral thigh 10 cm above the fibular head, and one distally 
towards the ankle 10 cm above the lateral malleolus. This sub-study will include at least 
60 patients randomized to the ricolinostat group and a similar number of patients randomized to 
the placebo group. Based on 1:1 randomization to the study treatment arms, among 24 week 
completers, approximately half the sample of patients participating in the IENFD sub-study will 
have 24 weeks of exposure to ricolinostat and approximately half will have 12 weeks of 
exposure to ricolinostat, providing an opportunity to assess magnitude of change as well as time 
course of change in IENFD. This sub-study is exploratory and the null hypothesis of greatest 
interest is that the change from baseline in nerve fiber density is zero in the group receiving 
6 months of ricolinostat. The power of this sample size to detect an effect is not known precisely. 
However, extrapolating from rates of nerve fiber regrowth in healthy subjects after capsaicin 
administration, assuming a moderate drug effect, and even assuming a slower rate of 
regeneration as compared with healthy subjects, the proposed sample is expected to provide 
approximately 80% power to detect an increase of 0.44 fiber/mm assuming a standard deviation 
of 1.2 fibers after 24 weeks of treatment. Because nerve fiber density may decrease with age, 
patients older than 75 years are not eligible to participate in the intraepidermal nerve fiber biopsy 
sub-study. To mitigate the risk that more than a simple ‘band-aid’ type dressing would be 
required after the biopsy, patients taking anticoagulants are not eligible for intraepidermal nerve 
fiber biopsy. 
A study flow diagram is presented in Figure 3. 


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Figure 3: 
Study Design 
  
 
 
 
 
 
 
7.2 
Discussion of Study Design, Including the Choice of Control Groups 
In order to accustom patients to the conditions they will encounter during the treatment portion 
of the study, during the pain observation period study medication will be administered under 
single-blind conditions (i.e site staff will be aware that placebo is being dispensed, but this will 
not be revealed to patients, who will not know whether they are receiving active drug or placebo 
during the pain observation period).  The randomized treatment portion of the study is designed 
as a double-blind, placebo-controlled study for the initial ~12 weeks. As noted above, because 
expectancy and other non-specific improvements are commonly seen in studies of pain drug 
efficacy, the use of placebo rather than active comparator is required to provide a definitive 
understanding of whether observed improvement is or is not treatment-specific. Placebo is 
justified on the scientific grounds of ensuring that the results of the study are interpretable, and is 
acceptable ethically as 1) there is no convincing evidence that the available active treatments 
change the course of the disease, and thus patients are not put at additional risk for disease 
worsening or long-term harm by not administering currently available treatments for a limited 
periods; and 2) rescue medication for acute episodes of pain is permitted in this protocol to 
ensure that patients are not at risk for excessive discomfort.  
While some effects in animal models appeared rapidly after dosing, in patients with diabetic 
neuropathic pain, ricolinostat’s proposed mechanism of action (restoration of axonal transport 
with consequent improvement in synaptic function and reduction in aberrant pain signaling) 
could require a longer period of time to reach its full effect, particularly as most patients will 
have had chronic pain with longstanding changes in peripheral nerve function; such chronic 
changes may require more extended treatment to reverse. Therefore, this study incorporates an 
acute (~4-week) as well as longer (~12-week) assessment of efficacy. This will allow 
characterization of the course of response as well as the stability of response over time, will 
inform the design of future studies, and is consistent with regulatory requirements for registration 
endpoints in pain studies in which an efficacy assessment at 12 weeks is generally required. The 
Screening 
 Days -45 to -14 
Pain Observation Period   
Placebo (Single-Blind)   
Days -14 to -1 
Double-Blind, Placebo-
Controlled Treatment Period     
Placebo (N=137)                  
Ricolinostat 120 mg (N=137)       
12 weeks 
Open-Label Safety 
Extension Period 
Ricolinostat 120 mg              
12 weeks                     
Follow-up Period 
4 weeks 
Daily dosing and diary completion 
Baseline Assessments 
Clinical Measures 
Baseline Skin Biopsy  
 
Endpoint 
Exploratory: Skin Biopsy  
 
Clinical Outcomes 
 Primary: Pain 
Key Secondary: Other 
Neuropathic Symptoms/ Signs 


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treatment durations planned for this study are supported by acute and chronic toxicology studies 
in animals that did not predict serious safety concerns in humans (details available in the 
Investigator’s Brochure), and the available safety and tolerability data from studies of 
ricolinostat in patients with hematologic malignancies also did not suggest serious safety or 
tolerability concerns during either short or long-term treatment. The ~12-week open label Safety 
Extension will allow further assessment of safety and tolerability, which is important as drugs to 
treat diabetic neuropathic pain are generally used on a long-term basis.  
In animal models, ricolinostat has been shown to reverse pathological reductions in IENFD. 
IENFD is also reduced in patients with diabetic neuropathy, and drug-induced increases in 
intraepidermal nerve density may represent a biomarker predictive of efficacy. Therefore, change 
from baseline to endpoint in IENFD will be measured in patients participating at a selected 
subgroup of sites.  
7.3 
Selection of Study Population 
Patients with Type 1 or Type 2 diabetes suffering from painful distal symmetric sensorimotor 
polyneuropathy (painful DPN) present for at least 6 months (to ensure that symptoms are stably 
present) will be eligible to participate if they meet all inclusion and exclusion criteria. The 
diagnosis will be confirmed by the Investigator through medical history and physical 
examination as established by medical history and physical examination.  
7.3.1 
Inclusion Criteria  
Eligible patients will meet the following criteria: 
1. 
Able to understand the study’s purpose and requirements, and able to voluntarily provide 
informed consent to participate. 
2. 
Age ≥ 18 years and < 80 years at the time of signing the ICF. 
3. 
FOCBP must agree to use reliable contraceptive methods for the duration of the study 
and for at least 3 months after completing treatment with study drug. For the purposes of 
this study, reliable methods of contraception include abstinence, oral contraceptives, 
hormonal contraceptive implants such as Nexplanon, hormonal vaginal ring such as 
NuvaRing, intrauterine devices in place for at least 3 months, or barrier methods used in 
conjunction with spermicide. To be considered post-menopausal and of non-child-bearing 
potential, women less than 60 years with less than 2 years since their last period must 
have FSH > 40 IU/L and estradiol < 20 pg/mL unless on hormone replacement.  
Male patients participating in the study must also agree to use these reliable contraceptive 
methods if sexually active with a FOCBP partner and also agree to abstain from sperm 
donation from Day 1 through 3 months after completing treatment with study drug. 


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4. 
Type 1 or Type 2 diabetes of at least 6 months duration that meets American Diabetes 
Association criteria (American Diabetes Association, 2020) with an HbA1c > 6.5% at the 
time of Screening. If the HbA1c at the time of Screening is less than 6.5%, evidence that 
the patient meets American Diabetes Association criteria for diabetes must be 
documented and reviewed with the Sponsor prior to entering the patient in the study. 
Additionally, the diabetes should be adequately controlled, with an HbA1c < 11% and no 
evidence of severe hypoglycemia requiring hospitalization within the past 6 months, and 
in the Investigator’s judgment sufficiently stable to allow participation in the study.  
5. 
Painful distal symmetric sensorimotor polyneuropathy due to diabetes as defined by 
having 1 or more relatively symmetric, distally accentuated (stocking or stocking-glove) 
neuropathic symptom(s) and 1 or more relatively symmetric, distally accentuated 
(stocking or stocking-glove) neuropathic sign(s), except that diminished reflexes are not, 
in the absence of at least 1 other neuropathic sign, sufficient to make the diagnosis. 
Neuropathic symptoms can include pain, numbness, tingling, or weakness in a distal to 
proximal (stocking and glove) distribution; signs can include impaired pinprick, light 
touch, vibration, or position sense. The neuropathy must have been present (by history) 
for at least 6 months and must be confirmed and documented by the Investigator based on 
clinical history and physical examination. 
6. 
DN4 score ≥ 4. 
7. 
Meets initial diary criteria during the 14 days in the Pain Observation period as 
determined by an algorithm that includes diary compliance, overall level of pain, and 
day-to-day variability in pain, including at least 5 of 7 daily entries completed the 7 days 
prior to Day 1, and a mean intensity and standard deviation within a pre-specified bound 
(the precise bounds are held as double-blind to avoid introducing bias into the ratings). 
Additionally, at least 5 of 7 doses of placebo must be taken the 7 days prior to Day 1 as 
prescribed during the Pain Observation period for patients to be eligible to continue in the 
study. 
8. 
Able to adhere to the study visit schedule and other protocol requirements. 
7.3.2 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. 
Females who are pregnant or lactating.  
2. 
Extremely overweight, defined as BMI > 40 kg/m2. 
3. 
Difficulty understanding instructions for diary use as determined by the Investigator or 
other issues that are likely to make compliance with study requirements difficult. 


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4. 
Presence of any neuropathy other than DPN and/or significant risk factors for neuropathy 
other than diabetes, including Charcot Marie Tooth disease; alcohol abuse; B12 
deficiency not adequately treated; uncontrolled hypothyroidism; evidence of paraproteins 
by serum immunofixation; history of chemotherapy with neurotoxic agents such as 
platinum analogs, taxanes, vinca alkaloids, eribulin, bortezomib and other proteasome 
inhibitors; or immunomodulatory agents such as thalidomide, lenalidomide, 
pomalidomide, neurotoxic check-point inhibitors, or any other chemotherapy known to 
have neurotoxic effects. 
5. 
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. In addition to a general history and clinical examination, this will be 
assessed using the MDT. Patients who screen positive on this tool for a potentially 
confounding disorder must be discussed with and approved by the Sponsor’s Medical 
Monitor prior to being randomized into the study. 
6. 
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. 
Individuals whose neuropathy is so severely advanced as to create a significant risk that 
the neuropathy will be poorly responsive to treatment as defined by a UENS score > 24 at 
the time of Screening are also excluded from participation. 
7. 
Have met DSM V criteria for opioid use disorder or DSM V criteria for alcohol use 
disorder (moderate or severe) within the past 2 years. 
8. 
Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days a week 
during the month prior to Screening. 
9. 
Active suicidal ideation or suicidal behavior as assessed by the Investigator and/or by a 
rating of 3 or greater on the C-SSRS (see Appendix II). 
10. 
The use of marijuana or CBD during the 30 days prior to starting study drug. 
11. 
A positive urine screen for illicit or non-prescribed controlled substances at baseline. 
12. 
Have been using non-drug interventions for pain (eg, acupuncture, mindfulness therapy, 
etc) for at least 3 months prior to starting study drug may continue these interventions, 
however such treatments may not be initiated during the study, and any patients who plan 
to initiate such treatment during the study are excluded from participation. 
13. 
Repeated use (greater than 3 occasions) of over-the-counter capsaicin on extremities 
within 3 months of Screening or prescription Qutenza use within 6 months of Screening. 
14. 
Implanted medical device (eg, spinal cord stimulator, intrathecal pump, or peripheral 
nerve stimulator) for the treatment of pain. 


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15. 
Has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec 
(male) or > 460 msec (female) or > 480 msec with right bundle branch block on 12 lead 
ECG at Screening, or requires treatment with drugs known to prolong the QT interval 
(including azithromycin, chloriquine/melfiloquine, clarithromycin, droperidol, 
erythromycin, moxifloxacin and sevoflurane), or has a known history of torsade de 
pointes or congenital long QT syndrome. 
16. 
Family or personal history of long QT syndrome or ventricular arrhythmias including 
ventricular bigeminy, previous history of QT prolongation not attributable to an identified 
and transient cause, or need for treatment with medications associated with QT 
prolongation. 
17. 
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. 
18. 
eGFR of < 45 mL/min/1.73 m2 (ie, patients with stage 3b or more severe renal disease are 
excluded). 
19. 
Serum bilirubin values > 2.0 mg/dL. Individuals with known hereditary benign 
hyperbilirubinemia (Gilberts’ syndrome) and a bilirubin < 3.0 may participate in the 
study after discussion and agreement with the Sponsor’s Medical Monitor. 
20. 
Serum ALT or AST values > 1.5 x the ULN.  
21. 
Known HIV positive or active hepatitis virus (A, B, or C) infection. 
22. 
Participation within 1 month of Screening in a clinical trial involving treatment with an 
investigational product. Concurrent participation in an observational study (ie, no 
investigational treatment being used) is allowed provided it does not interfere with the 
procedures and conduct of this protocol. 
23. 
Any serious medical condition or comorbidity, laboratory abnormality, or psychiatric 
illness not otherwise specified that could place the patient at undue risk during trial 
participation, that could confound the results of the study, or that could reasonably be 
expected to affect patient compliance with study requirements for treatment and 
evaluation, as judged by the Investigator. 
24. 
Any known recent exposure within the 14 days prior to initial Screening to 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. 
Note: Abnormal Screening laboratory values that appear to be spurious (eg, laboratory error), 
or that are the result of an identified transient event that if resolved is unlikely to recur, may 
be repeated once. Should this occur, the Investigator should document the reason for 
repeating the test, and if the repeat examination is within the acceptable range, the patient 
may participate. 


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7.4 
Randomization and Blinding 
7.4.1 
Patient Identification 
After giving informed consent, study candidates will be registered in the Medpace Interactive 
Response Technology (IRT) and assigned a unique identification number (i.e., patient number). 
Patients will not be randomized until all Screening, Washout, Pain Observation, and 
Pre-Treatment/Day 1 procedures are completed. The assigned patient number will be used 
throughout the study on all records for identification purposes. 
7.4.2 
Randomization  
Patients will be randomized 1:1 to receive either ricolinostat or placebo. The randomization 
schedule will be computer-generated and a blocked randomization by site with varying block 
sizes will be utilized. Specific block sizes will not be disclosed. 
Once a patient is confirmed to be eligible on Day 1, and all Pre-Treatment procedures have been 
completed, treatment assignment (active or placebo) will be requested using the IRT. After 
entering the patient number and responding to the eligibility questions, a randomization number 
that corresponds to the treatment kit(s) will be assigned by the IRT.  
7.4.3 
Blinding 
This is a double-blind study, meaning the patient, Investigator, and all site personnel will not 
know to which treatment arm a patient has been assigned. Furthermore, all Sponsor, contract 
research organization (CRO), and other clinical service provider personnel will remain blinded to 
treatment assignment throughout the study until database lock. In order to produce the 
randomization schedule and facilitate periodic data review by the DMC (see Section 10.3.8), an 
independent, unblinded statistician will be designated by the Sponsor. 
Blinding is not to be broken during the study unless considered necessary by the Investigator for 
emergency situations for reasons of patient safety. Unblinding the site for any other reason will 
be considered a protocol deviation. The Investigator should contact the Medical Monitor before 
breaking the blind, if time permits. When the blind is broken, the reason must be fully 
documented. The Investigator will be informed of treatment assignment via Medpace IRT. 
7.5 
Study Duration 
Patients will participate in the study for up to ~34 weeks, inclusive of the Screening, Pain 
Observation, double-blind, placebo-controlled Treatment, open label Safety Extension, and 
washout Follow-up periods.  
During the Pain Observation period, patients will be dosed daily with placebo under single-blind 
conditions. During the approximately 12-week double-blind, placebo-controlled Treatment 
period, patients will be dosed daily with ricolinostat or placebo under double-blind conditions. 


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During the approximately 12-week open-label Safety Extension, all patients will receive 
ricolinostat. 
7.6 
Study Discontinuation 
The Sponsor may choose to discontinue the study as a result of administrative, regulatory, or 
patient safety issues. The study may also be discontinued as a result of DMC review as described 
in Section 11.10.1.2. If the study is discontinued while patients are still on-study, the Sponsor 
will provide the Investigators with detailed instructions for stopping study drug and completing 
adequate safety follow-up. Similarly, if an Investigator decides to stop participating in the study, 
he/she will work with the Sponsor to identify a comprehensive plan for patient follow-up and 
study close-out. 
7.7 
Patient Discontinuation 
A patient may choose to discontinue prior to the completion of all study visits and assessments 
for any of the following reasons: 
• Patient withdraws consent or request discontinuation from the study for any reason. 
• Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol. 
• Any serious AE (SAE), clinically significant AE, or severe laboratory abnormality. 
• Pregnancy. 
• Requirement of prohibited concomitant medication. 
• Patient failure to comply with protocol requirements or study-related procedures. 
• The Investigator may discontinue study treatment if, in his/her clinical judgement, it is in the 
best interest of the patient. 
• Termination of the study by the Sponsor or regulatory authority. 
If a patient discontinues prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete a final set of evaluations in accordance with 
Section 9.8.  
8.0 
STUDY TREATMENTS 
8.1 
Study Drug Characteristics 
8.1.1 
Formulation 
Both ricolinostat and placebo are liquid formulations to be administered orally in the morning. 
Each bottle of ricolinostat contains 12 mL of a 10 mg/mL solution. Placebo consists of the same 


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liquid formulation, excluding the active ingredient (i.e., ricolinostat). Bitrex® is used in the 
placebo formulation to mimic the bitter taste of the active ingredient. 
8.1.2 
Container, Closure, Packaging, and Labeling 
Ricolinostat is supplied in 30 mL single use amber glass bottles with screw cap closures (see 
Figure 4 below). Placebo is supplied in identical containers. Bottles will be labeled in accordance 
with investigational product labeling requirements. Study kits will be labeled with the same 
information along with a code linked to the randomization schedule. When a patient is 
randomized through the IRT, a study kit code will be assigned. 
Figure 4: 
Ricolinostat, 120 mg (10 mg/mL) 
 
8.2 
Study Drug Dose and Regimen 
Study drug is to be administered once daily (QD) by mouth in the morning at least 30 minutes 
prior to eating and at least 2 hours after the last meal. Detailed dosing instructions will be 
provided in the Study Reference Manual, which will be reviewed with the Investigator and site 
personnel prior to the start of the study. Written instructions for patients (as reviewed/approved 
by the IRB) will also be provided. 
8.2.1 
Active Arm 
One bottle of ricolinostat (120 mg in 12 mL) will be taken by mouth daily for approximately 
24 weeks, which includes an approximately 12-week double-blind, placebo-controlled Treatment 
period and an approximately 12-week open label Safety Extension period. Kits will be assembled 
and labeled so that active and placebo supplies are indistinguishable; a single randomization 
code will be used for each patient. 


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8.2.2 
Placebo Arm 
One bottle of placebo (12 mL) will be taken by mouth each morning daily during the Pain 
Observation period and active treatment phase of the study. 
8.3 
Study Drug Handling and Management 
8.3.1 
Storage and Stability 
Study kits containing ricolinostat and placebo bottles should be stored at room temperature (20 to 
25°C [68 to 77°F]) away from direct sunlight. Patients will be instructed not to leave the study 
drug in the car for an extended period due to the potential for extreme temperature fluctuations. 
At the clinic, study kits must be stored in an area of controlled access under the supervision of 
the Investigator’s designated member of the study team. Patients will be instructed to keep the 
study drug in an area that cannot be accessed by children or other individuals who might tamper 
with it.  
8.3.2 
Study Drug Ordering, Shipment, Dispensing, and Accountability 
All study kits will be maintained, inventoried, and shipped by the Sponsor’s designated central 
distributor. The IRT will allow for ordering, monitoring of inventory, and automated shipment 
based on certain supply triggers. 
The first shipment of study kits to sites will be initiated by the Sponsor after receipt of the 
required IRB approvals and administrative documentation. A site initiation visit will be 
scheduled with each Investigator to review the key elements of study conduct, including study 
drug management. Records must be maintained to document the receipt and disposition of all 
study drug. 
Study drug will be dispensed as per the schedule of events. The first dose (Day 1) will be taken 
in the clinic so that an ECG can be performed ~one hour post-dose. Daily dosing will be 
recorded by the patient in the diary, which will be reviewed by site personnel at the next visit. 
Patients will be instructed to return all bottles (used and unused) to the clinic and any 
discrepancies between the diary and physical inventory will be discussed and documented. If 
necessary, site personnel will re-instruct the patient prior to dispensing the study drug for the 
following week. 
All used kits and their contents will be retained for review by the Sponsor’s designated study 
monitor. After the review is complete, empty bottles can be disposed in accordance with clinic 
policy for waste management. Any unused or partially used bottles should be retained. At the 
end of the study, or as directed by the Sponsor, the Investigator will be instructed to return or 
dispose of any unused product. All details of return or destruction must be documented and 
maintained with the study records. 


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8.4 
Concomitant Medications 
All prior and concomitant medications which are ongoing at the time of screening and those 
taken during the course of the study will be recorded in the patient’s record and the study 
database. Any pain medication taken 30 days prior to Screening will also be recorded. 
8.4.1 
Concomitant Pain Medications and Therapies 
Patients who have been on a stable regimen of an allowed pain medication (see Section 8.4.2 
below) for at least 3 months prior to Screening and who have ongoing diabetic neuropathic pain 
that meets entry criteria may continue those medications during the study provided there is no 
plan to change the regimen during the study. Any pain medication that a patient has been 
previously taking on a regular basis but no longer takes must have been discontinued for at least 
one month prior to starting the Pain Observation period. Pain medications taken on an occasional 
or as needed basis (3 or less days in most weeks) must have been discontinued for at least 7 days 
prior to starting the Pain Observation period.  
Patients who have continued to experience pain while using non-drug therapies for pain (eg, 
acupuncture, mindfulness therapy, etc) that have been ongoing for at least 3 months may 
continue these during the study, provided the type and intensity of such treatment remains stable 
during the course of the study. The following medications/devices are not permitted during the 
study: 
• Non-steroidal anti-inflammatory drugs (NSAIDs including Advil and Motrin [ibuprofen], 
Aleve [naproxen, Bayer and Ecotrin [aspirin], etc). 
• Opioid medications including, but not limited to, OxyContin (oxycodone), Percocet 
(oxycodone and acetaminophen), Vicodan (hydrocodone), Percodan (oxycodone and 
aspirin), Tylox (oxycodone and acetaminophen capsules), Demerol (meperidine), Ultram 
(tramadol), Nucynta (tapendatol), etc. 
• Cannabinoids, including CBD. 
• Topical preparations containing capsaicin, NSAIDs, or numbing agents (eg, lidocaine). 
• Implanted medical devices (eg, spinal cord stimulator, intrathecal pump, or peripheral nerve 
stimulator).  
No patient may participate in the study if he/she has enrolled or previously (prior 30 days before 
initiation of the Screening period) participated in a study of an investigational drug, biologic, or 
medical device. Participation in a concomitant observational study where no treatment 
intervention is planned is allowed, provided the demands of such a study do not, in the opinion 
of the Investigator, overly burden the patient or put treatment study objectives at risk. 
Patients will be queried about pain medications and therapies during each visit to determine if 
any of the prohibited items are being used. 


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8.4.2 
Allowed Medications and Therapies 
Patients will be permitted to continue using one medication for painful DPN from the list below, 
provided they have been taking the medication and the dose has been stable for at least 3 months 
prior to Screening and no changes in the regimen are planned or expected for the duration of the 
study. The requirements for pain eligibility must still be met regardless of whether a study 
candidate is taking one of the permitted medications during the Pre-Treatment Pain Observation 
period. 
• Amitriptyline, ≤ 75 mg per day or other tricyclic antidepressants at equivalent doses 
• Venlafaxine, ≤ 150 mg per day 
• Duloxetine, ≤ 60 mg per day 
• Gabapentin, ≤ 1200 mg per day 
• Pregabalin, ≤ 300 mg per day 
• Alpha lipoic acid < 600 mg/day 
• Carbamazepine <  800 mg/day 
Patients taking a higher dose of the one permitted medication for painful DPN in the above list 
can decrease their dose to the acceptable limit. A minimum of  7 days at the permitted dose 
should occur prior to starting the Pain Observation period.   
Aspirin, if prescribed for cardiac prophylaxis and not for pain, is permitted. Throughout the 
study, patients will be allowed to take acetaminophen as rescue pain medication at a maximum 
dose of 500 mg at 6-hour intervals up to 4 times in any given 24-hour period. Use of rescue 
medication will be captured in the daily diary, which will be reviewed at each clinic visit by 
study personnel. 
All other medications and therapies used to treat conditions other than pain are permitted at the 
discretion of the Investigator. All concomitant medication use will be recorded in the patient’s 
record and the study database.  
8.4.3 
Prohibited Medications 
Patients that requires treatment with drugs known to prolong the QT interval (including 
azithromycin, chloriquine/melfiloquine, clarithromycin, droperidol, erythromycin, moxifloxacin 
and sevoflurane) are not permitted. 


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9.0 
STUDY VISITS AND PROCEDURES 
9.1 
Schedule of Study Procedures 
The tabular schedule of assessments is provided in Table 1. The study is comprised of a 
Screening, Washout, Pain Observation, Treatment, Safety Extension, and Follow-up period as 
outlined in the sections below. 
9.2 
Screening and Washout Period (Day -45 to Day -14) 
The timing of Screening evaluations will depend in part on whether the patient is using pain 
medications other than those permitted and described in Section 8.4.2. Patients on pain 
medication that is not permitted and taken on a regular basis should be scheduled so as to allow 
for a minimum of at least one month (30 days) washout prior to the start of the Pain Observation 
period. Patients on pain medication that is not permitted and taken on an occasional or as needed 
basis (3 or less days in most weeks) should be scheduled so as to allow for a minimum washout 
of 7 days prior to the start of the Pain Observation period. Patients who are not taking pain 
medication and do not require washout can be scheduled for Screening evaluations at any time 
during the period with the understanding that it may take several days before laboratory results 
are available. All Screening and Washout procedures must be completed by Day -14 to allow for 
a 14-day Pain Observation period prior to randomization. 
9.2.1 
Screening Evaluation 
Obtain informed consent before any study procedures are performed. After the patient signs the 
ICF, the following assessments will be performed: 
• Assess eligibility based on inclusion/exclusion criteria; 
• Obtain demographics (including gender, date of birth, race, and ethnicity); 
• Record medical history (other than diabetes and painful DPN); 
• Record diabetes history, including prior medication/treatment history; 
• Record diabetic neuropathy history, including prior medication/treatment history; 
• Administer C-SSRS (Screening version- 3 month and lifetime history) (see Appendix II); 
• Perform MDT; 
• Measure height and weight and calculate BMI; 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Record prior medication history (other than diabetes and painful DPN); 


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• Perform physical examination (including general appearance; skin; head, eyes, ears, nose, 
and throat [HEENT]; chest [including heart/lungs], abdomen [including liver/kidneys], 
musculoskeletal, and sensory/neurological); 
• Perform 12-lead ECG (after the patient has been resting in the supine position); 
• Collect blood samples for the following: 
• Fasting chemistry (fasting of 8-10 hours), hematology, HbA1c, vitamin B12, and serum 
paraproteins; 
• FSH and estradiol (only for females less than 60 years of age with less than 2 years since 
last period); 
• HIV, hepatitis B virus surface antigen, and hepatitis C virus screen; 
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19) 
Qualitative PCR (only required if any recent exposure within past 14 days prior to 
Screening to COVID-19 and/or symptoms of COVID-19 along with reason to suspect 
COVID-19); 
• Collect urine samples for the following: 
• Urinalysis; 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen; 
• Obtain DN4 score; and  
• Perform UENS. 
9.3 
Pain Observation Period (Day -14 to Day -1/Pre-Treatment) 
9.3.1 
Day -14 Training Visit 
On Day -14, the results of all Screening assessments will be reviewed in relation to the study 
eligibility criteria (see Section 7.3) to make a preliminary determination as to whether the patient 
is qualified for the study. Qualified patients will enter the Pain Observation period.  As the pain 
observation period is conducted under single-blind conditions, site staff must take care not to 
reveal to patients that study medication during this time is placebo.  The pain observation period 
will be initiated as follows: 
• Review calendar and schedule Observation period (Day -14 to Day -1) with patient; 
• Review prohibited medications that must not be used and rescue medication guidelines; 
• Collect urine samples for the following: 
• Urine drug screen (performed at the discretion of the Investigator); 
• Urine pregnancy test (if FOCBP); 


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• Record medical history; 
• Record prior medications; 
• Dispense study drug assigned by IRT and instruct on dosing;  
• Instruct patient to complete the following training modules in the WCG aLearn Leaning 
Management System platform: Accurate Pain Reporting, Placebo Response Reduction and 
Research Subject Responsibility; and 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use. 
Patients will record the following information in the study diary on a daily basis: 
• NRS (worst and average pain experienced each day);  
• Daily dosing; and 
• Rescue medication use, as applicable. 
9.3.2 
Follow-Up Phone Contact (Day -7 to Day -5) 
A phone contact to the patient will be conducted for the following: 
• Review diary entries and dosing compliance; 
• Review NRS entries (worst and average pain experienced each day) and rescue 
medication for past week and correct any misunderstandings if present;  
• Schedule Day 1 clinic visit. A patient may be randomized after 10-14 days in the Pain 
Observation period if all eligibility requirements have been met.  
9.4 
Pre-Treatment/Baseline Visit (Day 1) 
On Day 1, a final determination of study eligibility will be completed and placebo lead-in 
accountability will be performed. The diary will apply the pain eligibility algorithm to the stored 
data to determine if the patient is qualified. Additionally, placebo accountability will be 
performed for eligibility. Patients who meet the pain eligibility and placebo accountability 
requirement, and continue to meet all other eligibility criteria, will proceed to randomization and 
treatment.  
The following Pre-Treatment assessments will be completed prior to randomization: 
• Record medical history; 
• Record prior medications; 
• Administer C-SSRS (Since Last Visit version); 


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• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Perform 12-lead ECG (after the patient has been resting in the supine position);  
• Collect blood samples for the following: 
• Fasting chemistry (fasting of 8-10 hours) and hematology; 
• Collect urine samples for the following: 
• Urinalysis; 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Administer BPI-SF (pain interference section only); 
• Administer NTSS-6; 
• Perform UENS; 
• Administer Norfolk Diabetic QOL-DN; and 
• Perform intraepidermal nerve biopsy (eligible patients at selected sites). 
Once all Pre-Treatment assessments have been completed, the patient will be randomized using 
the IRT. After randomization, the following will occur: 
• Dispense study drug kit assigned by IRT. The patient will be shown how to take the first 
dose, which will be administered at the site.  
• Perform 12-lead ECG (after the patient has been resting in the supine position) one hour (+/- 
10 minutes) post-dose. 
• Assess for post-dosing AEs. 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use. 
9.5 
Treatment Period (Week 1 to Week 12) 
Following randomization on Day 1, patients will return to the clinic for visits as outlined in the 
schedule of events. During each visit, the procedures specified by the schedule of events for that 
visit will be performed. 


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9.5.1 
Week 1 
The following procedures will be performed at Week 1: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Perform 12-lead ECG (after the patient has been resting in the supine position); 
• Collect blood samples for the following: 
• Fasting chemistry (fasting of 8-10 hours) and hematology; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator); and 
• Dispense study drug assigned by IRT. 
9.5.2 
Week 2 
The following procedures will be performed at Week 2: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Collect blood sample for the following: 
• Hematology; 
• Collect urine samples for the following: 


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• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator); and  
• Dispense study drug assigned by IRT. 
9.5.3 
Week 4 
The following procedures will be performed at Week 4: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Collect blood samples for the following: 
• Fasting chemistry (fasting of 8-10 hours) and hematology; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Administer BPI-SF (pain interference section only); 
• Administer PGIC; 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use; and  
• Dispense study drug assigned by IRT. 
9.5.4 
Week 8  
The following procedures will be performed at Week 8: 
• Administer C-SSRS (Since Last Visit version); 


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• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Collect blood sample for the following: 
• Hematology; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen; 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator); and 
• Dispense study drug assigned by IRT. 
At the conclusion of the 12-week Treatment period, patients will enter the Safety Extension 
period. 
9.6 
Safety Extension (Week 12 to Week 24)  
From Week 12 to Week 24, all patients will receive ricolinostat 120 mg daily. Patients will 
return to the clinic as outlined in the schedule of events and at each visit procedures specified in 
the schedule of events for that visit will be performed. 
9.6.1 
Week 12 
The following procedures will be performed at Week 12: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns;  
• Assess skin integrity and wound healing, if applicable; 
• Perform 12-lead ECG (after the patient has been resting in the supine position); 
• Collect blood samples for the following: 


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• Fasting chemistry (fasting of 8-10 hours), hematology, and HbA1c; 
• Collect urine samples for the following: 
• Urinalysis; 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Administer BPI-SF (pain interference section only); 
• Administer NTSS-6; 
• Perform UENS; 
• Administer Norfolk Diabetic QOL-DN; 
• Administer PGIC; 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator); and 
• Dispense study drug assigned by IRT. 
9.6.2 
Week 14 
The following procedures will be performed at Week 14: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Collect blood sample for the following: 
• Hematology; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 


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• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator); and 
• Dispense study drug assigned by IRT. 
9.6.3 
Week 18 
The following procedures will be performed at Week 18: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Collect blood sample for the following: 
• Hematology; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Record concomitant medications and AEs; 
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable; and 
• Dispense study drug assigned by IRT. 
9.6.4 
Week 24 
The following procedures will be performed at Week 24: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Assess skin integrity and wound healing, if applicable; 
• Perform 12-lead ECG (after the patient has been resting in the supine position); 


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• Collect blood samples for the following: 
• Fasting chemistry (fasting of 8-10 hours), hematology, and HbA1c; 
• Collect urine samples for the following: 
• Urinalysis; 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Administer BPI-SF (pain interference section only); 
• Administer NTSS-6; 
• Perform UENS; 
• Administer Norfolk Diabetic QOL-DN; 
• Administer PGIC; 
• Perform intraepidermal nerve biopsy (eligible patients at selected sites); 
• Record concomitant medications and AEs;  
• Collect returned study drug (used and unused bottles) and perform study drug accountability; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator). 
 
9.7 
Follow-Up Period (Week 26 and Week 28) 
Approximately 2 and 4 weeks after the last dose of study drug, study patients will have 
follow-up visits during which the assessments specified for those visits will be performed. 
9.7.1 
Week 26 
The following procedures will be performed at Week 26: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 


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• Administer BPI-SF (pain interference section only); 
• Administer NTSS-6; 
• Perform UENS; 
• Administer Norfolk Diabetic QOL-DN; 
• Administer PGIC; 
• Record concomitant medications and AEs; 
• Instruct patient on daily completion of NRS (worst and average pain experienced each day) 
and rescue medication use, as applicable (at the discretion of the Investigator). 
9.7.2 
Week 28 
The following procedures will be performed at Week 28: 
• Administer C-SSRS (Since Last Visit version); 
• Obtain vital signs (temperature, respiration rate, pulse, and blood pressure) while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained 
following sitting vital signs; 
• Perform directed physical exam to assess changes from the prior visit or new concerns;  
• Assess skin integrity and wound healing, if applicable; 
• Collect blood samples for the following: 
• Fasting chemistry (fasting of 8-10 hours), hematology, and HbA1c; 
• Collect urine samples for the following: 
• Urine pregnancy test (if FOCBP); 
• Urine drug screen (performed at the discretion of the Investigator); 
• Record concomitant medications and AEs. 
At the conclusion of these evaluations, the patient will have completed the study. 
9.8 
Premature Discontinuation 
If a patient is discontinued early from the study for any reason, the Investigator should make 
every effort to ensure that the final assessments at Week 24 are completed as outlined in the 
schedule of events. The reason for discontinuation will be recorded in the patient’s record and 
the study database. 


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If the timing of the early termination is during the Safety Extension (Week 12 to Week 24), 
collection of the intraepidermal nerve biopsy should occur if patient previously provided consent 
and intraepidermal nerve biopsy collection occurred at Day 1. 
10.0 
EVALUATIONS AND STATISTICAL ANALYSES 
10.1 
Data Management and Quality Assurance 
All study data resulting from protocol specified assessments will be entered into a 21 CFR 
Part 11 compliant database. At the clinical site, the data will be entered into an electronic data 
capture (EDC) system. Data entered in the study database will be reviewed against source 
documentation at clinical sites by the Sponsor’s designated study monitor. Furthermore, ongoing 
review of the database will be performed in a blinded manner by data managers, statisticians, and 
clinical members of the CRO and Sponsor teams. All incomplete or incorrect entries will be 
queried for clarification. Any errors noted will be corrected by changing the incorrect entry. All 
corrections will be tracked in the system via an audit trail. Upon completion of data entry, the 
database will receive a quality assurance check to ensure acceptable accuracy and completeness. 
The Sponsor’s data management vendor will be responsible for: 
• Database design and development (using a 21 CFR Part 11 compliant platform) 
• Data capture form design and creation 
• Study Investigator and research team instruction  
• Database maintenance 
• Study data review and quality assurance 
• Database lock 
• Raw dataset delivery for statistical analysis 
All process aspects of data entry, access, review, validation, correction, coding, and finalization 
will be described in a separate Data Management Plan developed in conjunction with the data 
management vendor. 
10.2 
Efficacy and Safety Evaluations 
10.2.1 
Efficacy Assessments 
10.2.1.1 
Primary Efficacy Assessment 
The primary efficacy assessment measure is the 11-point NRS where 0 represents no pain and 10 
is the worst pain possible assessed after 12 weeks. Patients will record the average pain 
experienced each day. Patients will also record the worst pain experienced each day, which will 
be used as a secondary efficacy assessment. The NRS is a validated tool commonly used for pain 
assessment (Farrar, 2001). The NRS will be recorded daily by patients. To ensure that patients 


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understand and can properly complete the NRS, patients will receive training on how to rate and 
complete the NRS prior to the Pain Observation period and may also receive repeat training 
during the course of the study to aid in maintaining consistency of ratings throughout the study.  
10.2.1.1.1 
Numerical Pain Rating Scale  
Data from the NRS, described previously in Section 10.2.1.1, will also form the basis of the 
following secondary endpoints: 
• Mean pain intensity from Pre-Treatment [mean NRSD-7 to D1] to each weekly assessment 
through Week 4, comparing weekly means calculated using daily scores for 1) worst pain, 
and 2) average pain 
• Percent change in mean pain intensity from Pre-Treatment [mean NRSD-7 to D1] to each 
weekly assessment through Week 4 and Week 12, comparing weekly means calculated using 
daily scores for 1) worst pain, and 2) average pain 
• Proportion of patients achieving ≥ 30% and ≥ 50% improvement in mean NRS score from 
Pre-Treatment [mean NRSD-7 to D1] to the last week of treatment [mean NRSD22 to D28], using 
means for 1) worst pain, and 2) average pain 
10.2.1.2 
Secondary Endpoints 
10.2.1.2.1 
Brief Pain Inventory Questionnaire – Short Form  
The BPI-SF is a validated tool commonly used in pain assessment (Zelman, 2005). 
The BPI-SF questionnaire includes a location of pain diagram (question 2) and a number of 
questions designed to rate pain over a specified time period (questions 1 and 3 to 5), to rate 
actual pain (question 6), to capture pain treatment currently received (question 7), and to 
establish how much relief the patient experiences from pain treatments (question 8). Question 9 
is designed to establish how pain interferes with the patient’s life over a specified time period 
and includes several sections: general activity (section A), mood (section B), walking ability 
(section C), normal work (section D), relations with other people (section E), sleep (section F), 
and enjoyment of life (section G).  
The BPI-SF produces two scores: pain intensity (questions 1-8) and pain interference 
(question 9, items A-G). For this study, the pain interference items only will be administered as 
detailed in the schedule of events and scored; pain intensity/severity is already captured in the 
NRS and therefore to avoid redundancy questions 1-8 will not be administered in this study.  
A secondary study endpoint is the change from Pre-Treatment/Day 1 to Week 4 and to Week 12 
in mean BPI-SF pain interference score. 


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10.2.1.2.2 
Patient Global Impression of Change 
The PGIC is a validated tool commonly used in pain assessment (Farrar, 2001). 
The PGIC is comprised of a single question administered at the end of the Treatment period 
(Day 28) to assess the overall quality of life since the beginning of study treatment. The answer 
is scored from 1 to 7 on a gradient where 1 = no change (or condition is worse), and 7 = a great 
deal better/considerable improvement. Examination of the PGIC scores at Weeks 4 and 12 will 
be a secondary study endpoint. 
10.2.1.2.3 
Neuropathy Total Symptom Score – 6  
The NTSS-6 is a validated tool commonly used in neuropathic assessment (Bastyr III, 2005). 
The NTSS-6 tool is a 6-item symptom score questionnaire that was developed to selectively 
identify the existence of, and evaluate the frequency and intensity of, individual neuropathy 
sensory symptoms experienced frequently by patients with painful DPN. The six questions 
interrogate: 1) numbness or insensitivity; 2) prickling or tingling; 3) burning sensation; 4) aching 
pain or tightness; 5) sharp, shooting, lancinating pain; and 6) allodynia or hyperalgesia. The 
Investigator or another qualified member of his/her team will assess the patient and complete the 
NTSS-6 questionnaire weekly during the Treatment period, or upon premature discontinuation if 
applicable. 
A secondary study endpoint is the change from Pre-Treatment/Day 1 to Week 12 in the NTSS-6. 
10.2.1.2.4 
Utah Early Neuropathy Scale 
The UENS 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 has been validated (Singleton JR et al, 2008) and shown to have satisfactory 
operating characteristics including high interrater reliability and reproducibility, as well as 
favorable characteristics for measuring change over time (Robinson et al, 2019). 
A secondary study endpoint is the change in non-pain neuropathic signs after 12 weeks in 
patients as assessed by change in the UENS. 
10.2.1.2.5 
Norfolk Diabetic Quality of Life-Diabetic Neuropathy  
The Norfolk Diabetic QOL-DN is a validated tool commonly used in diabetic neuropathy 
(Vinik, 2005).  
The Norfolk Diabetic QOL-DN is a 47-item, self-administered questionnaire designed to 
measure the relationship between symptomatic diabetic neuropathy and quality of life from the 
perspective of the patient. The questionnaire is composed of two parts: questions related to 


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symptoms experienced by the patient and questions related to the impact of the patient’s 
neuropathy on activities of daily life.  
A secondary study endpoint is the change from baseline to Week 12 in Norfolk Diabetic 
QOL-DN. 
10.2.1.2.6 
Use of Rescue Medication 
Use of rescue medication will be recorded by the patient in the daily diary beginning at the start 
of the Pain Observation period on Day -14 and ending on Week 12, the last day of the Treatment 
period, or upon premature discontinuation as applicable. 
10.2.1.3 
Intraepidermal Nerve Fiber Density Determination 
Intraepidermal nerve fibers are nociceptive C-fibers that are easily accessible from simple punch 
skin biopsies, and are quantifiable and reproducible. Small unmyelinated nerve fibers are easily 
and frequently damaged in diseases such as diabetes. A reduction in IENFD correlates with 
examination findings and symptoms of neuropathy. However, unlike large myelinated nerve 
fibers, small nerve fibers have a capacity for regeneration, even over short periods of time. There 
is a strong correlation between neuropathy severity and IENFD (Gibbons CH et al Neurology, 
2009), and results are highly reproducible and reliable. Intra-epidermal nerve fiber biopsy is a 
powerful tool for defining pathological changes to nerve fiber density and has the potential to 
provide a means of assessing drug effects in a smaller number of patients as compared with 
patientive pain measures.  
In preclinical studies, ricolinostat-associated functional improvements have consistently been 
associated with restoration of IENFD after experimentally induced nerve injury. Examination of 
IENFD in humans is intended to help understand whether any observed effects on pain and other 
neuropathic signs and symptoms are mediated by improvement in nerve function, and also to 
help assess whether ricolinostat has structural effects on peripheral nerves. The procedure is 
rapid (5-10 minutes), performed as an office procedure, and involves minimal discomfort or risk 
to patients. The biopsy site is ~ 3 mm, and heals with a ‘band-aid.’ Detailed procedural 
instructions will be provided in the Study Reference Manual. 
10.2.1.4 
Masquerading Disorders Tool 
The MDT is a brief Investigator-administered Screening instrument that identifies disorders 
potentially confounding or masquerading as painful DPN (eg, plantar fasciitis, ischemic pain). 
The MDT is administered at Screening. Patients who are identified as having a positive finding 
on the MDT must be discussed with the Sponsor’s Medical Monitor and approved before 
proceeding into the study. 


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10.2.2 
Safety Assessments 
The following safety assessments will be performed during the study as outlined in Table 1 and 
the data will be used for safety analyses as described in Section 10.3.7. 
• Vital signs 
• Physical examination (including skin integrity and wound healing, if applicable) 
• 12-lead ECG 
• Laboratory assessments (hematology, serum chemistry, and urinalysis) 
• AEs 
Skin integrity, the presence of wounds, and wound healing, if applicable, will be assessed 
Pre-Treatment (Day 1), weekly during the Treatment period and Safety Extension period, and at 
the final visit (Week 28). Examination of each wound, whether it was pre-existing on Day 1 or 
develops during the study, will include documentation of the wound's location, size, and depth 
along with assessment for signs of infection, such as erythema, edema, warmth, odor, or 
drainage. Signs of impaired healing or infection will be followed and evaluated to determine if 
they meet criteria for reporting as an AE. 
10.3 
Statistical Methods 
10.3.1 
Sample Size and Power 
The sample size for this study is planned to be approximately 274 evaluable patients, which 
provides a power of 0.8 for detecting a treatment difference of 0.8 points on the NRS. Assuming 
a pooled standard deviation of 2.35, this corresponds to a standardized effect size of 
approximately 0.34, an effect size comparable to effect sizes observed in recent diabetic 
neuropathic pain studies using efficacious agents such as duloxetine and pregabalin (Smith et al, 
Journal of Pain, 2018). An effect size of this magnitude or greater, if observed in this study, 
would support the further investigation of ricolinostat as a potential treatment for painful DPN. 
The estimates for power are conservative as the primary efficacy analysis will use an MMRM 
approach with 12 measures over time. 
10.3.2 
Analysis Approach 
After all patients have completed their last visit of the 12-week double-blind, placebo-controlled 
period, a formal blinded review of the data will take place and the database will be locked after 
this review is finalized. At this point all data will be analyzed except for the measures whose 
analyses are based on the 24-week data. The SAP will detail the formal blinded data review 
process. 


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10.3.3 
Primary Efficacy Outcome Measures 
The null hypothesis is that there is no difference between the average change from baseline in the 
NRS score in the ricolinostat and placebo groups; the null hypothesis is stated as H0: ΔR = ΔP, 
where ΔR denotes the average change from baseline in the NRS score in the ricolinostat group 
and ΔP denotes the average change from baseline in the NRS score in the placebo group. The 
alternative hypothesis is stated as HA: ΔR ≠ ΔP with a two-sided significance level of 0.05. 
The primary estimand for this study is defined by the following attributes: 
Estimand attribute 
Description 
Population 
Full analysis set population, which consists of all patients who receive at 
least one dose of study drug and have baseline average pain intensity score 
and at least one post-baseline average pain intensity score. 
Endpoint 
Weekly mean of daily average pain based on the 11-point NRS. 
Intercurrent events 
All observations in patients who are on stable permitted concomitant pain 
medication for DPN and who started at least 3 months prior to Screening 
will be included. If there is a dose change, pain scores after the dose change 
will be considered missing and will be imputed using Medical 
Administration Record (MAR) assumption.  
Summary measure 
Difference between ricolinostat arm and placebo arm as measured by 
change from baseline in average pain at Week 12. 
The primary estimand is the difference in the mean change from baseline through Week 12 in the 
average pain as measured by the NRS. Patients will record their average pain and worst pain on a 
daily basis in a diary starting seven days prior to randomization through the end of the study 
using the NRS, where 0 represents no pain and 10 represents worst possible pain. The baseline 
average pain score is the mean of the average daily pain scores recorded from day -7 to -1 of the 
study. (Note: For visits prior to randomization, study day=visit date-randomization date. For 
visits after randomization, study day=visit date-randomization date+1.) The weekly mean of the 
average pain will be calculated when four or more daily average pain scores exist for that week. 
If a patient has fewer than four daily average pain scores in a week, then the weekly mean pain 
will be set to missing for that week.  
A MMRM approach will be used to analyze the change from baseline to Week 12 in the average 
NRS pain score, with the mean change from baseline in the average NRS pain score at each 
week as the outcome in the model. The model will include the following covariates: treatment, 
visit, treatment by visit interaction, baseline NRS pain score, baseline NRS pain score by visit 
interaction, and use of concomitant medication for painful DPNDNP (yes vs. no). The 
within-patient correlation will be modeled by using an unstructured covariance matrix. If the 
model does not converge, then a Toeplitz covariance structure will be used, which assumes that 
observations closer together are more correlated than those further apart in time. If convergence 


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is still not attained, then the auto-regressive of order one will be used, which has the same 
assumption as the Toeplitz model but is more restrictive. If the model still does not attain 
convergence, then compound symmetry variance-covariance models will be used, which assume 
equal correlation between measurements from a patient. Restricted maximum likelihood will be 
used as the method of estimation with the degrees of freedom approximated using the Kenward 
Rogers approach. The primary estimand will be obtained from this model. 
It is assumed that short-term action of rescue medication does not affect the average daily pain 
score and scores that are collected during the use of rescue medication will be used in the 
analysis. Patients on a stable dose of permitted concomitant medication that has been started at 
least 3 months prior to starting the Pain Observation period will be included in the analysis. 
However, if there is a dose change, the pain scores after dose change will be set to missing and 
imputed under the assumption of MAR. 
In order to assess the robustness of the primary analysis, the following additional sensitivity 
analyses will be performed: 
1. A tipping point analysis with multiple imputation, in which the missing values in the 
ricolinostat arm will be assigned a shift parameter during imputation in order to determine 
the point where statistical significance changes. 
2. An MMRM analysis with jump to reference, in which all missing values are imputed based 
on the placebo arm. This is a worst-case scenario where missing values among patients in the 
ricolinostat arm are imputed as if they came from the placebo arm. 
3. An MMRM analysis using MAR and monotone missing assumptions.  
The results of the sensitivity analyses will be presented in tables, figures, and a forest plot. 
Details will be provided in the SAP.  
10.3.4 
Key Secondary Outcome Measures 
The key secondary outcome measures are the change from baseline in the mean NRS score at 
Week 4 and the change in non-pain neuropathic signs and symptoms after 12 weeks as assessed 
by change in the UENS.  
For the first outcome of the change from baseline in the mean NRS score at Week 4, the analysis 
approach will be identical to that for the primary outcome, with the outcome consisting of the 
Week 1 through Week 4 average NRS measures. The result will be obtained from the MMRM 
model that is fit for the primary analysis. The estimated difference in the change from baseline 
between the treated and placebo groups at Week 4 will be computed as part of the primary 
analysis. This outcome will only be formally tested if the p-value associated with the primary 


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outcome is less than 0.05. If the p-value associated with the primary outcome is not statistically 
significant, a nominal p-value for the key secondary outcome will be presented. 
The second endpoint of the change in the UENS from baseline to Week 12 will be formally 
tested only if the p-value associated with the key secondary outcome of change from baseline in 
mean NRS score at Week 4 is statistically significant. To assess this outcome, an ANCOVA 
model will be fit including the change from baseline in UENS at Week 12 as the outcome and 
baseline UENS score,  treatment group, and use of concomitant medication for painful DPN (yes 
vs. no) as covariates.   
10.3.5 
Secondary Outcome Measures 
The following secondary outcome measures will be analyzed as described for the primary 
efficacy analysis: change in mean BPI-SF pain interference score from Pre-Treatment/Day 1 to 
Week 4 and from Pre-Treatment/Day 1 to Week 12, change from baseline to Week 12 in the 
NTSS-6, and change from baseline to Week 12 in Norfolk Diabetic QOL-DN. ANCOVA models 
will be used for each of these analyses with the baseline value of the outcome, treatment group, 
and use of concomitant medication for painful DPN (yes vs. no) as covariates. 
Proportion of patients achieving ≥ 30% and ≥ 50% improvement in mean NRS score from 
Pre-Treatment to the last week of treatment will be analyzed using a chi-square test. The PGIC at 
Week 4 and Week 12 will be analyzed using a two-sample t-test. Rescue medication 
(acetaminophen) use will be analyzed using a chi-square test. 
10.3.6 
Exploratory Efficacy Outcome Measures 
The exploratory endpoint of change in IENFD from baseline to Week 24 will be analyzed in a 
subgroup of approximately 120 patients at selected sites. There are 3 comparisons of interest for 
this analysis: 
1. Change from baseline in the IENFD in the group of approximately 60 patients that received 
ricolinostat for 24 weeks. 
2. Change from baseline in the IENFD in the group of approximately 60 patients that received 
ricolinostat for 12 weeks. 
3. The difference in the change from baseline in the IENFD in the Intent-to-Treat population. 
For the first two comparisons, an ANCOVA model with baseline density will be fit and the test 
of difference will be based on the significance level of the intercept term in the model. For the 
third comparison, an ANCOVA model with baseline density and treatment group as covariates 
will be used to calculate the nominal p-value. 
10.3.7 
Safety Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by System 
Organ Class (SOC) and preferred term (PT). Only treatment-emergent AEs (TEAEs) will be 


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included in summary tables. A TEAE is defined as any AE that occurs after the start of study 
drug or was present at baseline and worsened after taking study drug. 
The number and percent of patients with at least one 1) AE, 2) severe AE, 3) SAE, 4) AE leading 
to discontinuation, and 5) treatment-related AE will be presented by treatment arm for the Safety 
Population. The number and percent of patients with AEs will be presented by MedDRA SOC 
and PT for each treatment arm and overall. AEs will also be summarized by PT; by SOC, PT, 
and severity; and by SOC, PT, and relationship to study treatment. SAEs and AEs leading to 
discontinuation will also be presented. 
The counts and percentages for AE summary tables will be based on the Safety Population. 
Patients with multiple unique events will be counted once per each unique PT and each unique 
SOC. If a patient has more than one AE that is coded to the same PT, the patient will be counted 
only once (using the maximum severity assigned) for that PT. 
Observed values and change from baseline will be presented by visit and treatment group for 
hematology and chemistry laboratory tests. The number and percent of patients with hematology, 
chemistry, and urinalysis results outside the normal range will be presented by visit for each 
treatment arm. A second table will present shifts with respect to the lower limit of normal; the 
table will be repeated for shifts with respect to the ULN. Laboratory tests with categorical results 
that cannot be analyzed by change from baseline or shift table analysis will not be included in 
these summaries, but will be listed. Another table will present findings of special interest, 
including selected hematology and serum chemistry abnormalities relevant to the assessment of 
safety. 
Descriptive statistics for vital signs and ECG results will be presented by treatment group. 
10.3.8 
Interim Analysis and Data Monitoring Committee 
An independent DMC composed of 3 physicians and a statistician not employed by the Sponsor 
will periodically review data from the study in planned meetings as described below. 
Additionally, the DMC may, at its discretion, convene additional, unscheduled meetings at any 
time during the study. 
Initial Safety Review: The DMC will review key safety data including the events of special 
interest specified in Section 11.10.2.2 after a vanguard cohort of at least 30 patients has had the 
opportunity to complete 4 weeks of treatment, and again after this cohort has had the opportunity 
to complete 12 weeks of treatment. Unless serious safety concerns have been observed, 
enrollment may continue while these reviews occur.  
Subsequent DMC Meetings to Review Safety: The DMC will have another planned meeting to 
review safety when approximately 50% of the planned number of patients have been enrolled. 


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The DMC may also meet for unplanned meetings should safety observations during the study 
warrant such meetings. 
Additional Planned Interim Analysis of Key Safety and Efficacy Data: an interim analysis of 
key safety and efficacy data may be conducted after approximately 50% of the planned number 
of patients enrolled and treated have had the opportunity to complete the 12-week double-blind, 
placebo-controlled treatment phase of the study to inform a decision regarding whether the study 
should stop for futility. To assess futility, the conditional power at the end of the study will be 
computed based on the data that are collected up to the interim analysis for the effect size of 0.34 
that was used to calculate the power for the study. If the conditional power is less than 20%, the 
DMC may recommend stopping the study for futility. The conditional power will be calculated 
based on a two-sided t-test. The futility analysis may not occur if, for example, the study accrues 
quickly, as all or the large majority of patients may already be enrolled before approximately 
50% of patients have finished the 12-week double-blind, placebo-controlled treatment phase.  
The significance level associated with the primary and key secondary efficacy analyses will be 
adjusted based on the number of DMC meetings as described in the SAP. 
11.0 
SAFETY MONITORING AND RISK MANAGEMENT 
11.1 
Safety Events and Reporting 
11.1.1 
Definitions 
Adverse Event (AE) 
An AE is any unfavorable and/or unintended medical occurrence that 
presents during the course of the study (i.e., from the signature of informed 
consent through the Follow Up visit or earlier discontinuation, whichever 
comes first) regardless of its relationship to use of the investigational 
product. In studies of investigational products, no distinction is made 
between the investigational and control treatments with respect to AE 
reporting. 
Serious AE (SAE) or 
Serious Suspected 
Adverse Reaction 
Any AE or suspected adverse reaction that is deemed by the Sponsor or 
Investigator to have resulted in any of the following outcomes: death, a 
life-threatening AE (i.e., places the patient, in the opinion of the Sponsor or 
Investigator, at immediate risk of death from the reaction as it occurs), 
inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and/or require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 


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Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse.  
Suspected Adverse 
Reaction 
An AE for which there is a reasonable possibility that the investigational 
product caused the AE. A “reasonable possibility” means there is evidence to 
suggest the investigational product is causally related to the AE. Examples 
include: 
A single occurrence of an event that is uncommon and known to be strongly 
associated with an active ingredient or other component regardless of 
formulation; 
One or more occurrences of an event that is not commonly associated with 
an active ingredient or other component, but is atypical in the study 
population; 
The observation, when looking at data summaries, that a condition expected 
for the study population is occurring with increased frequency in comparison 
to concurrent or historical controls. 
Treatment-Emergent 
AE (TEAE) 
An AE that occurs after the patient has received the investigational product. 
AEs that occur during the Screening and Washout periods prior to treatment 
with the investigational product are not TEAEs. 
Unexpected AE or 
Unexpected 
Suspected Adverse 
Reaction 
Any AE or suspected adverse reaction not listed in the current Investigator’s 
Brochure (IB) or for which the specificity or severity of the event is not 
consistent with the IB; or, if an IB is not required or available, the specificity 
or severity of which is not consistent with the risk information described in 
the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the IB only referred to elevated 
hepatic enzymes or hepatitis. 
11.1.2 
Documenting and Reporting Adverse Events 
The Investigator is responsible for routine assessments of AEs throughout the course of the 
study. All clinical complaints, symptoms, or signs that meet the AE definition will be 
documented in the patient’s record and entered in the study database. Source documentation 


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should be maintained that allows for clear identification of each AE and the following 
parameters: 
• Date of onset 
• Date of resolution (or indication that the event continues as of the final visit) 
• Intensity (mild, moderate, severe) 
• Seriousness (per SAE definition) 
• Relationship to study treatment 
• Outcome 
For study data collection purposes, the outcome of AEs captured in the database will be reviewed 
and made final at the time of the final study evaluation for each patient. If the AE is ongoing, this 
will be reflected in the record. However, the study Investigator is responsible for following all 
AEs until resolution or until no longer of clinical concern. 
11.1.2.1 
Assessment of Intensity (or Severity) 
The intensity of each AE will be assessed using the following categories: mild, moderate, and 
severe. 
• Mild: Easily tolerated by the patient, causes minimal discomfort and does not interfere with 
everyday activities. 
• Moderate: Sufficiently discomforting to interfere with normal everyday activities; 
intervention may be needed. 
• Severe: Prevents normal everyday activities; treatment or other intervention usually needed. 
There is an important distinction between a severe AE and a serious AE. The term “severe” 
designates the intensity of the event, while a “serious” AE meets specific criteria promulgated in 
21 CFR 312.32 and described in Section 11.1.1. 
11.1.2.2 
Assessment of Relationship to Study Treatment 
The relationship of an AE to the administration of the study drug is to be assessed according to 
the following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration 
of study drug and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal 


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relationship and no other cause (concomitant drugs, therapies, complications, etc) can be 
identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent disease- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
• Concomitant drug- 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
• Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a 
logical and better explanation for the event. 
• The pharmacology and pharmacokinetics of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study drug should be considered. 
11.1.3 
Special Procedures for Reporting Serious Adverse Events  
SAEs require additional detailed reports and follow-up. An SAE must be reported to the Sponsor 
immediately (within 24 hours) so as to facilitate discussion and implementation of necessary 
follow-up measures, and to enable the Sponsor to submit necessary reports to regulatory 
authorities, other Investigators, and IRBs. The Sponsor may request additional data and 
follow-up SAE reports to facilitate full disclosure to regulatory authorities, other Investigators, 
and IRBs in accordance with relevant regulation. 
Initial Reports 
All SAEs occurring from the time of first dose (start of Pain Observation period) of study drug 
until 30 days following the final dose of study drug must be reported to Medpace Clinical Safety 


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within 24 hours of the knowledge of the occurrence. After the 30-day reporting window, any SAE 
that the Investigator considers related to study drug must be reported to Medpace Clinical Safety 
or the Sponsor/designee.  
To report the SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, Medpace Safety personnel will be notified electronically by the EDC 
system and will retrieve the form. If the event meets serious criteria and it is not possible to access 
the EDC system, send an e-mail to Medpace Safety at medpace-safetynotification@medpace.com 
or call the Medpace SAE reporting line (phone number listed below), and fax/e-mail the completed 
paper SAE form to Medpace (fax number listed below) within 24 hours of awareness. When the 
EDC system becomes available, the SAE information must be entered within 24 hours of the 
system becoming available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-579-0444 
E-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
11.2 
Pregnancy Reporting 
If a patient becomes pregnant during the study or within the safety Follow-up period defined in 
the protocol, the Investigator is to stop dosing with study drug immediately and the patient should 
be withdrawn from the study. Early termination procedures should be implemented at that time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to Medpace 
Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax or e-mail it back to Medpace Clinical Safety.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety Follow-up period defined in the protocol, the Investigator should notify 
Medpace Clinical Safety as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/e-mailed to 
Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for immediate 


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classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
11.3 
Expedited Reporting 
The Sponsor will report all relevant information about SUSARs that are fatal or life-threatening as 
soon as possible to the FDA and in any case no later than 7 days after knowledge by the 
Sponsor/designee of such a case, and the relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also inform all Investigators as required. 
11.4 
Clinical Laboratory Evaluations 
Safety laboratory tests will include chemistry, hematology, and urinalysis. See Appendix I for a 
complete list of analytes. Chemistry laboratory tests will be collected after a minimum 8- to 
10-hour fast. 
Safety laboratory tests will be evaluated at the times indicated in the Schedule of Assessments 
table.  
Abnormal Screening laboratory values that appear to be spurious (eg, laboratory error), or that are 
the result of an identified transient event that if resolved is unlikely to recur, may be repeated once. 
Should this occur, the Investigator should document the reason for repeating the test. 
If, in the opinion of the Investigator, any patient has a clinically significant abnormal laboratory 
finding in comparison to the value at the time of randomization or unresolved TEAEs, additional 
follow-up visits will be scheduled. Patients will be followed approximately once a week (or more 
frequently as deemed appropriate) until the Investigator determines that repeat laboratory findings 
are clinically unremarkable in comparison to baseline, or unresolved AEs return to prestudy levels 
or clinically acceptable levels. 
If a patient experiences an SAE for which follow-up laboratories and review are required, the 
Investigator will schedule additional post dose visits as necessary. 
If, in the opinion of the Investigator, any patient has a clinically significant AE at the follow-up 
call, the Investigator will provide additional follow-up until the AE returns to clinically acceptable 
levels. 
The safety laboratory sample collection times may be refined based on emerging data to ensure 
study objectives are met. 
11.5 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiration rate, and temperature, will be measured 
at the times indicated in the schedule of assessments (Table 1) using the following standardized 
procedures: 


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• Prior to measuring vital signs, the patient should be sitting for a minimum of 5 minutes with 
his/her back supported, feet flat on the floor, and his/her measurement arm supported so that 
the midpoint of the manometer cuff is at heart level. 
• Standing pulse and blood pressure will be obtained following sitting vital signs. 
• An appropriately sized cuff should be used with the bladder centered over the brachial artery. 
• The cuff size and arm used for the measurement should be recorded. Whenever possible, the 
same arm should be used for all vital sign assessments throughout the study. 
• Blood pressure should be recorded to the nearest whole number on an automatic device. 
11.6 
Electrocardiograms 
Twelve-lead ECGs will be performed at the times indicated in the Schedule of Assessments table.  
Every effort will be made to eliminate any sources of physical (including any movement, eating, 
or drinking) or electrical interference. During these assessments, patients are not permitted to use 
cell phones, iPods, laptop computers, tablets, or any type of battery-operated or electrical device, 
and all of these devices must be turned off during the assessments. 
All 12-lead ECGs will be performed with the patient resting in the supine position. Twelve-lead 
ECGs will be printed and all ECGs must be evaluated for the presence of abnormalities by a 
qualified physician. A digital recording of all ECGs for randomized patients will be submitted to 
a central reviewer. In the case of a disagreement between the local (site) reading and the central 
overread, the central overread interpretation of the ECG data will be utilized for all safety analyses. 
Standard ECG parameters will be measured, and the following ECG parameters will be recorded: 
• QRS interval 
• Heart rate 
• RR interval 
• QT interval 
• QTc (QTcF) 
Investigators should contact the Sponsor or designee if any clinically meaningful changes from 
baseline are noted on review.  
11.7 
Physical Examinations 
A comprehensive physical examination will be performed at Screening. A comprehensive physical 
examination will consist of general appearance, skin, HEENT, chest (including heart/lungs), 
abdomen (including liver/kidneys), musculoskeletal, sensory/neurological.  
Subsequent directed physical examinations will be performed at the times indicated in the 
Schedule of Assessments table. The directed physical examination will assess changes from the 
prior visit or new concerns.  
Assessment of skin integrity and wound healing, if applicable, will also be performed at the times 
indicated in the Schedule of Assessments table. Skin breaches and wounds will be examined and 


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the following parameters recorded: location, size, depth, and evidence of erythema, edema, 
warmth, odor, or drainage. 
All complete and limited physical examination findings must be recorded. 
11.8 
Height and Weight 
Height and weight will be measured at the times indicated in the schedule of assessments (Table 
1) and will be used to calculate BMI. Height will be measured with the patient’s shoes off. 
Weight will be measured with the patient’s shoes off and after the patient’s bladder has been 
emptied. 
11.9 
Safety Data and Potential Risks 
Toxicology studies have been conducted in rats (up to 6 months) and dogs (up to 9 months), and 
in both species the results support the use of ricolinostat during acute and chronic dosing. The 
study report from the rat 6-month study reported ‘no ACY-1215-related macroscopic findings, 
organ weight changes, and microscopic findings at the Day 91 interim and Day 181/182 terminal 
sacrifice were noted.  At the highest exposure observed in the chronic toxicology study in dogs, 
at study endpoint changes in some hematologic and clinical chemistry parameters were noted.  
Most of these changes remained within normal historical ranges, and all are monitorable in 
humans.  Detailed descriptions of the design and results of these studies can be found in the 
Investigator’s Brochure.  
With respect to human data, clinical studies of ricolinostat have been conducted in 229 patients 
with multiple myeloma as described in Section 5.4 of this protocol and in the Investigator’s 
Brochure. In these studies, ricolinostat was administered at doses from 40 mg to 360 mg as 
monotherapy or in combination with chemotherapy for extended periods, with a maximum 
treatment duration in the monotherapy study of 29.5 weeks and a maximum treatment duration 
of 174 weeks (~3.3 years) in combination studies. Details of the overall safety profile from these 
studies are provided in the Investigator’s Brochure and above (see Section 5.4). Detailed safety 
results and descriptions of SAEs are also available in the Investigator’s Brochure. Briefly, the 
observed SAEs were consistent with the serious underlying illness and poor health status of the 
study populations and did not suggest safety concerns attributable to ricolinostat. Similarly, the 
observed AEs or laboratory changes in the monotherapy as well as the combination studies, 
including episodes of neutropenia, anemia and changes in renal function in some patients, 
appeared to be consistent with the underlying malignancy and general health status of the 
patients and the known profiles of the chemotherapeutic agents being administered concurrently 
rather than attributable to ricolinostat.  
No deaths occurred in healthy volunteers who received ricolinostat. Among the 229 individuals 
with refractory multiple myeloma treated with ricolinostat, 11 (5%) deaths occurred, of which 1 
was in the monotherapy study and 10 were in the combination studies. No clear dose relationship 
to ricolinostat was observed, and all deaths occurred in patients who were ill with advanced 


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multiple myeloma. The causes of death were attributed to several different events: cardiac 
arrest/sudden death (N=2), pulmonary embolism (N=2), sepsis/septic shock (N=3), pneumonia 
(N=2), bacterial meningitis (N=1), and ‘mental status changes,’ with a number of terminal events 
described in the narrative (N=1). None of these deaths was judged by the assessing Investigator 
as likely due to treatment with ricolinostat, and all were consistent with the severe and 
progressive underlying neoplastic disease (refractory multiple myeloma) of the patients being 
studied. Further details are available in the Investigator’s Brochure.  
In the one healthy volunteer study conducted to date, the most common adverse effect reported 
in a study of healthy volunteers administered ricolinostat doses of 120 and 160 mg in crossover 
fashion was throat irritation (3 patients), and no SAEs were reported.  
As described above, the overall body of safety data does not predict serious safety concerns 
specific to ricolinostat. However, as a result of their underlying disorder, patients with diabetes 
are at increased risk for a number of medical problems such as renal impairment and increased 
risk for infections. The available data do not suggest that ricolinostat is likely to increase these 
risks, but it is important to monitor these issues, and therefore the protocol will include specific 
monitoring for several potential AEs and laboratory changes designated as events of special 
interest and described in Section 11.10.2.2 below. Finally, with respect to skin biopsy, although 
patients with diabetes are at increased risk for poor wound healing related to vascular disease, the 
skin biopsy for IENFD is superficial, small, and commonly performed in patients with diabetic 
neuropathy, and poses minimal safety risk. 
11.10 Risk Mitigation 
11.10.1 
Study Level Risk Mitigation 
At the study level, risk will be mitigated through direct Investigator training, centralized safety 
data collection and monitoring, and periodic review of safety data by an independent DMC. 
11.10.1.1 Training and Data Management 
Measures specific to Investigator training and safety data management will be implemented as 
follows: 
• Investigator and site personnel training will include a focused review of expectations for 
monitoring safety and implementing risk mitigation. 
• Study data will be captured in real time using an EDC system, allowing for routine review of 
EDC data by the Sponsor’s Medical Monitor and clinical team, independent of the timing of 
on-site monitoring review. 
• Routine on-site review of study records and data by the Sponsor’s monitoring affiliate will 
begin directly after the first patient is treated at each study center. 


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• A central clinical laboratory will be used for hematology, serum chemistry, and urinalysis to 
provide standardization across study centers, rapid on-line access to results, and customized 
alerts for results requiring exclusion/discontinuation, thereby allowing Investigators as well 
as the Sponsor’s Medical Monitor to identify potential safety issues early; standardized 
reference ranges for each test will be provided on every report of results and will also be 
available in the laboratory manual. 
• A core cardiovascular laboratory will be used to provide standardization in ECG collection 
and interpretation across study centers, with rapid on-line access to results and customized 
alerts for exclusion/discontinuation. 
• SAE reports and associated data will be reviewed on an expedited basis by the Sponsor and 
its affiliates in order to meet reporting obligations and implement additional risk mitigation 
(if applicable). 
11.10.1.2 Data Monitoring Committee  
As described in Section 10.3.8, an independent DMC will meet periodically to perform a 
comprehensive review of accumulated safety data. In order to complete an informed review, the 
DMC will be provided with treatment assignment information for each patient (i.e., unblinded 
data). An independent, unblinded statistician will facilitate safety data review by the DMC. 
The DMC will be provided with event and case report data on an ad hoc basis when a patient is 
discontinued for any of the AEs of special interest outlined in Section 11.10.2.2. As with the 
formal scheduled reviews, treatment assignment information will be included. The DMC will 
assess safety data for evolving trends, with particular attention to the events of special interest 
described below. As described above (Section 10.3.8) the DMC may also perform an interim 
analysis to assess efficacy or futility.  
11.10.2 
Patient Level Risk Mitigation 
11.10.2.1 Patient Exclusion 
Given the potential for undue risk, certain patients will be excluded from study participation as 
follows: 
• Patients at risk for QT interval prolongation as a result of personal or family history, or with 
measured QTc prolongation on Screening ECG. 
• Patients with any hematologic or select serum chemistry abnormalities suggesting serious, 
ongoing medical problems, including significant renal or hepatic impairment. 
• Patients with significant comorbidities or other medical conditions, laboratory abnormalities, 
or psychiatric illnesses that would place the patient at increased risk. 


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• As the effect of ricolinostat on fetal development is not known, pregnant women or women 
wishing to become pregnant will be excluded from the study, as will FOCBP who do not 
agree to use contraception as outlined above. Breastfeeding mothers will also be excluded. 
11.10.2.2 Adverse Events of Special Interest and Monitoring Procedure 
The following AEs are designated as events of special interest, and, if observed as treatment-
emergent during the study, should be addressed as described below: Anemia, leukopenia, 
neutropenia, thrombocytopenia, renal impairment, congestive heart failure, suicidality. 
 
Observation 
Risk Management 
Clinical Laboratory Parameters for Adverse Events of Special Interest 
Cardiac Conduction: QTcF ≥ 500 ms or 
QTcF increase from baseline ≥ 60 ms and 
QTcF ≥ 480 ms 
• 
For any observed case, the investigator should 
repeat the ECG assessment twice and compare the 
average of these 3 measurements of QTcF to the 
average of the 2 pre-treatment (i.e. screening and 
baseline) QTcF values 
• 
If confirmed, patient should be discontinued and 
appropriate follow-up instituted 
Anemia: Hemoglobin decrease from 
baseline > 2 g/dL, or a decrease from 
baseline of at least 1.0 g/dL to a value 
below 11.5 g/dL (female) or 13 g/dL 
(male)  
  
• 
For any observed case, repeat laboratory test 
within one week to confirm: 
o If the abnormality persists on repeat 
laboratory test, refer to section 11.10.2.2.1 
for additional laboratory monitoring and 
initiate appropriate medical work-up to 
assess potential causes.   
 
 
 
 
 
Leukopenia: White blood cell count 
< 2500/mm3; or a decrease from baseline 
> 1500/mm3 
Neutropenia: Neutrophil count 
< 1250/mm3; or decrease from baseline 
> 500/mm3 
Platelet count < 100,000/mm3; or a  
decrease from baseline > 50,000/mm3 
eGFR <30 ml/min/1.73 m² 
• 
Confirm with repeat test within one week; if 
confirmed, patient should be discontinued and 
appropriate follow-up instituted 
C-SSRS: Response of “yes” to suicidal 
ideation questions 4 or 5; or 
response of “yes” to any suicidal behavior 
questions 
• 
For C-SSRS response of yes to suicidal ideation 
items: evaluate and ensure patient’s immediate 
safety; ensure patient has appropriate mental 
health follow up and any necessary intervention to 
assure patient’s safety. If patient describes intent 
to act or formed plan (i.e., more than passive 
suicidal ideation), discontinue patient from study 
treatment, ensure appropriate mental health 
follow-up and schedule for safety follow-up.  
Cardiac Function 


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New onset symptomatic bradycardia 
observed during Treatment period; i.e., 
heart rate < 50 bpm with weakness, 
confusion, shortness of breath, chest pain 
or hypotension, or evidence of new onset 
(i.e., not previously diagnosed) congestive 
heart failure 
• 
For bradycardia, repeat measurements at least 
30 minutes later to confirm. For confirmed 
bradycardia or new onset congestive heart failure, 
stop study drug and initiate appropriate medical 
workup.  
• 
If no underlying, non-study drug-related cause can 
be ascertained, no further study drug should be 
administered, study discontinuation measures 
should be obtained, and the patient should be 
followed until resolution. 
 
 
11.10.2.2.1 
Hematological Adverse Events of Special Interest Confirmatory Monitoring 
When an event is identified as meeting the pre-specified criteria for decrease from baseline in a 
laboratory sample at a post-randomization visit (sample 1) and confirmed in a second 
consecutively drawn sample (sample 2), the following additional monitoring will be put into 
place.  Confirmation is defined as a repeat value that 1) meets the magnitude of decrease 
criterion from baseline relative to sample 1 and 2) that does not show a meaningful increase 
relative to sample 1.  Baseline for this purpose is defined as the lowest of the available pre-
randomization values.  
If the decrease is confirmed, additional weekly samples for the ensuing 2 weeks (sample 3 and 
sample 4) will be collected (making a total of 4 samples over approximately 4 weeks) to ensure 
that parameters remain stable and do not go below pre-specified thresholds (see below) for 
discontinuation.  During this monitoring, the patient may remain on study drug provided each of 
the following conditions are met: 
• The observed values for all samples for the parameter in question remain above the following 
thresholds  
 
11.5/13.0 g/dL (Female/Male) for hemoglobin and at least 1 g/dL decrease from baseline 
 
2500/mm3 for white blood cell  count 
 
1250/mm3 for neutrophils  
 
100,000 mm3 for platelets 
• There is not, in sample 2, 3, or 4 a further decrease relative to sample 1 in the measure being 
monitored  
 
> 2 g/dL if the measure of interest is hemoglobin  
 
> 500/mm3 if the measure of interest is neutrophils,  
 
> 1500 mm3 if the measure of interest is white blood cell count,  
 
> 50,000/mm3 if the measure of interest is platelets. 


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• After samples 2, 3, and 4 have been obtained, and if no decrease relative to sample 1 meeting 
the criteria described in the above bullets has been observed, the patient may continue in the 
study on the usual visit schedule and the AESI is considered resolved.  
• In the event samples 2, 3 and 4 show a further decrease from sample 1 that exceeds the above 
criteria for the relevant measure, drug administration is halted.  A repeat laboratory sample 
should be obtained within one week. Provided this repeat sample shows an increase from the 
value among sample 2, 3 or 4 that triggered the halt, study drug may be reinstated, with 
weekly monitoring of the relevant parameter for at least 2 samples to ensure that values 
remain above 100,000/µL for platelets, 1250/mm3 for neutrophils and 2500/mm3 for WBCs. 
Confirmed Events of Special Interest are recorded in the EDC system by completing the AE 
form electronically and indicating the event as an AE of Special Interest. Since these protocol 
defined AESIs are intended for safety monitoring, they may not be considered untoward medical 
events and  their monitoring should not be used to infer relationship to drug. 
When a patient is discontinued, best efforts should be made by the Investigator to complete final 
safety assessments and follow ongoing AEs until resolution or no longer of clinical concern. 
12.0 
ADMINISTRATIVE AND REGULATORY OBLIGATIONS 
12.1 
Confidentiality 
12.1.1 
Confidential and Proprietary Information 
All information regarding the nature of the proposed investigation provided by the Sponsor to the 
Investigator (with the exception of information required by law or regulations to be disclosed to 
the IRB, the patient, or the appropriate national or local authorities) must be kept in confidence 
by the Investigator. The Investigator may share the information with study personnel under 
his/her direct supervision only for the purposes of conducting the study. 
12.1.2 
Publication and Media Inquiries 
All manuscripts or presentations based upon this study, including press statements and internal 
public notices and memoranda, must be submitted to the Sponsor for review and approval prior 
to release for publication or presentation. This review is necessary to ensure that proprietary, 
non-public information is protected in accordance with confidential disclosure agreement terms 
between the Sponsor and the Investigator.  
During and after this study, the Investigator may receive inquiries from reporters or financial 
analysts. Investigators are to refer these inquiries to the Sponsor for disposition. 
12.1.3 
Patient Identity and Protected Health Information 
In accordance with 45 CFR 160 and 164, Investigators must ensure that all information regarding 
the health of participating patients, including information generated during the course of this 


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study, is maintained in such a manner so as to prevent improper disclosure. Without prior 
authorization or waiver, information may not be released unless it has been edited to remove any 
and all identifiers (eg, names, addresses, contact information, dates of birth, social security 
numbers, medical record numbers, and all dates with the exception of year) that would allow for 
data to be linked to a specific individual. As a result, Investigators must provide a privacy notice 
to each study patient and obtain a release waiver as described below. 
For data analysis and reporting purposes, the patient will be asked to sign an authorization for 
release and use of protected health information as part of the initial informed consent process. 
This authorization will allow the Investigator to make study results available to the Sponsor and 
its designated representatives, as well as applicable regulatory authorities, without first removing 
all unique identifiers (eg, dates of birth important to establishing the eligibility of patients). 
However, in any communications of data for this study, patients will be identified only by their 
initials and a unique study identification number. 
12.2 
Independent Review Board 
The study protocol, ICF, and any other information that will be presented to study patients must 
be approved initially, and reviewed at least annually, by an IRB constituted in accordance with 
21 CFR 56 and ICH E6 GCP guidelines. A copy of the initial IRB approval letter must be 
submitted to the Sponsor prior to study initiation. Investigational product will not be released to 
an Investigator without an assurance that final IRB approval has been granted. Subsequently, 
copies of all IRB correspondence should be submitted to the Sponsor on an ongoing basis. 
12.3 
Patient Recruitment and Informed Consent 
12.3.1 
Patient Referrals 
Referrals are often an essential part of patient recruitment. Referrals to an Investigator can 
provide patients with access to investigational agents otherwise unavailable to the referring 
physician. It is important that the process of referring a patient to the Investigator conducting the 
study meets the requirements of ICH E6 GCP and 45 CFR 160 and 164 regarding the release of 
protected health information. Prior to referral, the patient should be asked if consent is given to 
share contact information and details of the medical condition with the Investigator. This consent 
should be documented by the referring physician. 
12.3.2 
Informed Consent and Other Written Information for Patients 
The ICF and any other written information for patients should meet local requirements of 
language and interpretation. One copy of the signed ICF and any other written information will 
be given to the patient and the original will be retained by the Investigator in the study files. The 
ICF must include eight basic elements (purpose/scope/duration, risks/discomforts, benefits, 
available alternative procedures/treatment, confidentiality, compensation for research-related 


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injury, voluntary participation/withdrawal, and contact information) in accordance with 21 CFR 
50. 
12.4 
Study Documentation 
All data relevant to the assessments outlined in this protocol must be entered in the patient’s 
record and the EDC system. Electronic data entered for each patient will be verified by 
comparison to source documents (medical records, study worksheets, diagnostic reports, ECG 
tracings, etc) at the study site by the designated study monitor. The Investigator must make 
patient data accessible to the designated study monitor, to other authorized representatives of the 
Sponsor, and to regulatory agency representatives. At the conclusion of the study, an electronic 
copy of each patient’s case record in the EDC system will be provided to the Investigator for 
retention in the study file. 
According to GCP, essential documents should be retained for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region. In addition, records should be retained 
for at least two years after the formal discontinuation of clinical development of an 
investigational product. These documents should be retained for a longer period, however, if 
required by local regulatory requirements or through an agreement with the Sponsor. No study 
documents will be destroyed or moved to a new location without prior written approval from the 
Sponsor. If the Investigator relocates, retires, or withdraws from the clinical study for any reason, 
responsibility for the records should be formally transferred to an agreed-upon designee. 
12.5 
Protocol Compliance 
Substantive changes in the protocol include alterations that affect the safety of patients or that 
alter the scope of the investigation, the scientific quality of the study, the experimental design, 
doses, assessment variable(s), the number of patients treated, or the patient selection criteria. 
These changes must be implemented via formal written protocol amendment only upon joint 
approval by the Sponsor and Investigator. Additionally, a protocol amendment must be reviewed 
and approved by the IRB prior to implementation. If a protocol amendment results in changes to 
the ICF, the revised form must also be approved by the Sponsor and the IRB prior to use. 
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
particular patient, and that are deemed crucial for the safety and wellbeing of that patient, may be 
instituted for that patient only. The Investigator or other attending physician will also contact the 
Sponsor as soon as possible in the case of such a departure. These departures do not require 
pre-approval by the IRB; however, the IRB and the Sponsor must be notified in writing as soon 
as possible after the departure occurs. Furthermore, the Investigator will document in the 
patient’s record and the electronic case report form (eCRF) the reasons for the departure from the 
protocol and the ensuing events. 


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12.6 
Investigational Drug Accountability 
It is the responsibility of the Investigator to ensure that proper procedures are implemented with 
regard to the receipt, storage, and dispensation of the investigational product(s). Shipping 
receipts, dispensing records, and inventory forms will be examined and reconciled periodically 
and at the end of the study by the designated study monitor. Both the study drug used during the 
course of the study and any remaining unused study drug must be accounted for on the 
Accountability Log provided to the Investigator by the Sponsor. 
12.7 
Study Monitoring 
The designated study monitor will review the progress of the study as frequently as is necessary 
to ensure proper study conduct and accurate data collections through: 
• Periodic on-site visits; 
• Frequent telephone communications with the site; and 
• Ongoing review of eCRF entries, clinical records, and administrative documents. 
All records pertaining to the study will be made available to the study monitor during each site 
visit. To allow adequate time to assemble all of the records, visits will be confirmed well in 
advance whenever possible. 
A separate Clinical Monitoring Plan will be prepared by the Sponsor and the designated clinical 
monitoring/site management CRO, which will include detailed guidance for site visit frequency, 
site-based data review and verification requirements, investigational product and essential 
document review, safety surveillance, remote eCRF data review, communications, and 
documentation (including reports of monitoring activity). 
12.8 
Reports 
The Investigator shall make accurate and adequate written progress reports to the IRB at 
appropriate intervals, not exceeding one year. 
The Investigator shall make an accurate and adequate final report to the IRB within 3 months 
after completion or termination of the study. 
The Investigator shall immediately make an accurate and adequate special report to the Sponsor 
and the IRB (as applicable) for any serious adverse experience. 
The Sponsor will prepare a final study report within a reasonable time frame after the data from 
the last completed patient has been tabulated. The final approved report will then be submitted to 
the appropriate regulatory authorities. 


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13.0 
COVID-19 RISK MITIGATION 
In March 2020, COVID-19, caused by infection with SARS-CoV-2, was characterized as a 
pandemic by the World Health Organization. The COVID-19 pandemic impacted clinical studies 
worldwide due to quarantines, site closures, travel limitations, diversion of resources, and/or 
general interruptions in study-related procedures. 
13.1 
Risk/Benefit Assessment in the Context of COVID-19 
In general, the DPN population possesses moderate risk of serious complications from any 
infection or febrile illness because the underlying condition of diabetes and possible 
complications of cardiovascular disease may pose risk for worse outcomes and complication 
associated with COVID-19. The emergence of COVID-19 crises increases the overall infection 
risk in affected communities, including DPN patients who reside in those communities.  
Participation in a clinical trial provides patients with increased access to healthcare resources and 
reinforcement of appropriate practices during a time of increased infection risk. Study patients 
will have access to healthcare professionals on a more intensive schedule than a normal clinical 
practice for the management of DPN.  
To mitigate any risk of COVID-19 infection associated with study participation, this protocol 
provides flexibility for conducting remote visits (through telemedicine and/or home health visits) 
that will maintain patient access to healthcare resources while limiting any infection risk 
associated with study participation.  
13.2 
Remote Visits 
In response to COVID-19 situations, remote visits consisting of telemedicine and/or home health 
visits may be conducted in lieu of certain in-clinic visits. The exceptions are the Screening visits 
and the baseline visit (Day 1), which must be conducted in the clinic. Table 3 specifies which 
activities can be conducted by a home health nurse or via telemedicine and which activities must 
be conducted in the clinic. 
Table 3: 
Categorization of Study Activities 
Remote Visits 
In-Clinic Only Activities 
Home Health Nurse Activities 
Telemedicine Activities 
Obtain samples for the 
following labs: 
• 
Pregnancy test 
• 
Clinical safety labs 
Review study diary/drug 
adherence 
Review new/ongoing AEs 
Screening visit assessments 
Pain Observation Day -14 
assessments 


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Vital signs 
12-lead ECG 
Confirm patient completion of 
patient-reported outcome 
measures: 
• 
Brief Pain Inventory Short 
Form (pain interference 
section only) 
• 
Neuropathy Total 
Symptoms Score – 6 
• 
Norfolk Diabetic QOL-DN 
• 
Patient Global Impression of 
Change 
Review concomitant 
medications 
Limited physical exam 
including skin integrity and 
wound healing, if applicable¹ 
Dispense study treatment 
(direct-to-patient shipping of 
study treatment) 
Study treatment accountability 
Confirm patient completion of 
patient-reported outcome 
measures: 
• 
Brief Pain Inventory Short 
Form (pain interference 
section only) 
• 
Neuropathy Total 
Symptoms Score – 6 
• 
Norfolk Diabetic QOL-DN 
• 
Patient Global Impression of 
Change 
• 
C-SSRS 
Day 1 (Pre-Treatment baseline) 
assessments 
UENS 
Physical exam including skin 
integrity and wound healing, if 
applicable¹ 
Intraepidermal nerve biopsy 
 
¹If a physical exam cannot be performed in the clinic, a limited physical examination should be performed via 
telemedicine. 
AE = adverse event; ECG = electrocardiogram; QOL-DN = Quality of Life-Diabetic Neuropathy; 
C-SSRS = Columbia Suicide Severity Rating Scale; UENS = Utah Early Neuropathy Scale. 
If a site closes or a patient resides in a location where a shelter-in-place order is issued, the 
Investigator must consult with the Medical Monitor to determine the best course of action, 
particularly for those patients who have not yet completed the baseline visit. For patients that 
have completed the baseline visit, remote visit activities can proceed as outlined in Table 3. A 
combination of home health visit and telemedicine activities may be used. If in-clinic visits are 
no longer possible, activities categorized as in-clinic-only activities will not be conducted. If the 
shelter-in-place order is lifted after a missed clinic visit, attempts should be made to conduct the 
missed in-clinic-only activities via an unscheduled visit.  
If a patient or a member of the patient’s household is suspected or confirmed to have COVID-19, 
the Investigator must consult with the Medical Monitor to determine the best course of action. In 
this situation, only telemedicine activities can proceed. If the patient misses in-clinic visits 
during this time, an unscheduled visit will be conducted once the patient or member of his/her 


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household no longer has suspected or confirmed COVID-19. At a minimum, safety labs must be 
performed at the unscheduled visit. Patients cannot go more than 12 weeks or 2 consecutive 
visits without labs being drawn.  
For scenarios not delineated here or for further clarification, the Investigator should consult the 
Medical Monitor to determine the best course of action.  
13.3 
Patient Disposition in the Context of COVID-19 
If a patient develops active COVID-19 infection (whether confirmed or suspected) during the 
course of the study, the Investigator will work with the Medical Monitor to determine the best 
course of action, taking into consideration the AE and SAE guidelines in Section 11.0. If the 
study drug is discontinued or a patient is withdrawn from the study because of COVID-19, the 
reason for early termination will be captured in the EDC system as such. 
13.4 
Regulatory and Oversight Considerations in the Context of COVID-19 
If planned onsite monitoring visits are not possible because of COVID-19, remote monitoring 
may occur, if allowed by local and federal legal and regulatory requirements. If source data are 
collected at a home health visit, those source documents will be maintained with the homecare 
staff until they can be transferred to the trial site. If a protocol deviation is the result of 
COVID-19-related circumstances, this information should be captured. The impacts of these 
implemented contingency measures on the outcomes of this study, including any protocol 
deviations that result from COVID-19 illness and/or COVID-19 control measures will be 
discussed in the Clinical Study Report . 
 
 


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14.0 
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15.0 
APPENDICES 
15.1 
APPENDIX I – Clinical Laboratory Evaluations 
Chemistry [Fasted]: 
Hematology: 
Albumin 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count  
Chloride 
Red blood cell count (RBC) 
Cholesterol 
White blood cell count (WBC) 
Creatinine 
White blood cell differential (% and Abs): 
Calculated creatinine clearance 
− 
Basophils 
GGT 
− 
Eosinophils 
Glucose 
− 
Lymphocytes 
LDH 
− 
Monocytes 
Phosphorus 
− 
Neutrophils 
Potassium 
 
Sodium 
Other: 
Total bilirubin 
Glycated hemoglobin (HbA1c) 
Total CO2 (measured as bicarbonate) 
Urine pregnancy test (FOCBP only): point-of-
care pregnancy test 
Total protein 
SARS-CoV-2 (COVID-19) Qualitative PCR 
Triglycerides 
Vitamin B12 and serum paraproteins 
Uric acid 
 
 
 
Complete Urinalysis: 
Urine Drug Screen: point-of-care drug test 
Color and appearance  
 
pH 
 
Specific gravity 
Serology 
Bilirubin 
Hepatitis B surface antigen 
Glucose 
Hepatitis C virus antibody 
Ketones  
Human immunodeficiency virus antibody 
Leukocytes  
 
Nitrite  
 
Occult blood  
 
Protein  
 
Microscopic (including RBCs and WBCs) 
 


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15.2 
APPENDIX II – Suicidal Ideation/Behavior Screening 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a validated questionnaire that helps to 
identify suicidal ideation and behavior (Posner, 2011) in clinical and research settings. The 
C-SSRS is referred to in the General Recommendations section of the FDA Guidance for 
Industry on Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical 
Trials (Draft Rev 1; Aug 2012). The scale consists of two sections, one to assess suicidal intent 
or ideation and the other to assess suicidal behavior. Each section asks a small number of yes/no 
questions followed by scoring to quantify the intensity of ideation or behavior. 
Two versions of the C-SSRS will be used in this study: Screening version (3 months and lifetime 
history) and the Since Last Visit version. The Screening version will be administered at the 
Screening visit. The Since Last Visit version of the C-SSRS will be administered at all 
subsequent assessment times. An investigator must review the C-SSRS data for each visit prior 
to the patient leaving the site and confirm that the patient did not express suicidal ideation or 
behavior that would require intervention. 
Suicidal Ideation 
There are 5 yes/no questions in the ideation section of the questionnaire that capture 1) a wish to 
be dead or not wake up, 2) non-specific thoughts of suicide, 3) specific thoughts of suicide 
method without intent to act, 4) some intent to act but without a specific plan, and 5) active 
ideation with specific plan and intent. When the patient responds yes to any of the ideation 
questions, the most severe (i.e., 1 – 5) ideation is further characterized on a scale of 0 – 5 with 
regard to frequency, duration and controllability of thoughts, as well as deterrents to and reasons 
for ideation. 
Suicidal Behavior 
The yes/no questions in the behavior section of the questionnaire ask about actual, interrupted, 
and aborted suicide attempts, as well as preparatory actions and non-suicidal injurious behaviors. 
The lethality of actual attempts is assessed on a scale of 0 – 4, and the potential lethality of 
non-lethal events (i.e., lethality = 0) is rated on a scale of 0 – 2. 
Study Application 
In this study, the C-SSRS will be used both to screen potential study candidates for suicidal 
ideation/behavior and to monitor enrolled patients for suicidality during the Treatment period. 


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At Screening, potential candidates who meet either of the following C-SSRS criteria will be 
excluded from study participation: 
1. Yes response to Question 4 (some intent to act but without a specific plan) or 5 (active 
ideation with specific plan and intent) in the Suicidal Ideation section, or 
2. Yes response to any of the Suicidal Behavior questions, including preparatory actions or 
injurious behaviors, for the 3 month period prior to Screening. 
Furthermore, these same criteria will result in patient discontinuation if observed during the 
Treatment period (see Section 7.7). 

SAP_001.pdf: 
CONFIDENTIAL 
 
Regenacy Pharmaceuticals, Inc. 
Protocol REGY-DN-201 
A Phase II, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study of Ricolinostat in Patients with  
Painful Diabetic Peripheral Neuropathy 
 
Statistical analysis plan 
 
Prepared by: 
Statistics Collaborative, Inc. 
© 2023 Statistics Collaborative, Inc.  
 
 


CONFIDENTIAL 
Protocol REGY-DN-201 
Statistical analysis plan 
Prepared by: Statistics Collaborative, Inc. 
Author: 
 
 
 
Date: 
 
 
Lisa Weissfeld, PhD 
Executive Director 
 
 
 
 
 
 
 
 
 
Approved by: Regenacy Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
Date: 
 
 
David Michelson, MD 
Chief Medical Officer 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 




REGY-DN-201 STATISTICAL ANALYSIS PLAN 
February 25, 2022 
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CONFIDENTIAL 
Contents 
1. Introduction ....................................................................................................................................... 1 
2. Study objectives ................................................................................................................................ 1 
2.1. 
Primary objective .................................................................................................................... 1 
2.2. 
Key secondary objectives ...................................................................................................... 1 
2.3. 
Secondary objective ................................................................................................................ 1 
2.4. 
Exploratory objective ............................................................................................................. 2 
3. Study design and conduct ............................................................................................................... 2 
3.1. 
Study design ............................................................................................................................ 2 
3.2. 
Study population .................................................................................................................... 2 
3.3. 
Study treatments .................................................................................................................... 5 
3.3.1. 
Active arm .................................................................................................................. 6 
3.3.2. 
Placebo arm ................................................................................................................ 6 
3.4. 
Schedule of events .................................................................................................................. 6 
4. Outcome variable definitions ........................................................................................................ 11 
4.1. 
Screening and baseline characteristics............................................................................... 11 
4.2. 
Efficacy assessments ............................................................................................................ 11 
4.2.1. 
Numerical Pain Rating Scale (NRS) ..................................................................... 12 
4.2.2. 
Brief Pain Inventory Questionnaire – Short Form (BPI-SF) .............................. 12 
4.2.3. 
Patient Global Impression of Change (PGIC) ..................................................... 12 
4.2.4. 
Neuropathy Total Symptom Scores – 6 (NTSS-6) ............................................... 12 
4.2.5. 
Utah Early Neuropathy Scale (UENS) ................................................................. 13 
4.2.6. 
Norfolk Diabetic Quality of Life-Diabetic Neuropathy (QOL-DN) ................. 13 
4.2.7. 
Use of rescue medication ....................................................................................... 13 
4.2.8. 
Intraepidermal Nerve Fiber Density Determination (IENFD).......................... 13 
4.3. 
Efficacy endpoints ................................................................................................................ 14 
4.3.1. 
Primary endpoint .................................................................................................... 14 
4.3.2. 
Key secondary endpoints ....................................................................................... 14 


REGY-DN-201 STATISTICAL ANALYSIS PLAN 
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4.3.3. 
Secondary endpoints .............................................................................................. 14 
4.3.4. 
Exploratory endpoints ............................................................................................ 15 
4.4. 
Safety assessments ................................................................................................................ 15 
4.4.1. 
Adverse events ........................................................................................................ 15 
4.4.2. 
Laboratory safety assessments .............................................................................. 16 
4.4.3. 
Vital signs ................................................................................................................. 16 
4.4.4. 
Electrocardiogram (ECG) ....................................................................................... 17 
4.4.5. 
Physical examinations ............................................................................................ 17 
4.4.6. 
Height and weight .................................................................................................. 17 
5. Database lock and unblinding ...................................................................................................... 17 
5.1. 
Blinded data review (BDR) review of selected data prior to database lock ................. 17 
5.2. 
Database lock ........................................................................................................................ 18 
5.3. 
Authorization for unblinding ............................................................................................. 18 
6. Statistical analyses .......................................................................................................................... 19 
6.1. 
Statistical methodology ....................................................................................................... 19 
6.1.1. 
Sample size determination ..................................................................................... 19 
6.1.2. 
Analysis populations .............................................................................................. 19 
6.1.3. 
General considerations ........................................................................................... 20 
6.1.4. 
Visit windows .......................................................................................................... 21 
6.1.5. 
Procedures for handling missing data ................................................................. 22 
6.2. 
Demographics and baseline characteristics ...................................................................... 24 
6.3. 
Patient disposition ................................................................................................................ 24 
7. Primary efficacy analyses .............................................................................................................. 25 
7.1. 
Primary analysis ................................................................................................................... 26 
7.2. 
Identification of the primary model ................................................................................... 26 
7.3. 
Primary efficacy analysis ..................................................................................................... 27 
7.3.1. 
Imputation of intermittent missing values .......................................................... 27 
7.3.2. 
Reference-based imputation .................................................................................. 29 
7.4. 
Sensitivity analyses .............................................................................................................. 31 


REGY-DN-201 STATISTICAL ANALYSIS PLAN 
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Contents, continued 
8. Key secondary analyses ................................................................................................................. 34 
8.1. 
Estimands .............................................................................................................................. 34 
8.2. 
Adjustment for multiplicity ................................................................................................ 36 
9. Secondary analyses ......................................................................................................................... 37 
10. Exploratory analyses ...................................................................................................................... 38 
11. Safety analyses ................................................................................................................................ 38 
11.1. Adverse events...................................................................................................................... 38 
11.2. Clinical laboratory evaluations ........................................................................................... 39 
11.3. Physical examination ........................................................................................................... 39 
11.4. Vital signs .............................................................................................................................. 39 
11.5. 12-lead electrocardiogram ................................................................................................... 39 
11.6. Concomitant medications ................................................................................................... 40 
12. References ........................................................................................................................................ 40 
 
Exhibits 
Exhibit 1. Inclusion criteria .................................................................................................................. 3 
Exhibit 2. Exclusion criteria ................................................................................................................. 4 
Exhibit 3. Schedule of events ............................................................................................................... 7 
Exhibit 4. Example of study days and analysis timepoints .......................................................... 22 
 
Tables 
Table 1. 
Estimand attributes for the primary efficacy analyses ................................................. 25 
Table 2. 
SAS code to create datasets satisfying monotone missing condition ........................ 28 
Table 3. 
SAS code for reference-based imputation ...................................................................... 29 
Table 4. 
SAS code for MMRM analysis as part of the imputation process .............................. 30 


REGY-DN-201 STATISTICAL ANALYSIS PLAN 
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Tables, continued 
Table 5. 
SAS code for Rubin’s rule ................................................................................................ 30 
Table 6. 
SAS code for missing at random imputation ................................................................ 32 
Table 7. 
SAS code for tipping point analysis ................................................................................ 34 
Table 8. 
Estimand attributes for the key secondary outcome of change from baseline 
in NRS at Week 4 ............................................................................................................... 35 
Table 9. 
Estimand attribute for the key secondary endpoint of UENS at Week 12 ................ 36 
 


REGY-DN-201 STATISTICAL ANALYSIS PLAN 
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Abbreviations 
AE 
adverse event 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BDR 
blinded data review 
BMI 
body mass index 
BPI-SF 
Brief pain inventory questionnaire – short form 
CBD 
cannabidiol 
COVID-19 
coronavirus disease 2019 
CS 
cumulative sum 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
diastolic blood pressure 
DN4 
Douleur Neuropathique 4 Questions 
DPN 
diabetic peripheral neuropathy 
DSM V 
Diagnostic and Statistical manual of Mental Disorders 
ECG 
Electrocardiogram 
ESI 
Event of special interest 
FAS 
full analysis set 
FOCBP 
female of child-bearing potential 
FSH 
follicle stimulating hormone 
HbA1c 
Glycated hemoglobin 
HbsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
HDAC6 
histone deacetylase 6 
HIV 
Human immunodeficiency virus 
IB 
Investigator brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IENFD 
Intraepidermal nerve fiber density 
ITT 
intent to treat 


REGY-DN-201 STATISTICAL ANALYSIS PLAN 
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Abbreviations, continued 
MAR 
missing at random 
MDT 
masquerading disorders tool 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini-Mental State Examination 
MMRM 
mixed model repeated measure 
NCS 
normalized cumulative sum 
NRS 
numerical pain rating scale 
NTSS-6 
neuropathy total symptom score - 6 
PCR 
polymerase chain reaction 
PGIC 
patient global impression of change 
PPP 
per protocol population 
pSAF 
pre-randomized safety population 
QOL-DN 
Norfolk diabetic quality of life – diabetic neuropathy 
SAE 
serious adverse event 
SAF 
safety population 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
TEAE 
treatment emergent adverse event 
UENS 
Utah Early Neuropathy Score 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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1. 
Introduction 
This statistical analysis plan (SAP) describes the planned analyses for Regenacy’s Protocol 
REGY-DN-201, entitled “A Phase II, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study of Ricolinostat in Patients with Painful Diabetic Peripheral Neuropathy”. This 
SAP is based on version 5 of the protocol, dated September 24, 2021. 
This SAP is to be interpreted in conjunction with the protocol. Should the SAP and protocol be 
inconsistent with respect to the planned analyses, the language of the SAP is governing. If the 
final clinical study report (CSR) contains changes to any planned statistical analyses, the 
justification for any such differences will be fully documented in the CSR. 
The statistical principles applied in the design and planned analyses of this study are 
consistent with the International Conference on Harmonization (ICH) guidelines E9 
(Statistical Principles for Clinical Trials) [1]. 
2. 
Study objectives 
2.1. 
Primary objective 
The primary objective is to evaluate the safety and efficacy of ricolinostat compared with 
placebo for painful diabetic peripheral neuropathy (DPN) as measured by an 11-point 
numerical pain rating scale (NRS) after 12 weeks.  
2.2. 
Key secondary objectives 
The key secondary objectives are: 
• 
Evaluating the efficacy of ricolinostat at 4 weeks as assessed by NRS, and 
• 
Evaluating the efficacy of ricolinostat in improving non-pain neuropathic signs after 
12 weeks as assessed by change in the UENS. 
2.3. 
Secondary objective 
The secondary objective of this study is to assess the efficacy of ricolinostat for non-pain 
diabetic peripheral neuropathic signs and to further assess efficacy in painful DPN. 


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2.4. 
Exploratory objective 
The exploratory objective of this study is to assess the effects of ricolinostat on intraepidermal 
nerve fiber density (IENFD), a potential biomarker for efficacy, in a subset of patients with 
painful DPN treated with ricolinostat at 24 weeks.  
3. 
Study design and conduct 
3.1. 
Study design 
This is a randomized, double-blind, 2-arm, parallel group study of approximately 274 
evaluable patients designed to evaluate the safety and efficacy of histone deacetylase 6 
(HDAC6) inhibitor ricolinostat for painful DPN. The study includes a 12-week randomized, 
double-blind, placebo-controlled treatment period in which patients will receive either 
ricolinostat or placebo, followed by a 12-week open-label safety extension period during 
which all patients will receive ricolinostat 120 mg daily.  
3.2. 
Study population 
This study will enroll patients at up to 50 sites in the United States. Patients with Type 1 or 
Type 2 diabetes suffering from painful distal symmetric sensorimotor polyneuropathy (painful 
DPN) present for ≥ 6 months who meet all inclusion and exclusion criteria are eligible to 
participate. Eligible patients will be randomized in a 1:1 ratio to receive either ricolinostat or 
placebo. 
Exhibit 1 and Exhibit 2 display the study’s inclusion and exclusion criteria, respectively. 


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Exhibit 1. Inclusion criteria 
1. Able to understand the study’s purpose and requirements, and able to voluntarily provide 
informed consent to participate. 
2. Age ≥ 18 years and < 80 years at the time of signing the ICF. 
3. FOCBP must agree to use reliable contraceptive methods for the duration of the study and 
for at least 3 months after completing treatment with study drug. For the purposes of this 
study, reliable methods of contraception include abstinence, oral contraceptives, hormonal 
contraceptive implants such as Nexplanon, hormonal vaginal ring such as NuvaRing, 
intrauterine devices in place for a least 3 months, or barrier methods used in conjunction 
with spermicide. To be considered post-menopausal and of non-child-bearing potential, 
women less than 60 years with less than 2 years since their last period must have 
FSH > 40 IU/L and estradiol < 20 pg/mL unless on hormone replacement. 
Male patients participating in the study must also agree to use these reliable contraceptive 
methods if sexually active with a FOCBP partner and also agree to abstain from sperm 
donation from Day 1 through 3 months after completing treatment with study drug.  
4. Type 1 or Type 2 diabetes of at least 6 months duration that meets American Diabetes 
Association criteria (American Diabetes Association, 2020) with an HbA1c > 6.5% at the time 
of Screening. If the HbA1c < 6.5% at the time of Screening, evidence that the patient meets 
American Diabetes Association criteria for diabetes must be documented and reviewed with 
the sponsor prior to entering the patient in the study. Additionally, the diabetes should be 
adequately controlled, with an HbA1c < 11% and no evidence of severe hypoglycemia 
requiring hospitalization within the past 6 months, and in the investigator’s judgement 
sufficiently stable to allow patients in the study. 
5. Painful distal symmetric sensorimotor polyneuropathy due to diabetes as defined by having 
1 or more relatively symmetric, distally accentuated (stocking or stocking-glove) neuropathic 
symptom(s) and 1 or more relatively symmetric, distally accentuated (stocking or 
stocking-glove) neuropathic sign(s), except that diminished reflexes are not, in the absence of 
at least 1 other neuropathic sign, sufficient to make the diagnosis. Neuropathic symptoms 
can include pain, numbness, tingling, or weakness in a distal to proximal (stocking and 
glove) distribution; signs can include impaired pinprick, light touch, vibration, or position 
sense. The neuropathy must have been present (by history) for at least 6 months and must be 
confirmed and documented by the investigator based on clinical history and physical 
examinations. 
6. DN4 score ≥ 4. 
7. Meets initial diary criteria during the 14 days in the pain observation period as determined 
by an algorithm that includes diary compliance, overall level of pain, and day-to-day 
variability in pain, including at least 5 of 7 daily entries completed the 7 days prior to Day 1, 
and a mean intensity and standard deviation within a pre-specified bound (the precise 
bounds are held as double-blind to avoid introducing bias into the ratings). Additionally, at 
least 5 of 7 doses of placebo must be taken the 7 days prior to Day 1 as prescribed during the 
pain observation period for patients to be eligible to continue in the study. 
8. Able to adhere to the study visit schedule and other protocol requirements. 
 
 
 


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Exhibit 2. Exclusion criteria 
1. Females who are pregnant or lactating. 
2. Extremely overweight, defined as BMI > 40 kg/m2 
3. Difficulty understanding instructions for diary use as determined by the investigator or 
other issues that are likely to make compliance with study requirements difficult. 
4. Presence of any neuropathy other than DPN and/or significant risk factors for neuropathy 
other than diabetes, including Charcot Marie Tooth disease; alcohol abuse; B12 deficiency 
not adequately treated; uncontrolled hypothyroidism; evidence of paraproteins by serum 
immunofixation; history of chemotherapy with neurotoxic agents such as platinum analogs, 
taxanes, vinca alkaloids, eribulin, bortezomib and other proteasome inhibitors; or 
immunomodulatory agents such as thalidomide, lenalidomide, pomalidomide, neurotoxic 
check-point inhibitors, or any other chemotherapy known to have neurotoxic effects.  
5. 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. In addition to a general history and clinical examination, this will be assessed 
using the MDT. Patients who screen positive on this tool for a potentially confounding 
disorder must be discussed with and approved by the sponsor’s Medical Monitor prior to 
being randomized into the study. 
6. 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. 
Individuals whose neuropathy is so severely advanced as to create a significant risk that the 
neuropathy will be poorly responsive to treatment as defined by a UENS score > 24 at the 
time of Screening are also excluded from participation. 
7. Have met DSM V criteria for opioid use disorder or DSM V criteria for alcohol use disorder 
(moderate or severe) within the past 2 years. 
8. Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days a week 
during the month prior to Screening. 
9. Active suicidal ideation or suicidal behavior as assessed by the investigator and/or by a 
rating of 3 or greater on the C-SSRS. 
10. The use of marijuana or CBD during the 30 days prior to starting study drug. 
11. A positive urine screen for illicit or non-prescribed controlled substances at baseline. 
12. Have been using non-drug interventions for pain (e.g., acupuncture, mindfulness therapy, 
etc.) for at least 3 months prior to starting study drug may continue these interventions, 
however such treatments may not be initiated during the study, and any patients who plan 
to initiate such treatment during the study are excluded from participation. 
13. Repeated use (greater than 3 occasions) of over-the-counter capsaicin on extremities within 
3 months of Screening or prescription Qutenza use within 6 months of Screening. 
14. Implanted medical device (e.g., spinal cord stimulator, intrathecal pump, or peripheral nerve 
stimulator) for the treatment of pain. 
 
 
 


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Exhibit 2. Exclusion criteria, continued 
15. Has a QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 450 msec (male) or > 460 msec (female) or > 480 msec with right bundle branch 
block on 12 lead ECG at Screening, or requires treatment with drugs known to prolong the 
QT interval (including azithromycin, chloriquine/melfiloquine, clarithromycin, droperidol, 
erythromycin, moxifloxacin and sevoflurane), or has a known history of torsade de pointes 
or congenital long QT syndrome.  
16. Family or personal history of long QT syndrome or ventricular arrhythmias including 
ventricular bigeminy, previous history of QT prolongation not attributable to an identified 
and transient cause, or need for treatment with medications associated with QT 
prolongation. 
17. 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. 
18. eGFR of < 45 mL/min/1.73 m2 (i.e., patients with stage 3b or more several renal disease are 
excluded). 
19. Serum bilirubin values > 2.0 mg/dL. Individuals with known hereditary benign 
hyperbilirubinemia (Gilberts’ syndrome) and a bilirubin < 3.0 may participate in the study 
after discussion and agreement with the sponsor’s medical monitor. 
20. Serum ALT or AST values > 1.5 × the ULN. 
21. Known HIV positive or active hepatitis virus (A, B, or C) infection. 
22. Participation within 1 month of Screening in a clinical trial involving treatment with an 
investigational product. Concurrent participation in an observational study (i.e., no 
investigational treatment being used) is allowed provided it does not interfere with the 
procedures and conduct of this protocol. 
23. Any serious medical condition or comorbidity, laboratory abnormality, or psychiatric illness 
not otherwise specified that could place the patient at undue risk during trial participation, 
that could confound the results of the study, or that could reasonably be expected to affect 
patient compliance with study requirements for treatment and evaluation, as judged by the 
investigator. 
24. Any known recent exposure within the 14 days prior to initial Screening to 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.  
Note: Abnormal Screening laboratory values that appear to be spurious (e.g., laboratory error), or that are the 
result of an identified transient event that if resolved is unlikely to recur, may be repeated once. Should this 
occur, the investigator should document the reason for the repeated test, and if the repeat examination is within 
the acceptable range, the patient may participate.  
 
 
3.3. 
Study treatments 
Both ricolinostat and placebo are liquid formulations to be administered orally in the morning. 
Each bottle of ricolinostat contains 12 mL of a 10 mg/mL solution. Placebo consists of the same 
liquid formulation, excluding the active ingredient (i.e., ricolinostat). Bitrex® is used in the 
placebo formulation to mimic the bitter taste of the active ingredient.  


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3.3.1. 
Active arm 
One bottle of ricolinostat (120 mg in 12 mL) will be taken by mouth daily for approximately 24 
weeks, which includes an approximately 12-week double-blind, placebo-controlled treatment 
period and an approximately 12-week open label safety extension period. Kits will be 
assembled and labeled so that active and placebo supplies are indistinguishable; a single 
randomization code will be used for each patient.  
3.3.2. 
Placebo arm 
One bottle of placebo (12 mL) will be taken by mouth each morning daily during the pain 
observation period and active treatment phase of the study.  
3.4. 
Schedule of events 
Exhibit 3 displays the schedule of events and assessments. 


REGY-DN-201 STATISTICAL ANALYSIS PLAN 
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Exhibit 3. Schedule of events 
 
Screening 
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
 
Screening 
Evaluation1 
Washout 
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
Day 
-45 to -14 
-14 to -7 
-7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
evaluation1 
× 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
Demographics 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
× 
 
× 
 
× 
 
 
 
 
 
 
 
 
 
 
C-SSRS3 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Diabetes & painful 
DPN history 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Masquerading 
disorders tool 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs4 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Height and weight 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination5 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Skin integrity and 
wound healing6 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
12-lead ECG7 
× 
 
 
 
× 
× 
 
 
 
× 
 
 
× 
 
 
Chemistry8 
× 
 
 
 
× 
× 
 
× 
 
× 
 
 
× 
 
× 
Hematology (CBC 
with differential) 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
(page 1 of 4) 
 


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Exhibit 3. Schedule of events, continued 
 
Screening 
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
 
Screening 
Evaluation1 
Washout 
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
Day 
-45 to -14 
-14 to -7 
-7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
HbA1c 
× 
 
 
 
 
 
 
 
 
× 
 
 
× 
 
× 
Vitamin B12 and 
serum paraproteins 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test (if FOCBP)9 
× 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
FSH and estradiol10 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 
(COVID-19) 
Qualitative PCR11 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen12 
× 
 
×12 
 
×12 
×12 
×12 
×12 
× 
×12 
×12 
×12 
×12 
×12 
×12 
Urinalysis 
× 
 
 
 
× 
 
 
 
 
× 
 
 
× 
 
 
HIV, HBsAg, HCV 
screen 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DN4 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intraepidermal 
nerve biopsy 
(eligible patients at 
selected sites only) 
 
 
 
 
× 
 
 
 
 
 
 
 
×15 
 
 
Numerical Pain 
Rating Scale 
 
 
Collected daily via diary 
Brief Pain 
Inventory Short 
Form (pain 
interference section 
only) 
 
 
 
 
× 
 
 
× 
 
× 
 
 
× 
× 
 
Neuropathy Total 
Symptom Score – 6 
 
 
 
 
× 
 
 
 
 
× 
 
 
× 
× 
 
(page 2 of 4) 
 


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Exhibit 3. Schedule of events, continued 
 
Screening 
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
 
Screening 
Evaluation1 
Washout 
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
Day 
-45 to -14 
-14 to -7 
-7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
UENS 
× 
 
 
 
× 
 
 
 
 
× 
 
 
× 
× 
 
Norfolk Diabetic 
QOL-DN 
 
 
 
 
× 
 
 
 
 
× 
 
 
× 
× 
 
Patient Global 
Impression of 
Change 
 
 
 
 
 
 
 
× 
 
× 
 
 
× 
× 
 
Patient training 
 
 
×13 
×13 
× 
×13 
×13 
× 
× 
×13 
×13 
×13 
×13 
×13 
 
Randomization14 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
Dispense, collect 
and perform study 
drug accountability 
 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Record study drug 
 
 
Collected daily via diary 
Prior & 
concomitant 
medications 
× 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Adverse events  
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Schedule 
observation period 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
(page 3 of 4) 
 


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Exhibit 3. Schedule of events, continued 
 
Screening 
Pain Observation Period2 
Placebo (Single-Blind) 
Lead-In 
Double-Blind, Placebo-Controlled Treatment 
Period 
Open Label Safety Extension 
Follow-up 
Period 
 
Screening 
Evaluation1 
Washout 
Training 
Visit 
Training 
Follow-up 
Pre-Treatment 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
14 
Week 
18 
Week 
24 
Week 
26 
Week 
28 
Day 
-45 to -14 
-14 to -7 
-7 to -5 
1 
5 to 9 
12 to 
16 
26 to 
30 
54 to 
58 
82 to 
86 
96 to 
100 
124 to 
128 
166 to 
170 
180 to 
184 
194 to 
198 
Review prohibited 
medications and 
rescue medication 
guidelines 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Phone contact and 
diary review 
 
 
 
×2 
 
 
 
 
 
 
 
 
 
 
 
Note: If a patient is discontinued early from the study for any reason, the investigator should make every effort to ensure that the final assessments at Week 24 are completed as outlined in the schedule of events. The 
reason for discontinuation will be recorded in the patient’s record and the study database. 
1. 
Screening evaluations for patients on pain medication that is not permitted should be scheduled so as to allow for a minimum washout of 7 days prior to the start of the Pain Observation period. Patients who 
are not taking pain medication and do not require washout can be scheduled for Screening evaluations at any time during the period with the understanding that it may take several days before laboratory 
results are available. 
2. 
All patients are required to complete the Pain Observation period from Day -14 to Day -1. During the Pain Observation Period, on Day -7 to -5, a phone contact to the patient will be conducted to review diary 
and dosing compliance and provide re-training as necessary. The Day 1 clinic visit will be scheduled during this call. A patient may be randomized after 10-14 days in the Pain Observation period if all eligibility 
requirements have been met. An algorithm comprised of several aspects of the diary data will determine final eligibility prior to randomization. 
3. 
C-SSRS Screening version used for Screening. Subsequent visits will use the Since Last Visit version. 
4. 
Vital signs include temperature, respiration rate, pulse, and blood pressure while patient is sitting after a minimum 5-minute rest. Standing pulse and blood pressure to be obtained following sitting vital signs. 
5. 
A comprehensive physical examination will be performed at Screening; subsequent physical examinations will be directed exams to assess changes from the prior visit or new concerns. 
6. 
Skin breaches and wounds will be examined and the following parameters recorded: location, size, depth, and evidence of erythema, edema, warmth, odor, or drainage. 
7. 
12-lead ECG after the patient has been resting in the supine position. On Day 1, an additional 12-lead ECG will be obtained 1 hour (+/- 10 minutes) post-dose. 
8. 
Chemistry will be collected in a fasting state (8 to 10 hours fasting). 
9. 
A urine pregnancy test is required at Screening and Day 1 (prior to randomization) for females of child-bearing potential, and must be negative for treatment to proceed. 
10. 
Only for females less than 60 years of age with less than 2 years since last period. 
11. 
Only required if any recent exposure within past 14 days prior to Screening to COVID-19 and/or symptoms of COVID-19 along with reason to suspect COVID-19. 
12. 
Urine drug screen is required at Screening and Week 8, and may be performed at any other visit at the discretion of the Investigator. 
13. 
Patient training is required at Day-14, Day 1, Week 4 and Week 8. Patient training may be repeated, as applicable, at other visits during the study at the discretion of the Investigator. Day-14 training is 
conducted in the WCG aLearn Learning Management System platform. The following training modules are to be completed: Accurate Pain Reporting, Placebo Response Reduction and Research Subject 
Responsibility. 
14. 
On Day 1, all assessments are to be performed prior to randomization. Once randomized, patients will be given the first dose of study drug in the clinic and an ECG will be performed 1 hour post-dose. 
15. 
If visit is being conducted as an early termination visit and the timing is during the Safety Extension (Week 12 to Week 24), collection of the intraepidermal nerve biopsy should occur if patient previously 
provided consent and intraepidermal nerve biopsy collection occurred at Day 1. 
(page 4 of 4) 


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4. 
Outcome variable definitions 
4.1. 
Screening and baseline characteristics 
Screening characteristics: The following will be collected at the Screening visit; inclusion and 
exclusion criteria; gender, date of birth, race, ethnicity, medical history, prior medications, 
diabetic history, prior diabetic medication and treatment history, C-SSRS, Masquerading 
Disorders Tool (MDT), height, weight, BMI, temperature, respiration rate, pulse (sitting and 
orthostatic), blood pressure (sitting and orthostatic), 12-lead ECG, fasting blood chemistry, 
blood samples including virus screen (HIV, hep B, hep C, SARS-CoV-2), urinalysis, urine 
pregnancy test (if FOCBP), urine drug screen, DN4, and UENS.  
The following will be collected during the pain observation period; urine drug screen (at 
Investigator’s discretion), urine pregnancy test (if FOCBP), medical history, prior medications, 
daily NRS diary, rescue medication use (as appropriate), and medication compliance.  
Baseline characteristics: The following will be collected at the baseline visit: medical history, 
prior medications, C-SSRS (update from Screening assessment), temperature, respiration rate, 
pulse (sitting and orthostatic), blood pressure (sitting and orthostatic), physical exam, skin 
integrity assessment, wound healing assessment (if applicable), ECG, fasting blood chemistry, 
hematology, urinalysis, urine pregnancy test (if FOCBP), urine drug screen (at Investigator’s 
discretion), brief pain inventory questionnaire – short form (BPI-SF) (pain interference section 
only), neuropathy total symptom score – 6 (NTSS-6), Utah early neuropathy scale (UENS), 
Norfolk diabetic quality of life – diabetic neuropathy (QOL-DN) assessment, and 
intraepidermal nerve biopsy (for eligible patients at selected sites). 
4.2. 
Efficacy assessments 
The effect of study drug will be evaluated using several validated instruments as described 
below. 


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4.2.1. 
Numerical Pain Rating Scale (NRS) 
NRS is an 11-point assessment measure where 0 represents no pain and 10 is the worst pain 
possible assessed after 12 weeks. The NRS is a validated tool commonly used for pain 
assessment. The NRS will be recorded daily by patients.  
4.2.2. 
Brief Pain Inventory Questionnaire – Short Form (BPI-SF) 
The BPI-SF questionnaire includes a location of pain diagram (question 2) and a number of 
questions designed to rate pain over a specified time period (questions 1 and 3 to 5), to rate 
actual pain (question 6), to capture pain treatment currently received (question 7), and to 
establish how much relief the patient experiences from pain treatments (question 8). 
Question 9 is designed to establish how pain interferes with the patient’s life over a specified 
time period and includes several sections: general activity (section A), mood (section B), 
walking ability (section C), normal work (section D), relations with other people (section E), 
sleep (section F), and enjoyment of life (section G). 
The BPI-SF produces two scores: pain intensity (questions 1-8) and pain interference (question 
9, items A-G). For this study, the pain interference items only will be administered as detailed 
in the schedule of events and scored; pain intensity/severity is already captured in the NRS 
and therefore to avoid redundancy questions 1-8 will not be administered in this study.  
4.2.3. 
Patient Global Impression of Change (PGIC) 
The PGIC is comprised of a single question administered at the end of the treatment period 
(Day 28) to assess the overall quality of life since the beginning of study treatment. The answer 
is scored from 1 to 7 on a gradient where the endpoint anchors are 1 = very much improved, 
and 7 = very much worse.  
4.2.4. 
Neuropathy Total Symptom Scores – 6 (NTSS-6) 
The NTSS-6 tool is a 6-item symptom score questionnaire that was developed to selectively 
identify the existence of, and evaluate the frequency and intensity of, individual neuropathy 
sensory symptoms experienced frequently by patients with painful DPN. The six questions 
interrogate: 1) numbness or insensitivity; 2) prickling or tingling; 3) burning sensation; 4) 


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aching pain or tightness; 5) sharp, shooting, lancinating pain; and 6) allodynia or hyperalgesia. 
The investigator or another qualified member of his/her team will assess the patient and 
complete the NTSS-6 questionnaire weekly during the treatment period, or upon premature 
discontinuation if applicable. 
4.2.5. 
Utah Early Neuropathy Scale (UENS) 
The UENS 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 has been validated and shown to have satisfactory operating 
characteristics including high interrater reliability and reproducibility, as well as favorable 
characteristics for measuring change over time.  
4.2.6. 
Norfolk Diabetic Quality of Life-Diabetic Neuropathy (QOL-DN) 
The Norfolk Diabetic QOL-DN is a 47-item, self-administered questionnaire designed to 
measure the relationship between symptomatic diabetic neuropathy and quality of life from 
the perspective of the patient. The questionnaire is composed of two parts: questions related to 
symptoms experienced by the patient and questions related to the impact of the patient’s 
neuropathy on activities of daily life.  
4.2.7. 
Use of rescue medication 
Use of rescue medication will be recorded by the patient in the daily diary beginning at the 
start of the pain observation period on Day -14 and ending on Week 12, the last day of the 
treatment period, or upon premature discontinuation as applicable.  
4.2.8. 
Intraepidermal Nerve Fiber Density Determination (IENFD) 
There is a strong correlation between neuropathy severity and a reduction in intraepidermal 
nerve fiber density. Intraepidermal nerve fiber biopsy is an effective tool for defining 
pathological changes to nerve fiber density and may have the potential to assess drug effects 
in a smaller number of patients as compared with subjective, symptom-based pain 
assessments. Examination of IENFD is intended to help understand whether any observed 


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effects on pain and other neuropathic signs and symptoms are mediated by improvement in 
nerve function. It may also help assess whether ricolinostat has structural effects on peripheral 
nerves. 
4.3. 
Efficacy endpoints 
4.3.1. 
Primary endpoint 
The primary efficacy endpoint for this study is change from baseline in mean average pain 
intensity following 12 weeks of treatment as measured by the NRS. 
4.3.2. 
Key secondary endpoints 
• 
Change in mean average pain intensity from baseline to Week 4 as measured by the 
NRS. 
• 
Change in non-pain neuropathic signs after 12 weeks in patients as assessed by 
change in the UENS. 
4.3.3. 
Secondary endpoints 
• 
Change in weekly mean worst pain from baseline to Week 12 and Week 4 as 
measured by the NRS. 
• 
Proportion of patients achieving ≥ 30% and ≥ 50% improvement in mean NRS score 
from baseline to Week 4 and to Week 12.  
• 
Change in mean BPI-SF pain interference score from Pre-Treatment/Day 1 to Week 
12.  
• 
Change in mean BPI-SF pain interference score from Pre-Treatment/Day 1 to Week 4. 
• 
Change from baseline to Week 12 in the NTSS-6. 
• 
Change from baseline to Week 12 in Norfolk diabetic QOL-DN score. 
• 
PGIC at Week 4 and Week 12. 
• 
Rescue medication (acetaminophen) use. 


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4.3.4. 
Exploratory endpoints 
The exploratory endpoints for this study are: 
• 
Change in intraepidermal nerve fiber density (IENFD) from baseline to Week 24 will 
be analyzed in a subgroup of approximately 120 patients at selected sites. Note that 
placebo subjects will have received ricolinostat for 12 weeks, while treated subjects 
will have received ricolinostat for 24 weeks. There are 4 comparisons of interest for 
this analysis:  
• 
Change from baseline in the IENFD in the group of approximately 60 patients 
that received ricolinostat for 24 weeks. 
• 
Change from baseline in the IENFD in the group of approximately 60 patients 
that received ricolinostat for 12 weeks. 
• 
The difference in the change from baseline in the IENFD in the Intent-to-Treat 
population at Week 24. 
• 
Other exploratory endpoints may be identified at the time of analysis of the study 
data. 
4.4. 
Safety assessments 
Safety will be assessed throughout the study by the monitoring for and recording of adverse 
events (AE), clinical laboratory test results (hematology, biochemistry, and urinalysis), vital 
sign measurements (systolic and diastolic blood pressures, pulse, respiratory rate, and 
temperature), ECG, physical examination, and height and weight findings as per the 
procedures detailed in the Schedule of Assessments (Exhibit 3). 
4.4.1. 
Adverse events 
An adverse event (AE) is defined as any unfavorable and/or unintended medical occurrence 
that presents at any time from when the informed consent is signed through the final 
follow-up visit or earlier discontinuation (whichever comes first), regardless of relationship to 
the investigational product.  


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A treatment-emergent adverse event (TEAE) is any event that occurs after the start of study drug 
or was present at baseline and worsened after taking study drug. 
Serious adverse events (SAE) are the subset of adverse events that are deemed by Regenacy or 
the Investigator to have resulted in any of the following: death, placing the patient at 
immediate risk of death, an inpatient hospitalization, a prolongation of existing 
hospitalization, a persistent or significant incapacity or disruption of the ability to conduct 
normal life functions, a congenital anomaly or birth defect, or an event that requires significant 
medical intervention to avoid those outcomes listed above.  
Suspected adverse reactions are the subset of AEs for where this is a reasonable possibility that 
the investigational product caused the adverse event. 
An unexpected AE is any suspected adverse reaction that is not listed in the current 
investigator’s brochure (IB) or for which the severity is more extreme than what is listed in the 
IB; or is inconsistent with the general investigational plan or current application if the IB is not 
available.  
Events of special interest (ESI): The following events are defined to be of special interest: anemia, 
leukopenia, thrombocytopenia, renal impairment, congestive heart failure, and suicidality. 
4.4.2. 
Laboratory safety assessments 
The laboratory tests that will be collected at the timepoints specified are presented in the 
schedule of events (Exhibit 3). Abnormal Screening laboratory values that appear to be 
spurious, or that are the result of a transient event, may be repeated once; in this circumstance 
the repeated value will be utilized as the value of record for analysis purposes.  
4.4.3. 
Vital signs 
Vital signs will be measured as per the schedule of events (Exhibit 3). At indicated timepoints, 
temperature, respiration rate, pulse, and blood pressure will be measured while patient is 
sitting after a minimum 5-minute rest. Standing pulse and blood pressure will be obtained 
following sitting vital signs.  


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Descriptive statistics for vital signs will be presented by treatment group. 
4.4.4. 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed at Screening Evaluation, Pre-Treatment baseline, Week 1, 
Week 12, and Week 24 after the patient has been resting in the supine position. On Day 1 
(Pre-Treatment Baseline), an additional 12-lead ECG will be obtained 1 hour (+/- 10 minutes) 
post-dose.  
Descriptive statistics for ECG results will be presented by treatment group.  
4.4.5. 
Physical examinations 
A standard physical examination will occur in accordance with the schedule of events 
(Exhibit 3). Post-baseline physical examinations will assess changes from the prior visit or new 
concerns.  
Assessment of skin integrity and wound healing, if applicable, will also be performed at the 
times indicated in Exhibit 3. Skin breaches and wounds will be examined, and the following 
parameters recorded: location, size, depth, and evidence of erythema, edema, warmth, odor, 
or drainage. 
4.4.6. 
Height and weight 
Height and weight will be measured at the times indicated in the schedule of events (Exhibit 3) 
and will be used to calculate BMI.  
5. 
Database lock and unblinding  
5.1. 
Blinded data review (BDR) review of selected data prior to database lock 
The clinical database will undergo a “soft lock” when the last patient that is still in the 
randomized control period has completed their Week 12 visit or early study discontinuation. 
During the soft lock, all variables will be locked for changes except for those variables that will 
continue collection during the 12-week open label period (e.g., adverse events, laboratory 
assessments, IENFD, etc.); the data from these variables will be locked for all records collected 


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prior to and through the Week 12 visit. To avoid inadvertent unblinding, any data collected 
after Week 12 during the open label period will remain unlocked, excluded from analysis, and 
blinded with respect to treatment group assignment.  
After the soft lock and prior to accessing the randomized treatment assignments, a review of 
locked blinded data will occur to accomplish the following objectives: 1) assess the impact of 
missing data on study analysis, 2) assess and correct the database for inconsistent data, 3) 
identify the per-protocol population and, 3) finalize the methods needed for analysis of the 
study objectives while still blinded to results. Outputs consisting of tables, listing, and figures 
without treatment groups or with randomly generated treatment group assignments will be 
produced, as needed, to accomplish the blinded data review. 
A second (unblinded) data review may occur after the final patient has completed the Week 28 
visit or early study discontinuation. The data collected after the initial soft lock will be 
analyzed during the second data review. The procedures and objectives for this data review 
are the same as those described above after study completion of the randomized control 
period.  
5.2. 
Database lock 
After completion of all BDR procedures, validation of the project databases and Regenacy’s 
approval of the BDR, the clinical database will be locked. After the database lock and the 
authorization for unblinding, the treatment codes will be merged to the analysis datasets. 
After database lock, final endpoint analysis may commence. Note that there will be two 
separate database locks that follow soft locks and data reviews; one after the randomized 
control period has completed and one after the Week 28 follow-up period has completed.  
5.3. 
Authorization for unblinding 
The fire-walled unblinded analysis team at Medpace will have access to the treatment codes 
for analysis purposes. After database lock, top-line results will be available to Regenacy. 


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6. 
Statistical analyses 
Statistical analyses will be performed using SAS® software version 9.4 or later. 
6.1. 
Statistical methodology 
6.1.1. 
Sample size determination 
The sample size for this study is planned to be approximately 274 evaluable patients. This 
sample size provides 80% power to detect a treatment difference of 0.8 points on the NRS. 
Assuming a pooled standard deviation of 2.35, this corresponds to a standardized effect size of 
approximately 0.34. 
6.1.2. 
Analysis populations 
The following populations are planned: 
• 
Pre-randomized safety population (pSAF): All patients who have at least one 
observation during the pain observation period (day -14 to day -1/pre-treatment) and 
who were not randomized. 
• 
Safety population (SAF): All patients who been randomized and received at least one 
dose of study drug 
• 
Intent to treat (ITT) population: All patients randomized regardless of study drug 
administration 
• 
Full analysis set (FAS) population: All patients who receive at least one dose of study 
drug, have a baseline average NRS score and, have at least one post-baseline average 
NRS score.  
• 
Per-protocol population (PPP): All patients in the FAS population who have no 
major protocol violations, a valid baseline value of the NRS, meet all 
inclusion/exclusion criteria, missing no more than 2 weeks of diary data, and have a 
mean compliance rate of at least 60% (i.e., on average provide ratings on 4 or more 
days of each week). 


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6.1.3. 
General considerations 
When presented, listings will be presented by patient number, treatment group, and 
measurement time.  
In all analyses, the same number of decimal places as in the raw data will be presented for 
point estimates and univariate analysis. One more decimal place than in the raw data will be 
presented when reporting mean and standard deviation. 
Continuous variables will be summarized by treatment group using descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). For categorical variables, 
frequencies and percentages will be presented by treatment. The denominator for all 
categorical variables is the number of randomized patients.  
All statistical testing will be based on a two-sided significance level of 0.05 unless otherwise 
stated.  
Baseline is defined as the last observation prior to initiation of study medication.  
Baseline assessment for the NRS is expected to be the mean of the values collected during the 
5-9 days that 1) follow the training visit follow-up assessment at the end of the first week of 
the pain observation phase and 2) immediately precede randomization (i.e., prior to the initial 
study drug dose administration). Should this value be unavailable (for example, if less than 5 
days were present between the training visit follow-up visit and randomization) or should the 
timing of the evaluation in relation to the first administration of study drug not be 
determinable (e.g., missing time for baseline assessment or missing time value for study drug 
administration) then the mean of the 5 days of the NRS ratings closest to and before 
randomization will be selected as the baseline value. Instead of relying solely on visit labels in 
the clinical database for post-baseline values, results collected at a particular time will be 
attributed to a specific time point by calculating the time relative to randomization.  
For all other assessments, the baseline assessment is the last value for that assessment collected 
prior to randomization and the first administration of study drug.  


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For visits (or events) that occur on or after randomization, study day is defined as: 
  
Study day = date of event – randomization date + 1 
For visits (or events) that occur before randomization, study day is defined as: 
  
Study day = date of event – randomization date  
6.1.4. 
Visit windows 
Analysis visits and their windows are defined using derived study day (Section 6.1.3) instead 
of relying on visit labels in the clinical database because clinical visits may occur outside 
protocol-specified windows. Study day and days after last dose are calculated using the actual 
date of each scheduled and unscheduled assessment and compared to the target for each 
analysis visit as specified in Exhibit 4.  
If a parameter is assessed or measured more than once within a visit window, the one that is 
closest to the protocol-scheduled time point (i.e., target) is used for the purposes of data 
analysis and summary. If two assessments are equidistant from a target, the earlier assessment 
is used. If the visit used for analysis includes two assessments on the same day, the average of 
the two measurements is used.  
Records from visits not closest to the target study day, and therefore not used in analyses, are 
presented in by-subject data listings. 


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Exhibit 4. Example of study days and analysis timepoints 
Analysis visit 
Label 
Study daya 
Analysis window 
0 
 Day 1b 
 
1 
1 
1 
 Week 1 
 
5 
2 ≤ study day ≤ 9 
2 
 Week 2 
 
14 
10 ≤ study day ≤ 18 
4 
 Week 4 
 
28 
24 ≤ study day ≤ 32 
8 
 Week 8c  
56 
52 ≤ study day ≤ 60 
12 
 Week 12d  
84 
14 ≤ days after last dose ≤ 32 
14 
 Week 14  
98 
94 ≤ study day ≤ 102 
18 
 Week 18  
126 
122 ≤ study day ≤ 130 
24 
 Week 24e  
168 
164 ≤ study day ≤ 172 
26 
 Week 26f  
182 
14 ≤ days after last dose ≤ 32 
28 
 Week 28  
196 
192 ≤ study day ≤ 200 
a) Study Day is relative to the date of randomization (Section 6.1.3).  
b) Day 1 is the last measurement prior to the first study drug administration.   
c) Week 8 is the end of the double-blind, placebo-controlled treatment period.  
d) Week 12 is the start of the open-label safety extension period. 
e) Week 24 is the end of the open-label safety extension period. 
f) Week 26 is the start of the follow-up period. 
 
6.1.5. 
Procedures for handling missing data 
6.1.5.1. Missing data on the primary efficacy endpoint 
The primary efficacy endpoint (e.g., NRS) is captured in a daily log. Missing daily NRS entries 
will be handled by performing a simple weekly average of the daily scores so long as four or 
more entries occur during the week. If three or fewer entries occur during the week, then the 
scores’ weekly average will be set to missing for that week. Missing values will be multiple 
imputed using missing at random multiple imputation for intermittent missing values and 
reference-based imputation for all other missing data. These data will be part of the blinded 
data review with the option to change the approach to the summary score during the blinded 
data review process.  
6.1.5.2. Missing UENS 


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The key secondary endpoint will be analyzed using missing at random imputation for 
intermittent missing data and reference-based imputation for all other missing data.  
6.1.5.3. Missing data for secondary endpoint 
Missing values for secondary endpoints will not be imputed. All results will be analyzed 
under the complete case scenario. 
6.1.5.4. Missing or partial stop- or start-dates for adverse events 
Missing or partial stop- or start-dates for adverse events will be imputed using the most 
conservative (e.g., worst case scenario) assumption. In all cases of missing or partial 
information, the site will be instructed to attempt to obtain the missing details. The rules for 
imputation follow: 
• 
If the starting day is missing, then the day will be imputed to the 1st of the month 
unless the starting month is the same as the randomization month. 
• 
If the starting day is missing and the starting month is the same as the randomization 
month, then the starting day will be imputed to the randomization day and the event 
will be assumed to be treatment emergent.  
• 
If the starting month or year is missing, then the starting date will be imputed to the 
randomization date and the event will be assumed to be treatment emergent. 
• 
If the end day is missing, then the end day will be imputed to be the last day of the 
month. 
• 
If the end month is missing and the end year is the same as the study termination 
year, then the event date will be set to missing and the event will be assumed to be 
“on going” at time of study termination.  
• 
If the end month is missing and the end year is before the year of study termination, 
then the end date will be imputed to the last day of the year (31DECXX).  
6.1.5.5.  Missing or partial stop- or start-dates for concomitant medications 
Missing or partial stop- or start-dates for concomitant medications will be imputed using the 
most conservative (e.g., worst case scenario) assumption. Study sites will be instructed to 


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attempt to obtain the missing details in all cases of missing or partial information. The rules for 
imputation follow: 
• 
If the starting day is missing, then the day will be imputed to the 1st of the month 
unless the starting month is the same as the randomization month. 
• 
If the starting day is missing and the starting month is the same as the randomization 
month, then the starting day will be imputed to the randomization day and the 
medication will be assumed to be treatment emergent.  
• 
If the starting month or year is missing, then the starting date will be imputed to the 
randomization date and the medication will be assumed to be treatment emergent. 
• 
If the end day is missing, then the end day will be imputed to be the last day of the 
month. 
• 
If the end month is missing and the end year is the same as the study termination 
year, then the event date will be set to missing and the patient will be assumed to be 
on the medication at time of study termination.  
• 
If the end month is missing and the end year is before the year of study termination, 
then the end date will be imputed to the last day of the year (31DECXX).  
6.2. 
Demographics and baseline characteristics 
The following demographics and baseline characteristics will be presented in summary tables 
by treatment for the ITT and SAF (excluding ITT) populations: demographic characteristics 
(age, sex, race, ethnicity), weight, height, BMI, pulse, medical history, prior medications, 
laboratory examinations, vital signs, and ECG.  
6.3. 
Patient disposition 
Patient disposition will include the number of patients who enroll in the study and the 
number and percentage of patients included in each analysis population. The frequency and 
percentage of patients who withdraw or discontinue from the study, along with the reason for 
withdrawal or discontinuation, will be summarized by treatment.  


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7. 
Primary efficacy analyses 
The efficacy analysis will be conducted within the estimand framework. A summary of the 
attributes of the estimand is provided in Table 1. 
Table 1. Estimand attributes for the primary efficacy analyses 
Estimand attribute 
Description 
Population 
Full analysis set population, which consists of 
all patients who receive at least one dose of 
study drug and have baseline average pain 
intensity score and at least one post-baseline 
average pain intensity score.  
Endpoint 
Change from baseline in weekly mean of daily 
average pain based on the 11-point NRS at 12 
weeks. 
Intercurrent events  
All values collected after treatment 
discontinuation will be included in the analysis. 
All missing values due to treatment or study 
discontinuation will be imputed using 
reference-based imputation with missing values 
imputed based on the placebo data. All other 
intermittent missing values will be imputed 
under the assumption of missing at random 
with each missing value imputed based on the 
treatment group assignment. Any missing 
values related to software issues with the 
electronic diary will be treated as missing at 
random. This hypothetical scenario assumes 
that the treatment had no further benefit in 
patients that discontinued study medication 
while accounting for the disease trajectory and 
trial effect. 
Summary measure 
Difference between ricolinostat arm and placebo 
arm as measured by change from baseline in 
average pain at Week 12.  
 
 
The primary estimand is the difference in the mean change from baseline through Week 12 in 
the average pain score as measured by the NRS. The null and alternative hypotheses to be 
tested for these estimands are H01: ∆ RIC = ∆PBO and HA1: ∆RIC ≠ ∆PBO where ∆RIC denotes the 
average change from baseline in the average NRS score at Week 12 in the ricolinostat arm, and 


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∆PBO for the placebo arm. The hypothesis will be tested using a mixed model repeated 
measures (MMRM) model as described Section 7.2. 
7.1. 
Primary analysis 
The primary analysis will use a mixed model repeated measure (MMRM) approach with all 
missing values imputed using the method of reference-based multiple imputation. Using this 
approach, missing values resulting from treatment and/or study discontinuation are imputed 
using the information in the placebo group. Reference-based imputation assumes that any 
missing data are not missing at random. Intermittent missing values will be imputed assuming 
MAR with imputed values estimated based on the patient’s treatment group assignment. The 
model and details of the imputation approach are discussed further in this section. The 
strategy for the analyses is as follows: 
1. Fit the MMRM using an unstructured covariance matrix. If the model fails to converge, 
additional covariance structures will be tested until a covariance structure is identified. Once 
the covariance structure is identified, the structure will be used for all modeling. (See 
Section 7.2) 
2. Using MAR multiple imputation, intermittent values will be imputed based on the 
treatment group to which the patient is randomized. (See Section 7.3) 
3. Apply reference-based multiple imputation to the data sets obtained from the MAR 
multiple imputation and obtain the results for the primary efficacy analysis. (See Section 7.3) 
4. Conduct the appropriate sensitivity analyses. (See Section 7.4) 
7.2. 
Identification of the primary model 
The primary endpoint is change from baseline in mean average pain intensity over the 
12 weeks of treatment as measured by the weekly average NRS in the FAS population. The 
primary endpoint will be analyzed using a MMRM analysis. The MMRM will be fit with the 
weekly mean change from baseline in the NRS score at Weeks 1, 2, 4, 8 and 12 as the outcome. 
The following covariates will be included in the model: baseline NRS score, visit, treatment 
group, concomitant medication for painful DPN (yes vs. no), treatment group by visit 
interaction term, and baseline NRS score by visit interaction. A restricted maximum likelihood 
will be used as the method of estimation with the degrees of freedom approximated using the 


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Kenward Rogers approach (see Table 4 for an example of the MMRM code to be used for the 
primary model). The model will be fit with an unstructured covariance matrix. If the MMRM 
with an unstructured covariance matrix does not converge, the following covariance structures 
will be substituted in the order listed below. Each subsequent covariance structure will be 
used only if each previous covariance structure fails to converge. The covariance structure for 
the final model will be the first structure in the sequence that produces a stable model that 
converges. 
1. Toeplitz covariance structure (assuming measurements taken closer together in time are 
more highly correlated than those taken farther apart). 
2. First order auto-regressive (AR[1]) covariance structure (assuming measurements taken 
closer together in time are more highly correlated than those taken farther apart, but more 
constrained than the Toeplitz structure). 
3. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time when they were taken). 
Once the primary model is established, this model will be used for all analyses. 
7.3. 
Primary efficacy analysis 
The primary model, as outlined in Section 7.2, will be used for this analysis. The analysis will 
consist of three steps: identify the primary model and covariance structure, impute all 
intermittent missing values under the assumption of MAR, and impute all remaining missing 
values under reference-based imputation. After the imputed datasets are created, Rubin’s rule 
is used to obtain the final estimates and significance levels.  
7.3.1. 
Imputation of intermittent missing values 
The imputation of the intermittent missing values is executed using the code below. Note that 
the code presented here is not final and will be vetted on blinded data prior to use for the final 
analyses. The variables to be included in the analyses are as follows: 
• 
DELT_NRS – change from baseline in NRS. Note that DELT_NRSX denotes the 
change from baseline in NRS at Week X. 
• 
BASE_NRS – baseline value of NRS 


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• 
AVISITN – denotes visit number 
• 
CONMED – a yes/no variable indicating use of concomitant pain medication 
• 
TRT – denotes treatment group 
• 
USUBJID – denotes patient ID 
Table 2. SAS code to create datasets satisfying monotone missing condition 
** Rearrange data for use in PROC MI; 
proc sort data= DATA_IMP(observed data set);  
 
by USUBJID TRT BASE_NRS;  
run; 
 
proc transpose data= DATA_IMP out=DATA_IMP1;  
 
by USUBJID TRT BASE_NRS; 
 
ID AVISITN; 
 
VAR DELT_NRS;  
run; 
 
proc sort data= DATA_IMP1;  
 
by USUBJID;  
run; 
 
proc mi data=DATA_IMP1 nimpute=100 round=0.1 seed= 
out=OUT_IMP_TRT_RIN; 
 
where TRT eq “RIN”; 
 
var  BASE_NRS(baseline) CONMED  
           DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7 DELT_NRS8  
           DELT_NRS9 DELT_NRS10 DELT_NRS11 DELT_NRS12; 
 
mcmc  chain=multiple impute=monotone; 
run; 
 
proc mi data=DATA_IMP1 nimpute=100 round=0.1 seed= 
out=OUT_IMP_TRT_PBO; 
 
where TRT eq “PBO”; 
 
var  BASE_NRS(baseline) CONMED  
           DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7 DELT_NRS8  
           DELT_NRS9 DELT_NRS10 DELT_NRS11 DELT_NRS12; 
 
mcmc  chain=multiple impute=monotone; 
run; 
 
data OUT_IMP_CONT; 
 
set OUT_IMP_TRT_RIN OUT_IMP_TRT_PBO; 
run; 
 
 
 


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7.3.2. 
Reference-based imputation 
The datasets created through the code in Table 2 are then used for the reference-based 
imputation. The code for the reference-based imputation is as follows: 
Table 3. SAS code for reference-based imputation 
proc sort data= OUT_IMP_CONT; 
   by _IMPUTATION_ USUBJID;  
run; 
 
proc mi data=OUT_IMP_CONT nimpute=1 round=0.1 seed= 
out=CONT_BASED_CONTROL; 
 by _IMPUTATION_; 
   
class CONMED; 
 
var  BASE_NRS CONMED 
           DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7   
           DELT_NRS8 DELT_NRS9 DELT NRS10 
 
 
     DELT_NRS11 DELT_NRS12; 
 
 
mnar modelDELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 NRS7  
           DELT_NRS8 DELT_NRS8 DELT_NRS10 
 
 
     DELT_NRS11 DELT_NRS12; 
 / modelobs=(TRT = “PBO”)); 
run; 
 
After the reference-based imputation is completed, the primary results are obtained, by first 
computing the outcome in each of the 100 imputed datasets and then combining the results 
across these datasets. The code for these analyses can be found below. 


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Table 4. SAS code for MMRM analysis as part of the imputation process 
proc mixed data=COMBINE method=reml alpha=0.025 covtest; 
 
by _IMPUTATION_; 
 
class  AVISITN(ref=LAST) TRT USUBJID CONMED; 
 
model DELT_NRS = BASE_NRS CONMED TRT AVISITN TRT*AVISITN 
 
BASE_NRS*AVISITN/ solution ddfm=kr; 
 
repeated VISITNUM / subject=USUBJID type=TBD r; 
 
estimate ‘RIN – PBO AT WK 12’ TRT 1 -1  
 
TRT*AVISITN 0 0 0 0 1 0 0 0 0 -1 
 
 
/ CL;  
 
lsmeans TRT*AVISITN/diff;  
 
ods output estimates=SI_ESTIMATES; 
run; 
 
 
 
The analysis outlined in Table 4 will produce 100 estimates of the difference between the 
ricolinostat and placebo groups in change from baseline in NRS at Week 12. These values are 
contained in SI_ESTIMATES. Note that the “type =” option in the repeated statement will need 
to be modified to include the covariance structure that is selected for the primary model. The 
output from the estimate statement should be compared to that of the lsmeans statement to 
ensure that the correct comparison is selected. Table 5 provides the code for the 
implementation of Rubin’s rules to obtain the combined estimates of treatment effect at the 
two dose levels. 
Table 5. SAS code for Rubin’s rule 
proc mianalyze data=LSM alpha=0.05; 
 by TRT VISITNUM; 
 
modeleffects estimate; 
 
stderr stderr; 
 
ods output ParameterEstimates=Week_12_MMRM_LSM; 
run; 
 
 


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7.4. 
Sensitivity analyses 
The following sensitivity analyses will be performed: 
1. MMRM based on the data as observed, noting that incomplete diary data for a given week is 
defined as missing (see Section 6.1.5.1). A MMRM will be fit to the data using all non-missing 
values. This analysis will use a modification of the code presented in Table 4. 
2. A MMRM model will be fit using missing at random imputation. Using this approach all 
missing values will be imputed based on the treatment group to which the patient was 
randomized. 
3. A tipping point analysis will be conducted to assess the robustness of the result and the 
validity of the missing at random assumption.  
The code for the use of missing at random multiple imputation is provided below. The input 
dataset to execute this code is OUT_IMP_CONT which is obtained from running the code 
provided in Table 2. After running the code in Table 6, the code provided in Table 4 and 
Table 5 is executed with the dataset names changed as needed. 


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Table 6. SAS code for missing at random imputation 
proc sort data= DATA_IMP_CONT;  
 
by USUBJID;  
run; 
 
proc mi data=OUT_IMP_CONT (where= (TRT=”RIC”)) nimpute=1 round=0.1 
 
seed= out=IMPDAT_RIC; 
  by _IMPUTATION_; 
 
class CONMED; 
 
var  BASE_NRS CONMED 
           DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7 DELT_NRS8  
           DELT_NRS9 DELT_NRS10 DELT_NRS11 DELT_NRS12; 
 
monotone reg (DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7 DELT_NRS8  
           DELT_NRS9 DELT_NRS10 DELT_NRS11 
 
 
     DELT_NRS12)/details); 
run; 
 
proc mi data=OUT_IMP_CONT (where= (TRT = “PBO”)) nimpute=1 
round=0.1  seed= out=IMPDAT_PBO; 
  by _IMPUTATION_; 
 
class CONMED; 
 
var  BASE_NRS CONMED 
           DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7  
           DELT_NRS8 DELT_NRS9 DELT_NRS10 
 
 
     DELT_NRS11 DELT_NRS12; 
 
monotone reg (DELT_NRS1 DELT_NRS2 DELT_NRS3 
 
 
     DELT_NRS4 DELT_NRS5 DELT_NRS6 
           DELT_NRS7 DELT_NRS8 DELT_NRS9 DELT_NRS10 
 
 
     DELT_NRS11 DELT_NRS12/details); 
run; 
 
data RANDOM_IMP_MAR; 
 
set IMPDAT_RIC IMPDAT_PBO; 
run; 
 
 
 
A tipping point analysis will be used to assess the validity of the MAR assumption. 
1. The datasets generated from the code in Table 2 will be used for this analysis. 
2. The PROC MI procedure in SAS is applied to each of the 100 datasets subsetted to the 
placebo group and all missing values in the placebo group are imputed. These 100 datasets 
will then be used for the tipping point analysis. These datasets can be obtained from the code 
for the placebo patients in Table 6. 


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3. For the tipping point analysis with a shift parameter, patients in the ricolinostat group with 
a missing value will be multiply imputed separately from the placebo-treatment arm and are 
assigned a shift parameter in the imputation procedure for progressively worse (higher) scores 
to find the point at which statistical significance is lost. Specifically, if the outcome of the 
hypothesis test favors ricolinostat over the placebo group (p-value <0.05), then one point is 
added as a shift parameter in the imputation for the ricolinostat group, while keeping the data 
for the placebo group unchanged. This is implemented using the code in Table 7.  
4. A mixed model repeated measures (MMRM) model is used to analyze each of the 100 
completed data sets. PROC MIANALYZE is used to combine these results to obtain the final 
estimates for the given value of the shift parameter. (See Table 4 and Table 5). 
5. This “NRS shifting”, as outlined in steps 3 and 4, is repeated with one shift point at a time 
until the hypothesis test no longer rejects the null hypothesis in favor of the ricolinostat group 
over the placebo group (i.e., when the p-value becomes greater than 0.05). Additional 
increments may be used to locate the tipping point. If the result is not quite statistically 
significant, progressively higher scores are added to find the point at which statistical 
significance is attained. The code to generate the imputed datasets for this analysis is provided 
in Table 7. 
All results will be summarized in tables and a forest plot.  


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Table 7. SAS code for tipping point analysis 
proc mi data= OUT_IMP_CONT (where=(TRT=“RIC”)) nimpute=1 round= 
 
seed= out=IMPDAT_TRT; 
  by _IMPUTATION_; 
 
var  BASE_NRS CONMED 
           DELT_NRS1 DELT_NRS2 DELT_NRS3 DELT_NRS4 
 
 
     DELT_NRS5 DELT_NRS6 DELT_NRS7 DELT_NRS8  
           DELT_NRS9 DELT_NRS10 DELT_NRS11 DELT_NRS12;  
 
monotone reg (/details); 
 
mnar adjust (DELT_NRS /shift=&S.); 
run; 
 
data COMBINE; 
 
set IMPDAT_TRT IMPDAT_PBO; 
run; 
proc sort data=COMBINE;  
 
by _IMPUTATION_; 
run; 
 
 
 
8. 
Key secondary analyses 
8.1. 
Estimands 
There are two key secondary outcomes: the change from baseline in the NRS at Week 4 and 
the change from baseline in the UENS at Week 12. The estimands for the NRS at Week 4 and 
the UENS at Week 12 are described in Table 8 and Table 9, respectively.  


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Table 8. Estimand attributes for the key secondary outcome of change from baseline in NRS 
at Week 4 
Estimand attribute 
Description 
Population 
Full analysis set population, which consists of 
all patients who receive at least one dose of 
study drug and have baseline average pain 
intensity score and at least one post-baseline 
average pain intensity score.  
Endpoint 
Change from baseline in the weekly mean of 
daily average pain based on the 11-point NRS at 
Week 4. 
Intercurrent events  
All values collected after treatment 
discontinuation will be included in the analysis. 
All missing values due to treatment or study 
discontinuation will be imputed using 
reference-based imputation with missing values 
imputed based on the placebo data. All other 
intermittent missing values will be imputed 
under the assumption of missing at random 
with each missing value imputed based on the 
treatment group assignment. This hypothetical 
scenario assumes that the treatment had no 
further benefit in patients that discontinued 
study medication while accounting for the 
disease trajectory and trial effect. 
Summary measure 
Difference between ricolinostat arm and placebo 
arm as measured by change from baseline in 
average pain at Week 4.  
 
 


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Table 9. Estimand attribute for the key secondary endpoint of UENS at Week 12 
Estimand attribute 
Description 
Population 
Full analysis set population, which consists of 
all patients who receive at least one dose of 
study drug and have baseline average pain 
intensity score and at least one post-baseline 
average pain intensity score.  
Endpoint 
Change from baseline in weekly mean of daily 
average pain based on the UENS at Week 12. 
Intercurrent events  
All values collected after treatment 
discontinuation will be included in the analysis. 
All missing values due to treatment or study 
discontinuation will be imputed using 
reference-based imputation with missing values 
imputed based on the placebo data. All other 
intermittent missing values will be imputed 
under the assumption of missing at random 
with each missing value imputed based on the 
treatment group assignment. This hypothetical 
scenario assumes that the treatment had no 
further benefit in patients that discontinued 
study medication while accounting for the 
disease trajectory and trial effect. 
Summary measure 
Difference between ricolinostat arm and placebo 
arm as measured by change from baseline in 
average pain at Week 12.  
 
 
The analyses will follow those used for the primary efficacy analyses with a MMRM and 
multiple imputation as described in Section 7. 
8.2. 
Adjustment for multiplicity 
If the significance level for the primary endpoint is statistically significant then each of the key 
secondary endpoints will be tested using a fixed sequence method with the following testing 
sequence: 
• 
Change in mean average pain intensity from baseline to Week 4 as measured by the NRS. 
• 
Change in non-pain neuropathic signs after 12 weeks in patients as assessed by change in 
the UENS. 


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Nominal p-values will be reported for all other analyses.  
9. 
Secondary analyses 
The secondary endpoints for this study and a description of the analysis approach for each 
endpoint are provided below: 
• 
Change in weekly mean worst pain from baseline to Week 12 and Week 4 as 
measured by the NRS will be analyzed using MMRM as outlined in Section 7.2. 
• 
Proportion of patients achieving ≥ 30% and ≥ 50% improvement in mean NRS score 
from baseline to Week 4 and to Week 12 – will be summarized descriptively. 
Comparisons between the ricolinostat and placebo groups will be made using a 
Fisher’s exact test. 
• 
Change in mean BPI-SF pain interference score from Pre-Treatment/Day 1 to 
Week 12 will be analyzed using MMRM as outlined in Section 7.2.  
• 
Change in mean BPI-SF pain interference score from Pre-Treatment/Day 1 to Week 4 
will be analyzed using MMRM as outlined in Section 7.2. 
• 
Change from baseline to Week 12 in the NTSS-6 will be analyzed using MMRM as 
outlined in Section 7.2. 
• 
Change from baseline to Week 12 in Norfolk diabetic QOL-DN score will be 
analyzed using MMRM as outlined in Section 7.2. 
• 
PGIC at Week 4 and Week 12 will be analyzed using an ANCOVA model with 
treatment group as a covariate. 
• 
Rescue medication (acetaminophen) use will be analyzed based on mean daily used 
from baseline to Week 12 and mean weekly used from baseline to Week 12. Mean 
weekly use from baseline to Week 12 will be analyzed using the MMRM approach 
outlined for the primary efficacy analysis. 


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10. 
Exploratory analyses 
The exploratory endpoints for this study and a description of the analysis approach for each 
endpoint are provided below. Change in intraepidermal nerve fiber density (IENFD) from 
baseline to Week 12 and Week 24 will be analyzed in a subgroup of approximately 120 
patients at selected sites. There are 4 comparisons of interest for this analysis:  
• 
Change from baseline in the IENFD in the group of approximately 60 patients that 
received ricolinostat for 24 weeks. The change from baseline in IENFD will be assessed at 
24 weeks using a t-test to test the null hypothesis that the change from baseline in IENFD 
is zero.  
• 
Change from baseline in the IENFD in the group of approximately 60 patients that 
received ricolinostat for 12 weeks. The change from baseline in IENFD will be assessed at 
12 weeks using a t-test to test the null hypothesis that the change from baseline in IENFD 
is zero. . 
• 
The difference in the change from baseline in the IENFD in the Intent-to-Treat 
population at Week 24. An ANCOVA model with change from baseline as the outcome 
and baseline value and treatment group will be used to test for a difference in groups. 
• 
Other exploratory endpoints may be identified at the time of analysis of the study data. 
11. 
Safety analyses 
All safety analyses will be performed using the safety population. Safety and tolerability will 
be assessed by clinical review of all safety parameters including AEs, laboratory values, and 
vital signs. The safety analyses will include all results collected from randomization through 
the end of the study. All safety presentations will be presented by treatment group ( 180µg, 
120µg, and placebo). 
11.1. Adverse events 
AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA) version 22.0 
coding system. Frequency tables will be presented by treatment groups summarizing: 
• 
All treatment-emergent AEs 


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• 
All treatment-emergent AEs by severity 
• 
All treatment-emergent AEs ≥ 3 in severity 
• 
All treatment-emergent treatment-related AEs 
• 
All ESIs 
• 
All treatment-emergent meeting the pre-specified criteria for serious AEs (SAEs) 
• 
All AEs leading to discontinuation 
11.2. Clinical laboratory evaluations 
Each laboratory value and change from baseline (when appropriate) will be summarized in 
tables and figures for hematology, blood chemistry and urinalysis for each treatment at 
Screening, discharge, and end of study. Boxplots of laboratory values will be provided. Shift 
tables may also be provided.  
11.3. Physical examination 
A listing of physical examination findings will be provided by patient.  
BMI will be summarized for each treatment group at Screening and is calculated from the 
patient’s height and weight.  
11.4. Vital signs 
Each resting vital sign observed value and change from baseline (when appropriate) will be 
summarized for each treatment group at Screening, pre-dose, 30 minutes, 1 hour, 2 hours, 
4 hours, 6 hours, 8 hours, and 24 hours post–dose administration. Each orthostatic vital sign 
observed value and change from baseline (when appropriate) will be summarized for each 
treatment group at Screening, pre-dose, 2 hours, 4 hours, 8 hours, and 24 hours post–dose 
administration. 
11.5. 12-lead electrocardiogram 
Each 12-lead ECG observed value and change from baseline (when appropriate) will be 
summarized for each treatment group at Screening, pre-dose (not required if Screening ECG is 
conducted on the day of dosing), 2 hours, and 24 hours post–dose administration. In addition, 


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frequency tabulation of the overall ECG results (Normal, abnormal normalized cumulative 
sum [NCS], and abnormal cumulative sum [CS]) will be summarized (to include any emergent 
arrhythmias and determination of resolution). Conduction intervals including PR, QRS, QT 
(>450, >500ms) and QTc (>450, >500 ms) will be summarized and tabulated. Shift tables of 
clinically significant findings will be reported for corresponding QT and QTc interval changes.  
11.6. Concomitant medications 
Concomitant medications will be summarized (n and %) by anatomical therapeutic chemical 
(ATC) class and preferred term (coded by WHO Drug coding dictionary March 2019) for each 
treatment group. This table will also include an overall total column. 
12. 
References 
1. 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). ICH 
Harmonized Tripartite Guideline; 1998. 
 
E:\Proj\Regenacy\2. SAP\REGY-DN-201 SAP v08.docx\LW