A Phase 2 Study to Evaluate the Safety and Efficacy of RTA 901 in Patients With Diabetic Peripheral Neuropathic Pain
Phase: PHASE2
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Reata, a wholly owned subsidiary of Biogen

COVER PAGE 
 
Oﬃcial Title: 
 
 
A Phase 2 Study to Evaluate the Safety and Eﬃcacy of RTA 901 in 
Patients With Diabetic Peripheral Neuropathic Pain 
 
NCT Number: NCT05895552 
Document Date: 09 May 2024 
 

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901-C-2102 
 
A PHASE 2 STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF RTA 901 IN PATIENTS WITH DIABETIC 
PERIPHERAL NEUROPATHIC PAIN  
 
RTA 901 
 
 
VERSION 4.0 – 9 MAY 2024 
 
 
 
 
 
 
The information contained herein is confidential and the proprietary property of  
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information without 
the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 
 
 

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SIGNATURE PAGE 
 
 
Protocol 901-C-2102 was approved by: 
 
 
__________________________________________ 
 
____________________ 
, MD 
Date (DD-MMM-YYYY) 
 
Biogen 

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INVESTIGATOR’S AGREEMENT 
 
I have read the 901-C-2102 protocol and agree to conduct the study as outlined.  I have received 
and read the Investigator’s Brochure for RTA 901.  I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
Date 

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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Medical Monitor 
and Study Medical 
Lead 
 
Medical Director, 
 
Biogen | 225 Binney Street | Cambridge, MA | 02142 
Email:
Tel: 
Cell:
 
Clinical Trial Lead 
 
CYPRESS Clinical Trial Lead 
Biogen | 225 Binney Street | Cambridge, MA | 02142 
Email:
Tel: 
Cell:
 
Serious Adverse 
Event Reporting 
Fax: 
 
Email:

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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Study Drug:  
RTA 901 
Title of Study:  
A Phase 2 Study to Evaluate the Safety and Efficacy of RTA 901 in Patients with Diabetic Peripheral 
Neuropathic Pain 
Study center(s): Approximately 75 study centers in the United States 
Studied period:  
Estimated date first subject first visit: Jun 2023 
Estimated date last subject last visit: Oct 2025 
Phase of development:  
2 
Objectives:  
Primary: 
Efficacy: 
• 
To assess the efficacy of RTA 901 based on change from baseline in the average daily pain 
intensity score using the Numeric Pain Rating Scale (NPRS) after 12 weeks of treatment 
Safety: 
• 
To assess the safety and tolerability of RTA 901 during and following the Treatment Period  
Secondary: 
• 
To assess the efficacy of RTA 901 in achieving at least 30% decrease in the NPRS pain intensity 
score after 12 weeks of treatment  
• 
To assess the efficacy of RTA 901 in achieving at least 50% decrease in the NPRS pain intensity 
score after 12 weeks of treatment  
• 
To assess the percentage of subjects using rescue medication for diabetic peripheral neuropathic 
pain (DPNP) treatment during the Treatment Period, as well as the quantity and timing of such 
medication use during the Treatment Period  
• 
To assess the Daily Sleep Interference Scale (DSIS) score after 12 weeks of treatment  
    
• 
 
 
• 
  
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• 
 
Endpoints: 
Primary, secondary, exploratory, 
 endpoints will be evaluated for each 
dose of RTA 901 compared to placebo. 
Primary:  
Efficacy: 
• 
Change from baseline in the average daily NPRS pain intensity score during Week 12   
Safety:  
• 
Frequency, intensity, and relationship to study drug of adverse events and serious adverse 
events and change from baseline in the following assessments: physical examinations, vital 
sign measurements, electrocardiograms, clinical laboratory measurements, and body weight.  
Secondary:  
• 
Proportion of subjects who achieve at least a 30% decrease from baseline in the Week 12 average 
NPRS pain intensity score  
• 
Proportion of subjects who achieve at least a 50% decrease from baseline in the Week 12 average 
NPRS pain intensity score  
• 
Proportion of subjects using rescue medication for DPNP, as well as the quantity and timing of 
such medication use during the Treatment Period  
• 
Change from baseline in the average DSIS score during Week 12   
  
• 
 
 
• 
  
• 
 
 
 
 
  
• 
 
 
• 
 
 

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Methodology:  
This is a 2-part, randomized, placebo-controlled, double-blind, Phase 2 study to evaluate the safety, 
tolerability, efficacy, 
 of RTA 901 in qualified subjects with DPNP. While on the study, 
subjects will take only 1 prescribed standard-of-care (SOC) pain medication (duloxetine, pregabalin, 
or gabapentin) at a stable dose (Section 7.8.1) and a single rescue medication, as needed,  to treat 
DPNP (Section 7.8.3).   
The duration of each part of the study will be approximately 20 weeks, including a Screening Period 
of up to 2 weeks, a Run-in Period of 2 weeks, a Treatment Period of 12 weeks, and a Follow-up 
Period of 4 weeks. All subjects in Part 1 and Part 2 of the study will follow the same visit and 
assessment schedule. Procedures will be performed according to the Schedule of Assessments. 
Screening Period (Days -28 to -15): Includes 1 clinic visit up to 2 weeks prior to the Run-in Period 
(within 28 [± 2] days prior to Day 1). Daily NPRS and DSIS will be collected using an e-diary from 
Screening to the end-of-study visit. Washout from prohibited medications is allowed if the 
Investigator deems it medically appropriate; the washout period must cover 5 half-lives of the 
prohibited medication and must be completed prior to the end of the Screening Period, or in the case 
of NSAIDs for DPNP, washout must be completed prior to the last 7 days of Screening. 
Run-in Period (Days -14 to -1):  Includes 1 clinic visit which must occur during a 14 (± 2)-day 
period prior to Day 1. Subjects who continue to successfully meet the Run-in eligibility criteria will 
receive single-blind placebo once daily in the morning in addition to their SOC pain medication. All 
study drug should be administered in an early fasted state, defined as having no food within at least 2 
hours prior to study drug administration and for 1 hour following study drug administration. Daily 
NPRS scores will continue to be collected using the e-diary. Pain intensity and rescue medication use 
will also continue to be recorded daily at bedtime in the e-diary. Subjects will also complete the DSIS 
upon waking. 
• 
Subjects in Part 1 who remain eligible after the Run-in period will be randomized 1:1:1 to 
either RTA 901 (10 or 80 mg) or placebo at Day 1 (randomization), 
• 
Subjects in Part 2 who remain eligible after the Run-in period will be randomized 1:1:1 to 
either RTA 901 (Dose 1 or Dose 2) or placebo at Day 1 (randomization).   
Treatment Period (Day 1 to Week 12): Includes 8 clinic visits over 12 weeks. Within each study 
part (ie, Part 1 or Part 2), subjects who successfully meet the randomization eligibility criteria will be 
randomized using randomization and trial supply management and stratified by SOC pain medication 
on Day 1. Post randomization, study drug will be dispensed according to the Schedule of 
Assessments. All study drug should be administered in an early fasted state (as described above). 
Follow-up/end of study (Week 16): Includes 1 clinic visit on Day 113 ± 2, which must occur 
approximately 4 weeks following the end of treatment visit.   

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Study Schema  
Part 1 
 
Part 2 
 
Abbreviations: EOS=end of study; EOT=end of treatment; Wk=Week 
A Dose Selection Committee (DSC) will select the 2 doses of RTA 901 for Part 2 using data from 
Part 1 based on E-R analysis. E-R analysis will be conducted using efficacy data up to Week 
12 of treatment with all subjects in Part 1 to provide a dosing recommendation for Part 2 to 
the DSC. 
Subjects enrolled in Part 1 will not be eligible for enrollment in Part 2.  
 
Number of subjects (planned):  
Approximately 384 subjects are expected to be randomized across Part 1 and Part 2 (approximately 
192 subjects per part, with 64 subjects per treatment arm within each part). 
Diagnosis and main criteria for inclusion:  
Run-in Inclusion Criteria:  
1. Adult male and female subjects ≥ 18 years of age upon study consent;  
2. Diagnosis of type 1 diabetes mellitus or type 2 diabetes mellitus at least 1 year prior to 
Screening;  
3. Clinical diagnosis of DPNP defined as symptomatic distal symmetric polyneuropathy 
(secondary to diabetes) in the lower extremities, which may include symptoms of pain that is 
burning, lancinating, tingling, or shooting (electric shock–like). Pain in the lower extremities 
may occur with paresthesia or dysesthesia (unpleasant sensations of burning). Neuropathic 
pain may be accompanied by an exaggerated response to painful stimuli (hyperalgesia) and 
pain evoked by light touch or contact, eg, with socks, shoes, and bedclothes (allodynia); 
4. Currently taking only 1 allowed prescribed SOC pain medication for managing DPNP at a 
stable dose (not exceeding the maximum dose in the prescribing information) for 
approximately 4 weeks prior to Screening (Section 7.8.1); 

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5. Stable glycemic control as indicated by hemoglobin A1C values over the 3 months prior to 
Screening;  
6. NPRS pain intensity score ≥ 4 on an 11-point scale at Screening;  
7. A score ≥ 2.5 on the Michigan Neuropathy Screening Instrument Part B;  
8. Body mass index < 45 kg/m2; 
9. A history of chronic pain related to DPNP present for at least 6 months prior to Screening; 
10. Estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 at Screening using the Chronic 
Kidney Disease Epidemiology Collaboration equation; 
11. Willing to sign and date an informed consent document indicating that the subject has been 
informed of all pertinent aspects of the study prior to initiation of any study-mandated 
procedures;   
12. A negative COVID-19 test result during Screening. 
Run-in Exclusion Criteria:  
1. Has neuropathy from a cause other than type 1 diabetes mellitus or type 2 diabetes mellitus;  
2. Has a condition other than DPNP that could confound the assessment of pain 
(eg, fibromyalgia or regional pain caused by lumbar or cervical compression);  
3. Hemoglobin A1C > 11% at Screening; 
4. Diabetic foot ulceration or infection within 90 days prior to Screening;  
5. Has had more than 1 episode of ketoacidosis or hyperosmolar state requiring hospitalization 
within 90 days prior to Screening;  
6. Has had more than 3 episodes of hypoglycemia requiring medical assistance within 90 days 
prior to Screening;  
7. Any acute or chronic medical condition, or concurrent therapy (pharmaceutical or otherwise) 
which, in the opinion of the Investigator could potentially adversely impact subject safety, 
response to study drug, or interfere with study assessments;  
8. Clinically significant and severe ophthalmologic disease, including but not limited to 
retinopathy, or visual field impairment which, in the opinion of the Investigator could 
potentially preclude enrollment in the study;   
9. Serum aminotransferase (alanine aminotransferase or aspartate aminotransferase) levels 
> 1.5× the upper limit of normal at Screening; 
10. Has HIV or active hepatitis B or C virus infection; 
11. History of malignancy within 3 years prior to Screening, except for non-melanoma skin 
tumor, cervical carcinomas in situ, or successfully treated malignancies in remission; 
12. Unwilling to practice a protocol-specified acceptable method of birth control (both males who 
have partners of child-bearing potential and females of child-bearing potential) during 
Screening, while taking study drug, and for at least 30 days after the last dose of study drug is 
ingested (Section 6.7); 
13. Females who are pregnant or breastfeeding; 
14. Subject is, in the opinion of the Investigator, unable to comply with the requirements of the 
study protocol or is unsuitable for the study for any reason; 
15. Known hypersensitivity to any component of the study drug; 
16. Systolic blood pressure < 90 mmHg after a period of rest at Screening; 
17. Pneumonia due to COVID-19 within 6 months prior to Screening or a history of COVID-19–
related hospitalization within 6 months prior to Screening; 

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18. Known or suspected active drug or alcohol abuse, per Investigator judgement; 
19. Use of the following medications: 
a. Use of another investigational drug or participation in an investigational study within 
30 days or 5 half-lives of that investigational drug (whichever is longer), prior to 
Screening;  
b. Prior participation in a study with RTA 901;  
c. Neuroleptics, monoamine oxidase inhibitors, N-methyl-D-aspartate receptor ligand for 
pain (ketamine, amantadine, dextromethorphan [except low dose intermittent use for 
cough], memantine, methadone, dextropropoxyphene, and/or ketobemidone), and/or 
alpha-lipoic acid within 7 days prior to Screening;  
d. Tricyclic antidepressants and other tricyclic drugs including cyclobenzaprine and 
promethazine; triptans (prescribed usage outside of DPNP allowed); and/or 5-HT3 
receptor antagonists, within 7 days prior to Screening; 
e. Exposure of drugs or chemicals that may cause neuropathy and interfere with clinical 
evaluation. Agents include but are not limited to pyridoxine, hydralazine, metronidazole, 
phenytoin, dapsone, amiodarone, nitrofurantoin, paclitaxel, vinblastine, vincristine, 
cisplatin, etoposide, didanosine, disulfiram, suramin, zalcitabine, anti-tuberculosis 
medications (eg, isoniazid, rifampin, ethambutol, ethionamide), heavy metals, and 
industrial solvents, within 7 days prior to Screening; 
f. Strong or moderate cytochrome P450 – isotype 3A4 inhibitors or inducers and 
P-glycoprotein inhibitors, within 14 days prior to Screening; 
g. Topical pain medications intended to treat pain associated with DPNP (including but not 
limited to lidocaine 5% patch, over-the-counter capsaicin, amitriptyline, and/or isosorbide 
dinitrate spray) within 7 days prior to Screening;  
h. Prescription patch containing 8% capsaicin use within 6 months prior to Screening; 
i. 
Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days per week 
in the 30 days prior to Screening; or planned treatment with opioid or opioid-based drugs, 
including but not limited to tapentadol and/or tramadol from Screening throughout the 
course of the study;   
j. 
Central nervous system active drugs detected in the urine such as cocaine, amphetamines, 
and cannabinoids (marijuana); 
k. Oral prednisolone or equivalent within 7 days prior to Screening.  
20. Use of the following devices or procedures: 
a. Transcutaneous electrical nerve stimulation unit for the treatment of DPNP within 
30 days prior to Screening; 
b. Implanted neurostimulators; 
c. Nerve decompression surgery or plans for such surgery for treatment of DPNP; 
d. Steroid or local anesthetic nerve blocks within the last 12 months prior to Screening; 
e. Cryotherapy, intrathecal/epidural opioids, or botulinum toxin if administered within the 
last 6 months prior to Screening; 
f. Alternative medicine products or treatments (eg, acupuncture, naturopathy, homeopathy, 
etc.) within 7 days prior to Screening;  
g. Major surgery within 30 days prior to Screening or planned to occur during the course of 
the study. 

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Randomization Inclusion Criteria:  
1. Subject has an average NPRS pain intensity score ≥ 4 on an 11-point NPRS calculated from 
pain assessments during the last 7 days prior to randomization. A minimum of 
5 measurements must be recorded;  
2. Subject must have a ≤ 3-point decline in NPRS pain intensity score during Run-in, which will 
be calculated using the average score during the last 7 days of Screening compared to the 
average score during the last 7 days of Run-In; 
3. If subject is on insulin treatment to maintain glycemic control, the subject must have a 
relatively stable insulin dose with no drastic changes during Screening per the Investigator’s 
judgement; 
4. If subject is taking oral anti-diabetic medication, the subject must have a < 50% change of 
routine oral anti-diabetic agent dose from Screening oral anti-diabetic agent dose to Day 1; 
5. Currently taking only 1 allowed prescribed SOC pain medication for managing DPNP at a 
stable dose (not exceeding the maximum dose in the prescribing information) for 
approximately 8 weeks prior to Day 1 with no anticipated changes to dose(s) during study 
(Section 7.8.1); 
6. Has had a complete diabetic eye exam within the 12 months prior to randomization, as per 
SOC. 
Randomization Exclusion Criteria: 
1. Pneumonia due to COVID-19 or COVID-19–related hospitalization during Screening or 
Run-in; 
2. Use of the following medications during Screening or Run-in: 
a. Neuroleptics, monoamine oxidase inhibitors, N-methyl-D-aspartate receptor ligand for 
pain (ketamine, amantadine, dextromethorphan [except low dose intermittent use for 
cough], memantine, methadone, dextropropoxyphene, and/or ketobemidone), and/or 
alpha-lipoic acid;  
b. Tricyclic antidepressants and other tricyclic drugs including cyclobenzaprine and 
promethazine; triptans (prescribed usage outside of DPNP allowed); and/or 5-HT3 
receptor antagonists; 
c. Exposure of drugs or chemicals that may cause neuropathy and interfere with clinical 
evaluation. Agents include but are not limited to pyridoxine, hydralazine, metronidazole, 
phenytoin, dapsone, amiodarone, nitrofurantoin, paclitaxel, vinblastine, vincristine, 
cisplatin, etoposide, didanosine, disulfiram, suramin, zalcitabine, anti-tuberculosis 
medications (eg, isoniazid, rifampin, ethambutol, ethionamide), heavy metals, and 
industrial solvents; 
d. Strong or moderate cytochrome P450 – isotype 3A4 inhibitors or inducers and 
P-glycoprotein inhibitors; 
e. Topical pain medications intended to treat pain associated with DPNP (including but not 
limited to lidocaine 5% patch, over-the-counter capsaicin, amitriptyline, and/or isosorbide 
dinitrate spray);  
f. Prescription patch containing 8% capsaicin; 
g. Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days per week 
during Screening or Run-in; or planned treatment with opioid or opioid-based drugs, 
including but not limited to tapentadol and/or tramadol throughout the course of the 
study;   
h. Central nervous system active drugs detected in the urine such as cocaine, amphetamines, 
and cannabinoids (marijuana); 
i. 
Oral prednisolone or equivalent. 

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3. Use of the following devices or procedures during Screening: 
a. Transcutaneous electrical nerve stimulation unit for the treatment of DPNP; 
b. Implanted neurostimulators; 
c. Nerve decompression surgery or plans for such surgery for treatment of DPNP; 
d. Steroid or local anesthetic nerve blocks; 
e. Cryotherapy, intrathecal/epidural opioids, or botulinum toxin; 
f. Alternative medicine products or treatments (eg, acupuncture, naturopathy, homeopathy, 
etc.); 
g. Major surgery during Screening or planned to occur during the course of the study. 
Study drug, dosage, and mode of administration:  
Part 1: RTA 901 capsules (10 mg or 80 mg) will be administered orally once daily 
Part 2: RTA 901 capsules (2 doses selected from dose range of 1 to 80 mg) will be administered 
orally once daily 
Duration of treatment:  
14 weeks, when including 2-weeks single-blind Run-In 
Reference therapy, dosage, and mode of administration:  
Matching placebo will be administered orally once daily 
Statistical methods:  
This study will be conducted in 2 parts. A total of approximately 192 subjects (64 subjects per 
treatment arm) are planned for randomization in Part 1, and approximately 192 subjects (64 subjects 
per treatment arm) are planned for randomization in Part 2, for a total of 384 subjects to be 
randomized. This sample size is based on a dose-ranging scheme to evaluate initial safety, efficacy, 
 of RTA 901 in this subject population. The primary comparisons for efficacy are between 
each of the RTA 901 treatment groups and the placebo treatment group. The overall Type I error rate 
will be controlled at the 0.05 significance level using a hierarchical testing strategy that will be 
defined in the Statistical Analysis Plan. Power calculations are based on a 2-sample t-test with no 
adjustments for multiple comparisons. The study assumes a mean difference in NPRS pain intensity 
of 1.2 between each RTA 901 treatment group and placebo and a standard deviation of 2.4.  
If doses selected for Part 2 do not include doses studied in Part 1, then an analysis by dose group for 
Part 1 or Part 2 doses will be performed following completion of each study part. With 64 subjects 
per treatment group, each study part has 80% power to compare treatment groups to placebo.  
If doses selected for Part 2 include any doses studied in Part 1 (ie, 10 or 80 mg), then an analysis by 
dose group will be performed using Part 1 and Part 2 combined, following completion of the study. 
The dose group that is enrolled in both parts will have 128 subjects. With 128 placebo subjects 
compared to 128 subjects in the RTA 901 dose group, there is 98% power to detect the same 
difference (1.2 NPRS points) assuming the same standard deviation (2.4). RTA 901 dose groups that 
are enrolled in only 1 part will have 64 subjects. With 128 placebo subjects compared to 64 subjects 
in each RTA 901 dose group, there is 90% power to detect the same difference (1.2 NPRS points) 
assuming the same standard deviation (2.4).     
The intent-to-treat analysis set is defined as all randomized subjects categorized by their randomized 
treatment group (whether or not they received study drug). The analysis population for the efficacy 
endpoints is the intent-to-treat population. Mixed-model repeated measures analyses will be used to 
analyze the primary efficacy endpoints. A detailed Statistical Analysis Plan will be developed prior to 
database lock.   

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The safety analysis set includes all randomized subjects who receive at least 1 dose of randomized 
study drug. The safety analysis set will be used for evaluation of safety variables. Subjects who 
receive at least 1 dose of RTA 901 will be classified in the RTA 901 group. Subjects who are 
randomized and receive at least 1 dose of placebo and no dose of RTA 901 will be classified in the 
placebo group. Subjects in the Run-in phase who fail to randomize into the Treatment Period will not 
be included in the placebo group. 
Safety and tolerability will be evaluated by adverse events, serious adverse events, clinical laboratory 
test results, vital signs, electrocardiogram findings, physical examinations, and weight. All analyses 
of the safety data will be performed using the safety analysis set. Descriptive statistics will be 
presented by treatment group assignment in the safety analysis set. No formal statistical testing is 
planned for safety analyses. 
An exposure-response (E-R) analysis for efficacy is planned for Part 1 using efficacy data up to Week 
12 including all Part 1 subjects. Results from this E-R analysis will be used to determine the doses of 
RTA 901 to be studied in Part 2. Details of the E-R analysis for efficacy will be described in a 
separate analysis plan and the results will be reported in a separate standalone report, outside the 
clinical study report.  
 
 
 
 
 
 

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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
CONTACTS IN CASE OF EMERGENCY ....................................................................................4 
PROTOCOL SYNOPSIS.................................................................................................................5 
ABBREVIATIONS AND DEFINITIONS OF TERMS ...............................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Clinical Experience .....................................................................................................25 
1.1.1. 
Safety and Tolerability ...............................................................................................26 
 
27 
1.2. 
Study Rationale ...........................................................................................................28 
1.3. 
Rationale for Study Population ...................................................................................29 
1.4. 
Dose Rationale ............................................................................................................29 
1.5. 
Risk/Benefit ................................................................................................................30 
2. 
STUDY OBECTIVES AND ENDPOINTS ...............................................................31 
2.1. 
Study Objectives .........................................................................................................31 
2.1.1. 
Primary Objectives .....................................................................................................31 
2.1.1.1. 
Efficacy .......................................................................................................................31 
2.1.1.2. 
Safety ..........................................................................................................................31 
2.1.2. 
Secondary Objectives .................................................................................................31 
 
31 
 
31 
2.2. 
Study Endpoints ..........................................................................................................32 
2.2.1. 
Primary Endpoints ......................................................................................................32 
2.2.1.1. 
Efficacy .......................................................................................................................32 
2.2.1.2. 
Safety ..........................................................................................................................32 
2.2.2. 
Secondary Endpoints ..................................................................................................32 
 
32 
 
32 
3. 
INVESTIGATIONAL PLAN .....................................................................................33 
3.1. 
Study Design ...............................................................................................................33 
3.2. 
Screening Period (Days -28 to -15) ............................................................................33 

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3.3. 
Run-in Period (Days -14 to -1) ...................................................................................34 
3.4. 
Treatment Period (Day 1 to Week 12) ........................................................................35 
3.5. 
Follow-up/End of Study (Week 16) ...........................................................................35 
3.6. 
Part 2 Dose Selection Process .....................................................................................35 
4. 
STUDY POPULATION .............................................................................................37 
4.1. 
Run-in Eligibility ........................................................................................................37 
4.1.1. 
Run-in Inclusion Criteria ............................................................................................37 
4.1.2. 
Run-in Exclusion Criteria ...........................................................................................37 
4.2. 
Randomization Eligibility ...........................................................................................39 
4.2.1. 
Randomization Inclusion Criteria ...............................................................................39 
4.2.2. 
Randomization Exclusion Criteria ..............................................................................40 
4.3. 
Protocol Waivers ........................................................................................................41 
4.4. 
Retesting and Rescreening ..........................................................................................41 
4.4.1. 
Retesting .....................................................................................................................41 
4.4.2. 
Screen Failures ............................................................................................................41 
4.4.3. 
Rescreening .................................................................................................................41 
4.5. 
Subject Enrollment and Randomization .....................................................................41 
4.5.1. 
Methods for Ensuring Blinding ..................................................................................42 
4.5.2. 
Methods for Unblinding .............................................................................................42 
4.5.2.1. 
Unblinding for Regulatory Submission ......................................................................42 
4.5.2.2. 
Data Monitoring Committee .......................................................................................43 
4.5.2.3. 
Dose Selection Committee .........................................................................................43 
4.6. 
Study Drug Discontinuation, Interruption, and Subject Termination .........................44 
4.6.1. 
Discontinuation of Study Drug ...................................................................................44 
4.6.2. 
Resuming Study Drug after Interruptions ...................................................................44 
4.6.3. 
Subject Discontinuation and Termination ..................................................................44 
4.6.4. 
Termination of the Study ............................................................................................45 
5. 
STUDY ASSESSMENTS ..........................................................................................46 
5.1. 
Administrative Procedures ..........................................................................................46 
5.1.1. 
Informed Consent .......................................................................................................46 
5.1.2. 
Inclusion/Exclusion ....................................................................................................46 
5.1.3. 
Demographics .............................................................................................................46 
5.1.4. 
Medical History ..........................................................................................................46 

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5.1.5. 
Prior and Concomitant Medications ...........................................................................46 
5.1.6. 
Adverse Events ...........................................................................................................47 
5.1.7. 
Electronic Diary Set-up ..............................................................................................47 
5.2. 
Clinical Procedures/Assessments ...............................................................................47 
5.2.1. 
Height Measurement ...................................................................................................47 
5.2.2. 
Weight Measurement ..................................................................................................47 
5.2.3. 
Comprehensive Physical Examination .......................................................................47 
5.2.4. 
Targeted Physical Examination ..................................................................................48 
5.2.5. 
Electrocardiogram .......................................................................................................48 
5.2.6. 
Vital Sign Measurements ............................................................................................48 
5.2.7. 
Michigan Neuropathy Screening Instrument ..............................................................49 
5.3. 
Laboratory Procedures/Assessments ..........................................................................49 
5.3.1. 
Pregnancy Tests for Females of Child-bearing Potential ...........................................49 
5.3.2. 
Follicle-Stimulating Hormone ....................................................................................49 
5.3.3. 
Serology ......................................................................................................................50 
5.3.3.1. 
Hepatitis Screen ..........................................................................................................50 
5.3.3.2. 
HIV Screen .................................................................................................................50 
5.3.4. 
COVID-19 Test ..........................................................................................................50 
5.3.5. 
Drugs of Abuse and Cotinine Screen ..........................................................................50 
5.3.6. 
Clinical Chemistry ......................................................................................................50 
5.3.6.1. 
Estimated Glomerular Filtration Rate Equation .........................................................50 
5.3.7. 
International Normalized Ratio ..................................................................................50 
5.3.8. 
Hematology .................................................................................................................51 
5.3.9. 
Urinalysis and Microscopy .........................................................................................51 
 
51 
5.3.11. 
Hemoglobin A1c .........................................................................................................51 
5.3.12. 
Fasting Lipid Profile ...................................................................................................51 
5.4. 
Patient Reported Outcome Assessments ....................................................................52 
5.4.1. 
Pain Evaluation ...........................................................................................................52 
5.4.1.1. 
Numeric Pain Rating Scale .........................................................................................52 
5.4.1.2. 
Daily Sleep Interference Scale ....................................................................................53 
 
53 
 
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54 
 
54 
 
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54 
 
54 
 
54 
 
 
54 
 
55 
5.5. 
Schedule of Assessments ............................................................................................55 
5.6. 
Unscheduled Visits .....................................................................................................59 
6. 
SAFETY REPORTING, MEDICAL MANAGEMENT, AND OVERSIGHT .........60 
6.1. 
Definition of Adverse Event .......................................................................................60 
6.1.1. 
Definition of Non-treatment-emergent Adverse Event ..............................................60 
6.1.2. 
Definition of Treatment-emergent Adverse Event .....................................................60 
6.2. 
Definitions of Serious Adverse Event ........................................................................60 
6.3. 
Recording of Adverse Events .....................................................................................61 
6.3.1. 
Adverse Events Based on Signs and Symptoms .........................................................62 
6.3.2. 
Adverse Events Based on Tests or Examinations .......................................................62 
6.3.3. 
Follow-up of Unresolved Adverse Events ..................................................................62 
6.3.4. 
Assessment of Causality .............................................................................................62 
6.3.5. 
Assessment of Severity ...............................................................................................63 
6.4. 
Reporting of Serious Adverse Events .........................................................................63 
6.5. 
Overdose .....................................................................................................................64 
6.6. 
Pregnancy ...................................................................................................................64 
6.7. 
Methods of Birth Control............................................................................................65 
6.8. 
Management of Elevated Aminotransferase Levels (ALT and/or AST) ....................66 
6.9. 
Management of Study Drug-Related Toxicities .........................................................66 
7. 
STUDY DRUG ...........................................................................................................67 
7.1. 
Dose and Treatment Regimens ...................................................................................67 
7.2. 
Identity of Study Drug ................................................................................................67 
7.3. 
Study Drug Packaging and Labeling ..........................................................................67 

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7.4. 
Study Drug Storage .....................................................................................................68 
7.5. 
Study Drug Administration .........................................................................................68 
7.6. 
Treatment Compliance ................................................................................................69 
7.7. 
Study Drug Accountability .........................................................................................69 
7.8. 
Concomitant and Other Treatments ............................................................................69 
7.8.1. 
Standard of Care Pain Medications ............................................................................69 
7.8.2. 
Allowed Medications ..................................................................................................70 
7.8.3. 
Rescue Medication ......................................................................................................70 
7.8.4. 
Prohibited Medications ...............................................................................................70 
7.8.5. 
Prohibited Devices/Procedures ...................................................................................71 
7.8.6. 
Recording of Concomitant Treatment ........................................................................71 
8. 
STATISTICS ..............................................................................................................73 
8.1. 
Sample Size Estimate .................................................................................................73 
8.2. 
Definitions of Analysis Sets .......................................................................................73 
8.2.1. 
Intent-to-Treat Analysis Set ........................................................................................73 
8.2.2. 
Safety Analysis Set .....................................................................................................73 
 
74 
8.3. 
Endpoints and Objectives ...........................................................................................74 
8.4. 
Methods for Statistical Analyses ................................................................................74 
8.4.1. 
Hypotheses ..................................................................................................................74 
8.4.2. 
Closed Testing Procedure ...........................................................................................74 
8.4.3. 
Analysis of the Primary Variable(s) ...........................................................................74 
8.4.4. 
Analysis of the Secondary Variables ..........................................................................74 
8.4.5. 
Subgroup Analysis ......................................................................................................75 
8.4.6. 
Interim Analysis ..........................................................................................................75 
8.4.7. 
Sensitivity Analysis ....................................................................................................75 
8.4.8. 
Analysis of Safety Variables ......................................................................................75 
8.4.9. 
Exploratory Analysis ..................................................................................................75 
 
75 
9. 
STUDY AND DATA MANAGEMENT ...................................................................76 
9.1. 
Training of Study Site Personnel ................................................................................76 
9.2. 
Monitoring of the Study ..............................................................................................76 
9.2.1. 
Risk-Based Quality Management ...............................................................................76 

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9.2.2. 
Source Data .................................................................................................................77 
9.2.3. 
Study Agreements .......................................................................................................77 
9.2.4. 
Archiving of Study Documents ..................................................................................78 
9.3. 
Study Timetable and End of Study .............................................................................78 
9.4. 
Data Management .......................................................................................................78 
9.4.1. 
Data Handling .............................................................................................................78 
9.4.2. 
Computer Systems ......................................................................................................78 
9.4.3. 
Data Entry ...................................................................................................................78 
9.4.4. 
Medical Information Coding ......................................................................................79 
9.4.5. 
Data Validation ...........................................................................................................79 
9.5. 
Clinical Study Insurance .............................................................................................79 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ..............................................80 
10.1. 
Ethical Conduct of the Study ......................................................................................80 
10.2. 
Subject Data Protection ..............................................................................................80 
10.3. 
Ethics and Regulatory Review ....................................................................................80 
10.4. 
Informed Consent .......................................................................................................80 
10.5. 
Changes to the Protocol and Informed Consent Form ................................................81 
10.6. 
Audits and Inspections ................................................................................................81 
11. 
LIST OF REFERENCES ............................................................................................82 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 3: 
Treatment Arms by Study Part ...................................................................................42 
Table 4: 
Schedule of Assessments (Part 1 & 2) ........................................................................56 
Table 5: 
Serious Adverse Event Reporting Contact Information .............................................63 
Table 6: 
Management of Elevated Aminotransferase Levels (ALT and/or AST) ....................66 
Table 7: 
Part 1 RTA 901 Drug Product Information ................................................................67 
Table 8: 
Placebo Information ....................................................................................................67 
Table 9: 
Study Drug Kit Configurations – Part 1 .....................................................................68 

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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................33 
Figure 2: 
Numeric Pain Rating Scale .........................................................................................53 
Figure 3: 
Daily Sleep Interference Scale ....................................................................................53 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
CI 
confidence interval 
 
 
 
 
 
 
 
CRA 
clinical research associate 
CS 
clinically significant 
CSR 
clinical study report 
CYP3A4 
cytochrome P450 – isotype 3A4 
DMC 
Data Monitoring Committee 
DPN 
diabetic peripheral neuropathy 
DPNP 
diabetic peripheral neuropathic pain 
 
 
DSC 
Dose Selection Committee 
DSIS 
Daily Sleep Interference Scale 
DSPN 
distal symmetric polyneuropathy  

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Abbreviation or Specialist Term 
Explanation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of treatment 
 
 
E-R 
exposure-response 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GLP 
good laboratory practice  
HbA1c 
Hemoglobin A1C 
Hsp70 
heat shock protein 70 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
LSM 
least squares mean 
MAD 
multiple ascending dose 
MMRM 
mixed model repeated measures 
MNSI 
Michigan Neuropathy Screening Instrument 
NCS 
not clinically significant 
 
 
NPRS 
Numeric Pain Rating Scale  
 
 
NSAID 
nonsteroidal anti-inflammatory drug 
P-gp 
P-glycoprotein 
 
 
  
 
 
 
 
 
PRO 
patient-reported outcome 

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Abbreviation or Specialist Term 
Explanation 
QD 
once daily 
RTSM 
randomization and trial supply management 
SAD 
single ascending dose  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
 
 
SOC 
standard-of-care 
 
 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
TENS 
transcutaneous electrical nerve stimulation 
 
 

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1. 
INTRODUCTION 
RTA 901, an orally bioavailable novobiocin derivative, is a potent C-terminal inhibitor of heat 
shock protein 90 (Hsp90) and is also an inducer of heat shock protein 70 (Hsp70) and the 
cytoprotective heat shock response. Activities of Hsp70 include, but are not limited to, support of 
the bioenergetic functions of mitochondria and direct involvement in the downregulation of 
inflammatory pathways controlled by nuclear factor-kappa B (NF-κB) signaling. Because of the 
sensitivity of the central and peripheral nervous system to inflammation and mitochondrial 
dysfunction, Hsp70 plays a critical role in models of neuronal injury (Ma, 2015; Ran, 2004; 
Lee, 2001; Park, 2012). RTA 901 has demonstrated marked activity in several animal models 
involving insensate and painful diabetic neuropathy, a model of L5+L6 (lumbar) spinal nerve 
ligation-induced painful neuropathy, a model involving motor dysfunction associated with 
neuronal inflammation and demyelination (ie, the experimental autoimmune encephalomyelitis 
[EAE] model of multiple sclerosis), as well as a model of c-jun driven demyelinating neuropathy 
(ie, a model of Charcot–Marie–Tooth disease and chronic inflammatory demyelinating 
polyneuropathy) (Zhang, 2018). The neuroprotective activities of RTA 901 have been shown to 
be dependent on Hsp70, as RTA 901 does not produce any effects in studies conducted in 
Hsp70-knockout mice (Ma, 2015; Zhang, 2018). 
Given the preclinical data, Reata Pharmaceuticals, Inc. (hereinafter referred to as Reata or the 
Sponsor) is interested in pursuing further clinical development of RTA 901. 
1.1. 
Clinical Experience 
The safety, tolerability, 
 of oral RTA 901 have been evaluated in a 
first-in-human Phase 1 clinical study in healthy volunteers (Study 901-C-1503). This study was a 
randomized, single-center study that was conducted in 2 parts. Forty-eight subjects (n=36 
RTA 901 versus n=12 Placebo) participated in Part 1, which consisted of a double-blind 
assessment of the safety, tolerability,
of single ascending dose (SAD) RTA 901 
administered orally. Thirty subjects (n=24 RTA 901 versus n=6 Placebo) participated in Part 2, 
which consisted of a double-blind assessment of the safety, tolerability, 
 of multiple 
ascending dose (MAD) RTA 901 administered orally once daily for 14 days. Therefore, a total of 
60 healthy volunteers have received oral RTA 901 over a dose range of 10 to 160 mg. 
 
 
This study found that administration of single and multiple 
ascending doses of RTA 901 was generally safe and well tolerated. 
The safety, tolerability, 
 of oral RTA 901 were also evaluated in 2 additional recently 
completed Phase 1 clinical studies: 
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1.1.1. 
Safety and Tolerability 
Overall, RTA 901 oral capsules were well tolerated in healthy volunteers who took a single dose 
(10 to 160 mg) and multiple doses (10 to 80 mg) in a 14-day Phase 1 study (Study 901-C-1503). 
No serious adverse events (SAEs) or treatment-emergent adverse events (TEAEs) reportedly 
lead to study drug discontinuation, or were considered related to RTA 901. Of the unrelated 
TEAEs, most were Grade 1 in severity. No deaths were reported during the study. 
During Part 1 (SAD) of Study 901-C-1503, the most common TEAE was contact dermatitis, 
which occurred in 2 subjects in the RTA 901 capsule cohorts (1 [16.7%] subject in the 120-mg 
cohort and 1 [16.7%] subject in the 160-mg cohort) and 1 (8.3%) subject in the pooled placebo 
cohort. Of note, the Investigator attributed the contact dermatitis TEAEs in the subjects who 
received RTA 901 to the electrocardiogram (ECG) electrode pads. No other specific TEAEs 
occurred in more than 1 subject. All TEAEs in Part 1 (SAD) were Grade 1 in severity. 
One subject who received placebo with the RTA 901 120-mg cohort during Part 1 (SAD) of the 
study had a Grade 1 TEAE of ECG QT prolonged. The event resolved on Study Day 1 and the 
subject continued in the study. To determine if the occurrence of this TEAE would impact the 
safety and dosing of future cohorts, the subject’s treatment assignment was unblinded during the 
study and identified as placebo. The Investigator did not change the original causality assessment 
of the TEAE following unblinding of the subject. There were no other clinically relevant ECG 
findings during Part 1 (SAD) of the study. 
The TEAEs reported during Part 2 (MAD) of the study were Grade 4 blood creatine 
phosphokinase increased (RTA 901 10-mg cohort), Grade 1 myalgia (RTA 901 10-mg cohort), 
and Grade 1 contact dermatitis (RTA 901 40-mg cohort); however, no specific TEAEs occurred 
in more than 1 subject. 
One subject in the RTA 901 10-mg cohort in Part 2 (MAD) of the study had a Grade 4 TEAE of 
blood creatine phosphokinase increased that began on Study Day 24 (10 days after completion of 
the 14-day dosing regimen). The event was assessed as unrelated to study drug by the 
Investigator. The subject completed the study following resolution of the TEAE at an 
Unscheduled Visit on Study Day 37. As a result of this TEAE, clinically relevant increases in 
mean creatine kinase at Study Day 24 and a mean change in creatine kinase from baseline to 
Study Day 24 were noted in the RTA 901 10-mg cohort in Part 2 (MAD) of the study. There 

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were no other clinically relevant mean or individual changes in laboratory parameters during 
Part 2 (MAD) of the study. 
More detailed information about the known and expected benefits and risks of RTA 901 capsules 
may be found in the Investigator’s Brochure (IB). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
   
• 
 
   
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• 
 
 
• 
 
• 
 
 
  
 
 
 
 
 
 
 
  
1.2. 
Study Rationale 
Diabetic neuropathy is the most common neurologic complication of diabetes mellitus and often 
used as a synonym of distal symmetric polyneuropathy (DSPN). Duration of diabetes mellitus 
and how well it is managed are important risk factors for the development of diabetic peripheral 
neuropathy (DPN) in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus 
(T2DM). It gradually affects the longest nerve fibers, with symptoms beginning distally and 
symmetrically in toes and feet. It may be present in at least 10% to 15% of patients newly 
diagnosed with T2DM with rates increasing to 50% after 10 years of disease duration 
(Pop-Busui, 2017). Treatment of diabetic peripheral neuropathic pain (DPNP) involves effective 
glycemic control, education and counseling on foot care and safety measures, and symptomatic 
treatment of pain. The pathogenesis of DPNP involves multiple differentially regulated pathways 
ultimately converging to mitochondrial dysfunction with bioenergetic failure and oxidative 
damage of axons, especially at the most distal portion.  
Although there are several approved therapies for this condition, they are limited by efficacy and 
tolerability. Many treatments are discontinued, suggesting low levels of satisfaction and/or poor 
tolerability (Yang, 2015). Given this, and the large and growing population of patients with 
diabetes, a significant unmet medical need remains. Nonclinical data suggest that RTA 901 is 
able to improve dysfunction resulting from pathogenic demyelination of sensory fibers, along 
with mitigation of mitochondrial dysfunction. In addition, the potent pharmacological effects of 
RTA 901 shown in animal models support the hypothesis that RTA 901 may have potential 
therapeutic benefit to treat the central pathology underlying the development of DPNP. 
Therefore, the current study is designed to investigate the efficacy and safety of multiple doses of 
RTA 901 in subjects with DPNP, when RTA 901 is added to the standard-of-care (SOC) pain 
medication. RTA 901 doses of 10 mg and 80 mg once daily (QD) will be investigated in Part 1 
of this study. Based on an exposure-response (E-R) analysis for efficacy in Part 1, 2 doses of 

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RTA 901 between 1 to 80 mg QD will be investigated in Part 2 of the study. This will allow the 
Sponsor to determine the optimal dose(s) for future development.  
1.3. 
Rationale for Study Population 
Diabetic peripheral neuropathic pain is a common condition seen in both T1DM and T2DM. 
Neuropathic pain can lead to interference with daily activities, disability, psychosocial 
impairment, 
 
. It may be associated with hyperalgesia and allodynia. Although there 
are approved therapies for this condition, they are limited by efficacy and tolerability. Many 
treatments are discontinued, suggesting low levels of satisfaction and/or poor tolerability 
(Yang, 2015). Given this, and the large and growing population of subjects with diabetes, a 
significant unmet medical need remains. 
According to the Centers for Disease Control National Diabetes Statistics Report (2022), 
37.3 million Americans have diabetes. The most common neuropathy associated with diabetes is 
DSPN (Pop-Busui, 2017). Although estimates of its incidence and prevalence vary, data suggests 
that DSPN occurs in at least 20% of subjects with T1DM after 20 years of disease. It may be 
present in at least 10% to 15% of subjects newly diagnosed with T2DM with rates increasing to 
50% after 10 years of disease duration. Neuropathic pain, specifically DPNP, is present in up to 
25% of subjects with DSPN. 
The development of DPNP is associated with a small-fiber neuropathy resulting from 
dysfunction of unmyelinated or thinly myelinated sensory fibers and the gradual degeneration of 
larger myelinated fibers. Further, although numerous pathologic mechanisms contribute to DPNP 
(Farmer, 2012), increased oxidative stress and mitochondrial dysfunction appear to be a central 
facilitator in its development (Fernyhough, 2010). Nonclinical data suggest that RTA 901 is able 
to improve dysfunction resulting from pathogenic demyelination of sensory fibers, along with 
mitigation of mitochondrial dysfunction. Taken together, the potent pharmacological effects of 
RTA 901 shown in animal models support the hypothesis that RTA 901 may have potential 
therapeutic benefit to treat the central pathology underlying the development of DPNP. 
1.4. 
Dose Rationale 
Dose selection for Part 1 was based on the established safety profile from the first-in-human 
study in healthy subjects (Study 901-C-1503), 
 
, no observed adverse effect levels established in 3-month good laboratory 
practice (GLP) toxicity studies in mice and monkeys, and exposures required to produce efficacy 
in rodent models of DPN.    
RTA 901 was generally safe and well tolerated following single doses of up to 160 mg and 
multiple daily doses (for 14 days) of up to 80 mg (Study 901-C-1503) 
 
 
Additionally, at the highest proposed dose of 
80 mg QD, there is at least a 40-fold safety margin based on the data from the 3-month GLP 
toxicity studies in mice and monkeys (Table 8 of the IB). 
 
 

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In summary, at the proposed doses for Part 1, RTA 901 is predicted to have efficacious and safe 
exposure in subjects with DPNP, with a 10 mg dose anticipated to be an efficacious dose and 
80 mg the highest feasible dose with potentially maximal efficacy and an acceptable safety 
profile. However, based on the exposures associated with efficacy in the nonclinical models, it is 
possible that a dose lower than 10 mg may need to be explored to identify the minimally 
effective dose in subjects with DPNP and thereby enable a robust phase 2 dose ranging study. 
Therefore, a planned E-R analysis for efficacy from the all subjects in Part 1 of this study will be 
incorporated to recommend the optimal doses for investigation in Part 2. Eligible doses for 
selection in Part 2 will be limited to a dose range of 1 to 80 mg. Part 2 doses will not exceed 80 
mg, at which there is at least a 40-fold safety margin based on the data from the 3-month GLP 
toxicity studies in mice and monkeys. 
1.5. 
Risk/Benefit 
There may be side effects and discomforts that are not yet known nor seen in previous studies. 
There may be risks or side effects that are related to the study drug and that are unknown at this 
time.  
The potent pharmacological effects of RTA 901 seen in preclinical data demonstrate marked 
therapeutic activity in rodent models of insensate and painful diabetic neuropathy and support 
the hypothesis that RTA 901 may have potential therapeutic benefit to treat the central pathology 
underlying the development of DPNP.  
Therefore, the risk-benefit profile for participating in the current study appears to be favorable. 

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2. 
STUDY OBECTIVES AND ENDPOINTS 
2.1. 
Study Objectives  
2.1.1. 
Primary Objectives 
2.1.1.1. 
Efficacy  
• To assess the efficacy of RTA 901 based on change from baseline in the average daily 
pain intensity score using the Numeric Pain Rating Scale (NPRS) after 12 weeks of 
treatment 
2.1.1.2. 
Safety  
• To assess the safety and tolerability of RTA 901 during and following the Treatment 
Period  
2.1.2. 
Secondary Objectives 
• To assess the efficacy of RTA 901 in achieving at least 30% decrease in the NPRS pain 
intensity score after 12 weeks of treatment  
• To assess the efficacy of RTA 901 in achieving at least 50% decrease in the NPRS pain 
intensity score after 12 weeks of treatment  
• To assess the percentage of subjects using rescue medication for DPNP treatment 
during the Treatment Period, as well as the quantity and timing of such medication use 
during the Treatment Period  
• To assess the Daily Sleep Interference Scale (DSIS) score after 12 weeks of treatment  
 
 
• 
 
 
• 
  
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2.2. 
Study Endpoints 
The primary, secondary, exploratory, 
 endpoints will be evaluated for each dose of 
RTA 901 compared to placebo. 
2.2.1. 
Primary Endpoints 
2.2.1.1. 
Efficacy  
• Change from baseline in the average daily NPRS pain intensity score during Week 12 
2.2.1.2. 
Safety  
• Frequency, intensity, and relationship to study drug of adverse events (AEs) and SAEs 
and change from baseline in the following assessments: physical examinations, vital 
sign measurements, ECGs, clinical laboratory measurements, and body weight 
2.2.2. 
Secondary Endpoints 
• Proportion of subjects who achieve at least a 30% decrease from baseline in the 
Week 12 average NPRS pain intensity score  
• Proportion of subjects who achieve at least a 50% decrease from baseline in the 
Week 12 average NPRS pain intensity score  
• Proportion of subjects using rescue medication for DPNP, as well as the quantity and 
timing of such medication use during the Treatment Period  
• Change from baseline in the average DSIS score during Week 12   
 
 
• 
  
• 
  
• 
  
 
 
• 
 
  
• 
 
 
  
 
 

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3. 
INVESTIGATIONAL PLAN  
Study procedures will follow the Schedule of Assessments (Table 4). 
3.1. 
Study Design 
This is a 2-part, randomized, placebo-controlled, double-blind, Phase 2 study to evaluate the 
safety, tolerability, efficacy,
of RTA 901 in qualified subjects with DPNP. 
Approximately 192 eligible subjects (64 subjects per treatment arm) will be enrolled in Part 1, 
and approximately 192 eligible subjects (64 subjects per treatment arm) will be enrolled in 
Part 2, for a total of 384 subjects randomized. Randomization within each part will be stratified 
by SOC pain medication using randomization and trial supply management (RTSM). A total of 
approximately 75 sites in the United States will be included in this study. 
The duration of each part of the study will be approximately 20 weeks, including a Screening 
Period of up to 2 weeks, a Run-in Period of 2 weeks, a Treatment Period of 12 weeks, and a 
Follow-up Period of 4 weeks. All subjects in Part 1 and Part 2 of the study will follow the same 
visit and assessment schedule.   
Figure 1: 
Study Design 
Part 1 
 
Part 2 
 
Abbreviations: EOS=end of study; EOT=end of treatment; Wk=Week 
3.2. 
Screening Period (Days -28 to -15)  
The Screening Period includes 1 clinic visit, up to 2 weeks prior to the Run-in Period (within 
28 days prior to Day 1, approximately, as the visit has a ± 2-day window). Upon Institutional 
Review Board (IRB) approval of the protocol, potential subjects will be required to sign a written 
informed consent form (ICF) for the study before any study-specific screening procedures are 
performed. See Section 10.4 for details on informed consent. Subjects who meet the Run-in 

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inclusion criteria (Section 4.1) and none of the exclusion criteria are considered eligible to 
proceed to Run-in. Washout from prohibited medications is allowed during the Screening Period 
if the Investigator deems it medically appropriate; the washout period must cover 5 half-lives of 
the prohibited medication and must be completed prior to the end of the Screening Period, Or, in 
the case of NSAIDs for DPNP, the washout must be completed prior to the last 7 days of 
screening. 
Subjects will be given access to an e-diary at Screening and will be trained on how to use it. 
Subjects will be directed to complete the NPRS and record their rescue medication usage in the 
e-diary at bedtime. Subjects will also complete the DSIS via their study-issued e-diary daily 
upon waking. Subjects who have been diagnosed with T1DM or T2DM at least 1 year prior to 
Screening, with hemoglobin A1c (HbA1c) ≤ 11% and who have been suffering from painful 
diabetic peripheral neuropathy in the lower extremities for at least 6 months, will be screened for 
diabetic polyneuropathy using the Michigan Neuropathy Screening Instrument (MNSI) Part B, 
and will be included if a score ≥ 2.5 is obtained. Subjects must have a score ≥ 4 on the 11-point 
NPRS for average pain intensity over the past 24 hours at Visit 1, denoting moderate to severe 
pain.  
Additional procedures 
 assessments are to be completed 
according to the Schedule of Assessments (Table 4).    
The rescreening process is described in Section 4.4.3.  
3.3. 
Run-in Period (Days -14 to -1)  
The Run-in Period includes 1 clinic visit, which must occur during a 14 (± 2)-day period prior to 
Day 1. Subjects who continue to successfully meet the Run-in eligibility criteria will be enrolled 
and receive single-blind placebo once daily in the morning. All study drug should be 
administered in an early fasted state, defined as having no food within at least 2 hours prior to 
study drug administration and 1 hour following study drug administration. Since the first dose 
will be taken in-clinic at the Run-in visit, subjects should fast for 2 hours prior to the visit. 
During the Run-in Period, NPRS and rescue medication use will continue to be recorded daily at 
bedtime in the e-diary. Subjects will also complete the DSIS upon waking. The baseline score 
will be calculated as the mean of the pain scores recorded daily by the subject within the last 7 
days prior to randomization (the average value is to be rounded to 1 decimal point). Fluctuations 
in the pain score are allowed. A minimum of 5 measurements must be recorded. Additional 
procedures 
 are to be completed according to the Schedule of Assessments (Table 4). 
The subjects should be reminded not to take the single-blinded study drug on the morning 
of the treatment Day 1 visit.  
If changes in the subject’s health occur during the Screening and Run-in Periods before 
randomization, including changes in medication affecting the status of the subject, the Medical 
Monitor should be notified. The Medical Monitor will advise the Investigator regarding any 
assessments that should be repeated to ensure eligibility requirements are met. 

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3.4. 
Treatment Period (Day 1 to Week 12) 
The Treatment Period includes 8 clinic visits over 12 weeks. Within each part of the study, 
subjects who successfully meet the Randomization eligibility criteria will be randomized using 
RTSM and stratified by SOC pain medication on Day 1, see Section 4.5. Post randomization, 
study drug will be dispensed, according to the Schedule of Assessments (Table 4). Once daily, 
subjects will self-administer 1 capsule from each bottle included in their study drug kits orally, 
according to Section 7.5. All study drug should be administered in an early fasted state, defined 
as having no food within at least 2 hours prior to study drug administration and 1 hour following 
study drug administration. 
 
 Subjects should also fast for at least 8 hours prior to clinic visits where 
fasting lipids are taken (Screening, Week 4, Week 8, Week 12, and Week 16). Additional study 
procedures and assessments will be performed according to the Schedule of Assessments (Table 
4). 
Subjects will be instructed to use rescue medication as needed for DPNP per Section 7.8.3. 
Subjects will be directed to continue completing the NPRS and recording their rescue medication 
usage in the e-diary at bedtime. Upon waking, subjects will be asked to complete the DSIS. 
Additional procedures 
 are to be completed according to the Schedule of Assessments 
(Table 4). 
Week 12/Day 85 will be the end of treatment (EOT) visit.  
3.5. 
Follow-up/End of Study (Week 16) 
The Follow-up Period includes 1 clinic visit on Day 113 ± 2, which must occur approximately 
4 weeks following the EOT visit. Procedures will be performed according to the Schedule of 
Assessments (Table 4). Completion of this visit concludes the subject’s participation in the 
study. 
Subjects will be directed to continue completing the NPRS and recording their rescue medication 
usage in the e-diary at bedtime. Upon waking, subjects will be asked to complete the DSIS. 
Additional procedures 
 are to be completed according to the Schedule of Assessments 
(Table 4). 
3.6. 
Part 2 Dose Selection Process  
A Dose Selection Committee (DSC) comprised of Sponsor personnel and an external 
pharmacometrics consultant will select the 2 doses of RTA 901 for Part 2 using data from Part 1. 
An E-R analysis for efficacy will be conducted with efficacy data from all subjects up to Week 
12 of treatment in Part 1 and provide a dosing recommendation for Part 2 to the DSC. The 
selected doses will be documented in a Note-to-File to the Investigators and IRBs (as 
appropriate) and will not require a protocol amendment.   
It is possible that enrollment in Part 2 of the study may begin while some Part 1 subjects are 
completing their remaining study visits. Subjects enrolled in Part 1 will not be eligible for 
enrollment in Part 2.  

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Details of the membership, objectives, and process to be followed by the DSC will be described 
in a separate charter. Additionally, a separate data management and analysis plan supporting this 
activity will be created. Results will be reported in a separate standalone report, outside the 
clinical study report (CSR). 

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4. 
STUDY POPULATION 
4.1. 
Run-in Eligibility 
4.1.1. 
Run-in Inclusion Criteria  
1. Adult male and female subjects ≥ 18 years of age upon study consent;  
2. Diagnosis of T1DM or T2DM at least 1 year prior to Screening;  
3. Clinical diagnosis of DPNP defined as symptomatic distal symmetric polyneuropathy 
(secondary to diabetes) in the lower extremities, which may include symptoms of pain 
that is burning, lancinating, tingling, or shooting (electric shock–like). Pain in the lower 
extremities may occur with paresthesia or dysesthesia (unpleasant sensations of burning). 
Neuropathic pain may be accompanied by an exaggerated response to painful stimuli 
(hyperalgesia) and pain evoked by light touch or contact, eg, with socks, shoes, and 
bedclothes (allodynia); 
4. Currently taking only 1 allowed prescribed SOC pain medication for managing DPNP at 
a stable dose (not exceeding the maximum dose in the prescribing information) for 
approximately 4 weeks prior to Screening (Section 7.8.1);  
5. Stable glycemic control as indicated by HbA1c values over the 3 months prior to 
Screening;  
6. NPRS pain intensity score ≥ 4 on an 11-point scale at Screening;  
7. A score ≥ 2.5 on the MNSI Part B;  
8. Body mass index < 45 kg/m2; 
9. A history of chronic pain related to DPNP present for at least 6 months prior to 
Screening; 
10. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 at Screening using the 
Chronic Kidney Disease Epidemiology Collaboration equation; 
11. Willing to sign and date an informed consent document indicating that the subject has 
been informed of all pertinent aspects of the study prior to initiation of any 
study-mandated procedures;   
12. A negative COVID-19 test result during Screening. 
4.1.2. 
Run-in Exclusion Criteria 
1. Has neuropathy from a cause other than T1DM or T2DM;  
2. Has a condition other than DPNP that could confound the assessment of pain (eg, 
fibromyalgia or regional pain caused by lumbar or cervical compression);  
3. HbA1c > 11% at Screening; 
4. Diabetic foot ulceration or infection within 90 days prior to Screening;  
5. Has had more than 1 episode of ketoacidosis or hyperosmolar state requiring 
hospitalization within 90 days prior to Screening;  

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6. Has had more than 3 episodes of hypoglycemia requiring medical assistance within 
90 days prior to Screening;  
7. Any acute or chronic medical condition, or concurrent therapy (pharmaceutical or 
otherwise) which, in the opinion of the Investigator could potentially adversely impact 
subject safety, response to study drug, or interfere with study assessments;  
8. Clinically significant and severe ophthalmologic disease, including but not limited to 
retinopathy, or visual field impairment which, in the opinion of the Investigator could 
potentially preclude enrollment in the study;   
9. Serum aminotransferase (alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST]) levels > 1.5× the upper limit of normal at Screening; 
10. Has HIV or active hepatitis B or C virus infection; 
11. History of malignancy within 3 years prior to Screening, except for non-melanoma skin 
tumor, cervical carcinomas in situ, or successfully treated malignancies in remission; 
12. Unwilling to practice a protocol-specified acceptable method of birth control (both males 
who have partners of child-bearing potential and females of child-bearing potential) 
during Screening, while taking study drug, and for at least 30 days after the last dose of 
study drug is ingested (Section 6.7); 
13. Females who are pregnant or breastfeeding; 
14. Subject is, in the opinion of the Investigator, unable to comply with the requirements of 
the study protocol or is unsuitable for the study for any reason; 
15. Known hypersensitivity to any component of the study drug; 
16. Systolic blood pressure < 90 mmHg after a period of rest at Screening; 
17. Pneumonia due to COVID-19 within 6 months prior to Screening or a history of 
COVID-19–related hospitalization within 6 months prior to Screening; 
18. Known or suspected active drug or alcohol abuse, per Investigator judgement; 
19. Use of the following medications: 
a. Use of another investigational drug or participation in an investigational study within 
30 days or 5 half-lives of that investigational drug (whichever is longer), prior to 
Screening;  
b. Prior participation in a study with RTA 901;  
c. Neuroleptics, monoamine oxidase inhibitors, N-methyl-D-aspartate receptor ligand 
for pain (ketamine, amantadine, dextromethorphan [except low dose intermittent use 
for cough], memantine, methadone, dextropropoxyphene, and/or ketobemidone), 
and/or alpha-lipoic acid within 7 days prior to Screening;  
d. Tricyclic antidepressants and other tricyclic drugs including cyclobenzaprine and 
promethazine; triptans (prescribed usage outside of DPNP allowed); and/or 5-HT3 
receptor antagonists, within 7 days prior to Screening; 
e. Exposure of drugs or chemicals that may cause neuropathy and interfere with clinical 
evaluation. Agents include but are not limited to pyridoxine, hydralazine, 
metronidazole, phenytoin, dapsone, amiodarone, nitrofurantoin, paclitaxel, 

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vinblastine, vincristine, cisplatin, etoposide, didanosine, disulfiram, suramin, 
zalcitabine, anti-tuberculosis medications (eg, isoniazid, rifampin, ethambutol, 
ethionamide), heavy metals, and industrial solvents, within 7 days prior to Screening; 
f. Strong or moderate CYP3A4 inhibitors or inducers and P-gp inhibitors, within 
14 days prior to Screening; 
g. Topical pain medications intended to treat pain associated with DPNP (including but 
not limited to lidocaine 5% patch, over-the-counter capsaicin, amitriptyline, and/or 
isosorbide dinitrate spray) within 7 days prior to Screening;  
h. Prescription patch containing 8% capsaicin use within 6 months prior to Screening; 
i. Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days per 
week in the 30 days prior to Screening; or planned treatment with opioid or 
opioid-based drugs, including but not limited to tapentadol and/or tramadol from 
Screening throughout the course of the study;   
j. Central nervous system active drugs detected in the urine such as cocaine, 
amphetamines, and cannabinoids (marijuana); 
k. Oral prednisolone or equivalent within 7 days prior to Screening.  
20. Use of the following devices or procedures: 
a. Transcutaneous electrical nerve stimulation (TENS) unit for the treatment of DPNP 
within 30 days prior to Screening; 
b. Implanted neurostimulators; 
c. Nerve decompression surgery or plans for such surgery for treatment of DPNP; 
d. Steroid or local anesthetic nerve blocks within the last 12 months prior to Screening; 
e. Cryotherapy, intrathecal/epidural opioids, or botulinum toxin if administered within 
the last 6 months prior to Screening; 
f. Alternative medicine products or treatments (eg, acupuncture, naturopathy, 
homeopathy, etc.) within 7 days prior to Screening;  
g. Major surgery within 30 days prior to Screening or planned to occur during the course 
of the study.   
4.2. 
Randomization Eligibility 
4.2.1. 
Randomization Inclusion Criteria  
1. Subject has an average NPRS pain intensity score ≥ 4 on an 11-point NPRS calculated 
from pain assessments during the last 7 days prior to randomization. A minimum of 5 
measurements must be recorded;  
2. Subject must have a ≤ 3-point decline in NPRS pain intensity score during Run-in, which 
will be calculated using the average score during the last 7 days of Screening compared 
to the average score during the last 7 days of Run-In; 
3. If subject is on insulin treatment to maintain glycemic control, the subject must have a 
relatively stable insulin dose with no drastic changes during Screening per the 
Investigator’s judgement; 
4. If subject is taking oral anti-diabetic medication, the subject must have a < 50% change 
of routine oral anti-diabetic agent dose from Screening oral anti-diabetic agent dose to 
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5. Currently taking only 1 allowed prescribed SOC pain medication for managing DPNP at 
a stable dose (not exceeding the maximum dose in the prescribing information) for 
approximately 8 weeks prior to Day 1 with no anticipated changes to dose(s) during study 
(Section 7.8.1); 
6. Has had a complete diabetic eye exam within the 12 months prior to randomization, as 
per SOC. 
4.2.2. 
Randomization Exclusion Criteria  
1. Pneumonia due to COVID-19 or COVID-19–related hospitalization during Screening or 
Run in; 
2. Use of the following medications during Screening or Run-in: 
a. Neuroleptics, monoamine oxidase inhibitors, N-methyl-D-aspartate receptor ligand 
for pain (ketamine, amantadine, dextromethorphan [except low dose intermittent use 
for cough], memantine, methadone, dextropropoxyphene, and/or ketobemidone), 
and/or alpha-lipoic acid;  
b. Tricyclic antidepressants and other tricyclic drugs including cyclobenzaprine and 
promethazine; triptans (prescribed usage outside of DPNP allowed); and/or 5-HT3 
receptor antagonists; 
c. Exposure of drugs or chemicals that may cause neuropathy and interfere with clinical 
evaluation. Agents include but are not limited to pyridoxine, hydralazine, 
metronidazole, phenytoin, dapsone, amiodarone, nitrofurantoin, paclitaxel, 
vinblastine, vincristine, cisplatin, etoposide, didanosine, disulfiram, suramin, 
zalcitabine, anti-tuberculosis medications (eg, isoniazid, rifampin, ethambutol, 
ethionamide), heavy metals, and industrial solvents; 
d. Strong or moderate CYP3A4 inhibitors or inducers and P-gp inhibitors; 
e. Topical pain medications intended to treat pain associated with DPNP (including but 
not limited to lidocaine 5% patch, over-the-counter capsaicin, amitriptyline, and/or 
isosorbide dinitrate spray);  
f. Prescription patch containing 8% capsaicin; 
g. Opioid use at a dose of ≥ 30 morphine milligram equivalents on 3 or more days per 
week during Screening or Run-in; or planned treatment with opioid or opioid-based 
drugs, including but not limited to tapentadol and/or tramadol throughout the course 
of the study;   
h. Central nervous system active drugs detected in the urine such as cocaine, 
amphetamines, and cannabinoids (marijuana); 
i. Oral prednisolone or equivalent. 
3. Use of the following devices or procedures during Screening: 
a. TENS unit for the treatment of DPNP; 
b. Implanted neurostimulators; 
c. Nerve decompression surgery or plans for such surgery for treatment of DPNP; 
d. Steroid or local anesthetic nerve blocks; 
e. Cryotherapy, intrathecal/epidural opioids, or botulinum toxin; 
f. Alternative medicine products or treatments (eg, acupuncture, naturopathy, 
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g. Major surgery during Screening or planned to occur during the course of the study. 
4.3. 
Protocol Waivers  
Protocol waivers are not allowed. If there is an immediate hazard to a subject, the Investigator 
may deviate from the protocol using his/her best medical judgment to ensure the subject’s safety. 
If such a deviation occurs, the site must notify the Sponsor and IRB within 48 hours. 
4.4. 
Retesting and Rescreening  
4.4.1. 
Retesting  
Retesting is defined as repeating abnormal laboratory tests within the same study part.    
Subjects who fail to qualify for the study based on an abnormal laboratory test may have any 
individual laboratory test retested once within the same study part at the discretion of the 
Investigator.  
4.4.2. 
Screen Failures  
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently assigned to the study drug or entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. Individuals who do not meet the criteria 
for participation in this study (screen failure) may be rescreened in accordance with 
Section 4.4.3. 
4.4.3. 
Rescreening  
Subjects who fail to meet all Run-in inclusion/exclusion criteria may be considered for 
rescreening at the discretion of the Investigator after consultation with the Medical Monitor. 
These subjects will be considered Screen Failures. 
Subjects may repeat Screening once to qualify for the study. If a subject is approved to rescreen, 
they will be given a new subject number and all screening procedures will be repeated. 
Subjects who participate in the Run-in Period but fail to meet the Randomization criteria will not 
be allowed to rescreen for the study. These subjects will be considered Randomization Failures. 
4.5. 
Subject Enrollment and Randomization  
Following a Screening Period of up to 2 weeks, eligible subjects will be enrolled and enter a 
single-blind placebo Run-in Period (14± 2 days). Subjects in Part 1 who remain eligible 
(according to Randomization eligibility criteria) will be randomized 1:1:1 to either RTA 901 (10 
or 80 mg) or placebo at Day 1, and subjects in Part 2 who remain eligible will be randomized 
1:1:1 to either RTA 901 (Dose 1 or Dose 2) or placebo at Day 1 (see Table 3). Approximately 
192 eligible subjects (64 subjects per treatment arm) will be enrolled in Part 1, and 
approximately 192 eligible subjects (64 subjects per treatment arm) will be enrolled in Part 2. 
Randomization within each part will be stratified using RTSM into 2 strata based on approved 

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SOC pain medication. One stratum will include subjects taking duloxetine, while the other 
stratum will include subjects taking pregabalin or gabapentin.   
Table 3: 
Treatment Arms by Study Part 
Study Part 
Treatment Arms 
Part 1 (N=192) 
10 mg RTA 901 (N=64) 
80 mg RTA 901 (N=64) 
Placebo (N=64) 
Part 2 (N=192) 
Dose 1 RTA 901 (N=64) 
(selected from dose range 
of 1 to 80 mg)a  
Dose 2 RTA 901 (N=64) 
(selected from dose range 
of 1 to 80 mg)a  
Placebo (N=64) 
Abbreviations: E-R=exposure-response 
a Dose selection in Part 2 will be determined by a Dose Selection Committee and based off an E-R analysis for 
efficacy from all subjects in Part 1. 
4.5.1. 
Methods for Ensuring Blinding 
In this 2-part, randomized, placebo-controlled, double-blind study, all subjects, Investigators, site 
personnel, and laboratories (except the bioanalytical laboratory) with direct involvement in the 
conduct of the study or their designees will be blinded to randomized treatment assignments. 
Subjects will be blinded throughout the study. Investigators will not be blinded in the single-
blind Run-in Period but will be blinded in the double-blind Treatment Period of the study. To 
prevent potential bias, appropriate measures will be taken to ensure the blind is maintained for 
the subjects and personnel mentioned previously. To maintain the blind, Investigators will 
distribute blinded study drug kits to subjects as assigned by the RTSM (Section 7.3). The Data 
Monitoring Committee (DMC) will review unblinded safety data and make recommendations as 
appropriate. Members of the DSC will be unblinded to recommend Part 2 doses of RTA 901, 
respectively. 
4.5.2. 
Methods for Unblinding 
For subject unblinding, the Investigator is encouraged to contact the Medical Monitor to discuss 
situations in which he or she believes that the blind should be broken, but ultimately the 
Investigator has the right to break the blind (eg, in the event of a serious or life-threatening 
medical situation). If unblinding is required, the Investigator will utilize RTSM to perform the 
unblinding. If a study drug assignment is unblinded, the Investigator must describe the event that 
required unblinding in the subject’s source documents. Subjects must discontinue taking the 
study drug if their treatment assignment has been unblinded to the Investigator (or designee). 
Such subjects must undergo the same study discontinuation procedures as those subjects who 
discontinue taking study drug for other reasons. Subject treatment assignments must not be 
unblinded in the case of an AE or SAE except as described above. 
4.5.2.1. 
Unblinding for Regulatory Submission  
In situations where regulation requires unblinding and reporting of a particular SAE, the 
appropriate bodies (eg, IRBs, regulatory agencies) must be provided with unblinded information 
according to the applicable regulatory requirement. This information must not be conveyed to 
any Investigator, site personnel or subject; therefore, this type of unblinding does not necessitate 

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that the subject discontinues taking study drug. In cases when unblinded information must be 
conveyed to local health authorities, the Clinical Program Operations and Data Management 
teams must be excluded. 
4.5.2.2. 
Data Monitoring Committee  
An independent DMC will review the accumulating unblinded safety 
 data throughout the 
study and make recommendations as appropriate.    
The DMC will consist of external experts supported by an independent statistical group which 
will prepare unblinded analyses for the DMC and will have no role in the Statistical Analysis 
Plan (SAP) after the study has started enrolling subjects. A separate statistical group not 
associated with the DMC will be responsible for producing and finalizing the SAP and executing 
the final data analysis of the study.   
The DMC will be governed by a charter that will describe the following: 
• Roles and responsibilities of the DMC members and the independent statistical group; 
• Meeting format and frequency; 
• Communication channels between the DMC, the independent statistical group, the 
Sponsor, and the blinded study statisticians; 
• Voting process and requirements (eg, requirement of consensus for issuance of a 
termination recommendation); 
• Provisions governing conflict of interest and confidentiality. 
Briefly, the DMC will review the progress of the study and the accumulating unblinded safety 
data while the study is ongoing. The DMC will make recommendations to Sponsor 
representatives following each meeting. The DMC may recommend that the study continue as is, 
be modified to protect subject safety, or be terminated for safety. The DMC can make 
recommendations for the study based specifically on the analysis of the primary endpoint.   
4.5.2.3. 
Dose Selection Committee  
The DSC will be comprised of Sponsor personnel and an external pharmacometrics consultant. 
The E-R analysis will be conducted for efficacy using unblinded data from all subjects in Part 1, 
which is the basis for dosing recommendation of Part 2 to DSC. Eligible doses for selection in 
Part 2 will be limited to a dose range of 1 to 80 mg of RTA 901. The selected doses will be 
documented in a Note-to-File to the Investigators and IRBs (as appropriate) and will not require 
a protocol amendment. 
Details of the membership, objectives, and process to be followed by the DSC will be described 
in a separate charter. Additionally, a separate data management and analysis plan supporting this 
activity will be created. Results will be reported in a separate standalone report, outside the CSR.   

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4.6. 
Study Drug Discontinuation, Interruption, and Subject Termination 
4.6.1. 
Discontinuation of Study Drug 
Discontinuation from study drug does not mean discontinuation from the study. Subjects who 
discontinue the study drug early for any reason should complete the procedures associated with 
the Week 12/EOT visit at the closest study visit. If the subject discontinued study drug during a 
study visit, the EOT procedures should be performed during that study visit. If the subject 
discontinues study drug in between visits, he/she will perform the EOT procedures at the next 
scheduled study visit. The subject will then complete the procedures associated with the 
Week 16/end of study (EOS) visit 4 weeks after discontinuation.   
If a clinically significant (CS) finding is identified (including, but not limited to changes from 
baseline) after enrollment, the Investigator or qualified designee will determine if any change in 
subject management is needed. Any new clinically relevant finding will be reported as an AE. 
4.6.2. 
Resuming Study Drug after Interruptions  
The term interruption generally refers to a temporary halt in study drug administration. This can 
be either at the direction of the site, or by the subject’s decision or non-compliance. An 
interruption from the study drug based on the subject’s decision or non-compliance will be 
defined as missing at least 3 consecutive days of study drug administration. There is no 
minimum timeframe for a site directed interruption. 
If study drug has been interrupted, the Investigator should conduct an evaluation to determine 
whether the subject is still eligible to receive study drug, and, if so, how to resume the assigned 
treatment. This should include a confirmation that the reason for discontinuation was not a per 
protocol specified reason (see Section 4.6.3) and that the subject’s circumstances have not 
changed in a manner that would prohibit administration of the study drug (eg, the subject is now 
taking a prohibited medication). 
4.6.3. 
Subject Discontinuation and Termination 
Subjects are free to withdraw from participation in the study at any time upon request. Subjects 
who wish to withdraw from the study should complete the procedures associated with the 
Week 12/EOT visit at the nearest study visit and the Follow-up Week 16/EOS visit 4 weeks 
later.   
At their discretion, an Investigator may discontinue or withdraw a subject. Participation of a 
subject in this clinical study may be discontinued for any of the following reasons: 
• Withdrawal by subject; 
• Investigator decision; 
• Adverse event; 
• Death; 
• Pregnancy; 
• Protocol deviation; 

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• Study terminated by Sponsor;  
• Significant study non-compliance, as per Run-in Exclusion Criteria 14 and Section 7.6; 
• Lost to follow-up; or 
• Other (specify). 
The term discontinuation refers to a permanent halt in study drug administration.  
The reason for subject discontinuation or withdrawal from the study will be recorded on the 
electronic Case Report Form (eCRF). A comprehensive physical examination, body weight, vital 
signs measurement, ECG, laboratory analysis, urine pregnancy test for females of child-bearing 
potential, urine sample for urinalysis, and an assessment of concomitant medications and AEs 
will be performed at the closest study visit, according to Section 4.6.1. 
 
 
Additional blood samples for drug measurement may be collected at the time of discontinuation 
from subjects who are discontinued due to AEs; the clock time, time in relation to dose, and date 
the sample was taken will be recorded. 
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory result 
that is significantly outside of the reference range, the Investigator will attempt to provide 
follow-up until a satisfactory clinical resolution of the laboratory result or AE is achieved. 
If a positive result is obtained on a pregnancy test for a subject, or a subject reports that they or 
their female partner become(s) pregnant during the study, the subject must be discontinued 
immediately. The Investigator must report the pregnancy within 1 business day of the site being 
aware, as described in Section 6.6. 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
4.6.4. 
Termination of the Study 
Although the Sponsor intends to complete the study, the Sponsor reserves the right to terminate 
the study at any time for clinical or administrative reasons, or if required by regulatory agencies. 
If the Sponsor terminates the study, all study drug will be discontinued, and the Investigator will 
be provided guidance on how to close out participation of all subjects enrolled in the study. 

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5. 
STUDY ASSESSMENTS 
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as outlined in the Schedule of Assessments (Table 4). However, it is anticipated that from time to 
time there may be circumstances outside the control of the Investigator that may make it 
unfeasible to perform a test. In these cases, the Investigator must take all necessary steps to 
ensure the safety and well-being of the subject. When a protocol required test cannot be 
performed, the Investigator will document the reason for the missed test and any corrective and 
preventative actions which were taken to ensure that the required procedures are adhered to as 
soon as possible. The Study Management Team must be informed of these incidents in a timely 
manner. 
5.1. 
Administrative Procedures 
5.1.1. 
Informed Consent  
Written informed consent (Section 10.4) must be obtained from the subject before any 
study-related procedures are performed. Re-consenting will be required when there is an update 
or change in the study procedures, safety information, or any other information that may affect 
the subject’s willingness to participate. 
5.1.2. 
Inclusion/Exclusion 
Both the Run-in and Randomization inclusion and exclusion criteria must be reviewed as 
indicated in Section 4.1 and Section 4.2. Subjects must meet all inclusion and no exclusion 
criteria for entry into the study and randomization on Day 1. Investigators should contact the 
Medical Monitor with any questions regarding randomization eligibility prior to randomizing the 
subject on Day 1. 
5.1.3. 
Demographics 
Demographic data including date of birth, age, sex, ethnicity, and race will be collected as 
indicated in Table 4. 
5.1.4. 
Medical History 
A complete medical history, including surgical history, alcohol, tobacco, and nicotine-containing 
product use histories for the past 5 years, will be taken at Screening. All relevant changes 
throughout the study after Screening will be recorded in the subject’s source document and eCRF 
as AEs. 
5.1.5. 
Prior and Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the subject is taking. 
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications. Trade or generic drug names 
should be used where possible. Prior and concomitant medications (ie, medications that the 
subject is taking or has taken within 30 days prior to Screening) will be reviewed per Table 4 and 
all changes throughout the study after Screening will be recorded in the subject’s source 

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document and eCRF. Prior opioid use to manage DPNP will be recorded for the past 5 years 
prior to Screening.  
5.1.6. 
Adverse Events 
Investigators and study staff are responsible for detecting, documenting, and reporting AEs and 
SAEs. For each subject, reporting of AEs and SAEs begins after written informed consent/assent 
is provided. Throughout the study, subjects will be provided opportunities to report AEs. For 
more information on AEs, see Section 6.3. 
5.1.7. 
Electronic Diary Set-up  
During Screening, subjects deemed likely to be eligible for the study will be given access to an 
e-diary and trained on how to record daily pain scores from Screening up to Day 1. The results 
will be reviewed on Day 1 to confirm that the subject is eligible for the study. The use of an 
e-diary will improve consistency and reliability of scoring for NPRS and DSIS, and timing of 
dosing and rescue medication.  
Subjects will be instructed to report the NPRS number that best indicates the average intensity of 
pain over the last 24 hours throughout the study daily at bedtime. Subjects will also complete the 
DSIS via their e-diary daily upon waking. Non-compliance is defined as recording less than 70% 
of expected PROs during any evaluation period (visit to visit). 
, treatment administration, and rescue medication usage will also be recorded in 
the e-diary. 
5.2. 
Clinical Procedures/Assessments 
5.2.1. 
Height Measurement 
Height will be measured only at Screening; the subject will not wear shoes during the 
measurement of height.  
5.2.2. 
Weight Measurement 
Body weight will be measured at the times indicated in Table 4. Weight should be taken with no 
shoes, hats, and outerwear. Body mass index will be calculated at Screening for eligibility.   
5.2.3. 
Comprehensive Physical Examination  
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner as indicated in Table 4 and as documented within the medical 
record. The comprehensive physical examination must include the following organ or body 
system assessments: head, eyes, ears, nose, throat, musculoskeletal, cardiovascular, lymphatic, 
respiratory, abdomen, skin, extremities, and neurological.   
Assessments of any specific signs or symptoms reported by the subject must also be performed 
and documented along with any other findings of note. Clinically significant findings at 
Screening must be addressed in medical history (ie, findings should be attributable to a diagnosis 
recorded in medical history). The physical examination performed at Screening will serve as the 
baseline physical examination for clinical assessments. Following the examination at Screening, 

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new or changed physical examination findings meeting the definition of an AE must be reported 
as an AE. If possible, the same individual should perform each physical examination on a subject 
during the study. 
5.2.4. 
Targeted Physical Examination  
Targeted physical examinations are symptom-directed examinations and involve the organ 
system(s) associated with the symptoms exhibited or reported. Targeted physical examinations 
are to be performed at visits indicated in Table 4. 
5.2.5. 
Electrocardiogram 
The 12-lead ECGs will be recorded at the times indicated in Table 4. 
The ECGs will be recorded after the subject has been in the supine position for at least 5 
minutes. Subjects will be instructed to remain completely stationary (no talking, laughing, deep 
breathing, or sleeping) during the rest period.  
Triplicate ECGs, approximately 1 minute apart, for the QT/QTc using Fridericia’s correction 
formula review will be obtained at the required nominal time points. 
Baseline for clinical assessments will be those measurements obtained prior to study drug 
administration on Day 1. Another ECG will be performed approximately 1-hour postdose on 
Day 1.  
Each ECG will be printed and evaluated by an appropriately qualified Investigator at the study 
site (the “local reader”). The local reader will sign and date each ECG and provide a global 
interpretation using the following categories or equivalent: 
• Normal ECG 
• Abnormal ECG – Not clinically significant (NCS) 
• Abnormal ECG – CS 
• Unable to evaluate 
The local reader evaluations of the triplicate ECGs will be entered into the electronic source 
documents or eCRFs. If the global interpretation is Abnormal (NCS or CS), the local reader will 
provide further information (eg, sinus bradycardia, arrhythmia). Only overall diagnosis CS 
Abnormal ECG findings will be reported as AE. 
All original ECG tracings will be retained as source documentation in the subject’s records at the 
study site. 
5.2.6. 
Vital Sign Measurements  
Vital signs, including blood pressure, heart rate, respiration rate, and body temperature, will be 
assessed on the study days indicated in Table 4 or at early discontinuation. The vital sign 
measurements obtained just prior to study drug administration on Day 1 will serve as the 
baseline measurements for clinical assessments. Blood pressure and heart rate will be measured 
after the subject has been sitting for at least 5 minutes. Three blood pressure recordings will be 

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obtained and recorded at each assessment; each recording should be a minimum of 2 minutes 
apart. The average of the second and third readings will be calculated and assessed. 
5.2.7. 
Michigan Neuropathy Screening Instrument 
The distal symmetrical peripheral neuropathy will be evaluated at Screening using MNSI.  
The MNSI is widely used for the evaluation of distal symmetrical peripheral neuropathy in 
diabetes (Herman, 2012). It has 2 parts: 1) history (subject portion) and 2) physical examination 
findings (clinician’s portion). The first part (Part A) is a 15-item self-administered questionnaire, 
and the second part (Part B) is a lower extremity examination that includes inspection and 
assessment of vibratory sensation and ankle reflexes and is scored by assigning points for 
abnormal findings. Scores vary from 0 to 1 for each abnormality in the foot appearance, Achilles 
reflexes presence and vibratory by tuning fork and monofilament testing. 
To be eligible for randomization, subjects must have a score ≥ 2.5 on MNSI Part B only; Part A 
will not be used in this study. The MNSI (Part B) will be assessed by the Investigator per  
Table 4. 
5.3. 
Laboratory Procedures/Assessments 
Samples will be obtained at a minimum for the clinical laboratory tests at the times indicated in 
Table 4. Samples will be stored under conditions stipulated in the Central Laboratory Manual 
until they are transported for measurement. Samples will be transported and measured by a 
central laboratory. The laboratory results will be reviewed, signed, and dated by an Investigator. 
• Clinical laboratory tests may be repeated at the discretion of the Investigator to verify 
any out-of-range value; 
• The Investigator will follow the CS, out-of-range value to a satisfactory clinical 
resolution or until the out-of-range value becomes NCS; and 
• A laboratory test value that requires a subject to be discontinued from the study or 
requires a subject to receive treatment will be recorded as an AE.  
5.3.1. 
Pregnancy Tests for Females of Child-bearing Potential 
A serum or urine pregnancy test will be performed at the times indicated in Table 4. A serum 
pregnancy test will be performed at Screening for females of child-bearing potential or at any 
point in time if a pregnancy is suspected. All other pregnancy assessments will be urine 
pregnancy tests. Additional pregnancy assessments will be performed more frequently if required 
by local law or requested by local regulatory authorities or IRBs. 
5.3.2. 
Follicle-Stimulating Hormone 
Follicle-stimulating hormone (FSH) will only be assessed at Screening for female subjects who 
have been post-menopausal for at least 1 year and are not surgically sterile (e.g., not had bilateral 
tubal ligation, bilateral oophorectomy, or a hysterectomy). The investigator, based on the 
available information (including the FSH result), uses their clinical judgment to determine 
whether or not the participant is of child-bearing potential. 
 

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5.3.3. 
Serology 
5.3.3.1. 
Hepatitis Screen 
Subjects will have blood tested for the presence of hepatitis B surface antigen and hepatitis C 
virus antibody at Screening. Only those subjects with negative results for the presence of 
hepatitis B surface antigen and hepatitis C virus antibody will be allowed to enroll in the study. 
5.3.3.2. 
HIV Screen 
Subjects will have blood tested for the presence of anti-HIV antibodies (HIV-1/HIV-2) at 
Screening. Only those subjects with negative results for the presence of antibodies will be 
allowed to enroll in the study. The results of the HIV antibody testing will be retained by the 
clinical unit under confidential restriction with the exception of reporting to government 
authorities as required by law. 
5.3.4. 
COVID-19 Test 
A COVID-19 test will be performed at the times indicated in Table 4 for all subjects.  
5.3.5. 
Drugs of Abuse and Cotinine Screen 
A urine screen for drugs of abuse and cotinine will be performed at Screening. The panel for 
drugs of abuse will minimally include cannabinoids, opiates, 
3,4-methylenedioxymethamphetamine, methadone, methamphetamine, oxycodone, 
phencyclidine, tricyclic antidepressants, barbiturates, amphetamines, cocaine, and 
benzodiazepines. Results of all tests will be retained by the investigative site. 
5.3.6. 
Clinical Chemistry 
Samples will be collected for the following clinical chemistry analyses as indicated in Table 4 
ferritin, creatine kinase, blood urea nitrogen, enzymatic creatinine, eGFR, total bilirubin, direct 
bilirubin, ALT, AST, alkaline phosphatase, amylase, lipase, sodium, potassium, calcium, 
phosphorus, uric acid, total protein, glucose, albumin, lactate dehydrogenase, magnesium, 
chloride, bicarbonate, and gamma-glutamyl transferase. 
5.3.6.1. 
Estimated Glomerular Filtration Rate Equation 
The equation used to calculate the eGFR is the Chronic Kidney Disease Epidemiology 
Collaboration equation: 
eGFR (mL/min/1.73 m2) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black] 
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males. Min indicates the minimum of Scr/κ or 1 and max indicates the 
maximum of Scr/κ or 1. Age indicates age at time of serum creatinine lab collection. 
5.3.7. 
International Normalized Ratio 
Samples will be collected for international normalized ratio as indicated in Table 4.   

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5.3.8. 
Hematology 
Samples will be collected for the following hematology assessments as indicated in Table 4: 
hematocrit, hemoglobin, red blood cell count, white blood cell count, neutrophils, bands (if 
detected), lymphocytes, monocytes, basophils (if detected), eosinophils (if detected), absolute 
platelet count, mean corpuscular hemoglobin , mean corpuscular volume, and mean corpuscular 
hemoglobin concentration. 
5.3.9. 
Urinalysis and Microscopy 
Samples will be collected for the following urinalysis and microscopy assessments as indicated 
in Table 4: specific gravity, ketones, pH, protein, blood, glucose, clarity, color, leukocytes, 
nitrite, bilirubin, and a microscopic examination (if indicated based on laboratory results). 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
5.3.11. 
Hemoglobin A1c 
Samples will be collected for HbA1c as indicated in Table 4. Detailed instructions on collection, 
storage, and shipment of the samples will be provided in the Central Laboratory Manual 
provided to the Investigator.   
5.3.12. 
Fasting Lipid Profile 
Samples will be collected for the following lipid assessments as indicated in Table 4: total 
cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides. Subjects should 

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fast for at least 8 hours prior to clinic visits where fasting lipids are taken (Screening, Week 4, 
Week 8, Week 12, and Week 16). 
5.4. 
Patient Reported Outcome Assessments  
5.4.1. 
Pain Evaluation  
Diabetic polyneuropathy is a common neurologic complication of diabetes and one of the most 
common causes of peripheral neuropathy. It is primarily a distal symmetric sensory 
polyneuropathy and early signs reflect the gradual loss of integrity of both large myelinated (loss 
of vibratory sensation and proprioception and reduced ankle reflexes) and small myelinated and 
unmyelinated nerve fibers (impairment of pain, light touch, and temperature sensation). Most 
sensory axons are unmyelinated, thus making them more susceptible to damage. In other words, 
distal portions of the longest myelinated and unmyelinated sensory axons are initially involved, 
with relative sparing of motor axons. Thus, symptoms begin presenting distally and 
symmetrically in the toes and feet and later, sensory loss ascends to the hands causing the typical 
“stocking-glove” sensory loss.  
Approximately 50% of subjects with diabetes experience DPN and around 15 to 20% of subjects 
with diabetic neuropathy have pain in the feet. Alleviation of pain is the is a primary goal and 
cornerstone of subject management. The approved treatments for DPNP include 3 oral 
medications (duloxetine, pregabalin, and tapentadol) and a topical patch (containing 8% 
capsaicin). Of these, tapentadol (an opioid medication) and the 8% capsaicin patches are 
prohibited per protocol, see Section 7.8.4. The approved medications are suboptimal and both 
effective pain relief and tolerability remain elusive. Thus, a large unmet need remains for the 
treatment of DPNP. 
The development of specific easy to use questionnaires for neuropathic pain-based essentially on 
verbal self-reporting of qualitative aspects of pain has improved the diagnosis and management 
of DPNP in the past decade. These instruments can serve 2 different purposes, for screening and 
assessing DPNP. They can be used in clinical and research settings to detect neuropathic pain 
and monitor treatment response. In addition, they are quick, easy to use and understandable for 
most subjects. Demonstration of effectiveness for pain reduction assessed via a PRO measure 
and interpretability, meaningfulness, and clinical significance on the pain scores are essential for 
approval of new pain treatments. 
5.4.1.1. 
Numeric Pain Rating Scale 
In order to highlight how people experience pain sensations differently and how the unpleasant 
aspects of pain can differ from pain intensity, subjects will report how they perceive their 
average pain intensity, worst pain intensity, and other characteristics of their pain during the past 
24 hours at bedtime, using the 11-point NPRS as per Table 4.  
The NPRS of pain intensity is a numeric scale, ranging from 0 (representing no pain at all) to 10 
(representing the worst pain imaginable) (Figure 3). The subject selects a whole number (0 to 10) 
that best indicates the intensity of his/her pain in the past 24 hours.  
Subjects must have a score ≥4 on the NPRS at Screening and an average NPRS pain intensity 
score ≥4 during the last 7 days prior to randomization with a minimum of 5 measurements 

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(Section 4.2.1). The results from this PRO will be used to determine the efficacy of RTA 901 in 
achieving at least a 30% or a 50% decrease in pain scores after 12 weeks of treatment.  
Figure 2: 
Numeric Pain Rating Scale 
 
5.4.1.2. 
Daily Sleep Interference Scale 
Often felt during the night, DPNP causes substantial interference in sleep and quality of life. The 
DSIS is a PRO that was developed to quantify sleep interference due to pain. The DSIS will be 
completed daily by subjects upon waking (3-minute self-administered questionnaire), preferably 
in the morning, to accurately capture variability in sleep interference due to pain, thus 
minimizing recall bias. Using the e-diary, subjects will assess how pain has interfered with their 
sleep during the past 24 hours as per Table 4.  
The DSIS is a numeric scale, ranging from; 0 representing no interference with sleep to 10 
representing complete inability to sleep (Figure 3, Vernon, 2008). The subject selects a whole 
number (0 to 10) that best indicates his/her ability to sleep in the past 24 hours.  
Figure 3: 
Daily Sleep Interference Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.5. 
Schedule of Assessments 
Table 4 lists the overall schedule of assessments for the study. 
 

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Table 4: 
Schedule of Assessments (Part 1 & 2) 
Study Period 
Screening 
Perioda 
Run-in  
Periodb 
Treatment Period 
Follow-up  
Period 
Study Visit 
Screening 
Run-in 
Day 1c Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 
/ EOT 
Week 16 / 
EOSd 
Study Day 
Day -28 
to -15 
Day-14 
to -1 (± 2) 
Day 1 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 29 
(± 2) 
Day 43 
(± 2) 
Day 57 
(± 2) 
Day 71 
(± 2) 
Day 85 
(± 2) 
Day 113 
(± 2) 
Administrative Procedures: 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Run-in Inclusion/Exclusione 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electronic Diary Set-up 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments: 
 
 
 
 
 
 
 
 
 
 
 
Height Measurementg 
X 
 
 
 
 
 
 
 
 
 
 
Weight Measurementh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Physical Examination 
X 
 
X 
 
 
 
 
 
 
X 
X 
Targeted Physical Examinationi 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
Xj 
X 
 
 
 
 
 
X 
X 
Vital Sign Measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MNSI 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Tests for Females of 
Child-bearing Potentialk 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSHl 
X 
 
 
 
 
 
 
 
 
 
 
Serology (Hepatitis and HIV Screening) 
X 
 
 
 
 
 
 
 
 
 
 
COVID-19 Test 
X 
 
X 
 
 
 
 
 
 
 
 
Drug of Abuse and Cotinine Screen 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and Microscopy  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Fasting Lipid Profilen 
X 
 
 
 
 
X 
 
X 
 
X 
X 

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Study Period 
Screening 
Perioda 
Run-in  
Periodb 
Treatment Period 
Follow-up  
Period 
Study Visit 
Screening 
Run-in 
Day 1c Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 
/ EOT 
Week 16 / 
EOSd 
Study Day 
Day -28 
to -15 
Day-14 
to -1 (± 2) 
Day 1 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 29 
(± 2) 
Day 43 
(± 2) 
Day 57 
(± 2) 
Day 71 
(± 2) 
Day 85 
(± 2) 
Day 113 
(± 2) 
Study Drug Procedures: 
 
 
 
 
 
 
 
 
 
 
 
Randomization Inclusion/Exclusion 
 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
 
 
X 
 
X 
 
 
 
Study Drug Administrationo 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
 
Collect / Review Study Drug  
 
 
X 
 
 
X 
 
X 
 
X 
 
Patient Reported Outcome 
Assessments: 
 
 
 
 
 
 
 
 
 
 
 
NPRSq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DSISr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: 
 DSIS=Daily 
Sleep Interference Scale; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; 
 FSH=follicle-stimulating hormone; 
HbA1c=Hemoglobin A1c; INR=International Normalized Ratio; IRB=Institutional Review Board; MNSI=Michigan Neuropathy Screening Instrument; 
; NPRS=Numeric Pain Rating Scale;
 

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a The Screening Period includes 1 clinic visit up to 2 weeks prior to the Run-in Period (within approximately 28 days prior to Day 1), see Section 3.2. 
b The Run-in Period includes 1 clinic visit and must occur during a 14 (± 2) day period prior to the Day 1 first dose, see Section 3.3. 
c Day 1 includes the first dose administration, and all procedures must be performed before study drug administration, except for adverse events, 1-hour postdose ECG, 
 
. 
d Subjects who discontinue study drug early for any reason should complete the procedures associated with the Week 12/EOT visit at the nearest study visit and the Follow-up 
Week 16/EOS visit 4 weeks later. 
e Run-in eligibility procedures do not need to be repeated at the Run-in visit; however, a review of any changes in eligibility criteria should be evaluated prior to Run-in visit 
procedures. 
f Adverse event assessments should be performed after the informed consent has been signed. 
g Height should be measured with no shoes. 
h Weight should be measured with no shoes, hats, or outerwear. 
i Investigator will evaluate if a targeted physical examination is needed, based on any symptomatology reported to the study team. 
j ECG on Day 1 should be recorded at predose and 1-hour postdose. 
k A serum pregnancy test will be performed at Screening for females of child-bearing potential or at any point in time if a pregnancy is suspected. All other pregnancy assessments 
will be urine pregnancy tests. Additional pregnancy assessments will be performed more frequently if required by local law or requested by local regulatory authorities or IRBs. 
l FSH will only be assessed at Screening for female subjects who have been post-menopausal for at least 1 year and are not surgically sterile. 
 
 
 
  
n Subjects should fast for at least 8 hours prior to clinic visits where fasting lipids are taken (Screening, Week 4, Week 8, Week 12, and Week 16). 
o All study drug administration should be performed in an early fasted state, defined as having no food within at least 2 hours prior to study drug administration and for 1 hour 
following study drug administration. Since the first dose will be taken in-clinic and there are no 
 or fasting lipids taken at the Run-in visit, subjects should fast for 2 hours 
prior to the visit. 
p On visits containing both labs with fasting and study drug administration, the longer fasting guidance (8 hours) is to be followed, these are not additive.  
q Subjects will complete the NPRS in the e-diary daily at bedtime.   
r Subjects will complete the DSIS in the e-diary daily upon waking. 

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5.6. 
Unscheduled Visits 
Unscheduled visits may be performed at any time and for any reason, including those not 
specifically mentioned in this section, as deemed necessary by the Investigator. 
Unscheduled visits conducted for the following reasons should include collection of AEs, 
clinical chemistry, hematology, concomitant medication collection, and vital signs: 
• Management of an AE or SAE; 
• Performance of additional laboratory tests for clinically abnormal laboratory test values 
or to confirm a possible pregnancy; 
• Subject safety evaluation. 
Unscheduled visits conducted for the following reasons do not require additional assessments 
unless deemed necessary by the Investigator: 
• Study drug dispensation; 
• Any operational need that would require the subject to return to the site between 
scheduled visits. 
 

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6. 
SAFETY REPORTING, MEDICAL MANAGEMENT, AND 
OVERSIGHT 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all safety assessments. Safety 
parameters include vital sign measurements, ECG results, AEs, SAEs, weight, and laboratory 
test results. 
6.1. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a subject regardless of its causal 
relationship to study drug. An AE can be any unfavorable and unintended sign (including any CS 
abnormal laboratory test result), symptom, or disease temporally associated with the use of the 
study drug, whether or not it is considered to be study drug related. Included in this definition is 
any newly occurring event or previous condition that has increased in severity or frequency since 
the administration of study drug.   
The definition above, provided for in the good clinical practice (GCP) International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline 
E6, is being extended for the purpose of Reata studies to include any events, intercurrent diseases 
and accidents observed while the subject is on study, ie, during the actual Treatment Period, as 
well as during drug-free, pre- and post-Treatment Periods. 
All AEs observed or reported by the subject during the study (from the time of consent until the 
final visit or 30 days following final study dose for subjects who terminate early) must be 
reported, regardless of their relationship to study drug or their clinical significance. All 
conditions present prior to time of consent should be documented as medical history. 
6.1.1. 
Definition of Non-treatment-emergent Adverse Event  
Adverse events that present after signing of the ICF and prior to the initiation of study drug will 
be categorized as non-TEAEs and considered “not applicable” for the causality assessment with 
study drug.   
6.1.2. 
Definition of Treatment-emergent Adverse Event 
Adverse events that present, or worsen in intensity or frequency, following the initiation of study 
treatment will be categorized as TEAEs. 
6.2. 
Definitions of Serious Adverse Event  
An SAE is any AE occurring at any dose and regardless of causality that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 

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• Is a congenital anomaly or birth defect in an offspring of a subject taking study drug 
• Is an important medical event  
The term “life-threatening” refers to an event in which the subject was at immediate risk of death 
at the time of the event. It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of consent until the final visit). Certain pregnancy 
outcomes will require submission as an SAE (Section 6.6). 
6.3. 
Recording of Adverse Events 
At every study visit, subjects must be asked a standard, non-directed question, such as, “How do 
you feel?” or “How have you been feeling since your last visit?” to elicit any medically related 
changes in their well-being. They will also be asked if they have been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication regimens (including 
prescription drugs, over-the-counter medications, vitamins, herbal products, and minerals). 
Responses should be recorded in the source documents. 
In addition to subject observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, ECG 
abnormalities, or other documents that are relevant to subject safety.  
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. Pre-existing 
conditions (present before the start of the AE collection period, prior to signed consent) are 
considered concurrent medical conditions and should NOT be recorded as AEs. However, if the 
subject experiences a worsening or complication of such a concurrent condition, the worsening 
or complication (except disease progression) should be recorded as an AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”). 
Elective procedures (surgeries or therapies) scheduled prior to the start of AE collection should 
not be recorded as AEs but rather documented in the subject’s source documents as elective 
(eg, elective periodontal surgery). However, if a preplanned procedure is performed early (eg, as 
an emergency) because of a worsening of the pre-existing condition, the worsening of the 
condition should be captured as an AE. 
While an AE is ongoing, changes in the severity (eg, worsening or improving) should be noted in 
the source documents but when documenting the AE, only the total duration and greatest severity 
should be recorded in the eCRF. Adverse events characterized as intermittent require 
documentation of onset and duration. 

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6.3.1. 
Adverse Events Based on Signs and Symptoms 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 
AE(s). 
6.3.2. 
Adverse Events Based on Tests or Examinations  
Changes in laboratory test values or ECG parameters are only considered to be AEs if they are 
judged by the Investigator to be CS (ie, if some action or intervention is required or if the 
Investigator judges the change to be beyond the range of normal physiological fluctuation). 
If abnormal laboratory test values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine levels in renal failure), only the diagnosis should be 
reported as an AE. 
6.3.3. 
Follow-up of Unresolved Adverse Events  
All drug-related (Section 6.3.4) AEs, including CS abnormal laboratory test results reported or 
observed during the study, must be followed to resolution (either return to baseline or within 
normal limits). All other AEs or non‒drug-related abnormal laboratory results will be followed 
through the final visit (ie, EOS or early termination). Information to be collected includes type of 
event, date of onset, date of resolution, Investigator-specified assessment of severity and 
relationship to study drug, seriousness, as well as any action taken.  
6.3.4. 
Assessment of Causality 
The relationship of an AE to the administration of the study drug is to be assessed according to 
the following definitions: 
Unrelated: This relationship suggests that there is no association between the study drug and the 
reported event. 
Unlikely: This relationship suggests that the temporal sequence of the event with study drug 
administration makes a causal relationship improbable and/or other factors also provide plausible 
explanations. 
Possible: This relationship suggests that treatment with the study drug caused or contributed to 
the AE. That is, the event follows a reasonable temporal sequence from the time of study drug 
administration and/or follows a known response pattern to the study drug but could have been 
produced by other factors. 
Probable: This relationship suggests that a reasonable temporal sequence of the event with study 
drug administration exists and based upon the known pharmacological action of the drug, known 
or previously reported adverse reactions to the drug or class of drugs, or judgment based on the 
Investigator’s clinical experience, the association of the event with study drug administration 
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Definitely: This relationship suggests that a definite causal relationship exists between the study 
drug administration and the AE, and other conditions (eg, concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
Not Applicable: AE occurred prior to administration of first dose of study drug. 
6.3.5. 
Assessment of Severity  
The Investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities 
Severe: Symptoms causing inability to perform usual social and functional activities 
6.4. 
Reporting of Serious Adverse Events  
Initial Reports 
Any AE, occurring from the time of consent until the final visit or 30 days following final study 
dose for subjects who terminate early, that meets the criteria of serious according to the 
previously described criteria must be reported within 24 hours from the time when site personnel 
first learn about the event. To report the SAE, fax or email the completed SAE form along with 
any supporting documentation (eg, subject discharge summary or autopsy reports) to 
 
 (fax number and email listed below in Table 5) within 24 hours of awareness. 
Table 5: 
Serious Adverse Event Reporting Contact Information 
E-mail: 
For questions regarding SAE reporting, contact your Study Manager, Monitor, or Medical 
Monitor at
. 
Follow-up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies.   
Within 24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (eg, subject discharge summary or autopsy reports), should be faxed 
or emailed to Sponsor/designee (Table 5). 
The Sponsor or its designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible, but no later than 
7 calendar days after the initial receipt of the information. Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency. For other 

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SAEs that do not meet the fatal or life-threatening unexpected criteria but are reported to be 
associated with the study drug, the Sponsor or its designee will notify the appropriate regulatory 
agencies in writing within the timeframe established by those regulatory agencies. The Sponsor 
or its designee will provide copies of any reports to regulatory agencies regarding serious and 
unexpected SAEs to the Investigators for their information and submission to their IRB, as 
appropriate.  
Investigators are responsible for informing their IRB of any SAEs at their site, as appropriate. 
The DMC will review all safety data in an unblinded manner throughout the study and make 
recommendations as appropriate. All SAE correspondence with regulatory authorities or IRBs 
must be submitted to the Sponsor or its designee for recording in the study file. 
6.5. 
Overdose  
An overdose is defined as a subject administering any dose as non-compliant (more than 120% 
of expected study drug visit to visit). Overall, the RTA 901 toxicity program has identified the 
liver and kidney as target organs at doses producing systemic exposures (based on AUC) at least 
50-fold above those observed in humans at the highest planned clinical dose of 80 mg. The 
adverse effects on liver and kidney identified in GLP toxicity studies were associated with 
readily monitorable and standard clinical pathology evaluations and were reversible after drug 
discontinuation. Overall, safety margins of > 40-fold were established, based on systemic 
exposures (ie, AUCs) at the no observed adverse effect levels from the 3-month GLP toxicity 
studies in mice and monkeys and the systemic exposure (ie, AUC) at the highest dose in human 
subjects (ie, 80 mg). 
Any overdose is required to be reported within 24 hours either as an AE or SAE. Overdose does 
not automatically make an AE serious, but if the consequences of the overdose are serious and 
meet the serious criteria (Section 6.2), the event must be reported as an SAE according to 
Section 6.4. 
6.6. 
Pregnancy 
During the study, all female subjects must be instructed to contact the Investigator immediately 
if they suspect they might be pregnant (eg, late or missed menstrual period). Male subjects must 
be instructed to contact the Investigator if a sexual partner suspects she may be pregnant. 
If a subject or Investigator suspects that the subject may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available. If pregnancy is confirmed with 
a serum pregnancy test, the subject must discontinue taking study drug and be discontinued from 
the study (Section 4.6.3).  
Pregnancy in a study subject must be reported to the responsible safety party within 1 business 
day of the site becoming aware of the pregnancy. Information regarding a pregnancy occurrence 
in a study subject and the outcome of the pregnancy will be collected. The Investigator must 
follow a pregnant subject or the pregnant female partner of a male subject (if consenting) and 
report follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants resulting from such pregnancies should be followed for a minimum of 
8 weeks. The Sponsor or its designee may contact the Investigator to request additional 
information throughout the course of the pregnancy. 

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Pregnancy in a study subject is not considered an AE. However, the following pregnancy 
outcomes must be considered SAEs and will require additional reporting in the eCRF and on an 
SAE form: 
• Congenital anomaly/birth defect; 
• Stillbirth; or 
• Spontaneous miscarriage. 
6.7. 
Methods of Birth Control 
During Screening, while taking study drug, and until 30 days following administration of the 
final dose of study drug, females of child-bearing potential must practice 1 of the following 
highly effective methods of birth control: 
• Use of hormonal contraceptives associated with inhibition of ovulation (oral, 
parenteral, intravaginal, or transdermal) as prescribed; 
• Use of a non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed); 
• Use of an intrauterine hormone-releasing system as prescribed; 
• Vasectomized partner (with vasectomy performed at least 6 months prior to Screening 
with the appropriate post-procedure documentation of surgical success). Partner must 
be the sole partner for that subject; 
• Abstain from sexual intercourse completely. Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual. 
Periodic abstinence is not permitted.   
In addition, female participants should not donate eggs for the duration of the study and for at 
least 30 days after their last dose of study treatment. 
During Screening, while taking study drug, and until 30 days after the final dose of study drug, 
fertile males who have female partners of child-bearing potential must practice 1 of the following 
methods of birth control: 
• Partner contraception methods; must be the sole partner for that subject: 
− Use of a non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed);  
− Use of hormonal contraceptives associated with inhibition of ovulation (oral, 
parenteral, intravaginal or transdermal) as prescribed; 
− Use of an intrauterine hormone-releasing system as prescribed; 
− Surgically sterile partner (bilateral tubal ligation, hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy); fallopian inserts with confirmed 
blockage (eg, x-ray, ultrasound); 
− Reproductive potential has been terminated by radiation; 

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− Postmenopausal (defined as no menses for at least 1 year without an alternative 
medical cause). 
• Abstain from sexual intercourse completely. Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual. 
Periodic abstinence is not permitted. 
In addition, male participants should not donate sperm for the duration of the study and for at 
least 90 days after their last dose of study treatment. 
6.8. 
Management of Elevated Aminotransferase Levels (ALT and/or 
AST) 
If a subject’s aminotransferases are elevated, follow the instructions outlined in Table 6. 
Table 6: 
Management of Elevated Aminotransferase Levels (ALT and/or AST) 
ALT and/or AST Level(s) 
Dose Discontinuation (Yes/No) 
> 8× ULN 
Yes 
 
> 5× ULN for more than 2 weeks 
> 3× ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%) 
> 3× ULN and 
(TBL > 2× ULN or INR > 1.5) 
> 3× ULN 
No 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized 
ratio; TBL=total bilirubin; ULN=upper limit of normal 
6.9. 
Management of Study Drug-Related Toxicities  
In the case of serious toxicities, the Investigator may choose to interrupt study drug 
administration. See Section 4.6.2 for details on resuming study drug after interruptions. 

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7. 
STUDY DRUG 
7.1. 
Dose and Treatment Regimens 
Study drug is defined as either RTA 901 or placebo. During the Run-in Period, subjects will be 
administered single-blind placebo once daily in the morning. During the Treatment Period, 
subjects will be administered double-blind study drug QD in the morning according to their 
randomized assignment (Table 3).  
7.2. 
Identity of Study Drug 
RTA 901 drug product information is shown in Table 7.  Information about the placebo is shown 
in Table 8. 
Table 7: 
Part 1 RTA 901 Drug Product Information 
Description 
RTA 901 capsule 
(10 mg size #4, 40 mg size #0) 
Ingredients 
Active Ingredients: RTA 901 
 
Inactive Ingredients: Lactose Monohydrate, 
Microcrystalline Cellulose, Sodium Starch Glycolate, 
Magnesium Stearate, Hypromellose Capsule Shell  
Route of Administration 
Oral 
Table 8: 
Placebo Information 
Description 
Placebo for RTA 901 capsule  
(size #4, size #0) 
Ingredients 
Active Ingredients: N/A 
Inactive Ingredients: Lactose Monohydrate, 
Microcrystalline Cellulose, Magnesium Stearate, 
Hypromellose Capsule Shell  
Route of Administration 
Oral  
7.3. 
Study Drug Packaging and Labeling 
The study drug will be supplied in tamper-evident kits containing high-density polyethylene 
bottles. Each bottle will utilize foil induction-seal liners and a child-resistant closure. In Part 1, 
each bottle of study drug will contain 30 capsules of 10 mg or 40 mg strength RTA 901 or the 
matching placebo capsules. In Part 2, each bottle of study drug will contain 30 capsules of 
RTA 901 or matching placebo capsules, depending on the doses of RTA 901 recommended by 
the DSC (see Section 3.6). 
In Part 1, the study drug kits will contain a combination of bottles, each containing active or 
placebo capsules in varying strengths to make up each dosing regimen. Table 9 shows the 
combination of bottles that will be used to comprise the dose for each treatment arm, while 
maintaining the study blind in Part 1. Kit configurations for Part 2 will depend on the doses 
recommended by the DSC. As in Part 1, the kits for each treatment arm will contain the same 

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number of bottles and the same configuration of capsule sizes necessary to maintain the study 
blind. 
Table 9: 
Study Drug Kit Configurations – Part 1 
Treatment Arm 
Bottles of 10 mg 
Size #4 RTA 901 
Bottles of Size #4 
Placebo 
Bottles of 40 mg 
Size #0 RTA 901 
Bottles of Size #0 
Placebo 
Placebo  
0 
1 
0 
2 
RTA 901 10 mg 
1 
0 
0 
2 
RTA 901 80 mg 
0 
1 
2 
0 
The label on each bottle will contain, at minimum, the following information:  
• Medication ID number; 
• Protocol 901-C-2102; 
• Expiry date; 
• Contains 30 capsules; 
• Study Drug Caution: New Drug – Limited by Federal (or United States) Law to 
Investigational Use. Keep out of reach of children;  
• Control or lot number; 
• Store at 15°C to 25°C (59°F to 77°F);  
• Reata Pharmaceuticals, Inc., Plano, TX 75024 
7.4. 
Study Drug Storage 
Clinical study sites must store the study drug in a secure location at 15° to 25°C (59° to 77°F) 
and maintain a temperature excursion log of the storage conditions. Temperature excursion logs 
must be available for review at each monitoring visit. If the study drug is stored outside of the 
designated conditions for 24 hours or more, a temperature excursion notification should be 
submitted to the Sponsor for review and approval for use of the affected study drug. 
7.5. 
Study Drug Administration 
Subjects must self-administer 1 capsule orally from each of the bottles included in their study 
drug kit QD, beginning at Run-in through the end of the Treatment Period, as indicated in  
Table 4. Each dose of study drug should be administered at approximately the same time each 
day and will be recorded in the e-diary. All doses should be taken in an early fasted state, defined 
as having no food within at least 2 hours prior to study drug administration and 1 hour following 
study drug administration. 
 
 

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A vomited dose must not be replaced. A double dose (eg, missed dose from previous day and 
dose for current day) must not be taken. 
It is the responsibility of the Investigator or designee to provide clear instructions to the subject 
regarding the number and type of capsules to be ingested at each study drug administration 
timepoint listed in Table 4. Subjects must be instructed to continue taking study drug once daily 
through Week 12 unless: 
1. The subject has been otherwise instructed by the Investigator, or 
2. The subject has been formally discontinued from study drug. 
7.6. 
Treatment Compliance 
The Investigator or his/her designated and qualified representatives will only dispense study drug 
to subjects enrolled in the study in accordance with the protocol. Subjects should administer 
study drug exactly as instructed by the site. Non-compliance is defined as taking less than 80% 
or more than 120% of expected study drug during any evaluation period (visit to visit).  
Subjects should record in the e-diary all administered and missed doses of study drug. The 
reason for a missed dose should be recorded in the e-diary. A missed dose includes drug holidays 
and temporary study drug discontinuations. Subjects will be asked to return all unused study 
drug (study drug bottles and any unused capsules). 
Refer to Section 5.1.7 for compliance related to PRO completion via the e-diary. 
7.7. 
Study Drug Accountability 
The Investigator, or designee, will maintain a record of all study drug received, dispensed, and 
returned to the Sponsors’ designee. An Investigator or his/her designated representatives will 
administer the study drug only to subjects enrolled in the study. A current (running) and accurate 
inventory of study drug will be kept by each Investigator and will include shipping invoices and 
the date on which study drug is dispensed/administered to the subject. An overall accountability 
of the study drug will be performed and verified by the study monitor throughout the study and 
at the closeout visit. Upon completion or termination of the study, all original containers 
(containing unused study drug) will be returned to the Sponsor or its designee, according to 
instructions from the Sponsor and according to local regulations. Labels must remain attached to 
the containers. Local study drug destruction is only allowed with prior Sponsor approval.  
7.8. 
Concomitant and Other Treatments 
7.8.1. 
Standard of Care Pain Medications 
Subjects are required to take only 1 SOC pain medication for neuropathic pain (consistent with 
regional or local SOC guidelines for DPNP) at a stable dose (defined as < 50% change in total 
dose) that does not exceed the maximum dose in the prescribing information for approximately 
4 weeks prior to Screening. Allowed SOC pain medications include duloxetine, pregabalin, and 
gabapentin. Attempts should be made to maintain the stable dose of pain therapy. If changes to 
the dose are necessary, the Investigator should discuss with the Medical Monitor. However, dose 

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level should not be above the maximum prescribed dose as instructed in the medication’s dosage 
and administration section of the prescribing information.  
7.8.2. 
Allowed Medications 
The following medications and therapeutics are allowed during the study:  
• Benzodiazepine, zolpidem, diphenhydramine, or related drugs for insomnia if the 
subject is on a stable dose for 3 months prior to entry and it is not anticipated to change 
during the study; 
• SSRI (selective serotonin reuptake inhibitor) for depression if the subject is on a stable 
dose for 3 months prior to entry and it is not anticipated to change during the study; 
• NSAIDs prescribed for conditions other than DPNP. 
• Aspirin ≤325 mg/day for cardiac prophylaxis.  
• Rescue medication, see Section 7.8.3. 
7.8.3. 
Rescue Medication 
Rescue medication for DPNP is in addition to standard of care medication (gabapentin, 
pregabalin or duloxetine) for DPNP. Rescue medication is intended to treat temporary elevations 
in a subject’s DPNP and is intended to be used occasionally and not meant to be used for 
prolonged periods of time.  
Subjects who enter screening after implementation of protocol Version 4.0 may only use 
acetaminophen as a rescue medication for DPNP as needed. If rescue medication is needed for 
DPNP, subjects will be instructed to take acetaminophen 500 mg every 4 to 6 hours as needed 
(not to exceed 3000 mg per day). 
Subjects currently in the study at the time of implementation of protocol Version 4.0 using 
ibuprofen as rescue medication for DPNP may switch their rescue medication to acetaminophen 
(i.e., no longer use ibuprofen as a rescue medication for DPNP) or continue to use as rescue 
medication for DPNP ibuprofen 200 to 400 mg every 4 to 6 hours as needed (not to exceed 600 
mg/day) for up to 3 days in a 7-day period (not calendar week). Subjects unable to comply with 
these conditions will need to discontinue study treatment and withdraw from the study; some or 
all of such subjects may be replaced at the discretion of the Sponsor.  
The daily maximum dosages stated in this section are inclusive of those used outside of 
treatment for DPNP. Any questions related to rescue medications should be directed to the 
Medical Monitor prior to administration when possible. 
7.8.4. 
Prohibited Medications  
The following medications and therapeutics are prohibited during the study:  
• Neuroleptics, monoamine oxidase inhibitors, N-methyl-D-aspartate receptor ligand for 
pain (ketamine, amantadine, dextromethorphan [except low dose intermittent use for 
cough], memantine, methadone, dextropropoxyphene, and/or ketobemidone), and/or 
alpha-lipoic acid;  

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• Tricyclic antidepressants and other tricyclic drugs including cyclobenzaprine and 
promethazine; triptans (prescribed usage outside of DPNP allowed); and/or 5-HT3 
receptor antagonists;  
• Drugs or chemicals that may cause neuropathy and interfere with clinical evaluation. 
Agents include but are not limited to pyridoxine, hydralazine, metronidazole, 
phenytoin, dapsone, amiodarone, nitrofurantoin, paclitaxel, vinblastine, vincristine, 
cisplatin, etoposide, didanosine, disulfiram, suramin, zalcitabine, anti-tuberculosis 
medications (eg, isoniazid, rifampin, ethambutol, ethionamide), heavy metals, and 
industrial solvents;  
• Strong or moderate CYP3A4 inhibitors or inducers and P-gp inhibitors; 
• Topical pain medications intended to treat pain associated with DPNP (including but 
not limited to lidocaine 5% patch, over-the-counter capsaicin, amitriptyline, and/or 
isosorbide dinitrate spray);  
• Prescription patch containing 8% capsaicin;  
• Opioid or opioid based drugs; 
• Central nervous system active drugs such as cocaine, amphetamines, and cannabinoids 
(marijuana); 
• Oral prednisolone or equivalent are excluded during the Screening and Run-in Periods; 
• NSAIDs for DPNP (applies only to subjects who enter the study following 
implementation of protocol Version 4.0) (see Section 7.8.2 for NSAIDs prescribed for 
conditions other than DPNP); 
• Muscle relaxers. 
7.8.5. 
Prohibited Devices/Procedures 
• TENS unit for the treatment of DPNP;  
• Implantation of neurostimulators; 
• Nerve decompression surgery for treatment of DPNP; 
• Steroid or local anesthetic nerve blocks; 
• Cryotherapy, intrathecal/epidural opioids, or botulinum toxin; 
• Alternative medicine products or treatments (eg, acupuncture, naturopathy, 
homeopathy, etc.).  
7.8.6. 
Recording of Concomitant Treatment 
Concomitant medications include those being taken at Screening or at any point throughout the 
study, up to and including the Week 16/EOS visit. Instructions to discontinue any medication to 
comply with the study protocol should take place only after the subject has signed the ICF. 
Concomitant medication will be recorded on eCRFs by their trade and/or generic name and will 
include dose and duration of treatment. Subjects requiring excluded medications will not be 

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eligible for the study. Planned deviations from the eligibility criteria, with regard to excluded 
medications, will not be approved. Subjects will be instructed to consult with the Investigator or 
other site personnel before taking any newly prescribed medications, over-the-counter 
medications, or supplements/herbal preparations. If a subject requires use of a prohibited 
medication during the study, the Medical Monitor should be contacted to determine whether an 
alternative drug is feasible and if not, how to handle dosing with study drug while the prohibited 
medication is being used. Documentation of these discussions must be maintained in the 
subject’s source records.   

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8. 
STATISTICS 
8.1. 
Sample Size Estimate 
This study will be conducted in 2 parts. A total of approximately 192 subjects (64 subjects per 
treatment arm) are planned for randomization in Part 1 and approximately 192 subjects (64 
subjects per treatment arm) are planned for randomization in Part 2, for a total of 384 subjects to 
be randomized. This sample size is based on a dose-ranging scheme to evaluate initial safety, 
efficacy, 
 of RTA 901 in this population. The primary comparisons for efficacy are 
between each of the 2 RTA 901 treatment groups and the placebo treatment group. The overall 
Type I error rate will be controlled at the 0.05 significance level. A hierarchical testing strategy 
to control the overall Type I error will be defined in the SAP. Power calculations are based on a 
2-sample t-test with no adjustments for multiple comparisons. The study assumes a difference in 
NPRS pain intensity means of 1.2 between each RTA 901 treatment group and the placebo 
treatment group and a standard deviation of 2.4.  
If doses selected for Part 2 do not include doses studied in Part 1, then an analysis by dose group 
for Part 1 or Part 2 doses will be performed following completion of each study part. Within each 
Part, with 64 subjects per treatment group, each study part has 80% power to compare treatment 
groups to placebo.  
If doses selected for Part 2 include any doses studied in Part 1 (ie, 10 or 80 mg), then an analysis 
by dose group will be performed using Part 1 and Part 2 combined, following completion of the 
study. The dose group that is enrolled in both parts will have 128 subjects. With 128 placebo 
subjects compared to 128 subjects in the RTA 901 dose group, there is 98% power to detect the 
same difference (1.2 NPRS points) assuming the same standard deviation (2.4). RTA 901 dose 
groups that are enrolled in only 1 part will have 64 subjects. With 128 placebo subjects 
compared to 64 subjects in each RTA 901 dose group, there is 90% power to detect the same 
difference (1.2 NPRS points) assuming the same standard deviation (2.4).     
8.2. 
Definitions of Analysis Sets 
A detailed SAP will be developed prior to database lock.   
8.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat analysis set is defined as all randomized subjects categorized by their 
randomized treatment group (whether or not they received study drug). The analysis population 
for the efficacy endpoints is the intent-to-treat population.   
8.2.2. 
Safety Analysis Set 
The safety analysis set includes all randomized subjects who receive at least 1 dose of 
randomized study drug. The safety analysis set will be used for evaluation of safety variables. 
Subjects who receive at least 1 dose of RTA 901 will be classified in the RTA 901 group. 
Subjects who are randomized and receive at least 1 dose of placebo and no dose of RTA 901 will 
be classified in the placebo group. Subjects in the Run-in phase who fail to randomize into the 
Treatment Period will not be included in the placebo group. 

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Safety and tolerability will be evaluated by AEs, SAEs, clinical laboratory test results, vital 
signs, ECG findings, physical examinations, and weight. All analyses of the safety data will be 
performed using the safety analysis set. Descriptive statistics will be presented by treatment 
group assignment in the safety analysis set. No formal statistical testing is planned for safety 
analyses. 
 
 
 
 
8.3. 
Endpoints and Objectives 
The SAP will describe in detail the methods used for the primary, safety, secondary, and 
exploratory endpoints and will serve as the final arbiter of all statistical analyses. The study 
endpoints are listed in Section 2.2. 
Data will be summarized using descriptive statistics. Continuous data will be summarized with 
statistics such as mean, standard deviation, median, minimum, and maximum. Categorical data 
will be summarized using frequency counts and percentages. 
If doses selected for Part 2 include any doses studied in Part 1 (ie, 10 or 80 mg), then the final 
analysis by dose group will be performed following final study database lock. Otherwise, if 
doses selected for Part 2 do not include doses studied in Part 1 then final analysis by dose group 
for Part 1 or Part 2 doses will be performed following the Part 1 or Part 2 database lock, 
respectively. 
8.4. 
Methods for Statistical Analyses 
8.4.1. 
Hypotheses 
Primary hypothesis: There will be a greater mean reduction from baseline in NPRS pain intensity 
for the RTA 901-treated groups compared with placebo after 12 weeks of double-blind 
treatment. 
8.4.2. 
Closed Testing Procedure 
The overall Type I error rate will be controlled at the 0.05 significance level. A hierarchical 
testing strategy to control the overall Type I error will be defined in the SAP. 
8.4.3. 
Analysis of the Primary Variable(s) 
The primary analysis will be performed using mixed model repeated measures (MMRM), and 
detail of the MMRM model will be specified in the SAP. Within the framework of the MMRM 
model, estimate and 95% CIs will be calculated for the mean changes within each treatment 
group as well as for the differences in mean changes relative to the placebo. 
8.4.4. 
Analysis of the Secondary Variables 
The secondary endpoints will be summarized, and analyses will be described in the SAP. 

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8.4.5. 
Subgroup Analysis 
Subgroup analysis will be described in the SAP. 
8.4.6. 
Interim Analysis 
No interim analysis  for efficacy or safety is planned. 
8.4.7. 
Sensitivity Analysis 
Sensitivity analyses will be described in the SAP. 
8.4.8. 
Analysis of Safety Variables 
The number and percent of subjects with an AE will be summarized for each treatment group. 
Changes from baseline to each scheduled time point for physical examinations, vital sign 
measurements, ECGs, clinical laboratory measurements, and body weight will be summarized by 
treatment group. 
In addition, the number and percent of subjects with a predefined abnormality in clinical 
laboratory tests will be summarized by treatment group. 
8.4.9. 
Exploratory Analysis 
The exploratory endpoints will be summarized and described in the SAP.  
 
 
 
 
 
 
 
 
 
 

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9. 
STUDY AND DATA MANAGEMENT 
9.1. 
Training of Study Site Personnel 
Prior to the start of the study, the Sponsor will review the protocol, eCRF, regulatory obligations, 
and other material or equipment relevant to the conduct of the study with each investigative site 
(Investigator, Sub-Investigator, and relevant study site personnel). It is the responsibility of the 
Investigator to ensure all staff are appropriately qualified and trained to perform study 
responsibilities, prior to the conduct of any study procedures, and as outlined on the delegation 
of authority log. Training will be documented, and relevant training records will ultimately be 
stored in the Trial Master File.   
9.2. 
Monitoring of the Study 
The study monitor, as a representative of the Sponsor, is obligated to follow the study conduct 
closely. In doing so, the monitor will visit the Investigator and study facilities periodically and 
will maintain necessary telephone and letter contact. The monitor will maintain current 
knowledge of the study activity of the Investigator and his/her staff through observation, review 
of study records and source documentation, and discussion of the conduct of the study with the 
Investigators and staff. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the ICH guideline E6(R2): Good Clinical Practice: 
Consolidated Guideline and current standard operating procedures. 
Each Investigator is expected to make a reasonable effort to accommodate the monitor when 
monitoring visits are necessary and to be available during the site visit. Furthermore, the monitor 
should be provided direct access to source data and documents for study-related monitoring and 
internet during the visit. 
9.2.1. 
Risk-Based Quality Management 
The Sponsor or its designee will monitor all aspects of the study for quality and risk management 
with respect to E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance 
for Industry and current standard operating procedures. 
The quality management system and risk management procedures help ensure the monitoring of 
the study is proportionate to the risks inherent in the study and the importance of the information 
collected. Full details for risk-based quality management will be outlined in a Risk Management 
Plan, or equivalent document. 
In case study sites are closed for any visitors and monitors over a certain period of time, a 
risk-based approach to monitoring will be taken, focusing on certain sites, certain data points, 
and certain processes that are critical to ensure the rights, safety, and well-being of study 
participants and the integrity of the study (and study data). The results of adjusted 
monitoring/review measures and their impact will be reported to the Sponsor in monitoring 
reports and in the CSR, where applicable. Adjusting monitoring activities may include a 
combination of on-site and off-site monitoring, where permitted by local regulations. Remote 
source data verification may also be taken into consideration, where permitted by local 
regulations. 

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9.2.2. 
Source Data 
All medical information obtained at each study visit must be recorded in the subject’s record 
(source documentation) in real time as it is collected. Source documentation consists of original 
subject documents, as well as data and records with information relevant to the subject and 
his/her participation in the study. 
Examples of source documents include e-diary, hospital records, clinical and office charts, 
laboratory notes, memoranda, signed ICF, evaluation checklists, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, and 
information initially recorded in an electronic format. The Sponsor may provide source 
documentation worksheets to record pertinent information.  
Data collection is the responsibility of the clinical study staff at each site under the supervision of 
the site Investigator. Each Investigator should ensure the accuracy, completeness, and timeliness 
of the data reported in the electronic data capture (EDC) and all other required reports. Data 
reported in the EDC, that are derived from other source documents, should be consistent with the 
source documents or the discrepancies should be explained. Any missing data must be explained. 
An audit trail will be maintained by the EDC system. Each Investigator should retain records of 
the changes and corrections to paper source documents. 
Subject completed forms are also considered to be source data. In no instance should an 
Investigator or study site personnel record any data or make changes to subject completed forms. 
Each Investigator or designee should review subject completed forms during study visits for 
completeness and accuracy. If an entry is found to be illegible or a mistake is found 
(eg, incorrect year was recorded), the subject should be instructed to edit the entry by drawing a 
single line through the original entry, entering the new information, and dating and initialing the 
change. 
The study monitor will be responsible for reviewing and verifying the data recorded in the 
eCRFs per the study Monitoring Plan utilizing the original source documentation and will query 
discrepant findings. Each Investigator and study site personnel will be responsible for answering 
all queries.  
Details regarding procedures used for data review, database cleaning, and issuing and resolving 
queries will be outlined in the Monitoring Plan and Data Management Plan. 
A copy of the complete subjects’ eCRFs and PROs for the site will be provided to each 
Investigator at the conclusion of the study, and the Investigator must ensure these data are stored 
in a secure place. 
9.2.3. 
Study Agreements 
The Sponsor will secure agreement from all involved parties to ensure direct access 
(Section 9.2.1) to all study related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities. Agreements, made by the Sponsor with each Investigator/institution and any other 
parties involved with the clinical study, will be in writing, as part of the protocol or in a separate 
agreement. 

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9.2.4. 
Archiving of Study Documents 
Each participating site will maintain appropriate medical and research records for this study, in 
compliance with ICH E6 GCP, and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
study.  
The Investigator/institution should maintain the study documents as specified in Essential 
Documents for the ICH E6 Section 8 and as required by applicable regulations and/or guidelines. 
The Investigator/institution should take measures to prevent accidental or premature destruction 
of these documents.  
Essential documents (written and electronic) should be retained for at least 2 years after the 
marketing approval for the drug or as required by regulatory authorities. 
9.3. 
Study Timetable and End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study. 
9.4. 
Data Management 
9.4.1. 
Data Handling 
Data will be reviewed by the clinical research associate (CRA) during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC 
system. An eCRF will be considered complete when all missing, incorrect, and/or inconsistent 
data have been accounted for. 
The CRA will verify the e-diary completion.  
9.4.2. 
Computer Systems 
All eCRF, e-diary, and lab data will be processed using a validated computer system conforming 
to regulatory requirements. 
9.4.3. 
Data Entry 
Data must be recorded using the EDC system and e-diary as the study is in progress. All site 
personnel must log into the EDC system using their secure username and password to enter, 

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review, or correct study data. Subjects must log into the e-diary using their secure username and 
password.  
These procedures must comply with Title 21 of the Code of Federal Regulations (21 CFR 
Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
In the event subject data are transferred from source documentation to eCRF, the Investigator 
will verify that all the information is accurately recorded on the eCRF by providing an electronic 
signature. Data transferred from source documents to eCRF must be traceable back to the source 
documents. 
9.4.4. 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Medical Dictionary for Regulatory Activities (latest) for medical history and AEs; and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
9.4.5. 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data to ensure accurate, 
consistent, and reliable data. Data identified as erroneous, or data that are missing, will be 
referred to the site for resolution through data queries.  
The eCRFs must be reviewed and electronically signed by an Investigator. 
9.5. 
Clinical Study Insurance 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This coverage is 
designed for the event that a fatality, physical injury, or damage to health occurs during the 
clinical study’s execution. 

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10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, ICH E6 GCP, the Declaration of 
Helsinki (2008), and all other applicable regulatory requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
10.2. 
Subject Data Protection 
All laboratory evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area 
with limited access. Clinical information will not be released without the written permission of 
the subject, except as necessary for monitoring and auditing by the Sponsor, its designee, the 
FDA or applicable regulatory authorities, or the IRB.  
The Investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other unpublished 
confidential information disclosed to them for the purpose of the study. Prior written agreement 
from the Sponsor or its designee must be obtained for the disclosure of any said confidential 
information to other parties. 
10.3. 
Ethics and Regulatory Review 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB before study start. Each site must provide the Sponsor or its designee a signed and dated 
statement that the protocol and ICF have been approved by the IRB before consenting subjects. 
Prior to study initiation, each Investigator is required to sign a protocol signature page 
confirming agreement to conduct the study in accordance with this protocol and to give access to 
all relevant data and records to the Sponsor, its designee, and regulatory authorities as required. 
The IRB chairperson or their designee must sign all IRB approvals and must identify the IRB by 
name and address, the clinical protocol, the date approval, and/or if a favorable opinion was 
granted. 
Each Investigator is responsible for obtaining reviews of the clinical research at intervals 
specified by the IRB, but not exceeding 1 year. The Investigator must supply the Sponsor or its 
designee with written documentation of reviews of the clinical research. 
10.4. 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
the Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH 
GCP, local regulatory requirements, and legal requirements. 

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An Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. An Investigator will obtain written 
informed consent from each subject before any study-specific activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the 
study. The original signed ICF must be maintained by an Investigator and is subject to inspection 
by a representative of the Sponsor, their representatives, auditors, the IRB, and/or regulatory 
agencies. A copy of the signed ICF will be given to the subject. 
10.5. 
Changes to the Protocol and Informed Consent Form 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments. The FDA must be notified of protocol amendments. The changes will become 
effective only after approval of the Sponsor, the Investigator, and the IRB. In cases when the 
protocol is modified to enhance subject safety, changes may be implemented, and the 
amendment must be immediately submitted to the IRB. 
Amendment number and date of the amendment will be recorded on the title page of the 
protocol. 
Changes to the ICF will be managed in accordance with the Sponsor’s Standard Operating 
Procedures. 
The Investigator is responsible for informing the IRB of all problems involving risks to subjects 
according to national legislation. In case of urgent safety measures, the Sponsor will immediately 
notify the FDA in accordance with United States CFR Title 21. 
10.6. 
Audits and Inspections 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
and IRB review, and regulatory inspections, by providing direct access to all study records. In 
the event of an audit, the Investigator agrees to allow the Sponsor, representatives of the 
Sponsor, the FDA, and other relevant regulatory authorities access to all study records. 
The Investigator should promptly notify the Sponsor or designee of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the Sponsor 
or designee. 

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11. 
LIST OF REFERENCES 
 
 
 
 
 
 
Centers for Disease Control and Prevention. National Diabetes Statistics Report website. 
https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed [April 13, 2022]. 
D’Amato C, Morganti R, Greco C, et al. Diabetic peripheral neuropathic pain is a stronger 
predictor of depression than other diabetic complications and comorbidities. Diab Vasc Dis Res. 
2016;13(6):418-28. 
 
 
Farmer KL, Li C, Dobrowsky RT. Diabetic peripheral neuropathy: Should a chaperone 
accompany our therapeutic approach? Pharmacol Rev 2012;64(4):880-900. 
Fernyhough P, Roy Chowdhury SK, Schmidt RE. Mitochondrial stress and the pathogenesis of 
diabetic neuropathy. Expert Rev Endocrinol Metab 2010;5(1):39-49. 
 
 
Herman WH, Pop-Busui R, Braffett BH. et al. Use of the Michigan Neuropathy Screening 
Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results 
from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and 
Complications. Diabet Med. 2012;29(7):937-44. 
Lee SH, Kim M, Yoon BW, et al. Targeted hsp70.1 disruption increases infarction volume after 
focal cerebral ischemia in mice. Stroke. 2001;32(12):2905-12. 
Ma J, Pan P, Anyika M, et al. Modulating molecular chaperones improves mitochondrial 
bioenergetics and decreases the inflammatory transcriptome in diabetic sensory neurons. ACS 
Chem Neurosci. 2015;6(9):1637-48.  
Park HK, Cho AR, Lee SC, et al. MPTP-induced model of Parkinson's disease in heat shock 
protein 70.1 knockout mice. Mol Med Rep. 2012;5(6):1465-8. 
Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the 
American Diabetes Association. Diabetes Care. 2017;40(1):136-54. 
Ran R, Lu A, Zhang L, et al. Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma 
and impairing NF-kappa B survival signaling. Genes Dev. 2004;18(12):1466-81. 

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Vernon MK, Brandenberg NA, Alvir JMJ, Griesing T, Revicki DA. Reliability, validity and 
responsiveness of the daily sleep interference scale among diabetic peripheral neuropathy and 
postherpetic neuralgia patients. J Pain Symptom Mgt. 2008;36(1):54-68. 
Yang M, Qian C, and Liu Y. Suboptimal treatment of diabetic peripheral neuropathic pain in the 
United States. Pain Med. 2015;16(11):2075-83. 
Zhang X, Li C, Fowler SC, et al. Targeting heat shock protein 70 to ameliorate c-jun expression 
and improve demyelinating neuropathy. ACS Chem Neurosci 2018;9:381-90. 

 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
5 Foundation Park 
Roxborough Way 
Maidenhead, Berkshire 
SL6 3UD 
United Kingdom 
 
 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 901-C-2102 
A Phase 2 Study to Evaluate the Safety and Efficacy of RTA 901 in Patients with Diabetic 
Peripheral Neuropathic Pain  
Version 4.0 
Date: 09 May 2024 
Version 4.0 of the protocol has been prepared for this amendment, which supersedes Version 3.0. 
 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 
PRIMARY REASON FOR AMENDMENT 
The primary reasons for this amendment to Protocol 901-C-2102 are: 
• To update the language of rescue medicine use to address recommendations from the 
Data Monitoring Committee (DMC). 
• To update the language regarding interim exposure-response (E-R) analysis (an E-R 
analysis including all participants will be performed at the completion of Part 1 instead of 
an interim analysis when 96 subjects complete treatment through Week 12 of Part 1).  
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 7.8.3, Rescue Medication 
Now reads: 
Subjects may use a single rescue medication (NSAID or acetaminophen) to treat DPNP as 
needed during study participation, in addition to their standard of care medication. Subjects may 
not alternate between NSAIDs and acetaminophen. The rescue medication of choice should 
remain consistent throughout the study. If rescue medication is needed, subjects will be 
instructed to take acetaminophen 500 mg every 4 to 6 hours as needed (not to exceed 3000 mg 
per day) or ibuprofen 200 to 400 mg every 4 to 6 hours as needed (not to exceed 1200 mg per 
day). 
This does not exclude the use of these rescue medications in other forms for other uses outside of 
treatment for DPNP. Subjects taking one form of rescue medication can take a medication 
containing the other form solely for use outside of DPNP. The daily maximum dosages are 
inclusive of those used outside of treatment for DPNP. Subjects should be encouraged NOT to 
take cough syrups or sleep aids containing NSAIDs (eg, Nyquil for cold/flu, or Tylenol PM for 
sleep), but if they do then it should be recorded as concomitant medication. The use of NSAIDs 
for cardiovascular health is allowed and should be documented as a concomitant medication. The 
daily maximum dosages of each medication should still be maintained. Any questions related to 
rescue medications should be directed to the Medical Monitor prior to administration when 
possible. 
Rescue medication for DPNP is in addition to standard of care medication (gabapentin, 
pregabalin or duloxetine) for DPNP. Rescue medication is intended to treat temporary 
elevations in a subject’s DPNP and is intended to be used occasionally and not meant to be 
used for prolonged periods of time.  
Subjects who enter screening after implementation of protocol Version 4.0 may only use 
acetaminophen as a rescue medication for DPNP as needed. If rescue medication is needed 
for DPNP, subjects will be instructed to take acetaminophen 500 mg every 4 to 6 hours as 
needed (not to exceed 3000 mg per day). 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
Subjects currently in the study at the time of implementation of protocol Version 4.0 using 
ibuprofen as rescue medication for DPNP may switch their rescue medication to 
acetaminophen (i.e., no longer use ibuprofen as a rescue medication for DPNP) or continue 
to use as rescue medication for DPNP ibuprofen  200 to 400 mg every 4 to 6 hours as 
needed (not to exceed 600 mg/day) for up to 3 days in a 7-day period (not calendar week). 
Subjects unable to comply with these conditions will need to discontinue study treatment 
and withdraw from the study; some or all of such subjects may be replaced at the 
discretion of the Sponsor.  
The daily maximum dosages in stated in this section are inclusive of those used outside of 
treatment for DPNP. Any questions related to rescue medications should be directed to the 
Medical Monitor prior to administration when possible. 
Rationale: The rescue medication language was updated in response to a DMC concern 
regarding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as a rescue medication in 
the target diabetic population. The DMC provided the following recommendations: 
• Newly enrolled subjects cannot use NSAIDs as rescue medication for DPNP. 
• Subjects in screening who had been using NSAIDs for DPNP pain must wash out 
before starting study medication. 
• Currently enrolled participants taking NSAIDs as rescue for DPNP will be asked to 
switch to acetaminophen or keep the NSAID dose within a cap of 600mg/day for no 
more than 2-3 days per week. If the participants are unable to abide by those limits or 
are exceeding them, they would have to exit the study or switch to acetaminophen. 
• New and continuing subjects can use NSAIDs if these are prescribed for conditions 
other than DPNP. As the Rx would be coming from a non-study MD, there would be 
no specific number of days the NSAID could be used for a condition other than 
DPNP. 
To implement the DMC recommendations, rescue medication language was updated. 
This change also affects the following sections:  
• Protocol Synopsis, Objectives 
• Protocol Synopsis, Endpoints 
• Section 2.1.2, Secondary Objectives 
• Section 2.2.2, Secondary Endpoints 
• Section 3.2, Screening Period (Days -28 to -15) 
• Section 3.4, Treatment Period (Day 1 to Week 12) 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
4 
• Section 7.8.2, Allowed Medications 
• Section 7.8.4, Prohibited Medications 
Section 3.6, Part 2 Dose Selection Process 
Now reads: 
A Dose Selection Committee (DSC) comprised of Sponsor personnel and an external 
pharmacometrics consultant will select the 2 doses of RTA 901 for Part 2 using data from Part 1. 
An E-R analysis for efficacy will be conducted with efficacy data from all subjects up to 
Week 12 of treatment in Part 1 and provide a dosing recommendation for Part 2 to the 
DSC. Once the first 96 subjects in Part 1 complete treatment through Week 12, the external 
pharmacometrics consultant will conduct the interim E-R analysis for efficacy using unblinded 
data and provide a dosing recommendation for Part 2 to the Sponsor personnel. The doses of 
RTA 901 for Part 2 will be selected from a dose range of 1 to 80 mg by the DSC based on this 
analysis. If the DSC determines that the interim E-R analysis for efficacy (N=approximately 32 
per arm) does not provide sufficient RTA 901 E-R information to make dose recommendations 
for Part 2, then an additional E-R analysis for efficacy will be conducted with all subjects in each 
treatment arm in Part 1 who completed treatment through Week 12. The selected doses will be 
documented in a Note-to-File to the Investigators and IRBs (as appropriate) and will not require 
a protocol amendment.   
It is possible that enrollment in Part 2 of the study may begin while some Part 1 subjects are 
completing their remaining study visits. Subjects enrolled in Part 1 will not be eligible for 
enrollment in Part 2.  
Details of the membership, objectives, and process to be followed by the DSC will be described 
in a separate charter. Additionally, a separate data management and analysis plan supporting this 
activity will be created. Results will be reported in a separate standalone report, outside the 
clinical study report (CSR). 
Figure 1: 
Part 2 Dose Selection Process 
 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
5 
Abbreviations: E-R=exposure-response 
Rationale: The original intent of the protocol was to conduct an interim E-R analysis after the 
first 96 participants completed Part 1 of the study to inform dose selection for Part 2 of the study. 
The updated language and removal of Figure 2 reflect the plan not to conduct an interim E-R 
analysis during Part 1 and instead to base dose selection decisions on an E-R analysis for 
efficacy conducted with data from all subjects up to Week 12 of treatment in Part 1. 
This change also affects the following sections:  
• Protocol Synopsis, Study Schema 
• Protocol Synopsis, Statistical Methods 
• Section 1.2, Study Rationale 
• Section 1.4, Dose Rationale 
• Section 4.5, Subject Enrollment and Randomization 
• Section 4.5.2.3, Dose Selection Committee 
• Section 8.4.6, Interim Analysis 
• 
 
 
 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
6 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Protocol Synopsis 
The Protocol Synopsis was revised to reflect changes made throughout the protocol. 
Section 5.3.2, Follicle-Stimulating Hormone 
Change: Added more information regarding assessment of child-bearing potential.  
Now reads: 
Follicle-stimulating hormone (FSH) will only be assessed at Screening for female subjects who 
have been post-menopausal for at least 1 year and are not surgically sterile (e.g., not had 
bilateral tubal ligation, bilateral oophorectomy, or a hysterectomy). The investigator, based 
on the available information (including the FSH result), uses their clinical judgment to 
determine whether or not the participant is of child-bearing potential. 
Rationale: To provide additional clarity regarding the assessment of child-bearing potential in 
the study. 
Section 6.7, Methods of Birth Control 
Change: The description of the allowed methods of contraception was updated from 
"acceptable" to "highly effective." Text noting restrictions on egg and sperm donation for 
participants is added. 
Now reads: 
During Screening, while taking study drug, and until 30 days following administration of the 
final dose of study drug, females of child-bearing potential must practice 1 of the following 
acceptable highly effective methods of birth control: 
• Use of hormonal contraceptives associated with inhibition of ovulation (oral, 
parenteral, intravaginal, or transdermal) as prescribed; 
• Use of a non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed); 
• Use of an intrauterine hormone-releasing system as prescribed; 
• Vasectomized partner (with vasectomy performed at least 6 months prior to Screening 
with the appropriate post-procedure documentation of surgical success). Partner must 
be the sole partner for that subject; 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
7 
• Abstain from sexual intercourse completely. Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual. 
Periodic abstinence is not permitted. 
In addition, female participants should not donate eggs for the duration of the study and 
for at least 30 days after their last dose of study treatment. 
During Screening, while taking study drug, and until 30 days after the final dose of study drug, 
fertile males who have female partners of child-bearing potential must practice 1 of the following 
methods of birth control: 
• Partner contraception methods; must be the sole partner for that subject: 
− Use of a non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed);  
− Use of hormonal contraceptives associated with inhibition of ovulation (oral, 
parenteral, intravaginal or transdermal) as prescribed; 
− Use of an intrauterine hormone-releasing system as prescribed; 
− Surgically sterile partner (bilateral tubal ligation, hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy); fallopian inserts with confirmed 
blockage (eg, x-ray, ultrasound); 
− Reproductive potential has been terminated by radiation; 
− Postmenopausal (defined as no menses for at least 1 year without an alternative 
medical cause). 
• Abstain from sexual intercourse completely. Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual. 
Periodic abstinence is not permitted. 
In addition, male participants should not donate sperm for the duration of the study and 
for at least 90 days after their last dose of study treatment. 
Rationale: The wording "highly effective" aligns with the Clinical Trials Facilitation Group 
Recommendations related to contraception and pregnancy testing in clinical trials guidance 
terminology. The added language on egg/sperm donation reflects the latest changes in the 
Investigator’s Brochure and the Patient Safety Information. 

Amendment Summary for Protocol 901-C-2102, Version 4.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
8 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate:  
• The version number and date were updated throughout the protocol.  
• Protocol version history was removed. 
• The Signature Page was updated to align with the applicable protocol template. 
• The Page of Contacts in Case of Emergency was updated. 
• Minor inconsistencies and formatting were corrected.  
 

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Reata Confidential 
 
 
 
 
 
 
 
 
 
AMENDMENT CHANGE SUMMARY DOCUMENT 
 
 
CLINICAL STUDY PROTOCOL 901-C-2102 
 
Study Title: A PHASE 2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF RTA 901 IN PATIENTS WITH DIABETIC 
PERIPHERAL NEUROPATHIC PAIN  
 
 
 
 
Protocol History 
Version 1.0 – 28 April 2022 
Version 2.0 – 27 September 2022 
Version 3.0 – 8 February 2023 
 
 
 
CONFIDENTIALITY STATEMENT 
 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc. Any unauthorized use or disclosure of 
such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 

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SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 2 to produce the text of Version 3. Additionally, the following 
points are provided: 
 
• 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis 
are not described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the current amended version of the protocol. 

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Section 
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Rationale 
Title Page 
RTA 901 
901-C-2102 
A PHASE 2 STUDY TO EVALUATE THE SAFETY AND EFFICACY 
OF RTA 901 IN PATIENTS WITH DIABETIC PERIPHERAL 
NEUROPATHIC PAIN (DPNP) 
CYPRESS 
RTA 901 
VERSION 2 3.0– 27 SEP 2022 8 FEB 2023  
The abbreviation “DPNP” was 
removed from the study title. 
 
The study name was removed 
from the title page, in lieu of the 
study title. 
 
The version and date were 
updated. 
Footer 
Version 23.0 – USA – 27-Sep-20228-FEB-2023 
The country was removed from 
the footer since this study will 
only be performed in the USA. 
The date was updated. 
SIGNATURE PAGE  
, MS 
 
Reata Pharmaceuticals, Inc. 
Clarification of 
 
title. 
SIGNATURE PAGE  
, MPH  
Clarification of 
 
credentials and middle initial. 
SIGNATURE PAGE  
{See Appended Electronic Signature Page} 
, PharmD, PhD 
 
Reata Pharmaceuticals, Inc.   
Addition of 
 as a 
signatory 
1.  INTRODUCTION 
Given the preclinical data, Reata Pharmaceuticals, Inc. (hereinafter 
referred to as Reata or the Sponsor) is interested in pursuing further 
clinical development of RTA 901. 
Clarification of the terms used to 
refer to Reata Pharmaceuticals 
1.1.  Clinical Experience 
The formulation used in this study was 
 of RTA 
901 
.   
Providing additional detail on the 
form of the study drug 
1.1.  Clinical Experience 
The safety, tolerability, 
 of oral RTA 901 is currently being were 
also evaluated in 2 additional recently completed Phase 1 clinical 
studies: 
• 
:
 
 
Additional detail was provided on 
prior clinical studies conducted 
with RTA 901. 

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1.1.  Clinical Experience 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Additional detail was provided on 
prior clinical studies conducted 
with RTA 901. 
 
 
1.1.1.  Safety and 
Tolerability 
Overall, RTA 901 oral capsules were well tolerated in healthy volunteers 
following single who took a single dose (10 to 160 mg) and multiple 
doses (10 to 80 mg) in a 14-day multiple ascending dose Phase 1 study 
(Study 901-C-1503). No serious adverse events (SAEs) or treatment-
emergent adverse events (TEAEs) leading reportedly lead to study drug 
discontinuation were reported. No deaths were reported during the study. 
Administration of RTA 901 during the study (Part 1 [SAD] and Part 2 
[MAD]) was generally safe and well tolerated, with no SAEs, or TEAEs 
that were considered related to RTA 901 study drug. Also. Of the 
unrelated TEAEs, most TEAEs were Grade 1 in severity and. No deaths 
were assessed as unrelated to reported during the study drug by the 
Investigator. 
This text was edited grammatically 
for clarity. 

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1.2.  Study Rationale 
Therefore, the current study is designed to investigate the efficacy 
and safety of multiple doses of RTA 901 in DPNP subjects with 
DPNP, when RTA 901 is added to the standard-of-care (SOC) pain 
medication. RTA 901 doses of 10 mg, 40 mg, and 80 mg once daily 
(QD) will be investigated in Part 1 of this study, so that. Based on an 
interim exposure-response (E-R) analysis for efficacy in Part 1, 
2 doses of RTA 901 between 1 to 80 mg QD will be investigated in 
Part 2 of the study. This will allow the Sponsor to determine the 
optimal dose(s)for future development can be selected based on the 
efficacy and safety data from this study.  
The study design was modified to 
better determine the optimal dose 
of RTA 901 for future studies. The 
study will be conducted in 2 parts 
with differing treatment arms in 
each part.   
1.3.  Rationale for Study 
Population 
1.3. 
Rationale for Study Population 
Diabetic peripheral neuropathic pain is a common condition seen in 
both T1DM and T2DM. Neuropathic pain can lead to interference 
with daily activities, disability, psychosocial impairment, and 
This text was moved from 
Section 3.7 of the protocol. 

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 It may be associated with 
hyperalgesia and allodynia. Although there are approved therapies 
for this condition, they are limited by efficacy and tolerability. Many 
treatments are discontinued, suggesting low levels of satisfaction 
and/or poor tolerability (Yang, 2015). Given this, and the large and 
growing population of subjects with diabetes, a significant unmet 
medical need remains. 
According to the Centers for Disease Control National Diabetes 
Statistics Report (2022), 37.3 million Americans have diabetes. The 
most common neuropathy associated with diabetes is DSPN (Pop-
Busui, 2017). Although estimates of its incidence and prevalence 
vary, data suggests that DSPN occurs in at least 20% of subjects with 
T1DM after 20 years of disease. It may be present in at least 10% to 
15% of subjects newly diagnosed with T2DM with rates increasing 
to 50% after 10 years of disease duration. Neuropathic pain, 
specifically DPNP, is present in up to 25% of subjects with DSPN. 
The development of DPNP is associated with a small-fiber 
neuropathy resulting from dysfunction of unmyelinated or thinly 
myelinated sensory fibers and the gradual degeneration of larger 
myelinated fibers. Further, although numerous pathologic 
mechanisms contribute to DPNP (Farmer, 2012), increased oxidative 
stress and mitochondrial dysfunction appear to be a central facilitator 
in its development (Fernyhough, 2010). Nonclinical data suggest that 
RTA 901 is able to improve dysfunction resulting from pathogenic 
demyelination of sensory fibers, along with mitigation of 
mitochondrial dysfunction. Taken together, the potent 
pharmacological effects of RTA 901 shown in animal models 
support the hypothesis that RTA 901 may have potential therapeutic 
benefit to treat the central pathology underlying the development of 
DPNP. 
1.4.  Dose Rationale 
1.4. 
Dose Rationale 
Dose selection for Part 1 was based on the established safety profile 
from the first-in-human study in healthy subjects 
(Study 901-C-1503), 
 
, no observed adverse effect levels established in 
3-month good laboratory practice (GLP) toxicity studies in mice and 
This text was moved from 
Section 3.8 of the protocol with 
additional updates to provide 
justification for planned interim 
analysis for efficacy in Part 1 of 
the study. 

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monkeys, and exposures required to produce efficacy in rodent 
models of DPN.    
RTA 901 was generally safe and well tolerated following single 
doses of up to 160 mg and multiple daily doses (for 14 days) of up to 
80 mg (Study 901-C-1503) using 
RTA 901
 
 
Additionally, at the highest proposed dose of 80 mg QD, there is at 
least a 40-fold safety margin based on the data from the 3-month 
GLP toxicity studies in mice and monkeys (Table 8 of the IB). 
Based on the clinical multiple dose study (901-C-1503), 
 
 
 
 
 
These exposures are similar to or above the exposures at the 
efficacious doses in the rodent models of diabetic neuropathy
 
 
 
In summary, at the proposed doses for Part 1, RTA 901 is predicted 
to have efficacious and safe exposure in subjects with DPNP, with a 
10 mg dose anticipated to be an efficacious dose and 80 mg the 
highest feasible dose with potentially maximal efficacy and an 
acceptable safety profile. However, based on the exposures 
associated with efficacy in the nonclinical models, it is possible that 
a dose lower than 10 mg may need to be explored to identify the 
minimally effective dose in subjects with DPNP and thereby enable a 
robust phase 2 dose ranging study. Therefore, a planned interim E-R 
analysis for efficacy from the first 96 subjects in Part 1 of this study 
has been incorporated to recommend the optimal doses for 
investigation in Part 2. Eligible doses for selection in Part 2 will be 
limited to a dose range of 1 to 80 mg. Part 2 doses will not exceed 
80 mg, at which there is at least a 40-fold safety margin based on the 
data from the 3-month GLP toxicity studies in mice and monkeys. 
2.1.1. Primary Objectives 
2.1.1. Primary Objectives 
2.1.1.1.  Efficacy  
•  To assess the efficacy of RTA 901 based on change from baseline in 
Subheadings were added to denote 
the primary efficacy and safety 
objectives of the study. 

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the average daily pain score using the Numeric Pain Rating Scale 
(NPRS) after 812 weeks of treatment 
2.1.1.2. Safety  
•  To assess the safety and tolerability of RTA 901 during and 
following the Treatment Period  
 
Additional detail was included on 
the method for determining the 
primary efficacy objective based 
upon recommendation from the 
FDA.  
 
The Treatment Period of the study 
was lengthened to 12 weeks. 
2.1.2. Secondary 
Objectives 
• 
To assess the efficacy of RTA 901 in achieving at least 30% 
decrease in the Numeric Pain Rating Scale (NPRS) pain 
intensity score after 812 weeks of treatment  
• 
To assess the efficacy of RTA 901 in achieving at least 50% 
decrease in the NPRS pain intensity score after 812 weeks of 
treatment 
• 
To assess the Daily Sleep Interference Scale (DSIS) score after 
812 weeks of treatment 
The pain intensity score on the 
NPRS is the data point used for 
these objectives. 
 
The Treatment Period of the study 
was lengthened to 12 weeks. 
2.2. 
Study Endpoints 
The primary, secondary, exploratory, 
 endpoints will be 
evaluated for each dose of RTA 901 compared to placebo. 
This text was added to describe the 
endpoints of the study. 
2.2.1. Primary Endpoints 
2.2.1.1.  Efficacy  
• 
Change from baseline in the average pain intensity as assessed by 
Subheadings were added to denote 
the primary efficacy and safety 

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the daily NPRS pain intensity at score during Week 8 12 
2.2.1.2.  Safety  
• 
Frequency, intensity, and relationship to study drug of AEs and 
SAEs and change from baseline in the following assessments: 
physical examinations, vital sign measurements, 12-lead ECGs, 
clinical laboratory measurements, and body weight. 
endpoints of the study. 
 
Additional detail was included on 
the method for determining the 
primary efficacy endpoint based 
upon recommendation from the 
FDA.  
 
The Treatment Period of the study 
was lengthened to 12 weeks. 
 
The description of the 12-lead 
ECGs was redundant with later 
text and was removed. 
2.2.2. Secondary 
Endpoints 
• 
Proportion of subjects who achieve at least a 30% decrease in 
the NPRS score from baseline to in the Week 8 12 average 
NPRS pain intensity score  
• 
Proportion of subjects who achieve at least a 50% decrease in 
the NPRS score from baseline to in the Week 8 12 average 
NPRS pain intensity score 
• 
Change from baseline in the average DSIS at score during 
Week 8 12   
The treatment period of the study 
was lengthened to 12 weeks. 
 
The pain intensity score on the 
NPRS is the data point used for 
these endpoints. 
 
Additional detail was included on 
the method for determining the 
secondary endpoint based upon 
recommendation from the FDA. 

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3.1.  Study Design 
This is a 2-part, randomized, placebo-controlled, double-blind, Phase 2 
study to evaluate the safety, tolerability, efficacy, 
 of RTA 901 in 
qualified subjects with Diabetic Peripheral Neuropathic Pain (DPNP).  
The duration of the study will be approximately 16 weeks, including a 
Screening Period of up to 2 weeks, a Run-in Period of 2 weeks, a 
Treatment Period of 8 weeks, and a Follow-up Period of 4 weeks. 
Following the Run-in Period, subjects who remain eligible will be 
randomized 1:1:1:1 to either RTA 901 (10, 40, or 80 mg) or placebo at 
Day 1 (randomization).. Approximately 368 192 eligible subjects (92 
64 subjects per treatment arm) will be enrolled, and randomization in 
Part 1, and approximately 192 eligible subjects (64 subjects per 
treatment arm) will be enrolled in Part 2, for a total of 384 subjects 
randomized. Randomization within each part will be stratified by SOC 
pain medication using randomization and trial supply management 
(RTSM). A total of approximately 75 sites in the United States will be 
included in this study. 
The duration of each part of the study will be approximately 
20 weeks, including a Screening Period of up to 2 weeks, a Run-in 
Period of 2 weeks, a Treatment Period of 12 weeks, and a Follow-up 
Period of 4 weeks. All subjects in Part 1 and Part 2 of the study will 
follow the same visit and assessment schedule.   
The study design was modified to 
better determine the optimal dose 
of RTA 901 for future studies. The 
study will be conducted in 2 parts 
with differing treatment arms in 
each part.   
 
The Treatment Period of the study 
was lengthened to 12 weeks. 
Figure 1: Study Design  
The study design was replaced 
with the 2-part design and 
extended Treatment Period. 
Figure 1: Study Design 
Part 1 
 
The study design was updated with 
the 2-part design and extended 
Treatment Period. 

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Part 2 
 
Abbreviations: EOS=end of study; EOT=end of treatment; Wk=Week 
3.2.  Informed Consent 
3.2. 
Informed Consent 
The informed consent form (ICF) must be signed prior to the 
initiation of any Screening or study-specific procedures. See Section 
10.4 for details on informed consent. 
Redundant text was consolidated 
to Section 10.4. 
3.2.  Screening Period 
(Days -28 to -15)  
The Screening Period includes 1 clinic visit, up to 2 weeks prior to 
the Run-in Period (within approximately 28 days prior to Day 1, 
approximately, as the visit has a ±2-day window). Upon Institutional 
Review Board (IRB) approval of the protocol, potential subjects will 
be required to sign a written informed consent form (ICF) for the 
study before any study-specific screening procedures are performed. 
See Section 10.4 for details on informed consent. Subjects who meet 
the Run-in inclusion criteria (Section 4.1) and none of the exclusion 
criteria are considered eligible to proceed to Run-in. Washout from 
prohibited medications is allowed during the Screening Period if the 
Investigator deems it medically appropriate.  The; the washout period 
must cover 5 half-lives of the prohibited medication and must be 
completed prior to the end of the Screening Period. 
Added clarity around the timing 
of the Day 1 visit relative to the 
Screening visit. 
 
 
 
 
 
 
Text added to clarify that the 
washout must be completed 
during the Screening Period. 
3.2.  Screening Period 
(Days -28 to -15) 
Subjects will be given access to an e-diary at Screening and will be 
trained on how to use it. Daily pain score/status utilizing Subjects 
will be directed to complete the NPRS will be collected in the e-diary 
for 2 consecutive weeks. Starting after this visit, pain intensity and 
record their rescue medication use will be recorded daily usage in the 
e-diary at bedtime in the e-diary. Subjects will enter their average 
pain intensity, worst pain intensity, pain on walking, and whether 
rescue medication was used during the past 24 hours. Subjects will 
also complete the DSIS via their study-issued e-diary daily upon 
waking, preferably in the morning. 
Text was modified for clarity and 
repeated text was deleted. 

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3.2.  Screening Period 
(Days -28 to -15)  
Subjects must have a score of ≥ 4 on the 11-point NPRS for average 
pain intensity over the past 24 hours at Visit 1, denoting moderate to 
severe pain. 
Additional procedures during Screening (Visit 1) will include the 
administration of the following
 (Section 5.4.2): 
are to be completed according to the Schedule of 
Assessments (Table 4).    
The pain intensity score on the 
NPRS is the data point used for this 
criterion. 
 
 
 
 
3.3.  Run-in Period 
(Days -14 to -1)  
Since the first dose will be taken in-clinic at the Run-in visit, subjects 
should fast for 2 hours prior to the visit. 
During the Run-in Period, daily NPRS scores will continue to be 
collected using the e-diary.  Pain intensity and rescue medication use 
will also continue to be recorded daily at bedtime in the e-diary. 
Subjects will also complete the DSIS upon waking, preferably in the 
morning.. The baseline score will be calculated as the mean of the 
pain scores recorded daily by the subject within the last 7 days prior 
to randomization (the average value is not to be rounded). to 
1 decimal point). Fluctuations in the pain score are allowed. A 
minimum of 5 measurements must be recorded. The other Additional 
procedures 
 are to be completed according to the Schedule 
of Assessments (Table 4). 
Additional guidance on fasting 
prior to the Run-in visit was 
provided. 
 
Redundant text was removed. 
 
 
The DSIS average will be 
rounded to 1 decimal point. 
 
 
3.4.  Treatment Period 
(Day 1 to Week 12) 
The Treatment Period includes 98 clinic visits over 812 weeks. 
Subjects Within each part of the study, subjects who successfully 
meet the Randomization eligibility criteria will be randomized using 
RTSM and stratified by SOC pain medication with 3 groups 
(duloxetine, pregabalin/gabapentin, or other) on Day 1, see 
Section 4.5. 
The Treatment Period of the 
study was adjusted to 8 visits in 
12 weeks. 
3.4.  Treatment Period 
(Day 1 to Week 12) 
Subjects should also fast for at least 8 hours prior to clinic visits where 
fasting lipids are taken (Screening, Week 4, Week 8, Week 12, and 
Week 16). Additional study procedures and assessments will be 
performed according to the Schedule of Assessments (Table 4). 
Subjects will also be instructed to use rescue medication for DPNP if 
needed and reminded not to exceed 3000 mg/day of acetaminophen 
or 1200 mg/day of NSAIDs. Subjects will be directed to continue 
entering completing the average of pain intensity, worst pain 
intensity, NPRS and pain upon walking and whether they needed to 
use recording their rescue medication, usage in the e-diary at 
Additional guidance was 
provided for fasting on days 
when fasting lipids would be 
taken. 
 
Text was modified for clarity and 
repeated text was deleted. 

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bedtime. Upon waking in the morning, subjects will be asked to 
complete the DSIS. Additional procedures 
 are to be 
completed according to the Schedule of Assessments (Table 4). 
3.4.  Treatment Period 
(Day 1 to Week 12) 
The other Additional procedures 
 are to be completed 
according to the Schedule of Assessments (Table 4). 
Week 812/Day 5785 will be the end of treatment (EOT) visit.  
The Treatment Period of the 
study was lengthened to 12 
weeks. 
3.5.  Follow-up/End of 
Study (Week 16) 
3.5.  Follow-up/End of Study (Week 1216) 
The Follow-up Period includes 1 clinic visit on Day 113 ± 2, which 
must occur approximately 4 weeks following the EOT visit on Day 
85 ± 3.  Procedures will be performed according to the Schedule of 
Assessments (Table 4). Completion of this visit concludes the 
subject’s participation in the study. 
Subjects will be directed to continue entering completing the average 
of pain intensity, worst pain intensity, NPRS and pain upon waking 
and whether they needed to use recording their rescue medication, 
usage in the e-diary at bedtime. Upon waking in the morning, 
subjects will be asked to complete the DSIS. Additional procedures 
 are to be completed according to the Schedule of 
Assessments (Table 4). 
The follow-up visit is now on 
Week 16. 
 
 
Text was modified for clarity and 
repeated text was deleted. 
3.6.  Part 2 Dose Selection 
Process  
A Dose Selection Committee (DSC) comprised of Sponsor personnel and 
an external pharmacometrics consultant will select the 2 doses of 
RTA 901 for Part 2 using data from Part 1. Once the first 96 subjects in 
Part 1 complete treatment through Week 12, the external 
pharmacometrics consultant will conduct the interim E-R analysis for 
efficacy using unblinded data and provide a dosing recommendation for 
Part 2 to the Sponsor personnel. The doses of RTA 901 for Part 2 will be 
selected from a dose range of 1 to 80 mg by the DSC based on this 
analysis. If the DSC determines that the interim E-R analysis for efficacy 
(N=approximately 32 per arm) does not provide sufficient RTA 901 E-R 
information to make dose recommendations for Part 2, then an additional 
E-R analysis for efficacy will be conducted with all subjects in each 
treatment arm in Part 1 who completed treatment through Week 12. The 
selected doses will be documented in a Note-to-File to the Investigators 
and IRBs (as appropriate) and will not require a protocol amendment.   
It is possible that enrollment in Part 2 of the study may begin while some 
Part 1 subjects are completing their remaining study visits. Subjects 
enrolled in Part 1 will not be eligible for enrollment in Part 2.  
Text from other sections of the 
protocol was merged into this 
new section. 

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Details of the membership, objectives, and process to be followed by the 
DSC will be described in a separate charter. Additionally, a separate data 
management and analysis plan supporting this activity will be created. 
Results will be reported in a separate standalone report, outside the 
clinical study report (CSR). 
Figure 2: Part 2 Dose 
Selection Process 
 
Abbreviations: E-R=exposure-response 
This figure was added to 
illustrate the dose selection 
process for Part 2.  
3.7.  Rationale for Study 
Population  
3.7.  Rationale for Study Population 
DPNP is a common condition seen in both T1DM and T2DM. 
Neuropathic pain can lead to interference with daily activities, disability, 
psychosocial impairment, 
 
It may be 
associated with hyperalgesia and allodynia. Although there are approved 
therapies for this condition, they are limited by efficacy and tolerability. 
Many treatments are discontinued, suggesting low levels of satisfaction 
and/or poor tolerability (Yang, 2015). Given this, and the large and 
growing population of subjects with diabetes, a significant unmet 
medical need remains. 
According to the Centers for Disease Control National Diabetes Statistics 
Report (2022), 37.3 million Americans have diabetes. The most common 
neuropathy associated with diabetes is DSPN (Pop-Busui, 2017). 
Although estimates of its incidence and prevalence vary, data suggests 
that DSPN occurs in at least 20% of subjects with T1DM after 20 years 
of disease. It may be present in at least 10% to 15% of subjects newly 
diagnosed with T2DM with rates increasing to 50% after 10 years of 
disease duration. Neuropathic pain, specifically DPNP, is present in up to 
25% of subjects with DSPN. 
The development of DPNP is associated with a small-fiber 
neuropathy resulting from dysfunction of unmyelinated or thinly 
This text was moved to 
Section 1.3 of the protocol. 

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myelinated sensory fibers and the gradual degeneration of larger 
myelinated fibers. Further, although numerous pathologic 
mechanisms contribute to DPNP (Farmer, 2012), increased oxidative 
stress and mitochondrial dysfunction appear to be a central facilitator 
in its development (Fernyhough, 2010). Nonclinical data suggest that 
RTA 901 is able to improve dysfunction resulting from pathogenic 
demyelination of sensory fibers, along with mitigation of 
mitochondrial dysfunction. Taken together, the potent 
pharmacological effects of RTA 901 shown in animal models support 
the hypothesis that RTA 901 may have potential therapeutic benefit 
to treat the central pathology underlying the development of DPNP. 
3.8.  Dose Rationale  
3.8.  Dose Rationale  
Dose selection was based on the established safety profile from the first-
in-human study in healthy subjects (Study 901-C-1503), no-observed-
adverse-effect levels (NOAELs) established in 3-month good laboratory 
practice (GLP) toxicity studies in mice and monkeys, and exposures 
required to produce efficacy in rodent models of diabetic peripheral 
neuropathy.    
RTA 901 was generally safe and well tolerated following single doses of 
up to 160 mg and multiple once a daily dose (for 14 days) of up to 80 mg 
(Study 901-C-1503). Additionally, at the highest proposed dose of 80 mg 
QD, there is at least a 40-fold safety margin based on the data from the 
3 month GLP toxicity studies in mice and monkeys (Table 8 of the 
Investigator’s Brochure). 
Based on the clinical multiple dose study (901-C-1503), 
 
 These exposures 
are similar to or above the exposures at the efficacious doses in the 
rodent models of diabetic neuropathy 
 
 
In summary, at the proposed doses, it is predicted to have efficacious 
and safe exposure in the subjects with DPNP with 10 mg anticipated 
to be the minimum efficacious dose and 80 mg the highest feasible 
dose with optimal efficacy and acceptable safety profile. 
This text was moved to 
Section 1.4 of the protocol. 

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4.1.1.  Run-in Inclusion 
Criteria 
4.  Currently taking ≤ only 1 allowed prescribed standard-of-care 
SOC pain medication for managing DPNP at a stable dose (not 
exceeding the maximum dose in the prescribing information) for 
approximately 4 weeks prior to Screening (Section 7.8.1); or failed to 
respond or tolerate SOC (approved medications for DPNP) and are 
receiving alternative pain medications; 
The subjects must be taking only 
1 SOC pain medication. 
Refractory subjects are now 
excluded. 
4.1.1.  Run-in Inclusion 
Criteria  
5. Stable glycemic control as indicated by Hemoglobin A1C (HbA1c) 
value ≤ 11% at values over the 3 months prior to Screening;  
Inclusion criterion modified 
based on recommendation from 
the FDA. 
4.1.2.  Run-in Exclusion 
Criteria 
3. HbA1c > 11% at Screening; 
This exclusion criterion was 
moved from the Run-in Inclusion 
criteria. 
4.1.2.  Run-in Exclusion 
Criteria  
12.  Unwilling to practice methods a protocol-specified acceptable 
method of birth control (both males who have partners of 
childbearing potential and females of child-bearing potential) during 
Screening, while taking study drug, and for at least 30 days after the 
last dose of study drug is ingested (Section 6.7); 
Added clarity to denote the 
protocol-approved methods of 
birth control. 
4.1.2.  Run-in Exclusion 
Criteria 
f.  Chronic treatment with s Strong or moderate CYP3A4 inhibitors 
or inducers and P-gp inhibitors, within 14 days prior to Screening; 
Any treatment with CYP3A4 or 
P-gp inhibitors within 14 days of 
Screening is excluded. 
4.2.1.  Randomization 
Inclusion Criteria  
2.  Subject must have a ≤ 3-point decline in NPRS pain intensity 
score during Run-in, which will be calculated using the average score 
during the last 7 days of Screening compared to the average score 
during the last 7 days of Run-In; 
Additional detail added to 
describe how the decline in 
NPRS will be measured. 
4.2.1.  Randomization 
Inclusion Criteria 
5.  Currently taking ≤ only 1 allowed prescribed SOC pain 
medication for managing DPNP at a stable dose (not exceeding the 
maximum dose in the prescribing information) for approximately 
8 weeks prior to Day 1 with no anticipated changes to dose(s) during 
study (Section 7.8.1), or failed to respond or tolerate SOC (approved 
medications for DPNP) and are receiving alternative pain 
medications;); 
The subjects must be taking only 
1 SOC pain medication. 
Refractory subjects are now 
excluded. 
4.2.2. Randomization 
Exclusion Criteria 
d.  Chronic treatment with s Strong or moderate CYP3A4 inhibitors 
or inducers and P-gp inhibitors; 
Any treatment with CYP3A4 or 
P-gp inhibitors is excluded. 
4.4.1.  Retesting 
Retesting is defined as repeating abnormal laboratory tests within the 
same Screening Period. study part.    
The repeated testing is to be 
performed during the same part 

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Subjects who fail to qualify for the study based on an abnormal 
laboratory test may have any individual laboratory test retested once 
within the same Screening Period study part at the discretion of the 
Investigator. 
of the study, not limited to the 
Screening Period. 
4.5.  Subject Enrollment and 
Randomization  
Following a Screening Period of up to 2 weeks, eligible subjects will 
be enrolled and enter a 14-day single-blind placebo Run-in Period 
(14± 2 days). During Run- Subjects in, subjects will be administered 
single-blind placebo study drug once daily in the morning. All study 
drug should be administered in a fasted state, defined as having no 
food within 2 hours prior to study drug administration and for 1 hour 
following study drug administration. Following the Run-in Period, 
subjects  Part 1 who remain eligible (according to Randomization 
eligibility criteria) will be randomized 1:1:1:1 to either RTA 901 (10, 
40, or 80 mg) or placebo at Day 1., and subjects in Part 2 who remain 
eligible will be randomized 1:1:1 to either RTA 901 (Dose 1 or Dose 
2) or placebo at Day 1 (see Table 3). Approximately 368192 eligible 
subjects (92 64 subjects per treatment arm) will be enrolled, and 
randomization in Part 1, and approximately 192 eligible subjects 
(64 subjects per treatment arm) will be enrolled in Part 2. 
Randomization within each part will be stratified by using RTSM 
into 2 strata based on approved SOC pain medication with 3 groups (. 
One stratum will include subjects taking duloxetine, while the other 
stratum will include subjects taking pregabalin/ or gabapentin, or 
other) using RTSM.  The “other” stratification group includes 
subjects who failed treatment, could not tolerate/are unable to take 
on-label medications for DPNP, or use only an NSAID or 
acetaminophen as a treatment option.  For additional detail on the use 
of rescue medications, see Section 7.8.3..   
The study design was modified to 
better determine the optimal dose 
of RTA 901 for future studies. 
The study will be conducted in 
2 parts with differing treatment 
arms in each part. Additional 
detail on the number of subjects 
in each group was provided. 
 
The study will now be stratified 
into 2 strata, subjects taking 
duloxetine and subjects taking 
pregabalin or gabapentin. 
Refractory subjects are now 
excluded. 
 
Table 3: Treatment Arms by 
Study Part 
Study Part 
Treatment Arms 
Part 1 
(N=192) 
10 mg RTA 901 
(N=64) 
80 mg RTA 901 
(N=64) 
Placebo 
(N=64) 
Part 2 
(N=192) 
Dose 1 RTA 901 
(N=64) 
Dose 2 RTA 901 
(N=64) 
Placebo 
(N=64) 
This table was included to 
describe the possible treatment 
arms in each part of the study. 

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Table 3: Treatment Arms by Study Part 
Abbreviations: E-R=exposure-response 
aDose selection in Part 2 will be determined by a Dose Selection 
Committee and based off an interim E-R analysis for efficacy with 
approximately 32 subjects from each treatment arm in Part 1. 
(selected from 
dose range of 1 
to 80 mg)a  
(selected from 
dose range of 1 
to 80 mg)a  
4.5.1.  Methods for 
Ensuring Blinding 
In this 2-part, randomized, placebo-controlled, double-blind study, all 
subjects, Investigators, site personnel, and laboratories (except the 
bioanalytical laboratory) with direct involvement in the conduct of 
the study or their designees will be blinded to randomized treatment 
assignments. Subjects will be blinded throughout the study. 
Investigators will not be blinded in the single-blind Run-in Period but 
will be blinded in the double-blind Treatment Period of the study. To 
prevent potential bias, appropriate measures will be taken to ensure 
the blind is maintained for the subjects and personnel mentioned 
previously. To maintain the blind, Investigators will distribute 
blinded study drug kits to subjects as assigned by the RTSM, see 
(Section 7.3). The study drug kits will contain a combination of three 
bottles of capsules, each containing active or placebo capsules in 
varying strengths to make up each dosing regimen. Table 11 shows 
the combination of bottles that will be used to comprise the dose for 
each treatment arm, while maintaining the study blind. Subjects will 
be blinded throughout the study. Investigators will not be blinded in 
the single-blind Run-in Period but will be blinded in the double-blind 
Treatment Period of the study. The Data Monitoring Committee 
(DMC) will review unblinded safety data and make recommendations 
as appropriate. Members of the DSC will be unblinded to recommend 
Part 2 doses of RTA 901, respectively. 
The bioanalytical lab will be 
unblinded. 
 
Text was moved from later in the 
paragraph. 
 
 
 
Redundant text regarding study 
drug was removed. 
 
 
 
 
 
The DMC and specific members 
of the DSC are unblinded.  
 
4.5.2.2.  Data Monitoring 
Committee 
An independent Data Monitoring Committee (DMC) will review the 
accumulating unblinded safety 
 data throughout the study and 
make recommendations as appropriate.   
The DMC will also review the 
 data as needed. 
4.5.2.3.  Dose Selection 
Committee  
4.5.2.3. 
Dose Selection Committee  
The DSC will be comprised of Sponsor personnel and an external 
pharmacometrics consultant. The external pharmacometrics consultant 
will conduct the interim E-R analysis for efficacy using unblinded data 
Section added to describe the 
DSC used to select the dose for 
Part 2. 

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from the first 96 subjects in Part 1 (approximately 32 subjects per 
treatment arm) who complete treatment through Week 12 and provide a 
dosing recommendation for Part 2 to Sponsor personnel. Eligible doses 
for selection in Part 2 will be limited to a dose range of 1 to 80 mg of 
RTA 901. If the DSC determines that the interim E-R analysis with the 
first 96 subjects from Part 1 does not a provide sufficient RTA 901 E-R 
information to make dose recommendations for Part 2, then an additional 
E-R analysis will be conducted with all subjects per treatment arm in Part 
1 who complete treatment through Week 12, see Figure 2. The selected 
doses will be documented in a Note-to-File to the Investigators and IRBs 
(as appropriate) and will not require a protocol amendment. 
Details of the membership, objectives, and process to be followed by 
the DSC will be described in a separate charter. Additionally, a 
separate data management and analysis plan supporting this activity 
will be created. Results will be reported in a separate standalone 
report, outside the CSR.   
4.6.1.  Discontinuation of 
Study Drug 
Discontinuation from study drug does not mean discontinuation from 
the study. Subjects who discontinue study drug early should be 
encouraged to continue participation in the study. Subjects who 
discontinue the study drug early for any reason should complete the 
procedures associated with the Week 812/EOT visit at the closest 
study visit. If the subject discontinued study drug during a study visit, 
the EOT procedures should be performed during that study visit. If 
the subject discontinues study drug in between visits, he/she will 
perform the EOT procedures at the next scheduled study visit. The 
subject will then complete the procedures associated with the Week 
1216/end of study (EOS) visit 4 weeks after discontinuation. 
Subjects who discontinue study 
drug early will then proceed to 
the EOT and EOS visits. 
 
The Treatment Period of the 
study was lengthened to 
12 weeks.   
 
 
 
The follow-up visit is now on 
Week 16. 
4.6.3.  Subject 
Discontinuation and 
Termination 
Subjects who wish to withdraw from the study should complete the 
procedures associated with the Week 8 12/EOT visit at the nearest study 
visit and the Follow-up Week 12 16/EOS visit 4 weeks later.   
The treatment period of the study 
was lengthened to 12 weeks.  
The follow-up visit is now on 
Week 16. 
4.6.3.  Subject 
Discontinuation and 
Termination  
The term discontinuation generally refers to a permanent halt in study 
drug administration.  
The reason for subject discontinuation or withdrawal from the study 
will be recorded on the electronic Case Report Form (eCRF). A 
complete comprehensive physical examination, body weight, vital 
Subjects who discontinue study 
drug early will not be required to 
do 
 procedures. 

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signs measurement, 12-lead ECG, laboratory analysis, urine 
pregnancy test for females of child-bearing potential, urine sample 
for urinalysis, 
, and an assessment of concomitant 
medications and AEs will be performed at the closest study visit, 
according to Section 4.6.1.
 
 
5.1.3. Demographics 
5.1.3. Demographics 
Demographic data including date of birth, age, sex, ethnicity, and 
race will be collected as indicated in Table 4. 
A demographics section was 
added to align with the Schedule 
of Assessments. 
5.1.4. Medical History 
5.1.4.  Demographic/Medical and Surgical History 
A complete medical history, including surgical history, alcohol, 
tobacco, and nicotine-containing product use histories for the past 
5 years, will be taken at Screening for the last 5 years. All relevant 
changes throughout the study after Screening will be recorded in the 
subject’s source document and electronic case report form (eCRF) as 
AEs. 
Demographics were moved to 
Section 5.1.3. to align with the 
Schedule of Assessments. 
 
Only relevant changes from 
baseline will be recorded as AEs. 
5.1.5. Prior and Current 
Concomitant Medications 
Prior opioid use to manage DPNP will be recorded for the past 
5 years prior to Screening.  
Collecting additional details on 
history of opioid use. 
5.1.5. Safety Assessments  
5.1.5. Safety Assessments  
Overall safety and tolerability will be assessed by the incidence of 
TEAEs and SAEs and by evaluations of change from baseline in 
physical examination, vital signs, 12-lead ECGs, and clinical 
chemistry, hematology, coagulation, and urinalysis lab tests. 
This section was replaced with 
Section 5.1.6. Adverse Events. 
5.1.6. Adverse Events 
5.1.6. Adverse Events 
Investigators and study staff are responsible for detecting, 
documenting, and reporting AEs and SAEs. For each subject, 
reporting of AEs and SAEs begins after written informed 
consent/assent is provided. Throughout the study, subjects will be 
provided opportunities to report AEs. For more information on AEs, 
see Section 6.3. 
This section is to replace 
Section 5.1.5. Safety 
Assessments to align with the 
Schedule of Assessments. 
5.1.7. Electronic Diary Set-
up  
Subjects will also complete the DSIS via their e-diary daily upon 
waking, preferably in the morning. 
Redundant text was removed. 
5.2.  Clinical 
Procedures/Assessments 
5.2.1. Height and Weight Measurement 
Height will be measured only at Screening; the subject will not wear 
Height and weight were separated 
into 2 sections to align with the 

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shoes during the measurement of height.  
5.2.2. Weight Measurement 
Body weight will be measured at the times indicated in Table 4. 
Weight should be taken with no shoes, hats, and outerwear. Body 
mass index will be calculated at Screening for eligibility.   
Schedule of Assessments. 
5.2.3.  Comprehensive 
Physical Examination 
5.2.3. Comprehensive Physical Examination  
Physical Examination was 
separated into 2 sections to align 
with the Schedule of 
Assessments. 
5.2.4.  Targeted Physical 
Examination 
5.2.4.  Targeted Physical Examination 
Physical Examination was 
separated into 2 sections to align 
with the Schedule of 
Assessments. 
5.2.5. Electrocardiogram 
Baseline for clinical assessments will be those measurements 
obtained prior to study drug administration on Day 1. Another ECG 
will be performed approximately 1-hour postdose on Day 1. 
An additional ECG at 1-hour 
postdose was added based upon 
recommendation from the FDA. 
5.2.6.  Vital Signs 
Measurements 
The average of the second and third readings will be assessed and 
calculated as part of the submission data processing and assessed. 
Additional detail was removed, 
as this will be covered in the 
SAP. 
5.3.  Laboratory 
Procedures/Assessments 
Samples will be stored under conditions stipulated in the Central 
Laboratory Manual until they are transported for measurement. 
Samples will be transported and measured by a central laboratory. 
Additional guidance provided for 
the care of lab samples. 
5.3.1. Pregnancy Tests for 
Females of Child-bearing 
Potential 
5.3.1. Pregnancy Tests for Women Females of Child-bearing 
Potential 
A serum and or urine pregnancy test will be performed at the times 
indicated in Table 4. A serum pregnancy test will be performed at 
Screening for women females of child-bearing potential (WOCBP) 
or at any point in time if a pregnancy is suspected. 
The word “woman” was replaced 
by “female” throughout the 
protocol for consistency.  
5.3.6. Clinical Chemistry 
Samples will be collected for the following clinical chemistry 
analyses as indicated in Table 4: ferritin, creatine kinase, blood urea 
nitrogen , enzymatic creatinine, eGFR, total bilirubin , direct 
bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (, AST), alkaline phosphatase , amylase, lipase, 
sodium, potassium, calcium, phosphorus, uric acid, total protein, 
glucose, albumin, lactate dehydrogenase , magnesium, chloride, 
Amylase and lipase will now be 
included in the clinical 
chemistries. 

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bicarbonate, and gamma glutamyl transferase. 
5.3.7. Hemoglobin A1c 
5.3.7. Hemoglobin A1c 
Samples will be collected for HbA1c as indicated in Table 6.  
Detailed instructions on collection, storage, and shipment of the 
samples will be provided in the Central Laboratory Manual provided 
to the Investigator.   
This text was moved to 
Section 5.3.11. of the protocol. 
5.3.8. Fasting Lipid 
Profile 
5.3.8. Fasting Lipid Profile 
Samples will be collected for the following lipid assessments as 
indicated in Table 6: total cholesterol, low-density lipoprotein 
(LDL), high-density lipoprotein (HDL), and triglycerides. 
This text was moved to 
Section 5.3.12. of the protocol. 
5.3.11.  Hemoglobin A1c 
5.3.11. Hemoglobin A1c 
Samples will be collected for HbA1c as indicated in Table 4. Detailed 
instructions on collection, storage, and shipment of the samples will 
be provided in the Central Laboratory Manual provided to the 
Investigator.   
This text was moved from 
Section 5.3.7. of the protocol. 
5.3.12.  Fasting Lipid 
Profile 
5.3.12. Fasting Lipid Profile 
Samples will be collected for the following lipid assessments as 
indicated in Table 4: total cholesterol, low-density lipoprotein, high-
density lipoprotein, and triglycerides. 
Subjects should fast for at least 8 hours prior to clinic visits where 
fasting lipids are taken (Screening, Week 4, Week 8, Week 12, and 
Week 16). 
This text was moved from 
Section 5.3.8. of the protocol. 
 
Additional guidance on fasting 
was provided, 
5.4.1.  Rescue Medication 
5.4.1. Rescue Medication  
Allowed rescue medication includes NSAIDs or acetaminophen to be 
used as needed and not to exceed the maximum dose stipulated in this 
protocol (Section 7.8.3). Subjects will be instructed to take no more 
than 3000 mg per day of acetaminophen (eg, 500 mg every 4 to 6 
hours and not exceeding the daily limit) or 1200 mg/day of ibuprofen 
(eg, 200-400 mg every 4 to 6 hours as needed and not exceeding the 
daily limit). 
This text also included in Section 
7.8.3. The duplicated text was 
removed. 

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5.4.1.  Pain Evaluation 
Diabetic peripheral neuropathy (DPN) occurs in approximately 
Approximately 50% of subjects with diabetes experience DPN and at 
around 15- to 20% of subjects with diabetic neuropathy have pain in 
the feet. Alleviation of pain is the is a primary goal and cornerstone 
of subject management. Treatment is available and to date there are 
three The approved treatments for DPNP include 3 oral medications 
to treat DPNP (duloxetine, pregabalin, and tapentadol) and a topical 
patch (containing 8% capsaicin), though). Of these, tapentadol (an 
opioid medication) and the 8% capsaicin patches are prohibited per 
protocol, see Section 7.8.4. The approved medications are suboptimal 
and both effective pain relief and suboptimal effectiveness and 
tolerability remain elusive and is. Thus, a large unmet medical need 
remains for the treatment of DPNP. 
This text was edited to clarify 
that although tapentadol and 8% 
capsaicin patches are approved to 
treat DPNP, they are prohibited 
per the protocol. 
5.4.1.1.  Numeric Pain 
Rating Scale 
In order to highlight how people experience pain sensations 
differently and how the unpleasant aspects of pain can differ from 
pain intensity, subjects will report how they perceive their average 
pain intensity, worst pain intensity, and pain upon walking other 
characteristics of their pain during the past 24 hours at bedtime, using 
the 11-point NPRS as per Table 4.  
The NPRS of pain intensity is a numeric scale, ranging from 0 
(representing no pain at all) to 10 (representing the worst pain 
imaginable) (Figure 3). The subject selects a whole number (0 to 10) 
that best indicates the intensity of his/her pain in the past 24 hours.  
Subjects must have a score of at least ≥4 on the NPRS at Screening 
and an average NPRS pain intensity score of at least ≥4 during the 
last 7 days prior to randomization. with a minimum of 
5 measurements (Section 4.2.1).  
The results from this PRO will be used to determine the efficacy of 
RTA 901 in achieving at least a 30% and or a 50% decrease in pain 
scores after 8 12 weeks of treatment. 
The description of the NPRS was 
edited for clarity.  
 
The treatment period of the study 
was lengthened to 12 weeks.   
5.4.1.2. Daily Sleep 
Interference Scale 
The DSIS is will be completed daily by subjects upon waking 
(3-minute self-administered questionnaire), preferably in the 
morning, to accurately capture variability in sleep interference due to 
pain, thus minimizing recall bias. 
Repeated text about DSIS was 
consolidated into this section. 

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Table 4: Schedule of 
Assessments (Part 1 & 2) 
Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 
10 
Week 8 
Week 12 
/ EOT 
Week 12 16 / 
EOSd 
The treatment period of the study 
was lengthened to 12 weeks. The 

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Day 22 
(±2) 
Day 29 
(±2) 
Day 36 
(±2) 
Day 43 
(±2) 
Day 50 
(±2) 
Day 57 
(±2) 
Day 71 
(±2) 
Day 
5785 
(±2) 
Day 85 113 
(±2) 
 
visits on Weeks 3, 5, and 7 were 
removed and additional visits 
were included on Weeks 10 and 
16. The EOT visit will now by at 
Week 12 and the follow-up visit 
is now on Week 16. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
Adverse events were added to the Screening visit. 
Adverse events were included in 
the Screening visit, as AEs are 
collected after the ICF is signed. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
c Day 1 includes the first dose administration, and all procedures must 
be performed before study drug administration, except for adverse 
events, 1-hour postdose ECG, 
. 
An additional ECG at 1-hour 
postdose was added based upon 
recommendation from the FDA. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
d Subjects who discontinue study drug early for any reason should 
complete the procedures associated with the Week 812/EOT visit at 
the nearest study visit and the Follow-up Week 1216/EOS visit 4 
weeks later. 
The treatment period of the study 
was lengthened to 12 weeks.  
The follow-up visit is now on 
Week 16. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
g Height should be measured with no shoes. 
The height should be measured 
without shoes. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
j ECG on Day 1 should be recorded at predose and 1-hour postdose. 
An additional ECG at 1-hour 
postdose was added based upon 
recommendation from the FDA. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
n Subjects should fast for at least 8 hours prior to clinic visits where 
fasting lipids are taken (Screening, Week 4, Week 8, Week 12, and 
Week 16). 
Additional guidance provided for 
fasting on days where fasting 
lipids are measured. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
o All study drug administration should be performed in an early fasted 
state, defined as having no food within at least 2 hours prior to study 
drug administration and for 1 hour following study drug 
administration. Since the first dose will be taken in-clinic and there 
Additional guidance for fasting 
prior to visits was provided. 

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are no 
 fasting lipids taken at the Run-in visit, subjects should 
fast for 2 hours prior to the visit. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
p On visits containing both labs with fasting and study drug 
administration, the longer of the fasting guidance (8 hours) is to be 
followed, these are not additive. 
Additional guidance provided for 
managing fasting based on the 
visit. 
Table 4: Schedule of 
Assessments (Part 1 & 2) 
q Subjects will complete the NPRS in the e-diary daily at bedtime.  
r Subjects will complete the DSIS in the e-diary daily upon waking. 
Additional guidance to denote the 
PROs performed daily on the 
e-diary. 
6.3.2. Adverse Events 
Based on Tests or 
Examinations 
In the first-in-human SAD/MAD study for RTA 901 (901-C-1503), 
study drug was generally safe and well tolerated. In Part 1 (SAD) 
there were no clinically relevant mean or individual changes in 
laboratory parameters. 
In Part 2 (MAD), one subject in the RTA 901 10mg cohort of the 
study had a Grade 4 TEAE (preferred term) of blood creatine 
phosphokinase increased that began on Study Day 24. The event was 
assessed as unrelated to study drug by the investigator. The subject 
completed the study following resolution of the TEAE at an 
Unscheduled Visit on Study Day 37. As a result of this TEAE, 
clinically relevant increases in mean creatine kinase (CK or CPK) at 
Study Day 24 and mean change in creatine kinase from baseline to 
Study Day 24 were noted in the RTA 901 10-mg cohort in Part 2 
(MAD) of the study. There were no other clinically relevant mean or 
individual changes in laboratory parameters during Part 2 (MAD) of 
the study. Elevated CPK levels leading to study drug interruptions 
should be recorded. However, elevated CPK levels which require 
more frequent laboratory testing without study drug interruptions 
should be reported as AEs. 
Duplicated text from the 
Introduction Section was 
removed. 
6.6. Pregnancy 
During the study, all female subjects must be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (eg, 
late or missed menstrual period). Male subjects must be instructed to 
contact the Investigator if a sexual partner suspects she may be 
pregnant. 
If a subject or Investigator suspects that the subject may be pregnant, 
the study drug must be withheld until the results of a serum 
pregnancy test are available. If pregnancy is confirmed with a serum 
pregnancy test, the subject must discontinue taking study drug and be 
This text was moved from 
Section 6.7.1. of the protocol. 

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discontinued from the study (Section 4.6.3). 
6.6. Pregnancy 
Pregnancy in a study subject or the female partner of the subject must 
be reported to the responsible safety party within 1 business day of 
the site becoming aware of the pregnancy. Subjects who become 
pregnant or whose female partner becomes pregnant during the study 
must be discontinued (Section 4.6.3). Information regarding a 
pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected. Pregnancy is not considered an adverse 
event; however, the The Investigator must follow a pregnant subject 
or the pregnant female partner of a male subject (if consenting) and 
report follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants resulting from such 
pregnancies should be followed for a minimum of 8 weeks. Reata 
Pharmaceuticals, Inc.The Sponsor or its designee may contact the 
Investigator to request additional information throughout the course 
of the pregnancy. 
Clarified guidance for pregnancy 
in study subjects and female 
partners of subjects. 
6.6. Pregnancy 
Pregnancy in a study subject is not considered an adverse event. 
However, the medical outcome of an elective or spontaneous 
abortion, stillbirth, or congenital anomaly is considered an SAE and 
must be reported to the responsible safety party within 24 hours of 
the site becoming aware of the event.AE. However, the following 
pregnancy outcomes must be considered SAEs and will require 
additional reporting in the eCRF and on an SAE form: 
• Congenital anomaly/birth defect; 
• Stillbirth; or 
• Spontaneous miscarriage. 
 
 
Clarified guidance for pregnancy 
in study subjects and female 
partners of subjects. 
 
 
This text was moved from 
Section 6.7.1. of the protocol. 
6.7.  Methods of Birth 
Control 
• Use double barrier contraception method, defined as male use of a 
condom and female use of a barrier method (eg, contraceptive 
sponge, spermicidal jelly or cream, diaphragm [always use with 
spermicidal jelly/cream]); 
• Use of hormonal contraceptives associated with inhibition of 
ovulation (oral, parenteral, intravaginal, or transdermal) as 
prescribed for at least 60 days prior to start of study drug 
administration; 
• Use of a non-hormonal intrauterine device with appropriate 
re-insertion period (as prescribed); 
Additional detail was provided on 
the approved female birth control 
methods. 

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• Use of an intrauterine device hormone-releasing system as 
prescribed; 
6.7.  Methods of Birth 
Control 
• Use double barrier contraception method, defined as male use of a 
condom and female use of a barrier method (eg, contraceptive 
sponge, spermicidal jelly or cream, diaphragm [always used with 
spermicidal jelly/cream]); 
• Partner contraception methods; must be the sole partner for that 
subject: 
⎯ Use of an intrauterine device; 
⎯ Use of a non-hormonal intrauterine device with appropriate 
re-insertion period (as prescribed);  
⎯ Use of hormonal contraceptives associated with inhibition of 
ovulation (oral, parenteral, intravaginal or transdermal) as 
prescribed for at least 60 days prior to start of study drug 
administration; 
⎯ Use of an intrauterine hormone-releasing system as 
prescribed; 
Additional detail was provided on 
the approved male birth control 
methods. 
6.7.1. Maternal exposure 
6.7.1. Maternal exposure 
During the study, all female subjects must be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (eg, 
late or missed menstrual period). Male subjects must be instructed to 
contact the Investigator if a sexual partner suspects she may be 
pregnant. 
If a subject or Investigator suspects that the subject may be pregnant, 
the study drug must be withheld until the results of a serum 
pregnancy test are available. If pregnancy is confirmed with a serum 
pregnancy test, the subject must discontinue taking study drug and be 
discontinued from the study. The Investigator must immediately 
report a pregnancy associated with study drug exposure and record 
the event. 
Pregnancy is not considered an adverse event; however, the 
Investigator must follow a pregnant subject or the pregnant female 
partner of a male subject (if consenting) and report follow-up 
information regarding the course of the pregnancy, including 
perinatal and neonatal outcome. Infants resulting from such 
pregnancies should be followed for a minimum of 8 weeks. Reata 
Pharmaceuticals, Inc. or its designee may contact the Investigator to 
Duplicated text was consolidated 
to Section 6.6. 

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request additional information throughout the course of the 
pregnancy. 
The following pregnancy outcomes must be considered SAEs and 
will require additional reporting in the CRF and on an SAE form: 
• Congenital anomaly/birth defect; 
• Stillbirth; or 
• Spontaneous miscarriage. 
Table 6: Management of 
Elevated Aminotransferase 
Levels (ALT and/or AST) 
ALT and/or AST 
Level(s) 
Dose 
Interrup
tion 
Disconti
nuation 
(Yes/No) 
Procedure 
> 8x ULN 
Yes 
Discontinue study drug 
temporarily  
Contact the medical monitor  
The study drug may be restarted 
with Sponsor approval after all the 
following criteria are met:  
Ultrasound or MRI of the 
hepatobiliary tree*; 
ALT and AST returned to ≤ ULN; 
TBL is within normal range; 
Other relevant labs (eg, albumin, 
INR, PT) are within normal range; 
No clinical signs or symptoms of 
liver injury are present. 
*Based on imaging results, if 
additional tests/studies are 
warranted, this should be 
discussed with the medical 
monitor.  
> 5x ULN for more 
than 2 weeks 
> 3x ULN with the 
appearance of fatigue, 
nausea, vomiting, 
right upper quadrant 
pain or tenderness, 
fever, rash, and/or 
eosinophilia (>5%) 
> 3x ULN and 
(TBL > 2x ULN or 
INR > 1.5) 
> 3x ULN 
No 
Check aminotransferase levels (as 
well as TBL, GGT, ALP), and 
INR within 48 to 72 hours 
Updated guidance for the 
management of elevated 
aminotransferases. Study drug 
cannot be resumed following a 
drug interruption due to elevated 
aminotransferases. 
 
 
 
 
List of abbreviations moved to the 
general text in Section 6.8.   

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Continue testing for ALT/AST 
every 72 to 96 hours until 
aminotransferase levels are below 
3x the ULN for at least one week 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; GGT=gamma-
glutamyl transferase; INR=international normalized ratio; 
MRI=magnetic resonance imaging; PT=prothrombin time; TBL=total 
bilirubin; ULN=upper limit of normal  
6.8.  Management of 
Elevated Aminotransferase 
Levels (ALT and/or AST) 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; INR=international normalized ratio; 
PT=prothrombin time; TBL=total bilirubin; ULN=upper limit of 
normal 
This text was moved from Table 
6. 
6.8.  Management of 
Elevated Aminotransferase 
Levels (ALT and/or AST) 
The hepatobiliary tree must be assessed by ultrasound or magnetic 
resonance imaging (MRI) for subjects who meet temporary 
discontinuation criteria. Based on imaging results, if study drug 
additional tests/studies are warranted, this should be discussed with 
the medical monitor. 
Updated guidance for the 
management of elevated 
aminotransferases. Study drug 
cannot be resumed following a 
drug interruption due to elevated 
aminotransferases. 
6.9. Management of Study 
Drug-Related Toxicities 
See Section 4.6.2 for details on resuming study drug after 
interruptions. 
Reference added for additional 
details. 
7.1. Dose and Treatment 
Regimens 
Approximately 368 eligible subjects (92 subjects per treatment arm) 
will be randomized 1:1:1:1 to either RTA 901 (10, 40, or 80 mg) or 
placebo at Day 1 (randomization) and will remain on the assigned 
treatment arm through Week 8. 
Study drug is defined as administration of either RTA 901 or placebo. 
During the Run-in Period, subjects will be administered single-blind 
placebo once daily in the morning. During the Treatment Period, 
subjects will be administered double-blind study drug QD in the 
morning according to their randomized assignment (Table 3). 
Text updated to match the revised 
study design and remove 
duplicated text. 
Table 8: Placebo 
Information 
Placebo for RTA 901 capsule  
(10 mg size #4, 40 mg size #0) 
Text updated to match the revised 
study design. 
7.3. Study Drug Packaging 
and Labeling 
The study drug will be supplied in tamper-evident kits containing 
three high-density polyethylene bottles. Each bottle will utilize foil 
induction-seal liners and a child-resistant closure. Each In Part 1, 
each bottle of study drug will contain 30 capsules of 10 mg or 40 mg 
Text updated to match the revised 
study design. 

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strength RTA 901 or the matching placebo capsules. In Part 2, each 
bottle of study drug will contain 30 capsules of RTA 901 or matching 
placebo capsules, depending on the doses of RTA 901 recommended 
by the DSC (see Section 3.6). 
The In Part 1, the study drug kits will contain a combination of three  
bottles, each containing active or placebo capsules in varying 
strengths to make up each dosing regimen. The following table 
(Table 9) shows the combination of bottles that will be used to 
comprise the dose for each treatment arm, while maintaining the 
study blind. in Part 1. Kit configurations for Part 2 will depend on the 
doses recommended by the DSC. As in Part 1, the kits for each 
treatment arm will contain the same number of bottles and the same 
configuration of capsule sizes necessary to maintain the study blind. 
Table 9: Study Drug Kit 
Configurations – Part 1 
Table 9: Study Drug Kit Configurations – Part 1 
Treatment 
Arm 
Bottles of 10 
mg Size #4 
RTA 901 
Bottles of 10 
mg Size #4 
Placebo 
Bottles of 40 
mg Size #0 
RTA 901 
Bottles of 40 
mg Size #0 
Placebo 
Placebo  
0 
1 
0 
2 
RTA 901 10 
mg 
1 
0 
0 
2 
RTA 901 40 
mg 
0 
1 
1 
1 
RTA 901 80 
mg 
0 
1 
2 
0 
Text updated to match the revised 
study design. 
7.5. Study Drug 
Administration 
Subjects must be instructed to continue taking study drug once daily 
through Week 8 12 unless: 
The treatment period of the study 
was lengthened to 12 weeks.   
7.7. Study Drug 
Accountability 
A current (running) and accurate inventory of study drug will be kept 
by each Investigator and will include shipping invoices and the date 
on which study drug is dispensed/administered to the subject. An 
overall accountability of the study drug will be performed and 
verified by the study monitor throughout the study and at the closeout 
visit.  Upon completion or termination of the study, all original 
containers (containing unused study drug) will be returned to Reata 
the Sponsor or its designee, according to instructions from Reata the 
Sponsor and according to local regulations. Labels must remain 
attached to the containers. Local study drug destruction is only 
allowed with prior Sponsor approval. 
Sponsor approval is required for 
local IP destruction. 

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7.8.1. Standard of Care Pain 
Medications 
Subjects are allowed required to enter the study with a maximum of 
take only 1 SOC pain medication for neuropathic pain (consistent 
with regional or local standard of care SOC guidelines for DPNP) 
that has been taken at a stable dose (defined as < 50% change in total 
dose) that does not exceed the maximum dose in the prescribing 
information for approximately 4 weeks prior to Screening. Allowed 
SOC pain medications include: duloxetine, pregabalin, and 
gabapentin. Attempts should be made to maintain the stable dose of 
SOC pain therapy. If changes to the dose are necessary, the 
Investigator should discuss with the Medical Monitor. However, dose 
level should not be above the maximum prescribed dose as instructed 
in the medication’s dosage and administration section of the 
prescribing information. Subjects who failed to respond or tolerate 
SOC (approved medications for DPNP) and are receiving alternative 
pain medications are also allowed. 
Clarified text on SOC pain 
medications. 
7.8.2. Allowed Medications 
The following medications and therapeutics are allowed during the 
study:  
• Benzodiazepine, zolpidem, diphenhydramine, or related drugs for 
insomnia, if subject is anticipated to be on a stable dose for 3 months 
prior to entry and it will is not anticipated to change during the study; 
• SSRI (selective serotonin reuptake inhibitor) for depression, if the 
subject is anticipated to be on a stable dose for 3 months prior to 
entry and it will is not anticipated to change during the study; 
• Analgesics, see Section 7.8.3. 
Clarified text on allowed 
medications. 
7.8.3. Rescue Medication 
Subjects may use a single rescue medication (NSAID or 
acetaminophen) to treat DPNP as needed during study participation, 
in addition to their standard-of-care medication.  
Clarified text on rescue 
medications. 
7.8.6. Recording of 
Concomitant Treatment 
Concomitant medications include those being taken at Screening or at 
any point throughout the study, up to and including the Week 12 
16/EOS visit. 
The follow-up visit is now on 
Week 16. 
8.1. Sample Size Estimate 
This study will be conducted in 2 parts. A total of 368 subjects 
(92 subjects approximately 192 subjects (64 subjects per treatment 
arm) are planned for randomization. in Part 1 and approximately 
192 subjects (64 subjects per treatment arm) are planned for 
randomization in Part 2, for a total of 384 subjects to be randomized. 
This sample size is based on a dose-ranging scheme to evaluate initial 
The study design was modified to 
better determine the optimal dose 
of RTA 901 for future studies. 
The study will be conducted in 
2 parts with differing treatment 
arms in each part.   

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safety, efficacy, 
 of RTA 901 in this population. The primary 
comparisons for efficacy are between each of the 32 RTA 901 
treatment groups and the placebo treatment group. Each comparison 
between RTA 901 and placebo will be at the 0.019 level from 
Dunnett’s adjustment so that the The overall Type I error rate will be 
controlled at the 0.05 significance level. With 92 subjects per 
treatment group, there is 80% power to detect A hierarchical testing 
strategy to control the overall Type I error will be defined in the SAP. 
Power calculations are based on a 2-sample t-test with no adjustments 
for multiple comparisons. The study assumes a difference in NPRS 
pain intensity means of 1.2 between each RTA 901 treatment group 
and the placebo treatment group, assuming and a standard deviation 
of 2.4 and a missing data rate of 10%. 
 
 
 
Additional detail was provided 
for the statistics analyses of the 
revised of the study design. 
8.1.  Sample Size Estimate 
8.1.1.  Blinded Sample Size Recalculation  
In order to maintain sufficient study power to detect the pre-specified 
treatment effect for the primary efficacy endpoint (i.e., change from 
baseline in NPRS of 1.2 points) a sample size recalculation may be 
performed to evaluate on a blinded basis the study assumptions 
(variability and drop-out rate) used to calculate sample size.  A 
Sample Size Recalculation Committee (SRC), comprised of Sponsor 
personnel and the study’s blinded statistician, will be established to 
recalculate sample size based on blinded assessment of study 
assumptions.  The SRC will review available data (e.g., baseline 
characteristics, study drug discontinuations, variability in NPRS 
change from baseline) when approximately 70% of the subjects have 
been enrolled in the study.  The Sponsor may increase the sample 
size of the study up to 468 subjects.  There will be no sample size 
decrease under this procedure.  An increase of sample size within this 
range will be documented in a Note-to-File (NTF) to the Investigators 
and IRBs (as appropriate) and will not require a protocol amendment.  
Because these analyses will be based on pooled, blinded data they 
will not impact the Type I error rate.  A Blinded Sample Size 
Recalculation Plan will present details regarding the planned 
recalculation of sample size. 
The sample size recalculation 
section was removed from the 
study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional detail was provided 
for the statistics analyses of the 
revised of the study design. 

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If doses selected for Part 2 do not include doses studied in Part 1, 
then an analysis by dose group for Part 1 or Part 2 doses will be 
performed following completion of each study part. Within each Part, 
with 64 subjects per treatment group, each study part has 80% power 
to compare treatment groups to placebo.  
If doses selected for Part 2 include any doses studied in Part 1 (ie, 
10 or 80 mg), then an analysis by dose group will be performed using 
Part 1 and Part 2 combined, following completion of the study. The 
dose group that is enrolled in both parts will have 128 subjects. With 
128 placebo subjects compared to 128 subjects in the RTA 901 dose 
group, there is 98% power to detect the same difference (1.2 NPRS 
points) assuming the same standard deviation (2.4). RTA 901 dose 
groups that are enrolled in only 1 part will have 64 subjects. With 
128 placebo subjects compared to 64 subjects in each RTA 901 dose 
group, there is 90% power to detect the same difference (1.2 NPRS 
points) assuming the same standard deviation (2.4).     
8.2.  Definitions of Analysis 
Sets 
A detailed SAP will be developed prior to database lock.   
This text was moved from 
Section 8.2.1. 
8.2.1.  Intent-to-Treat 
Analysis Set 
Mixed-model repeated measures (MMRM) analyses will be used to 
analyze the primary efficacy endpoints.  A detailed SAP will be 
developed prior to database lock. 
This text was consolidated to 
Section 8.4.3. and duplicated text 
was removed. 
8.2.2. Safety Analysis Set 
The safety analysis set includes all randomized subjects who received 
at least 1 dose of randomized study drug. The safety analysis set is 
will be used for evaluation of safety variables. Subjects who received 
at least 1 dose of RTA 901 will be classified in the RTA 901 group. 
Subjects who will be are randomized and receive at least 1 dose of 
placebo and no dose of RTA 901 will be classified in the placebo 
group. Subjects in the Run-in phase who fail to randomize into the 
Treatment phase will not be included in the placebo group. 
Subjects who are not eligible for 
randomization will not be 
included in the placebo group of 
the safety analysis set. 
 
 
 
8.3. Endpoints and 
Objectives 
The SAP will describe in detail the methods used for the primary, 
safety, secondary, and exploratory endpoints and will serve as the 
final arbiter of all statistical analysis analyses. The study endpoints 
are listed in Section 2.2. 
Additional detail was provided 
for the statistics analyses of the 
revised of the study design. 

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Data will be summarized using descriptive statistics. Continuous data 
will be summarized with statistics such as mean, standard deviation, 
median, minimum, and maximum. Categorical data will be 
summarized using frequency counts and percentages. 
If doses selected for Part 2 include any doses studied in Part 1 (ie, 
10 or 80 mg), then the final analysis by dose group will be performed 
following final study database lock. Otherwise, if doses selected for 
Part 2 do not include doses studied in Part 1 then final analysis by 
dose group for Part 1 or Part 2 doses will be performed following the 
Part 1 or Part 2 database lock, respectively. 
8.4.1. Hypotheses 
Primary hypothesis: There will be a greater mean reduction from 
baseline in NPRS pain intensity for the RTA 901-treated groups 
compared with placebo after 812 weeks of double-blind treatment. 
The pain intensity score on the 
NPRS is the data point used for 
this analysis. 
 
The treatment period of the study 
was lengthened to 12 weeks.   
8.4.2. Closed Testing 
Procedure 
For primary analysis, each comparison between RTA 901 (10, 40, 80 
mg) and placebo will be at the 0.019 level from Dunnett’s adjustment 
so that tThe overall Type I error rate will be controlled at the 
0.05 significance level. A hierarchical testing strategy to control the 
overall Type I error will be defined in the SAP. 
Additional detail was provided 
for the statistics analyses of the 
revised of the study design. 
8.4.6. Interim Analysis 
No formal interim analysis is planned for this study. 
An interim E-R analysis for efficacy is planned for the Part 1 interim 
E-R analysis cohort (ie, the first 96 subjects in Part 1 (approximately 
32 subjects per treatment arm) who complete treatment through 
Week 12). Results from this interim E-R analysis will be used to 
determine the doses of RTA 901 in Part 2. An additional E-R analysis 
for efficacy may also be conducted with all subjects who complete 
treatment through Week 12 in Part 1 (approximately 64 subjects per 
treatment arm) of the study to determine the doses of RTA 901 in 
Part 2 if the results from the interim E-R analysis using the first 96 
subjects who complete treatment through Week 12 from Part 1 do not 
provide sufficient RTA 901 E-R information to make dose 
recommendations for Part 2. Details of the interim E-R analysis will 
be described in a separate analysis plan and the results will be 
reported separately from the CSR. No formal interim analysis for 
efficacy or safety by dose is planned. 
Additional detail was provided 
for the planned interim E-R 
analysis(es) for efficacy of the 
revised study design. 

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8.4.8.  Analysis of Safety 
Variables 
The number and percent of subjects with an AE will be summarized 
for each treatment group. Changes from baseline to each scheduled 
time point for each physical examinations, vital sign measurements, 
ECGs, clinical laboratory test, blood pressure measurements, and 
heart rate body weight will be summarized by treatment group. 
Analysis updated to match the 
Primary Safety Endpoint. 
 

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Reata Confidential 
 
 
 
 
 
 
 
 
 
AMENDMENT CHANGE SUMMARY DOCUMENT 
 
 
CLINICAL STUDY PROTOCOL 901-C-2102 
 
Study Title: A PHASE 2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF RTA 901 IN PATIENTS WITH DIABETIC 
PERIPHERAL NEUROPATHIC PAIN (DPNP)  
CYPRESS 
 
 
 
 
Protocol History 
Version 2.0 – 27 September 2022 
Version 1.0 – 28 April 2022 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc. Any unauthorized use or disclosure of 
such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 

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SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 1 to produce the text of Version 2. Additionally, the following 
points are provided: 
 
• 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis 
are not described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 

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SIGNATURE PAGE 
& 
CONTACTS IN CASE OF 
EMERGENCY 
 
 
 
Office: 
 
Reata personnel change  
3.3.  Screening Period (Days -
28 to -15) 
The Screening Period includes 1 clinic visit, which should not occur 
more than up to 2 weeks prior to the Run-in Period (within 
approximately 28 days prior to Day 1).   
To clarify that the Screening Period 
can be less than 2 weeks 
3.3.  Screening Period (Days -
28 to -15) 
Michigan Neuropathy Screening Instrument Part B, and will be 
included if a score ≥ 3.0 2.5 is obtained. 
The MNSI inclusion criteria was 
lowered to 2.5 to ensure that patients 
with early neuropathy are not 
excluded 
3.3.  Screening Period (Days -
28 to -15) 
Additional procedures during Screening (Visit 1) will include the 
administration of the following 
 
 
 
To avoid duplication of the 
instructions as both the DSIS and 
NPRS were mentioned in the previous 
paragraph. 
3.4.  Run-in Period (Days -14 
to -1) 
 
 
Direction to Table 6, SOA to look at 
 
3.5.  Treatment Period (Day 1 
to Week 8) 
Other scales The 
 are to be completed on Day 1 of 
randomization according to the Schedule of Assessments (Table 6). 
. 
Direction to Table 6, SOA to look at 
 
3.6.  Follow-up/End of Study 
(Week 12) 
Subjects will be directed to continue entering the average of pain 
intensity, worst pain intensity, and pain upon walking and whether 
they needed to use rescue medication, in the e-diary at bedtime. 
Upon waking in the morning, subjects will be asked to complete the 
DSIS.  
 
 

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4.1.1.  Run-in Inclusion 
Criteria 
4.  Currently taking ≤ 1 allowed prescribed standard-of-care 
medication for managing DPNP at a stable dose (not exceeding the 
maximum dose in the prescribing information) for approximately 
4 weeks prior to Screening (Section 7.8.1); failed to respond or 
tolerate SOC (approved medications for DPNP) and are receiving 
alternative pain medications; 
To specify that the stable dose of the 
standard of care drug taken must be 
within the maximum dose of the 
drug’s prescribing information and the 
SOC refers to medications approved 
for DPNP 
4.1.1.  Run-in Inclusion 
Criteria 
7.  A score of ≥ 3.0 2.5 on the Michigan Neuropathy Screening 
Instrument (MNSI) Part B; 
The MNSI inclusion criteria was 
lowered to 2.5 to ensure that patients 
with early neuropathy are not excluded 
4.1.1.  Run-in Inclusion 
Criteria 
11.  Willing to sign and date an informed consent document 
indicating that the subject (or a legally acceptable representative) 
has been informed of all pertinent aspects of the study prior to 
initiation of any subject study-mandated procedures;   
Removal of the consent of a legally 
acceptable representative for 
consistency with Reata standard 
4.1.1.  Run-in Inclusion 
Criteria 
12.  A negative COVID-19 Polymerase Chain Reaction (PCR) test 
result during Screening. 
To specify the COVID-19 test will be 
a rapid COVID-19 antigen test 
4.1.2.  Run-in Exclusion 
Criteria 
d.  Tricyclic antidepressants (other than amitriptyline) and other 
tricyclic drugs including cyclobenzaprine and promethazine; 
triptans (prescribed usage outside of DPNP allowed); 5-HT3 
receptor antagonists, within 7 days prior to Screening; 
Amitriptyline is no longer allowed. 
 
To allow the usage of Triptans for 
causes other than DPNP 
4.1.2.  Run-in Exclusion 
Criteria 
f.  Chronic treatment with strong or moderate cytochrome P450 
isotype 3A4 (CYP3A4) inhibitors or inducers and P-glycoprotein 
(P-gp) inhibitors, within 14 days prior to Screening; 
To exclude the use of P-gp inhibitors 
based on DDI study data  
4.2.1.  Randomization 
Inclusion Criteria 
5.  Currently taking ≤ 1 allowed prescribed SOC medication for 
managing DPNP at a stable dose (not exceeding the maximum dose 
in the prescribing information) for approximately 8 weeks prior to 
Day 1 with no anticipated changes to dose(s) during study 
(Section 7.8.1), or failed to respond or tolerate SOC (approved 
medications for DPNP) and are receiving alternative pain 
medications; 
To specify that the stable dose of the 
standard of care drug taken must be 
within the maximum dose of the 
drug’s prescribing information and the 
SOC refers to medications approved 
for DPNP 
4.2.2.  Randomization 
Exclusion Criteria 
b.  Tricyclic antidepressants (other than amitriptyline) and other 
tricyclic drugs including cyclobenzaprine and promethazine; 
triptans (prescribed usage outside of DPNP allowed); 5-HT3 
receptor antagonists; 
Amitriptyline is no longer allowed. 
 
To allow the usage of Triptans for 
causes other than DPNP 

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4.2.2.  Randomization 
Exclusion Criteria 
d.  Chronic treatment with strong or moderate CYP3A4 inhibitors 
or inducers and P-gp inhibitors; 
To exclude the use of P-gp inhibitors 
based on DDI study data 
4.4.3.  Rescreening 
Subjects who fail to meet all Run-in inclusion/exclusion criteria 
may be considered for rescreening at the discretion of the 
Investigator after consultation with the Medical Monitor.  These 
subjects will be considered Screen Failures. 
Subjects may repeat Screening once to qualify for the study. If a 
subject is approved to rescreen, they will be given a new subject 
number and all screening procedures will be repeated. 
Subjects who participate in the Run-in Period but fail to meet the 
Randomization criteria will not be allowed to rescreen for the study.  
These subjects will be considered Randomization Failures. 
To clarify the nomenclature for Screen 
Failures and Randomization Failures 
4.5.  Subject Enrollment and 
Randomization 
The “other” stratification group includes subjects who failed 
treatment, could not tolerate/are unable to take on-label medications 
for DPNP, or use only an NSAID or acetaminophen as a treatment 
option.  For additional detail on the use of rescue medications, see 
Section 7.8.3. 
To clarify the “other” stratification 
group 
4.6. Study Drug 
Discontinuation, Interruption, 
and Subject Termination 
4.6.  Study Drug Subject Discontinuation, Interruption, and Subject 
Termination 
Updating section title to match new 
sub-sections 
4.6.1.  Discontinuation of 
Study Drug 
Discontinuation from study drug does not mean discontinuation 
from the study.  Subjects who discontinue study drug early should 
be encouraged to continue participation in the study, completing all 
study visits, including Week 8/EOT and Week 12/EOS, according 
to the Schedule of Assessments (Table 6).  Subjects who 
discontinue the study drug early for any reason should complete the 
procedures associated with the Week 8/EOT visit at the closest 
study visit.  If the subject discontinued study drug during a study 
visit, the EOT procedures should be performed during that study 
visit. If the subject discontinues study drug in between visits, they 
will perform the EOT procedures at the next scheduled study visit.  
The subject will then complete the procedures associated with the 
Week 12/end of study (EOS) visit 4 weeks after discontinuation.  
The subject should continue to follow the remaining study 
scheduled visits, including Week 8/EOT and Week 12/EOS. 
To clarify that a patient discontinuing 
the study should only do the EOT and 
EOS visits, not the entire remaining 
schedule. 

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4.6.2.  Resuming Study Drug 
after Interruptions 
The term interruption generally refers to a temporary halt in study 
drug administration.  This can be either at the direction of the site, 
or by the patient’s decision or non-compliance.  An interruption 
from the study drug based on the patient’s decision or non-
compliance will be defined as missing at least 3 consecutive days of 
study drug administration.  There is no minimum timeframe for a 
site directed interruption. 
To add clarity on the definition of a 
study drug interruption 
4.6.3.  Subject Discontinuation 
and Termination 
Subjects are free to withdraw from participation in the study at any 
time upon request.  Subjects who wish to withdraw from the study 
should complete the procedures associated with the Week 8/EOT 
visit at the nearest study visit and the Follow-up Week 12/EOS visit 
4 weeks later.   
To clarify the procedures done at the 
EOT visit 
4.6.3.  Subject Discontinuation 
and Termination 
If a positive result is obtained on a pregnancy test for a subject, or a 
subject reports that they or their female partner become(s)ing 
pregnant during the study, the subject must be discontinued 
immediately. 
Clarifying that a patient whose female 
partner becomes pregnant must also 
discontinue the study 
5.1.3.  Demographic/Medical 
and Surgical History 
A complete medical history, including alcohol, tobacco, and 
nicotine-containing product use histories, will be taken at Screening 
for the last 5 years. 
To specify the time period of the 
medical history 
5.1.4.  Prior and Current 
Concomitant Medications 
Prior and concomitant medications (ie, medications that the subject 
is taking or has taken within 30 days prior to Screening Day 1) will 
be reviewed per Table 6 and all changes throughout the study after 
Screening will be recorded in the subject’s source document and 
eCRF. 
Adjusting timeframe for consistency 
with Inclusion/Exclusion Criteria 
5.1.6.  Electronic Diary 
During Screening, subjects deemed likely to be eligible for the 
study will be given access to an   e-diary and trained on how to 
record daily pain scores from Visit 1 Screening up to Visit 3Day 1. 
The results will be reviewed on Day 1 (Visit 3) to confirm that the 
subject is eligible for the study. 
To clarify reference to the visit name 
instead of the visit number  

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5.2.1.  Height and Weight 
Height will be measured only at Screening; the subject will not 
wear shoes during the measurement of height. The physical 
examination performed on Day 1 will serve as the baseline physical 
examination for clinical assessments. Any clinically significant 
physical examination findings after study drug administration will 
be recorded as AEs. 
Body weight will be measured at the times indicated in Table 6. 
Weight should be taken at the same time each day, with no shoes, 
hats, and outerwear. BMI Body mass index will be calculated at 
Screening for eligibility.   
To move the reference to the physical 
exam to section 5.2.2. Physical 
Examination 
 
There will not be daily weights taken 
on this study 
5.2.2.  Physical Examination 
The physical examination performed on Day 1 will serve as the 
baseline physical examination for clinical assessments.   
 
Moving the physical examination text 
from section 5.2.1 Height and Weight 
to section 5.2.2 Physical Examination 
5.2.4.  Vital Signs 
Vital signs, including blood pressure, heart rate, respiration rate, 
and body temperature, will be assessed on the study days indicated 
in Table 6 or at early discontinuation. 
Including respiration rate in the vital 
signs 
5.2.5.  Michigan Neuropathy 
Screening Instrument (MNSI) 
To be eligible for randomization, subjects must have a score of ≥ 
3.0 2.5 on MNSI Part B only; Part A will not be used in this study. 
The MNSI inclusion criteria was 
lowered to 2.5 to ensure that patients 
with early neuropathy are not excluded 
5.3.4.  COVID-19 Test 
5.3.4. COVID-19 PCR Test 
A COVID-19 PCR test will be performed at the times indicated in 
Table 6 for all subjects. 
To specify the COVID-19 test will be 
a rapid COVID-19 antigen test 
5.3.5.  Drugs of Abuse, and 
Cotinine Screen 
5.3.5. Drugs of Abuse, Alcohol, and Cotinine Screen 
A urine screen for drugs of abuse and cotinine, and alcohol test, will 
be performed at Screening. 
There will not be an alcohol test 

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5.4.1.  Rescue Medication 
The percentage of subjects using rescue medication for DPNP 
during the Treatment Period, including baseline and average weekly 
and cumulative dose, as well as the quantity and timing of such 
medication intake must be recorded for posterior analysis. Thus, 
subjects will be trained to enter the use of rescue therapy daily at 
bedtime. 
Removing repeated text 
Table 6:  Schedule of 
Assessments 
Week 8 / EOT 
To clarify the visit names 
Table 6:  Schedule of 
Assessments 
Day 8 (±32) 
Day 15 (±32) 
Day 22 (±32) 
Day 29 (±32) 
 
Day 36 (±32) Day 43 (±32) 
Day 50 (±32) 
Day 57 (±32) 
 
Day 85 (±32) 
The visit windows will be ±2 days 
Table 6:  Schedule of 
Assessments 
COVID-19 PCR Test 
To specify the COVID-19 test will be 
a rapid COVID-19 antigen test 
Table 6:  Schedule of 
Assessments 
Drug and, Cotinine, and Alcohol Screen 
There will not be an alcohol test 
Table 6:  Schedule of 
Assessments 
Study Drug Administration 
Adding an “x” to the table to indicate 
study drug will be administered 
during Run-in 
Table 6:  Schedule of 
Assessments 
Numeric Pain Rating Scale (NPRS) (at home) 
Daily Sleep Interference Score (DSIS) (at home) 
To indicate that the NPRS and DSIS 
will be performed at home 
Table 6:  Schedule of 
Assessments 
a The Screening Period includes 1 clinic visit and should not occur 
more than up to 2 weeks prior to the Run-in Period (within 
approximately 28 days prior to Day 1), see Section 3.3. 
To clarify that the Screening Period 
can be less than 2 weeks 
Table 6:  Schedule of 
Assessments 
d Subjects who discontinue treatment early should be encouraged to 
complete all study visits, including Week 8/EOT and Week 
12/EOS. Subjects who discontinue the study drug early for any 
reason should complete the procedures associated with the Week 
8/EOT visit at discontinuation the nearest study visit and the 
Follow-up Week 12/EOS visit 4 weeks later. 
To clarify that a patient discontinuing 
the study should only do the EOT and 
EOS visits, not the entire remaining 
schedule. 
Table 6:  Schedule of 
Assessments 
f Weight should be taken at the same time each day (with no shoes, 
hats, and outerwear). 
There will not be daily weights taken 

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Table 6:  Schedule of 
Assessments 
 
 
 
 
 
 
5.6.  Unscheduled Visits 
5.6. 
Unscheduled Visits 
Unscheduled visits may be performed at any time and for any 
reason, including those not specifically mentioned in this section, as 
deemed necessary by the investigator. 
Unscheduled visits conducted for the following reasons should 
include collection of AEs, clinical chemistry, hematology, 
concomitant medication collection, and vital signs: 
• 
Management of an AE or SAE; 
• 
Performance of additional laboratory tests for clinically 
abnormal laboratory test values or to confirm a possible pregnancy; 
• 
Patient safety evaluation. 
Unscheduled visits conducted for the following reasons do not 
require additional assessments unless deemed necessary by the 
investigator: 
• 
Study drug dispensation; 
• 
Any operational need that would require the patient to return 
to the site between scheduled visits. 
Included new section on unscheduled 
visits 
6.1.2.  Definition of Treatment 
Emergent Adverse Event 
Adverse events that present, or worsen in intensity or frequency, 
following the initiation of study treatment will be categorized as 
TEAEs. 
Inclusion of missing text 
6.2.  Definitions of Serious 
Adverse Event 
Pregnancy is not considered an AE; however, information will be 
collected for any pregnancies that occur during the study (from the 
time of first dose of study drug consent until the final visit).   
Clarification pregnancies will be 
tracked from consent, not from first 
dose of study drug 

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6.3.2.  Adverse Events Based 
on Tests or Examinations 
Changes in laboratory test values or ECG parameters are only 
considered to be AEs if they are judged by the Investigator to be 
clinically significant (ie, if some action or intervention is required 
or if the Investigator judges the change to be beyond the range of 
normal physiological fluctuation). except for the following 
laboratory test values which should be considered AEs regardless of 
their clinical significance: 
Removal of text to facilitate clarity 
on how the PI should evaluate an AE 
based on changes in laboratory test 
values  
6.6.  Pregnancy 
Pregnancy in a study subject or the female partner of the subject 
must be reported to the responsible safety party within 1 business 
day of the site becoming aware of the pregnancy. Subjects who 
become pregnant or whose female partner becomes pregnant during 
the study must be discontinued (Section 4.6.3). 
Clarifying that a patient whose 
female partner becomes pregnant 
must also discontinue the study 
6.8.  Management of Elevated 
Aminotransferase Levels 
(ALT and/or AST) 
6.8.  Management of Elevated Transaminase Aminotransferase 
Levels (ALT and/or AST) 
Some subjects may experience more rapid increases in ALT/AST 
values than others during the dose titration period.  Investigators 
may consider extending the time between each dose increase to 
manage ALT/AST elevations. 
If a subject’s transaminases aminotransferases are elevated, follow 
the instructions outlined in Table 8. 
Removed reference to dose titration 
 
Transaminases were renamed to 
aminotransferases 
7.5.  Study Drug 
Administration 
 
  
To add detail
 
 

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7.8.1.  Standard of Care 
Medications 
Subjects are allowed to enter the study with a maximum of 1 SOC 
medication for neuropathic pain (consistent with regional or local 
standard of care guidelines for DPNP) that has been taken at a 
stable dose (defined as < 50% change in total dose) for 
approximately 4 weeks prior to Screening. Allowed SOC 
medications include: duloxetine, pregabalin, and gabapentin, 
amitriptyline, and venlafaxine. Attempts should be made to 
maintain the stable dose of SOC therapy.  If changes to the dose are 
necessary, the Investigator should discuss with the Medical 
Monitor. However, dose level should not be above the maximum 
prescribed dose as instructed in the medication’s dosage and 
administration section of the prescribing information. Subjects who 
failed to respond or tolerate SOC (approved medications for DPNP) 
and are receiving alternative pain medications, or are treatment 
naïve, are also allowed. 
Amitriptyline and venlafaxine are 
excluded as these medications are not 
FDA approved for DPNP 
 
To specify that the stable dose of the 
standard of care drug taken must be 
within the maximum dose of the 
drug’s prescribing information 
 
Treatment naïve patients are not 
allowed  
7.8.2.  Allowed Medications 
•  SRI for depression, subject is anticipated to be on a stable dose 3 
months prior to entry and it will not change during the study; 
•  Analgesics that are non-opioid, non-sedative and do not interfere 
with subject’s pain reporting., see Section 7.8.3. 
To clarify the allowed stable dose  
7.8.3. Rescue Medication 
This does not exclude the use of these rescue medications in other 
forms for other uses outside of DPNP. Subjects taking one form of 
rescue medication can take a medication containing the other form 
solely for use outside of DPNP.  The daily maximum dosages are 
inclusive of those used outside of DPNP.  Subjects should be 
encouraged NOT to take cough syrups or sleep aids containing 
NSAIDs (eg, Nyquil for cold/flu, or Tylenol PM for sleep), but if 
they do then it should be recorded as concomitant medication.  
NSAIDs taken for cardiovascular health are allowed and should be 
documented as a concomitant medication.  The daily maximum 
dosages of each medication should still be maintained. 
Allowing the use of NSAIDs or 
acetaminophen in other forms outside 
of treating DPNP symptoms 
7.8.4.  Prohibited Medications 
Tricyclic antidepressants (other than amitriptyline) and other 
tricyclic drugs including cyclobenzaprine and promethazine; 
triptans (prescribed usage outside of DPNP allowed); 5-HT3 
receptor antagonists; 
Amitriptyline is no longer allowed 
 
To allow the usage of Triptans for 
causes other than DPNP 

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7.8.4.  Prohibited Medications Strong or moderate CYP3A4 inhibitors or inducers and P-gp 
inhibitors; 
To prohibit the use of P-gp inhibitors 
based on DDI study data 
7.8.4.  Prohibited Medications Muscle relaxers. 
To prohibit the use of muscle relaxers 
as this is a confounding factor for 
pain improvement 
8.1.1.  Blinded Sample Size 
Recalculation 
8.1.1. Blinded Sample Size Recalculation 
In order to maintain sufficient study power to detect the pre-
specified treatment effect for the primary efficacy endpoint (i.e., 
change from baseline in NPRS of 1.2 points) a sample size 
recalculation may be performed to evaluate on a blinded basis the 
study assumptions (variability and drop-out rate) used to calculate 
sample size.  A Sample Size Recalculation Committee (SRC), 
comprised of Sponsor personnel and the study’s blinded statistician, 
will be established to recalculate sample size based on blinded 
assessment of study assumptions.  The SRC will review available 
data (e.g., baseline characteristics, study drug discontinuations, 
variability in NPRS change from baseline) when approximately 
70% of the subjects have been enrolled in the study.  The Sponsor 
may increase the sample size of the study up to 468 subjects.  There 
will be no sample size decrease under this procedure.  An increase 
of sample size within this range will be documented in a Note-to-
File (NTF) to the Investigators and IRBs (as appropriate) and will 
not require a protocol amendment.  Because these analyses will be 
based on pooled, blinded data they will not impact the Type I error 
rate.  A Blinded Sample Size Recalculation Plan will present details 
regarding the planned recalculation of sample size. 
To include a blinded sample size 
recalculation to maintain the study 
assumptions for variability and drop-
out rate and detect the effect for 
primary efficacy endpoint. 
8.2.1.  Intent to Treat Analysis 
Set (ITT) 
The intent-to-treat (ITT) analysis set is defined as all enrolled 
randomized subjects categorized by their randomized treatment 
group (whether they received study drug).   
To clarify the ITT population 
includes randomized patients