Clinical trial NCT04447404
Conditions: SARS-CoV-2
Sponsor: Durect
Start date: 2020-09-21; Completion date: 2021-03-04
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate safety and efficacy of DUR-928 in treatment of acute organ failure in subjects infected with SARS-CoV-2

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: DUR-928 intervention 2: Placebo
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
Official Title: 
A Randomized, Double-Blind, Placebo Controlled Study to Evaluate Safety and 
Efficacy of DUR-928 in Subjects Infected with SARS-CoV-2 with Acute Lung, 
Liver or Kidney Injury 
NCT Number: 
NCT04447404 
Document Date: 
December 08, 2020 
 


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 1 of 66 
Clinical Protocol 
Protocol No. 
C928-020 
Title: 
A Randomized, Double-Blind, Placebo Controlled Study to Evaluate Safety and 
Efficacy of DUR-928 in Subjects Infected with SARS-CoV-2 with Acute Lung, 
Liver or Kidney Injury 
Phase 
2 
IND: 
149343 
Versions: 
Original: 22 April2020 
 
Amendment 1: 11 May 2020   
 
Amendment 2: 08 Dec 2020 
 
 
Sponsor: 
DURECT Corporation  
10260 Bubb Road 
Cupertino, CA  95014, USA 
TEL: 
 
FAX: 
 
GCP 
Statement: 
The trial will be conducted in accordance with the principles of Good Clinical 
Practice (GCP) set forth in the International Conference on Harmonization 
(ICH) Good Clinical Practice, the US Code of Federal Regulations (CFR Title 
21), the Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
and any local requirements. 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of DURECT Corporation 
(hereafter, DURECT). Acceptance of this document constitutes agreement by the recipient that 
no previously unpublished information contained herein will be published or disclosed without 
the prior written approval of DURECT with the exception that this document may be disclosed 
to trial personnel under your supervision who need to know the contents for conducting the trial 
and appropriate Institutional Review Boards (IRBs)/Ethics Committees (EC) under the condition 
that the personnel have agreed to keep this information confidential. The foregoing shall not 
apply to disclosure required by governmental regulations or laws; however, DURECT shall be 
promptly notified of any such disclosure. 
 
 
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 2 of 66 
Investigator Agreement Page 
DURECT Corporation 
 
 
I have read and understood the information in this protocol and agree to conduct the trial 
according to the protocol (subject to any amendments), in accordance with the principles of 
Good Clinical Practice, the Investigator responsibilities stated in this protocol, and in 
compliance with all federal, state and local regulations, as well as with the requirements of the 
appropriate IRB/IEC and any other institutional requirements.  Any changes in procedure will 
only be made if necessary to protect the safety, rights or welfare of subjects. 
I agree to conduct in person or to supervise the trial.  I will provide copies of the protocol, any 
subsequent protocol amendments, and access to all information provided by the Sponsor to 
the trial personnel under my supervision. I will discuss this material with them to ensure that 
they are fully informed about the test drug, the trial protocol, are aware of their obligations, 
are qualified to perform the tasks required, and are trained in any trial specific procedures 
Principal Investigator: 
 
 
Principal Investigator: 
 
 
 
 
 
Date 
Title and Institution: 
 
Sponsor Approval: 
Date 
This document contains proprietary and confidential information of DURECT Corporation (hereafter, 
DURECT). Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written 
approval of DURECT with the exception that this document may be disclosed to trial personnel under 
your supervision who need to know the contents for conducting the trial and appropriate Institutional 
Review Boards (IRBs)/Ethics Committees (EC) under the condition that the personnel have agreed to 
keep this information confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws; however, DURECT shall be promptly notified of any such 
disclosure.
DocuSign Envelope ID: BDD55C8A-0842-4936-A118-10C915752FF9
09-Dec-2020
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 3 of 66 
SPONSOR CONTACTS 
 
DURECT Corporation 
10260 Bubb Road 
Cupertino, CA  95014 
USA 
 
Project Leader 
 
 
 
Team Leader 
 
 
 
Biostatistician 
 
 
 
PPD/CCI
PPD/CCI
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 4 of 66 
CONTRACT RESEARCH ORGANIZATION 
Medical Monitor  
 
 
 
 
 
 
LABORATORIES 
 
 
 
 
 
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 5 of 66 
TABLE OF CONTENTS 
1.0 
TRIAL SYNOPSIS .................................................................................................9 
2.0 
LIST OF ABBREVIATIONS ..............................................................................20 
3.0 
DUR-928:  BRIEF DEVELOPMENT HISTORY .............................................22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.8 
CURRENT TRIAL .....................................................................................27 
3.9 
Trial Objectives and Primary Endpoints .....................................................27 
3.10 
Trial Design .................................................................................................29 
3.11 
Population ...................................................................................................30 
3.11.1 
Inclusion Criteria ........................................................................30 
3.11.2 
Exclusion Criteria .......................................................................31 
3.11.3 
Number of Subjects ....................................................................32 
3.11.4 
Dosage and Regimen ..................................................................32 
4.0 
TRIAL CONDUCT ...............................................................................................32 
4.1 
Investigative Sites .......................................................................................32 
4.2 
Sponsor Obligations of Trial Conduct ........................................................32 
4.3 
Duration.......................................................................................................32 
4.4 
Discontinuation of Trial ..............................................................................32 
5.0 
TRIAL PROCEDURES .......................................................................................32 
5.1 
Trial Test Drug ............................................................................................32 
5.1.1 
Randomization ...........................................................................32 
5.1.2 
Maintenance of the Blind ...........................................................33 
5.1.3 
Administration of Test Drug ......................................................33 
5.1.4 
Packaging and Labeling of Test Drug ........................................33 
5.1.5 
Storage of Test Drug ..................................................................34 
5.1.6 
Preparation of Test Drug ............................................................34 
5.1.7 
Drug Accountability ...................................................................34 
PP
D/
CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 6 of 66 
5.2 
Trial Visits and Study Procedures ...............................................................34 
5.2.1 
Screening (Day -4 to Day-1) ......................................................35 
5.2.2 
Day 1 (In-hospital, Study Treatment) ........................................35 
5.2.3 
Day 2 ..........................................................................................36 
5.2.4 
Day 3 ..........................................................................................36 
5.2.5 
Day 4 ..........................................................................................36 
5.2.6 
Day 5 and Day 6 .........................................................................36 
5.2.7 
Day 7 (± 1 day) ...........................................................................37 
5.2.8 
Days8-14 (±3 days) ....................................................................37 
5.2.9 
Day 28 (±3 day) Trial Completion / Early Termination ............37 
5.2.10 
Day 60 (±3 day) End of Study Follow up ..................................38 
5.3 
Concomitant Medication(s) .........................................................................38 
6.0 
ASSESSMENT OF EFFICACY ..........................................................................38 
6.1 
Efficacy Assessments ..................................................................................38 
6.2 
Method and Timing of Assessments ...........................................................40 
7.0 
ASSESSMENT OF SAFETY ...............................................................................40 
7.1 
Safety Assessments .....................................................................................40 
7.2 
Method and Timing of Assessments ...........................................................42 
7.2.1 
Adverse Event Recording ...........................................................42 
7.2.2 
Spontaneously Reported Adverse Events...................................42 
7.2.3 
12-Lead ECGs ............................................................................42 
7.2.4 
Safety Laboratory Tests .............................................................42 
7.2.5 
Vital Signs ..................................................................................43 
7.2.6 
Physical Examination .................................................................43 
7.2.7 
Biomarkers .................................................................................43 
7.3 
Adverse Events............................................................................................44 
7.3.1 
Definitions ..................................................................................44 
7.3.2 
Adverse Event Reporting ...........................................................47 
7.3.3 
Reporting of Serious Adverse Events ........................................47 
7.3.4 
Adverse Event Follow-up ...........................................................48 
7.4 
Pregnancy ....................................................................................................49 
8.0 
PHARMACOKINETICS .....................................................................................49 
9.0 
STATISTICAL METHODS AND DATA ANALYSIS .....................................50 


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 7 of 66 
9.1 
Research hypotheses ...................................................................................50 
9.2 
Sample Size Determination .........................................................................50 
9.3 
Subject Randomization ...............................................................................50 
9.4 
General Statistical Methods ........................................................................51 
9.4.1 
Safety analyses ...........................................................................51 
9.4.2 
Demographic and Baseline Characteristics ................................51 
9.5 
Planned Interim Analyses ...........................................................................51 
9.6 
Tabulation of Individual Subject Data ........................................................51 
9.7 
Changes and Deviations to the Protocol and Statistical Analysis Plan .......52 
10.0 
ACCESS TO SOURCE DATA/DOCUMENTATION ......................................52 
10.1 
Confidentiality ............................................................................................52 
10.2 
Data Identification .......................................................................................52 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................52 
11.1 
Monitoring ..................................................................................................52 
11.2 
Protocol Deviations .....................................................................................53 
11.3 
Case Report Forms ......................................................................................53 
11.4 
Coding .........................................................................................................53 
11.5 
Data Monitoring Committee (DMC) ..........................................................53 
12.0 
ETHICAL CONSIDERATIONS .........................................................................55 
12.1 
Institutional Review Board / Ethics Committee..........................................55 
12.2 
Regulatory Compliance ...............................................................................55 
12.3 
Regulatory Status ........................................................................................55 
12.4 
Subject Information and Informed Consent ................................................55 
12.4.1 
Subject Withdrawal ....................................................................56 
13.0 
DATA HANDLING AND RECORD RETENTION .........................................56 
13.1 
Data Ownership ...........................................................................................56 
13.2 
Retention of Trial Records ..........................................................................56 
 
 
 
 
16.0 
REFERENCES ......................................................................................................58 
17.0 
APPENDICES .......................................................................................................60 
PPD/
CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 8 of 66 
List of Appendices 
 
 
 
 
 
 
List of Tables 
 
 
List of Figures 
 
 
 
PPD/CCI
PPD/CCI
PPD/CCI








DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 12 of 66 
b. AKI: 
• Creatinine increase ≥ 0.3 mg/dL (26.52 µmol/L) in 48 hours or 
increase ≥ 1.5 times baseline within the prior 7 days. 
c. Moderate COVID-19 pneumonia defined by the following: 
• Severe bilateral diffuse infiltrates & ground glass opacities 
involving more than 50% of the lung fields  
OR 
• PaO2 to FiO2 ratio 100 to 300.   
5. Women of child-bearing potential (defined as women gender assigned at 
birth) who are not surgically sterile or who are not over the age of 52 and 
amenorrhoeic for at least 12 months) must utilize appropriate birth control 
throughout the study duration. Acceptable methods that may be used are 
abstinence, birth control pills (“The Pill”) or patch, diaphragm, IUD (coil), 
vaginal ring, condom, surgical sterilization or progestin implant or injection, 
or sexual activity limited to a sterile (e.g., vasectomized) male partner. 
6. Male subjects must agree to use a medically acceptable method of 
contraception/birth control and refrain from sperm donation throughout the 
study duration 
Exclusion 
Criteria: 
1. Critical COVID-19 illness: 
• MAP < 60 mm Hg  
• On mechanical ventilator for ≥ 5 days 
2. On maintenance (chronic) hemodialysis or peritoneal dialysis 
3. History of end stage renal disease (ESRD) or CKD with eGFR 
<15 mL/min/1.73 m2 
4. Child Pugh C cirrhosis or cirrhosis with any decompensation event (ascites, 
hydrothorax, hepatic encephalopathy, or clinically significant variceal 
bleed) within the past 3months. 
5. The presence of acute liver AND kidney injury defined as meeting criteria 
for AKI in the presence of ALT >1.5x ULN and bilirubin >1.5 mg/dL 
6. Participant of other clinical trials 
7. Receipt of other concomitant experimental therapies except antiviral drugs 
8. Underlying diseases that, in the opinion of the principal investigator, might 
be complicated or exacerbated by proposed treatments or might confound 
assessment of study drug 
9. Any active malignancies other than skin cancer (basal cell carcinoma or 
squamous cell carcinoma) amenable to local curative therapy.  Patients with 
other potentially curable malignancies that have been treated and are in 


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 13 of 66 
remission for at least three years shall be eligible for enrollment in the 
study. Women who are pregnant or breast feeding 
Efficacy 
Evaluations 
Evaluate efficacy of DUR-928 in treatment of acute organ failure, especially 
acute liver or kidney injury, in subjects infected with SARS-CoV-2.  The 
primary efficacy endpoint is the composite of being alive and free of acute 
organ failure at Day 28.  This is specifically defined as being: 
1. Alive at Day 28 
2. Free of mechanical ventilation at Day 28 
3. Free of acute liver failure (i.e., free of the simultaneous presence of 
jaundice, coagulopathy, ascites, and hepatic encephalopathy) at Day 28 
4. Free of renal replacement therapy at Day 28 
Safety Evaluation: Each subject will be followed up for 60 days for safety assessment. Day 60- 
assessment will be conducted by phone interview. 
Safety will be determined based on clinical and laboratory monitoring. 
Clinical: Vital signs, and physical examination (when feasible) should be 
recorded and examined daily while in hospital or during scheduled clinical visits 
with specific attention to pulmonary abnormalities, worsening liver and kidney 
functions. Other decompensation events, including ascites and hepatic 
encephalopathy, will be monitored clinically. 
Laboratory: Biochemical parameters that are monitored daily while in hospital 
or during scheduled clinical visits include liver biochemistry (daily assessment 
of PT in subjects with coagulopathy may be affected), hematology, creatinine, 
urinalysis, and serum chemistries. MELD Na, Child’s Pugh Turcotte, and CLIF 
scores in subjects with acute on chronic liver disease will also be monitored 
when feasible and available. 
Viral Test: Viral RNA will be monitored for as long as it continues to be shed in 
nasopharyngeal oropharyngeal and stool samples of each subject by the standard 
quantitative RT-PCR. 
Data Monitoring Committee (DMC): The mission of the DMC will be to 
safeguard patient interests and to enhance trial integrity.  To address this 
mission, DMC will meet on a regular basis to review unblinded data on efficacy, 
safety and quality of trial conduct. 
Monitoring Process: During the trial, individual subjects will be evaluated by the 
site PI if any of the following SAE occurs. The PI and medical monitor, based 
on the nature and severity of the event(s), will determine if the event(s) warrants 


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 14 of 66 
the early termination of the study therapy in the best interest of the subject. The 
DMC may also provide recommendations as needed. 
1. Appearance of DILI: 
a) If baseline measurements (BLM) were <2x ULN, discontinue if ALT or 
AST increases to >5x BLM; 
b) If BLM ≥2x ULN but <5x ULN, discontinue if ALT or AST increases to 
>3x BLM; 
c) If BLM ≥ 5x ULN, discontinue if ALT or AST increases to >2x BLM; 
d) Discontinue if ALT or AST increase > 2x BLM AND the increase is 
accompanied by a concomitant increase in TBL to >2x BLM OR the INR 
concomitantly increases by >0.2 in absence of COVID-19 coagulopathy; 
e) In any subjects with signs and symptoms of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(> 5% or > 500/µL) 
2. Worsening of COVID-19 severity 
3. SAE events associated with cardiac, kidney, liver, or secondary infection. 
The PI and medical monitor, based on the nature and severity of the event(s), 
will determine if the event(s) warrants the early termination of the study therapy 
in the best interest of the subject. The DMC may also provide recommendations 
as needed. 
The DMC also will be contacted on an as needed basis by the medical monitor 
to review available data, unblinded by intervention group, providing insights 
about whether any unexpected SAE (or SUSAR) could be due to study drug 
rather than the underlying COVID-19 disease and to provide advice regarding 
study conduct. 
In accordance with the Charter, the DMC review of unblinded data will occur 
promptly to address situations listed in Section 11.5, for example, 
1. 
 
2. more than 2 subjects have an AE grade 3 or above on the CTCAE scale 
that is determined to be possibly or probably attributable to study drug as 
per the medical monitor; 
3. more than 3 deaths, and the overall percentage of study patients with 
deaths within 60 days exceeds 10%. 
Based on data review, DMC could recommend termination of the trial, pausing 
of randomization, discontinuation of treatment, or continuation of the trial. 
Refer to Section 11.5.   
The following parameters will be recorded daily for the safety evaluation: 
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 15 of 66 
1. Serious adverse events 
2. Standard 12-lead ECG 
3. Safety Laboratory Tests (clinical chemistry, hematology, coagulation, 
and urinalysis) 
4. Vital Signs  
5. Physical examination (when feasible) 
Refer to Section 9.4.1. 
Statistical 
Considerations: 
In this Phase 2 randomized placebo-controlled study, the principal objectives are 
to provide screening evaluations of safety and efficacy of DUR-928. 
Safety analyses 
Treatment emergent SAEs will be listed and summarized.  All SAEs reported in 
this study will be coded using the current Medical Dictionary for Regulatory 
Activities (MedDRA).   
Particular attention will be given to assessment of treatment emergent SAEs in 
the domains of respiratory failure events, liver events, and renal events. 
The overall incidences of SAEs in each system organ class (SOC) and preferred 
term (PT) will be tabulated.  In addition, incidences rates (frequencies and 
percentages) will be broken down by severity and/or relationship to study drug. 
Treatment emergent changes from baseline in clinical laboratory tests, ECG, and 
vital signs will be derived by treatment group. 
Safety will be evaluated by assessment of serious adverse events, clinical 
laboratory tests, and vital signs, starting at Screening. 
Status and severity of comorbid conditions such as diabetes (e.g. last known 
HbA1C, medications), cardiac disease (e.g. previous MI, Stroke, 
echocardiogram, 12 lead EKG, baseline troponin, WHO heart failure definition), 
and immunocompromised status will be documented. 
Data regarding the use of experimental anti-viral therapies will be collected. 
Data on other supportive measures, such as proning, received by subjects who 
are on invasive mechanical ventilation will be collected. 
For subject deaths, data will be collected on whether the death occurred after 
withdrawal of care and, if so, the reason for withdrawal of care. 
For each subject, the reason for hospital admission, the standard of care 
followed for each subject/site, and if care decisions are made based on resource 
limitation will all be document. 
Refer to Section 9.0. 
Efficacy analyses 






DURECT Corporation 
 
Protocol # C928-020 
 
 
Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 18 of 66 
Table 1: Schedule of Events 
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
 
 Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 19 of 66 
Footnotes for Schedule of Events Table 
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 20 of 66 
2.0 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AH  
Alcoholic Hepatitis 
AKI  
Acute kidney injury 
ALD 
Alcoholic Liver Disease 
ALT 
Alanine aminotransferase 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CL 
Clearance 
Cmax 
Maximum serum concentration 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
COVID-19 
Coronavirus 2019 
Cr 
Creatinine 
CRF 
Case Report Form  
CRP 
C-reactive protein 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ESRD 
End stage renal disease  
GGT 
Gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
hERG 
Human ether-a-go-go related gene 
HR 
Heart rate 
Ht 
Height 
HV 
Healthy volunteer 
IL 
Interleukin 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IP 
Investigational product 
ITT  
Intention to Treat 
IV 
Intravenous 
LDL 
Low-density lipoprotein 
LPS 
Lipopolysaccharide 
MELD 
Model for End Stage Liver Disease 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 21 of 66 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NASH 
Nonalcoholic Steatohepatitis 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
Oral 
PPARγ 
Peroxisome proliferator activated receptor-gamma 
PT 
Prothrombin time 
RR 
Respiratory rate 
SAH 
Severe Alcoholic Hepatitis 
SAE 
Serious adverse event 
SARS 
Severe acute respiratory syndrome 
SC 
Subcutaneous 
sCr 
Serum creatinine 
SST  
Serum Separating Tube 
T1/2 
Half-life 
Tmax 
Time to maximum serum concentration 
ULN 
Upper limit of normal 
USAE 
Unexpected serious adverse event 
Vd 
Volume of distribution 
Wt 
Weight


PPD/CCI


PPD/CCI


PPD/CCI


PPD/CCI


PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 27 of 66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
3.8 
CURRENT TRIAL 
3.9 
Trial Objectives and Primary Endpoints 
Primary:  
• 
Evaluate safety in subjects treated with DUR-928 as evidenced by treatment-emergent 
serious adverse events (TESAEs), including 
1. Respiratory failure events 
PPD/CCI






DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 30 of 66 
Figure 1: Trial Schema 
3.11 
Population 
Subjects diagnosed with SARS-CoV-2 infection with acute liver or kidney injury will be 
enrolled. The target number of participants to complete the study is 80. During the trial, 
subjects should receive standard of care as determined by their PI. 
3.11.1 
Inclusion Criteria 
To participate in this study, subjects must meet all of the following criteria:  
1. Age 18-80 years old and able to provide written informed consent (either from subject or 
subject’s legally acceptable representative)  
2. Hospitalized with documented COVID-19 infection diagnosed by standard RT-PCR or 
equivalent testing other than anti-COVID-19 antibody testing (either upon entry into the 
hospital, in the hospital, upon admission to the ICU, or in the ICU) 
3. Hospitalized with moderate, severe, or early critical COVID-19 illness: 
c. Mean arterial pressure (MAP) ≥ 60 mm Hg, including patients who require no more 
than one intravenous pressor at the time of enrollment;  
d. If the subject is on ventilator at the time of Day 1 dosing, the total days on ventilator 
should be < 5 days (< 120 hours). 
4. Subject meets one (lung only) or two (lung with liver or kidney) of the following criteria 
at the time of enrollment: 
a. Acute liver injury irrespective of known, suspected, or unknown hepatic fibrosis 
or cirrhosis:  
• In subjects without a known history of liver disease and/or with a documented 
normal ALT level within past 12 months, acute liver injury will be defined as 
ALT > 2x ULN and bilirubin <2.5.   
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 31 of 66 
• In subjects with a known abnormal baseline ALT level within past 12 months, 
acute liver injury will be defined as ALT >2x baseline level and bilirubin <2.5. 
b. AKI: 
• Creatinine increase ≥ 0.3 mg/dL (26.52 µmol/L) in 48 hours or increase ≥ 1.5 
times baseline within the prior 7 days 
c. Severe COVID-19 pneumonia defined by the following: 
• Severe bilateral diffuse infiltrates & ground glass opacities involving more than 
50% of the lung fields  
OR 
• PaO2 to FiO2 ratio 100 to 300.   
5. Women of child-bearing potential (defined as women gender assigned at birth) who are 
not surgically sterile or who are not over the age of 52 and amenorrhoeic for at least 
12 months) must utilize appropriate birth control throughout the study duration. 
Acceptable methods that may be used are abstinence, birth control pills (“The Pill”) or 
patch, diaphragm, IUD (coil), vaginal ring, condom, surgical sterilization or progestin 
implant or injection, or sexual activity limited to a sterile (e.g., vasectomized) male 
partner. 
6. Male subjects must agree to use a medically acceptable method of contraception/birth 
control and refrain from sperm donation throughout the study duration 
3.11.2 
Exclusion Criteria 
To participate in this study, subjects must NOT meet any of the following exclusion 
criteria: 
1. Critical COVID-19 illness: 
• MAP < 60 mm Hg 
• On mechanical ventilator for ≥ 5 days 
2. On maintenance (chronic) hemodialysis or peritoneal dialysis 
3. History of end stage renal disease (ESRD) or CKD with eGFR < 15 mL/min/1.73 m2 
4. Child Pugh C cirrhosis or cirrhosis with any decompensation event (ascites, hydrothorax, 
hepatic encephalopathy, or clinically significant variceal bleed) within the past 3 months.  
5. The presence of acute liver AND kidney injury defined as meeting criteria for AKI in the 
presence of ALT >1.5x ULN and bilirubin >1.5 mg/dL 
6. Participant of other clinical trials 
7. Receipt of other concomitant experimental therapies except antiviral drugs 
8. Underlying diseases that, in the opinion of the principal investigator, might be 
complicated or exacerbated by proposed treatments or might confound assessment of 
study drug 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 32 of 66 
9. Any active malignancies other than skin cancer (basal cell carcinoma) amenable to local 
curative therapy.  Patients with other potentially curable malignancies that have been 
treated and are in remission for at least five years shall be eligible for enrollment in the 
study.    
10. Women who are pregnant or breast feeding 
3.11.3 
Number of Subjects 
A total of 80 subjects will be enrolled. 
3.11.4 
Dosage and Regimen 
Assigned study treatment (DUR-928 or placebo) will be administered on Day 1 and on Day 4 
in 
 by intravenous infusion over approximately 
2 hours 
 until entire dose is given. 
4.0 
TRIAL CONDUCT 
4.1 
Investigative Sites 
This will be a multi-center study with up to 8 clinical sites located in the United States.  
4.2 
Sponsor Obligations of Trial Conduct 
Sponsor responsibilities such as data management site management, site monitoring, and 
medical monitoring may be transferred to one or more contract research organizations 
(CROs).   
4.3 
Duration 
Subject participation is approximately 60 days. 
4.4 
Discontinuation of Trial 
DURECT Corporation reserves the right to terminate the trial at any time. 
5.0 
TRIAL PROCEDURES 
The study procedures are listed in Section 5.0and in the Schedule of Events (Table 1). 
5.1 
Trial Test Drug 
5.1.1 
Randomization 
Subjects will be assigned randomly at a 3:1 ratio to the following treatment groups:  
• DUR-928, 150 mg in 
 administered over 
approximately 2 hours via IV infusion. 
• Sterile Water for Injection, 5mL (placebo) in 
 
 administered over approximately 2 hours via IV infusion 
PPD/CCI
PPD/CCI
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 33 of 66 
More details on preparation and administration of study drug will be provided in the 
Pharmacy Manual for this study. 
5.1.2 
Maintenance of the Blind 
For the best chance of achieving a valid and reliable test of efficacy, the blind must be 
maintained despite the fact that the site pharmacist will be unblinded to treatment assignment 
for the purpose of treatment preparation. 
The un-blinded pharmacist must not disclose which test drug the subject received, or bias the 
subject or blinded staff by discussing the group assignments with them.  Any documentation 
in the medical records must not reveal treatment assignment by indicating the specific study 
treatment and/or dose volumes added to the 
 IV bag. 
If in a medical emergency knowledge as to which treatment assignment has been 
administered is critical for the supportive therapy of the subject or will influence further 
medical treatment of the subject, the Investigator or designee should obtain the subject’s test 
drug treatment assignment from the pharmacist, medical monitor, or Sponsor.   
The date, time, reasons for breaking the blind and person doing so must be documented in the 
source record as it will be reviewed by Sponsor representatives.  Unless medically indicated, 
the treatment should not be disseminated further or shared with the subject to prevent 
introduction of bias. 
5.1.3 
Administration of Test Drug 
The 1st dose, or Day 1 dose, of the assigned study treatment (test drug) will be administered 
in a hospital setting immediately after the subject is enrolled. 
The second dose of the assigned study treatment (test drug) will be given on Day 4, or 3 days 
after the 1st dose. 
A total of no more than two doses of study treatment (test drug) will be given. 
5.1.4 
Packaging and Labeling of Test Drug 
The sponsor will supply the sterile ready to use DUR-928for Injection:  
• 
 
 
The concentration of the DUR-928 Injection product to be used in this study is
 
 
The sponsor will supply 5 mL vials of Sterile Water for Injection, USP (placebo).   
Each vial is labeled with product name, lot number, and quantity. 
PPD/CCI
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 34 of 66 
5.1.5 
Storage of Test Drug 
Both DUR-928 Injection and Sterile Water for Injection, USP (placebo) should be stored at 
 
5.1.6 
Preparation of Test Drug 
The assigned study treatment (DUR-928 Injection or placebo) will be diluted into a 
 
 
 
 
 
 
More details will be provided in the Pharmacy Manual for this study. 
5.1.7 
Drug Accountability 
All materials supplied are for use only in this clinical study and should not be used for any 
other purpose. 
The Investigator is responsible for investigational product accountability, reconciliation, and 
record maintenance at the investigational site.  In accordance with all applicable regulatory 
requirements, the Investigator or designated site staff (e.g. unblinded pharmacist) must 
maintain investigational product accountability records throughout the course of the study.  
This person will document the amount of investigational product received from 
 
the amount administered to subjects, and the amount of investigational product remaining. 
A Drug Dispensing Log must be kept current and will contain the following information: 
• 
Study identification of the subject to whom the drug was dispensed; 
• 
Date(s), study treatment, and quantity of the drug dispensed to each subject.  
The inventory must be available for inspection by the unblinded study monitor during the 
study.  Drug supplies will either be returned by the Investigator or designee to DURECT or, 
if requested in writing by the Sponsor, unused drug supplies may be destroyed by the clinical 
study unit according to local standard operating procedures (SOPs).  Records shall be 
maintained by the Investigator of any such alternate disposal of the test drug.  These records 
must show the identification and quantity of each unit disposed of, the method of destruction 
(taking into account the requirements of local law), and the person who disposed of the test 
substance.  Documentation of the disposition of all IP will be provided to DURECT.  If the 
clinical study unit is unable to dispose of the investigational product, unused drug will be 
returned to DURECT.   
5.2 
Trial Visits and Study Procedures 
Refer to Table 1for an overview of the schedule of events by visit. 
PPD/CCI
PPD/CCI
PPD/CCI








DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 38 of 66 
• 
Vital signs (BP, HR, respiratory rate, temperature) 
• 
Urine or serum pregnancy test (females of childbearing potential) performed locally  
• 
Safety labs (chemistry, hematology, urinalysis, coagulation) 
• 
Biomarker samples collection (blood) when feasible 
• 
12-lead ECG  
• 
Adverse events and Concomitant medications 
5.2.10 
Day 60 (±3 day) End of Study Follow up 
The following procedures will be performed by phone: 
• 
Adverse events and Concomitant medications 
5.3 
Concomitant Medication(s) 
Any required treatment deemed necessary for treatment of the subject will be under the 
treating physician’s discretion and given as medically required.  All concomitant medications 
will be recorded on the appropriate eCRF. 
6.0 
ASSESSMENT OF EFFICACY 
6.1 
Efficacy Assessments 
Primary:  
• 
Evaluate safety in subjects treated with DUR-928 as evidenced by treatment-emergent 
serious adverse events (TESAEs), including 
1. Respiratory failure events 
2. Liver failure events  
3. Renal failure events  
4. Heart failure events 
5. Secondary infection (regardless viral or non-viral) 
• 
Evaluate efficacy of DUR-928 in treatment of acute organ failure, especially acute liver 
or kidney injury, in subjects infected with SARS-CoV-2.  The primary efficacy endpoint 
is the composite of being alive and free of acute organ failure at Day 28.  This is 
specifically defined as being: 
o Alive at Day 28 
o Free of mechanical ventilation at Day 28 
o Free of acute liver failure (i.e., free of the simultaneous presence of: jaundice, 
coagulopathy, ascites, and hepatic encephalopathy) at Day 28 
o Free of renal replacement therapy at Day 28 
Secondary: 






DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 41 of 66 
Monitoring Process and Individual Subject Stopping Rule: During the trial, individual 
subjects will be evaluated by the site PI if any of the following SAE occurs. The PI and 
medical monitor, based on the nature and severity of the event(s), will determine if the 
event(s) warrants the early termination of the study therapy in the best interest of the subject. 
The DMC may also provide recommendations as needed. 
1. Appearance of DILI: 
a. If baseline measurements (BLM) were <2x ULN, discontinue if ALT or AST 
increases to >5x BLM; 
b. If BLM ≥2x ULN but <5x ULN, discontinue if ALT or AST increases to >3x BLM; 
c. If BLM ≥ 5x ULN, discontinue if ALT or AST increases to >2x BLM; 
d. Discontinue if ALT or AST increase > 2x BLM AND the increase is accompanied by 
a concomitant increase in TBL to >2x BLM OR the INR concomitantly increases by 
>0.2 in absence of COVID-19 coagulopathy; 
e. In any subjects with signs and symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% or > 500/µL)  
2. Worsening of COVID-19 severity 
3. SAE events associated with cardiac, kidney, liver, or secondary infection. 
The DMC also will be contacted on an as needed basis by the medical monitor to review 
available data, unblinded by intervention group, providing insights about whether any 
unexpected SAE (or SUSAR) could be due to study drug rather than the underlying COVID-
19 disease and to provide advice regarding study conduct. 
In accordance with the Charter, the DMC review of unblinded data will occur promptly to 
address situations listed in Section 11.5, for example, 
• 
 
• 
more than 2 subjects have an AE grade 3 or above on the CTCAE scale that is 
determined to be possibly or probably attributable to study drug as per the medical 
monitor; 
• 
more than 3 deaths, and the overall percentage of study patients with deaths within 60 
days exceeds 10%. 
Based on data review, DMC could recommend termination of the trial, pausing of 
randomization, discontinuation of treatment, or continuation of the trial. 
Refer to Section 11.5. 
The following parameters will be recorded daily for the safety evaluation: 
• 
Serious adverse events 
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 42 of 66 
• 
Standard 12-lead ECG 
• 
Safety Laboratory Tests (clinical chemistry, hematology, coagulation, and urinalysis) 
• 
Vital Signs  
• 
Physical examination (when feasible) 
7.2 
Method and Timing of Assessments 
Safety will be evaluated using serious adverse events, vital signs, clinical laboratory tests and 
electrocardiograms. Refer to Table 1for the frequency and timing of assessments. 
Where time-points of different measurements and/or blood samples coincide, the following 
sequence applies: 
1. Vital Signs 
2. ECG 
3. Safety labs 
4. Biomarkers (blood) 
5. Pharmacokinetic sample collection 
7.2.1 
Adverse Event Recording 
Adverse events will be recorded from the time the subject signs the informed consent form 
through trial completion final visit/early termination. 
7.2.2 
Spontaneously Reported Adverse Events 
Spontaneously reported AEs; either volunteered by the subject, prompted by non-directed 
questioning or reported by an investigator will be documented on the CRF. 
7.2.3 
12-Lead ECGs 
Standard resting 12-lead ECGs will be obtained after subject is resting in the supine position 
for 10 minutes at the time points listed in Table 1.Additional ECGs may be obtained if 
clinically indicated. 
Overall interpretation and machine read intervals (HR, PR, QRS, QT, and QTc) will be 
recorded on the ECG eCRF.  Clinically significant ECG findings, per the Investigator’s 
clinical judgment, that emerge after treatment will be recorded on the AE CRF. 
7.2.4 
Safety Laboratory Tests 
All safety laboratory analyses will be conducted at local laboratory and have been listed 
below.  Laboratory tests will be obtained as indicated on the Schedule of Events (Table 1). 
Female subjects of childbearing potential will have a urine or serum pregnancy test 
performed locally at Screening and on Day 28. 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 43 of 66 
Chemistry: Alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin, 
alkaline phosphatase (ALP), total bile acids, sodium, potassium, chloride, bicarbonate, urea, 
glucose, calcium, uric acid, serum creatinine, creatinine kinase, albumin, total cholesterol, 
(LDL and HDL), triglycerides, gamma-glutamyl transpeptidase (GGT), and C-reactive 
Protein (CRP). 
Hematology: White cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils), red blood cell count, hemoglobin, hematocrit, platelet count, mean 
corpuscular volume, and red cell distribution width. 
Urinalysis: Macroanalysis for bilirubin, blood, specific gravity, pH, protein, glucose, 
ketones,urobilinogen. Dipstick urinalysis is permitted. 
Coagulation: PT, INR 
7.2.5 
Vital Signs 
Systolic/diastolic blood pressure, heart rate, respiratory rate, oxygen saturation, and 
temperature will be measured with specific attention to pulmonary abnormalities.  Vital signs 
will be measured prior any blood collection.  Measurements will be taken at the times 
specified in the Schedule of Events (Table 1) and will be recorded on the appropriate source 
document and CRF. 
7.2.6 
Physical Examination 
Due to restrictions in patient contact related to COVID-19infection, a physical examination 
will only be performed when feasible. The exam includes general appearance, evaluation of 
head, eyes, ears, nose, throat, neurological exam, weight with specific attention to worsening 
in liver function as noted by increasing jaundice, ascites (based on International Ascites Club 
Criteria), or hepatic encephalopathy (based on West Haven Criteria) and presence of 
infection.  The Physical Exams will be taken at the times specified in the Schedule of Events 
(Table 1) and will be recorded on the appropriate source document and CRF.  Any changes 
from baseline outside the normal range that emerge after treatment will be recorded on the 
AE CRF. 
7.2.7 
Biomarkers 
Biomarkers will only be assessed when feasible.  
 
 
  
The time window for sample collection can be within 12 hours. Serum samples should be 
stored at -650C to -800C until analysis or according to local laboratory instruction.  
The following is a list of planned biomarkers.  However, additional non-genetic biomarkers 
may be included if warranted. 
• 
Subset of cytokines: 
 
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 44 of 66 
• 
High-sensitivity C-reactive protein (hsCRP) 
• 
Lactate dehydrogenase (LDH) 
• 
Ferritin and D-dimer 
• 
Soluble urokinase plasminogen activator receptor (suPAR) 
The biomarker data at baseline and at each post-dose time point will be plotted and listed for 
each subject for evaluation of any change from baseline over time.  Since the baseline level 
of each marker may vary from subject to subject, percent change from baseline will be 
derived at each post-dose time points for each subject.   
See Section 7.2 for sequencing when time-points of different measurements and blood 
sample types coincide. 
The nominal sample times will be provided in the CRFs. The actual sample times (times 
when samples are actually taken) will be recorded alongside the nominal times in the CRF 
and will be entered at the time of or as soon as possible after sampling. 
Blood Volume to be taken during the study: 
No more than 
 of blood will be collected for protocol-related samples collection. 
7.3 
Adverse Events 
7.3.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign or symptom, including clinically significant laboratory 
values and test results, concomitant illness, accident, or worsening of an existing medical 
condition. 
The following should not be recorded as an AE if noted at screening: 
• 
A pre-planned procedure for an illness included in the subject’s medical history, 
unless the condition for which the procedure was planned has worsened since 
subject’s informed consent.  Please observe that complications to pre-planned 
procedures should be recorded as AEs 
• 
A pre-existing condition found as a result of screening procedures 
Any worsening in severity or frequency of a baseline concomitant illness or any new illness 
diagnosed in the trial period must be regarded as an AE. 
Serious Adverse Event 
A serious adverse event (SAE) is any adverse event that, at any dose: 
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 45 of 66 
• 
Results in death 
• 
Is life-threatening 
Life-threatening refers to an event in which the subject is at risk of death at the time 
of the event.  It does not include an event that, had it occurred in a more severe form, 
might have caused death 
• 
Requires inpatient hospitalization≥ 24 hours or prolongation of existing 
hospitalization 
Prolongation of hospitalization as determined by the Investigator 
• 
Results in persistent or significant disability/incapacity  
Disability is defined as a substantial disruption of a person’s ability to conduct 
normal life functions 
• 
Results in the birth of a child with a congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE (when based upon appropriate medical 
judgment).  These events may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Unexpected Serious Adverse Event 
An unexpected serious adverse event (USAE) is any serious adverse event that is 
independent of the underlying liver disease causality and is not consistent with information in 
the current Investigator’s Brochure, the protocol, and the consent document. 
Adverse Reaction  
An adverse reaction (AR) is any untoward and unintended response to a test drug that has 
been considered to have a causal relationship with the treatment. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction that is 
serious and where the nature or severity of which is not consistent with information in the 
current Investigator’s Brochure. 
Abnormal Laboratory Value as an AE 
An abnormal laboratory value (i.e. any clinical laboratory abnormality or change that 
suggests a disease and/or organ toxicity and is of a severity that requires active management 
[i.e. change of test drug dose, discontinuation of test drug, medical treatment, more frequent 
follow-up or diagnostic investigation]), will be regarded as an AE.  If clinical sequelae have 
been associated with a laboratory abnormality the diagnosis or medical condition should be 
reported (e.g. renal failure, hematuria) to replace the laboratory abnormality (e.g. elevated 
creatinine, urine RBC increased).   


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 46 of 66 
7.3.1.1 Classifications 
Severity  
The Investigator will evaluate the severity of each adverse event using the following 
definitions: 
Mild - Transient symptoms, no interference with the subject’s activities of daily living 
Moderate – Marked symptoms, moderate interference with the subject’s activities of daily 
living 
Severe – Considerable interference with the subject’s activities of daily living 
In the event of the occurrence of a severe adverse event, the Investigator will be instructed to 
immediately inform the medical monitor. 
An AE that has been assessed as severe should not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed 
as severe.  An event should be described as ‘serious’ when it meets one of the pre-defined 
outcomes as described in Section7.3.1. 
Toxicity Grade 
The Investigator will also provide AE severity grading per CTCAE (Version 5.0) 
Causality  
The Investigator is obligated to assess the relationship between test drug and the occurrence 
of each AE/SAE.  The Investigator will use clinical judgment to determine if there is a 
reasonable possibility that the pharmacological action of the test drug was responsible for the 
AE/SAE being reported.  Alternative causes such as natural history of the underlying 
diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to 
the test drug will be considered and investigated.  The Investigator will also consult the 
Clinical Investigator’s Brochure and/or Product Information, for marketed products, in the 
determination of his/her assessment. 
After careful medical consideration, the Investigator will evaluate the relationship of each 
adverse event to test drug applying the following definitions: 
Probably Related – Good reasons and sufficient documentation to assume a causal 
relationship 
Possibly related – A causal relationship is conceivable 
Unlikely related – The event is most likely related to etiology other than the test drug   
Not Related – Good reasons and sufficient documentation to exclude a causal relationship. 
There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report.  However, it is very important that the Investigator 
always assess causality for every event prior to transmission of the SAE Report Form to the 
Sponsor (or designee). 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 47 of 66 
7.3.2 
Adverse Event Reporting 
All events that meet the definition of an AE and occur in the period from when the subject 
has signed the informed consent form (ICF) through trial completion (final visit), or early 
termination, must be recorded on the adverse event CRF. All SAEs will be recorded on the 
appropriate CRF and on the Serious Adverse Event Report Form from the time written 
informed consent has been obtained through trial completion (final visit), or early 
termination. 
At each contact between the investigative site and the subject (visit or phone), after the 
subject has had an opportunity to spontaneously mention any problems, the Investigator 
should inquire about the occurrence of AEs.  The following are examples of open-ended 
questions that may be used to obtain this information:  
“How are you feeling?” 
“Have you had any medical problems since your last visit/assessment?”  
“Have you taken any new medicines, other than those given to you in this study, since your 
last visit/assessment?”  
All AEs and SAEs will be documented in source records at each assessment time or when 
otherwise volunteered by the subject and recorded on the appropriate CRF. Information to be 
collected includes the nature, date and time of onset, severity, duration, relationship to test 
drug, and outcome of the event.  Even if the Investigator assesses the AE as not reasonably 
attributable to the test drug, its occurrence must be recorded in the source documents and 
reported on the CRF along with the assessment of association. 
The Investigator will treat the subject as medically required, and this may extend beyond the 
duration of the trial.  The Investigator will record treatment and medications required to treat 
AEs on the appropriate CRF(s). All SAEs, and any possibly/probably related severe AEs will 
be followed until resolution. Resolution of an AE is defined as that point in time when no 
further changes in the event are expected, that is, the point at which a subject experiencing 
such an AE is appropriately treated and stabilized even though they may continue to 
experience lingering sequelae that may never resolve.   
DURECT’s designee will evaluate all AEs with respect to seriousness, causality and 
expectedness in accordance with Directive 2001/20/EC (3) and FDA Guidelines.  The 
expectedness of an AE will be determined according to the current version of the 
Investigators Brochure. 
7.3.3 
Reporting of Serious Adverse Events 
Regardless of causality, the investigator must complete and submit an SAE report form to 
 within 24 hours of 
knowledge of the event for all serious adverse events.    
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 48 of 66 
Submit SAE Report Forms via facsimile or email to: 
 
  
 
 
The Investigator must indicate the SAE’s relationship to test drug and sign the SAE report 
form.  When additional relevant information (final diagnosis, outcome, results of specific 
investigations, etc.) becomes available, the investigator must record that follow-up 
information in the eCRF.  Follow-up information should be recorded according to the process 
used for reporting the initial event as described above.  The investigator will follow all 
reportable events (i.e., SAEs) until resolution. Resolution means no further changes in the 
event would be expected, i.e., the point at which a subject experiencing such an AE is 
appropriately treated and stabilized even though they may continue to experience lingering 
non-serious sequelae that may never resolve.    
 will follow all SAEs until resolution (See Section 7.3.2).  
 
 will report all SAEs to DURECT within 1 business day of receipt.  
All serious adverse events will also be reported on the AE CRF and concomitant medications 
administered in association with the serious AE will be documented on the CM CRF. 
If a serious adverse event occurs and comes to the attention of the Investigator after trial 
completion/termination within 30 days of test drug dosing or within 30 days of the last trial 
visit (whichever occurs later), it must be reported immediately to 
 in the 
same manner as the serious adverse events occurring during the trial. Investigators are not 
obligated to actively seek AEs from former study participants. 
The Investigator must report SAEs to the IRB/IEC (per the IRB/IEC guidelines/SOPs), 
including all SAEs that have occurred at the investigative site and all trial related SAEs that 
have resulted in an expedited safety report to a regulatory agency.  Concurrently, the 
Investigator must send DURECT documentation of such IRB/IEC notification or if reporting 
is not required immediately per IRB/IEC guidelines, then a copy of the local SOP stating the 
reporting guidelines should be supplied by the site to DURECT and the CRO.   
DURECT complies with applicable regulatory requirement(s) related to the reporting of 
SUSARs to the competent authorities and the IRBs/IECs.  In addition, DURECT will prepare 
annual safety reports covering all SUSARs that have occurred in clinical studies with the 
concerned test drug during the reporting period. 
7.3.4 
Adverse Event Follow-up 
During and after participation by a subject in a clinical trial, the Investigator will ensure that 
adequate medical care has been provided to the subject for any AEs including clinically 
significant laboratory values related to the trial.  The Investigator will inform the subject 
when medical care will be needed for intercurrent illness (es) of which Investigator becomes 
aware.  
PPD/CCI
PPD/CCI
PPD/
CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 49 of 66 
All SAEs and possibly/probably related severe AEs must be followed by the Investigator 
until resolution (See Section 7.3.2), until the subject is lost to follow-up, or died and until all 
queries related to the AEs have been resolved.   
If a subject dies during participation in the study or during a recognized follow-up period, the 
Sponsor (or designee) must be notified immediately and then provided with a copy of any 
post-mortem findings, including autopsy and histopathology. 
7.4 
Pregnancy 
Pregnancy tests will be done at screening visit and on Day 28 for females of child-bearing 
potential 
Female subjects will be advised to notify the Investigator immediately if they become 
pregnant during the course of the trial.   
The Investigator must complete the appropriate pregnancy reporting forms and send them to 
DURECT (or DURECT’s designee) within 14 calendar days of obtaining information of the 
pregnancy.  The Investigator will follow the pregnancy through its course and complete the 
appropriate documentation and forward immediately to DURECT (or DURECT’s designee).  
The infant must be followed at least until one month of age.  Consent of a parent must be 
obtained before registration of infant data. 
Abortion, stillbirth and any malformation/disease must be reported as an SAE.  A pregnancy 
outcome other than abortion, stillbirth and any malformation/disease as well as follow-up of 
the infant must be reported by the Investigator within 14 calendar days of obtaining the 
information using the appropriate pregnancy reporting forms. 
8.0 
PHARMACOKINETICS 
Plasma samples will be collected from each of the first 10 patients enrolled. These samples 
will be used to calculate relevant pharmacokinetic parameters of DUR-928 determined using 
standard non-compartmental method with linear/log-trapezoidal rule utilizing an appropriate 
pharmacokinetic data analysis program. 
Pharmacokinetic parameters, such as Cmax, Tmax, T1/2, AUC0-last, AUCinf, CL, and Vd, for 
DUR-928 will be calculated and summarized by dose group and Part A or B using 
descriptive statistics. 
Additionally, if appropriate, PK/PD analysis will be undertaken. MELD score, serum 
chemistry, and/or biomarker(s) may be used as PD variables for PK/PD analysis.  
PK Sample Timepoints: 
 
  
PPD/CCI




DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 51 of 66 
Above study treatments will be diluted in 
 
and administered at 
 for approximately 2 hours or until the bag is empty. 
9.4 
General Statistical Methods 
In this Phase 2 randomized placebo-controlled study, the principal objectives are to provide 
screening evaluations of safety and efficacy of DUR-928. 
9.4.1 
Safety analyses 
Treatment emergent SAEs will be listed and summarized.  All SAEs reported in this study 
will be coded using the current Medical Dictionary for Regulatory Activities (MedDRA).   
Particular attention will be given to assessment of treatment emergent SAEs in the domains 
of respiratory failure events, liver events, and renal events. 
The overall incidences of SAEs in each system organ class (SOC) and preferred term (PT) 
will be tabulated.  In addition, incidences rates (frequencies and percentages) will be broken 
down by severity and/or relationship to study drug. Treatment emergent changes from 
baseline in clinical laboratory tests, ECG, and vital signs will be derived by treatment group. 
Safety will be evaluated by assessment of serious adverse events, clinical laboratory tests, 
and vital signs, starting at Screening. 
Status and severity of comorbid conditions such as diabetes (e.g. last known HbA1C, 
medications), cardiac disease (e.g. previous MI, Stroke, echocardiogram, 12 lead EKG, 
baseline troponin, WHO heart failure definition), and immunocompromised status will be 
documented. 
Data regarding the use of experimental anti-viral therapies will be collected. 
Data on other supportive measures, such as proning, received by subjects who are on 
invasive mechanical ventilation will be collected. 
For subject deaths, data will be collected on whether the death occurred after withdrawal of 
care and, if so, the reason for withdrawal of care. 
For each subject, the reason for hospital admission, the standard of care followed for each 
subject/site, and if care decisions are made based on resource limitation will all be document.     
9.4.2 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by descriptive 
statistics.  When appropriate, 95% confidence intervals will also be provided when 
appropriate. 
9.5 
Planned Interim Analyses 
Not applicable. 
9.6 
Tabulation of Individual Subject Data 
Listings by subject will be provided of all data collected in this study 
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 52 of 66 
9.7 
Changes and Deviations to the Protocol and Statistical Analysis Plan 
Any deviations from the planned analyses methods and the rationale for such deviations will 
be carefully documented in the SAP and as a protocol amendment, if applicable.   
10.0 
ACCESS TO SOURCE DATA/DOCUMENTATION 
The investigative site will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspections by providing direct access to source data/documentation (e.g. medical 
records, original laboratory records and original informed consent forms).  The Investigator 
should immediately notify DURECT of any Health Authority inspection.  Essential 
documents must be maintained at the investigative site throughout the trial. 
10.1 
Confidentiality 
By consenting to participate in this trial, each subject will agree that Sponsor personnel, their 
representatives or the respective Health Authorities personnel may require direct access to 
the subject’s data/personal records including photocopying source data in an anonymous 
form.  The subject will also agree that his/her data will be processed and stored in an 
anonymous form for evaluation of this trial and any later overviews.  Data may also be 
transferred in an anonymous form to third parties (e.g., other companies or authorities that 
may be located in other countries with potentially different regulations for data).  Data will 
follow the development of the test drug and will be used for documentation of the product’s 
efficacy and safety.  Data will be transferred to involved parties only within the authority 
given by official agencies.  The informed consent form will state that any data already 
obtained during trial participation will be kept if consent is withdrawn. 
10.2 
Data Identification 
Data for each subject will be identified by a unique subject ID number that will be assigned 
at the time of screening.   
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
DURECT or DURECT’s designee will monitor the trial for regulatory and protocol 
adherence at all stages of trial conduct from inception to completion in accordance with 
ICH-GCP.  This monitoring will be in the form of site visits and other communication and 
will include review of original source documents and CRFs.  DURECT’s monitor or 
designee will notify the Investigator prior to conducting any site visit.  These visits will 
include monitoring to assess facilities, required certifications, IRB/IEC records, equipment, 
subject recruiting ads, record-keeping, protocol adherence, data verification and 
transmission, adverse event reporting.  Participating investigators should expect final quality 
assurance visits by the Sponsor, and possibly by the FDA. 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 53 of 66 
The completed CRFs will be reviewed against source documents by the monitor at each 
monitoring visit.  If any data, signatures, or forms are missing or discrepant, the Investigator 
will be informed and appropriate written corrections will be made in a timely manner. 
11.2 
Protocol Deviations 
All departures from the protocol will be referred to as protocol deviations and not protocol 
violations (ICH E3R1 Guidance, June 2012). 
Definitions: 
A protocol deviation is “any change, divergence, or departure from the study design or 
procedures defined in the protocol.” 
An important protocol deviation is “a subset of protocol deviations that might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject's rights, safety, or well-being” 
The Investigator should not deviate from the protocol.  Except for changes intended to 
eliminate any immediate hazard to subjects, the trial should be conducted as described in the 
approved protocol.  In medical emergencies, the Investigator will use medical judgment and 
will remove the trial participant from immediate hazard followed by notification to DURECT 
and the IRB/IEC regarding the type of emergency and the course of action taken.  All 
protocol deviations will be documented by the investigative site or monitor on the designated 
log. 
11.3 
Case Report Forms 
Paper case report forms will be used for this trial. All data will be recorded on a source 
document prior to being entered into the CRF.  Data entry will occur at the investigative site 
and will be performed by trained and qualified site personnel.  The Investigator will ensure 
all the CRFs are completed after each subject visit in a timely manner. Specific instructions 
are provided in the CRF completion guidelines. 
11.4 
Coding 
MedDRA will be used to code adverse events.  WHO-Drug will be used to code concomitant 
medications. 
11.5 
Data Monitoring Committee (DMC) 
An independent, external DMC that includes a hepatologist, a nephrologist and an ICU 
specialist will convene prior to study start, once the 
 enrolled and their PK 
data available, once 
 have been treated and followed for 
 to monitor the 
study for safety events including SAEs, death, premature discontinuation of treatment for 
SAEs, or any treatment-emergent laboratory abnormalities. 
DMC will evaluate (based on an unblinded review of safety data) if there is:  
1. PK data and safety review of the 
; 
PPD/CCI
PPD/CCI
PPD/CCI
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 54 of 66 
2. a >20% of subjects in the DUR-928 group than in the placebo group with treatment-
emergent, treatment-related serious adverse event(s) of a specific type;  
3. more than 3 deaths, and the overall percentage of study patients with deaths within 60 
days exceeds 10%. 
4. more than 2 subjects have an AE grade 3 or above on the CTCAE scale that is 
determined to be possibly or probably attributable to study drug as per the medical 
monitor. 
The DMC also will be contacted on an as needed basis by the medical monitor to review 
available data, unblinded by intervention group, providing additional insights about whether 
any unexpected SAE (or SUSAR) to an individual subject could be due to study drug rather 
than the underlying COVID-19 disease and to provide advice regarding study conduct. The 
PI and medical monitor, based on the nature and severity of the event(s) under the Individual 
Subject Stopping Rule as listed below, will determine if such event(s) warrant the early 
termination of the study therapy in the best interest of the subject. The DMC may also 
provide recommendations as needed. 
Individual Subject Stopping Rule: 
1. Appearance of DILI: 
a) If baseline measurements (BLM) were <2x ULN, discontinue if ALT or AST 
increases to >5x BLM; 
b) If BLM ≥2x ULN but <5x ULN, discontinue if ALT or AST increases to >3x 
BLM; 
c) If BLM ≥ 5x ULN, discontinue if ALT or AST increases to >2x BLM; 
d) Discontinue if ALT or AST increase > 2x BLM AND the increase is accompanied 
by a concomitant increase in TBL to >2x BLM OR the INR concomitantly 
increases by >0.2 in absence of COVID-19 coagulopathy;  
e) In any subjects with signs and symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% or > 500/µL) 
2. Worsening of COVID-19 severity 
3. SAE events associated with cardiac, kidney, liver, or secondary infection. 
The DMC will provide recommendations to DURECT on whether the nature, frequency, and 
severity of adverse effects associated with study treatment warrant the early termination of 
the study in the best interest of the participants, whether the study should continue as 
planned, or the study should continue with modifications. The DMC may also provide 
recommendations as needed regarding study design.  
The DMC’s specific activities will be defined by a mutually agreed charter, which will define 
the DMC’s membership, conduct and meeting schedule. While the DMC will be asked to 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 55 of 66 
advise the sponsor regarding future conduct of the study, including possible early study 
termination, DURECT retains final decision-making authority on all aspects of the trial. 
Based on data review, DMC could recommend termination of the trial, pausing of 
randomization, discontinuation of treatment, or continuation of the trial. 
12.0 
ETHICAL CONSIDERATIONS 
This trial will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and ICH guidance E6) for all studies. 
12.1 
Institutional Review Board / Ethics Committee 
The protocol, consent form, advertisements and any other information for subjects will be 
reviewed and approved by DURECT Corporation (or DURECT’s designee) and by the 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) of the participating 
investigative site prior to the start of the trial at that site in accordance with the International 
Conference on Harmonization (ICH) and institutional IRB/IEC policies.  All protocol 
amendments and changes to the consent form occurring during the trial must also be 
approved by the IRB/IEC. 
12.2 
Regulatory Compliance 
The trial will be conducted in accordance with the principles of Good Clinical Practice 
(GCP) set forth in the International Conference on Harmonization (ICH) Good Clinical 
Practice, the US Code of Federal Regulations (CFR Title 21), the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA) and any local requirements. 
12.3 
Regulatory Status 
DUR-928 is an investigational product. 
12.4 
Subject Information and Informed Consent 
Prior to participation in the trial, the Investigator or designee will obtain written consent from 
each subject or legally acceptable representative using the IRB/IEC-approved informed 
consent form that explains the nature, purpose, possible risks and benefits of the trial, and the 
duration of an individual’s participation.  The basic elements of the informed consent as 
specified by the FDA (21 CFR §50.25), and HIPAA will be followed.   
Before consenting, the subject must be left with ample time to consider and to pose 
questions.  The Investigator and/or the designated investigative site personnel who conduct 
the informed consent discussion must also sign and date the consent form.  This consent 
discussion will be done using remote communication methods (e.g. video) to maintain social 
distancing in the efforts to prevent the spread of SARS-CoV-2.  Each subject will be given a 
copy of the signed consent form.  The original, signed consent forms will be maintained at 
the investigative site.   


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 56 of 66 
12.4.1 
Subject Withdrawal 
Subjects will be informed during the informed consent process (in writing and verbally) that 
they are free to withdraw from the trial at any time.  The Investigator may exercise his 
medical judgment to terminate a subject’s participation in the trial due to clinically relevant 
changes in any clinical or laboratory parameter.  DURECT Corporation also reserves the 
right to terminate the trial at any time.  All trial procedures normally performed at completion 
of the trial must be done at the time of the subject’s early termination, before the scheduled 
final clinic visit, or on the scheduled final clinic visit as described in Section 5.2.9 unless the 
subject withdraws consent.  If a subject withdraws consent they will be encouraged to 
complete an early termination visit and AE follow-up.  Subjects with ongoing SAEs and any 
possibly/probably related severe AEs will be followed until resolution. (See Section 7.3.2).  
Subjects with ongoing adverse events (other than SAEs, and any possibly/probably related 
severe AEs) will be followed until resolved or until 30 days after the subject’s last trial visit, 
whichever comes first. 
Subjects who withdraw prior to assignment of test drug will be considered as screen failures. 
13.0 
DATA HANDLING AND RECORD RETENTION 
13.1 
Data Ownership 
The CRFs, associated documents and reports from the trial are the property of DURECT.  
DURECT has the right to use the results for registration purposes, internal presentation and 
promotion. 
13.2 
Retention of Trial Records 
The Investigator will retain all trial documents (e.g., approved protocol, copies of completed 
CRFs, original informed consent forms, relevant source documents) in a secure place 
protected from fire and theft until:  
At least 2 years after the last approval of an NDA by the US FDA; 
At least 2 years after the last approval of a marketing application in an ICH region; 
There are no pending or contemplated marketing applications in an ICH region; or 
At least 2 years have elapsed since the formal discontinuation of the clinical development of 
the test drug 
These documents should be retained for a longer period if required by the local/regional 
regulations or by an agreement with DURECT.  It is the responsibility of the Sponsor to 
inform the Investigator/Institution when these documents no longer need to be archived. 
The medical files of trial subjects must be retained in accordance with national legislation 
and in accordance with the maximum period of time permitted by the hospital, institution or 
private practice. 


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 57 of 66 
DURECT will maintain the documentation pertaining to the trial as long as the test drug is on 
the market. 
Trial records must be made available by the Investigator for inspection upon reasonable 
request by authorized representatives of DURECT, the Food and Drug Administration 
(FDA), or the corresponding regulatory Health Authorities of the relevant countries. 
DURECT will provide the Investigator with information concerning the current status of the 
test drug as it relates to the Investigator’s responsibility for the retention of trial records.  The 
Investigator should contact DURECT prior to disposing of any such records.  DURECT will 
arrange for continued storage of all records, if necessary. 
 
 
 
 
 
 
 
PPD/
CCI




DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 59 of 66 
 
 
 
 
 
 
 
PPD/CCI


DURECT Corporation 
 
Protocol # C928-020 
                                                                         Protocol Amendment 2 Date: 08 December 2020 
CONFIDENTIAL 
Page 60 of 66 
17.0 
Appendices 
 
 
 
 
 
 
PPD/CCI


PPD/CCI


PPD/CCI


PPD/CCI


PPD/CCI


PPD/CCI


PPD/CCI