Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, Placebo-Controlled Phase 2/3 Study, in Adult Subjects Hospitalized With Severe SARS-CoV-2 Positive Pneumonia
Phase: PHASE2
Conditions: COVID-19, Lung Infection
Sponsor: RedHill Biopharma Limited

 
 
 
RedHill Biopharma Ltd. 
 
 
CLINICAL STUDY PROTOCOL: ABC-201 
 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: 
a Randomized, Double-blind, Placebo-Controlled Phase 2/3 Study, in Adult 
Subjects Hospitalized with Severe SARS-CoV-2 Positive Pneumonia 
 
Study: ABC-201, NCT04467840 
Phase: Phase 2/3 
Date: 15 April 2021 
Version: 5.0 
 
 
 

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Protocol ABC-201 Version 5.0 15 April 2021 
 
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CLINICAL STUDY PROTOCOL: ABC-201 
Title: 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 
Pneumonia: a Randomized, Double-blind, Placebo-Controlled 
Phase 2/3 Study, in Adult Subjects Hospitalized with Severe 
SARS-CoV-2 Positive Pneumonia 
Name of Investigational 
Product: 
Opaganib (ABC294640) 
Phase of Development: 
Adaptive Phase 2/3, with Futility Analysis 
Protocol Identification: 
ABC-201 
Sponsor Name and Address: RedHill Biopharma Ltd. 
21 Ha’arba’a St. 
Tel-Aviv 6473921, Israel 
Tel: +972 (0)3 541 3131 
Fax: +972 (0)3 541 3144 
 
Compliance Statement: 
The study will be conducted in accordance with standards of 
Good Clinical Practice, as defined by the International 
Conference on Harmonisation and all applicable national and 
local regulations., including the Rules of Good Clinical 
Practice of the Eurasian Economic Union, the EU Commission, 
the European Medicines Agency (EMA), and the Heads of 
Medicines Agency (HMA). In addition, the study complies with 
Interim guidelines: Prevention, diagnostics and treatment of a 
new coronavirus infection (COVID-19), MOH of the Russian 
Federation and specific guidance to the Sponsor from the Italian 
Medicines Agency (AIFA). The study has also taken into account 
the FDA COVID-19 Public Health Emergency: General 
Considerations for Pre-IND Meeting Requests for COVID-19 
Related Drugs and Biological Products Guidance for Industry and 
Investigators (May 2020) as well as the WHO Working R&D 
Blueprint for COVID-19: Informal consultation on the potential 
inclusion of Immunomodulators in a clinical trial 06 May 2020. 
Date of Protocol 
Amendment: 
Original: Version 1.0, 03 June 2020 
                Version 1.1, dated 15 June 2020 
                Version 2.0, dated 2 September 2020 
    Version 3.0 dated 9 November 2020 

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    Version 4.0 dated 18 January 2021 
    Version 5.0 dated 15 April 2021 
Name: 
Title: 
Phone: 
 
 
Signature 
 
Name: 
Title: 
Phone: 
 
 
Signature 
 
CONFIDENTIAL- PROPRIETARY INFORMATION  
The information in this document is confidential and is the property of RedHill Biopharma Ltd. It is understood 
that this information will not be disclosed to any third party, in any form, without prior written authorization from 
RedHill Biopharma, Ltd. 
 
 

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1 
TABLE OF CONTENTS  
CLINICAL STUDY PROTOCOL: ABC-201 ................................................................................ 0 
1 
TABLE OF CONTENTS .................................................................................................. 3 
2 
Approvals ........................................................................................................................... 5 
3 
PROTOCOL SYNOPSIS .................................................................................................. 6 
4 
STUDY SCHEMATIC .................................................................................................... 19 
5 
SCHEDULE OF ASSESSMENTS ................................................................................. 20 
6 
LIST OF ABBREVIATIONS ......................................................................................... 22 
7 
BACKGROUND INFORMATION ............................................................................... 24 
7.1 
COVID-19 Disease ............................................................................................ 24 
7.2 
Investigational Product ...................................................................................... 24 
7.3 
Preclinical Rationale .......................................................................................... 24 
7.4 
Prior Clinical Experience .................................................................................. 26 
8 
RATIONALE FOR OPAGANIB IN COVID-19 .......................................................... 29 
9 
STUDY OBJECTIVES ................................................................................................... 30 
9.1 
Primary ............................................................................................................... 30 
9.2 
Secondary ........................................................................................................... 30 
9.3 
Exploratory ......................................................................................................... 30 
9.4 
Safety .................................................................................................................. 30 
10 
STUDY POPULATION .................................................................................................. 31 
11 
ELIGIBILITY CRITERIA .............................................................................................. 32 
11.1 
Inclusion Criteria................................................................................................ 32 
11.2 
Exclusion Criteria .............................................................................................. 32 
11.3 
Women of Childbearing Potential Definition .................................................. 33 
12 
STUDY DESIGN............................................................................................................. 35 
12.1 
Overall Investigation Plan ................................................................................. 35 
12.2 
Randomization Strategy .................................................................................... 35 
12.3 
Study Assessments ............................................................................................. 36 
12.4 
Patient Discontinuation Criteria ........................................................................ 36 
12.5 
Study Drug Information and Dosage ................................................................ 36 
12.6 
Study Drug Administration ............................................................................... 37 
13 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................... 39 
14 
SCHEDULE OF ASSESSMENTS ................................................................................. 41 

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14.1 
Procedures and Assessments ............................................................................. 41 
15 
STUDY ENDPOINTS ..................................................................................................... 44 
15.1 
Primary ............................................................................................................... 44 
15.2 
Secondary ........................................................................................................... 44 
15.3 
Exploratory ......................................................................................................... 44 
15.4 
Safety .................................................................................................................. 45 
16 
SAFETY REPORTING ................................................................................................... 46 
17 
ADVERSE EVENTS DEFINITIONS ............................................................................ 47 
17.1 
Assessment of Casual Relationship .................................................................. 47 
17.2 
Adverse Event Grading ..................................................................................... 48 
17.3 
Handling of Serious Adverse Events ................................................................ 49 
17.4 
Pregnancy ........................................................................................................... 50 
17.5 
Laboratory Abnormalities ................................................................................. 50 
17.6 
Other Safety Considerations.............................................................................. 50 
18 
ETHICS ............................................................................................................................ 54 
18.1 
Investigator Responsibilities ............................................................................. 54 
18.2 
Sponsor Responsibilities ................................................................................... 56 
19 
STATISTICAL METHODS ........................................................................................... 58 
19.1 
Sample Size Considerations .............................................................................. 58 
19.2 
Stratification ....................................................................................................... 58 
19.3 
Populations for Analysis.................................................................................... 58 
19.4 
Analysis of the Primary Efficacy Endpoint ...................................................... 59 
19.5 
Analysis of the Secondary Efficacy Endpoints ................................................ 60 
19.6 
Safety Analyses .................................................................................................. 61 
19.7 
Type 1 error control ........................................................................................... 62 
19.8 
Interim Analysis ................................................................................................. 62 
20 
INVESTIGATOR’S STATEMENT ............................................................................... 63 
21 
REFERENCES ................................................................................................................. 64 
Appendix 1 
WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT .. 66 
Appendix 2 
List of Prohibited Concomitant Medications that May Potentially 
Interact with Opaganib ...................................................................................... 67 
 

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2 
APPROVALS 
Sponsor Representatives 
 
 
 
 
 
 
___________________________ 
 
 
 
____________ 
Reza Fathi, PhD 
 
 
 
 
 
Date 
Senior Vice President, Research and Development 
RedHill Biopharma Ltd. 
 
 
___________________________ 
 
 
 
____________ 
Mark L. Levitt MD PhD 
 
 
 
 
Date 
Medical Monitor 
 
 

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3 
PROTOCOL SYNOPSIS 
Study Title 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a 
Randomized, Double-blind, Placebo-Controlled Phase 2/3 Study, in Adult 
Subjects Hospitalized with Severe SARS-CoV-2 Positive Pneumonia 
Protocol 
Number 
ABC-201 
Sponsor 
RedHill Biopharma Ltd. 
Investigational 
Product 
Opaganib (ABC294640) 
Opaganib 
Opaganib [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-
ylmethyl)amide, hydrochloride salt] is an orally available inhibitor of the enzyme 
sphingosine kinase-2 (SK2) (French, 2010).  SK2 is an innovative molecular 
target due to its critical role in sphingolipid metabolism, which is known to 
regulate many cellular functions, including the replication-transcription complex 
(RTC) of +single-strand RNA viruses  
Rationale- 
Preclinical 
Opaganib is an investigational product in mid-stage clinical development with 
anti-viral properties targeting RNA viruses, such as coronaviruses, by inhibiting 
viral replication, combined with anti-inflammatory effects as detailed below. 
Opaganib has been studied in pre-clinical models of RNA viral disease, 
inflammation and cancer (see Investigator Brochure). Recent pre-clinical studies 
have demonstrated that opaganib is a potent inhibitor of SARS-CoV-2 replication, 
at concentrations that are achievable in human serum. Inhibition of the enzyme 
sphingosine kinase-2 (SK2) with opaganib has demonstrated a decrease in viral 
titers of influenza virus in an in vitro model system (with an EC50 well within the 
achievable concentrations of opaganib in humans, based on the phase 1 human 
trial) as well as improved survival in a preclinical study of influenza infected 
mice receiving opaganib daily for two days. Opaganib has also demonstrated a 
substantial inhibitory effect in a dose dependent manner in a preliminary Ebola 
cell-based inhibition assay with near complete inhibition of Ebola cellular 
infection with the same achievable concentrations of opaganib in humans. 
Targeted knockdown of SK2 also inhibited Hepatitis C virus replication and 
substantially reduced Chikungunya Virus in infected HepG2 cells.  The pre-
clinical effect on Chikungunya Virus is particularly relevant as they also contain a 
+single stranded RNA genome like SARS-CoV-2 and other corona viruses. In 
chikungunya viral infection, SK2 has been shown to be recruited to the viral 
replication transcription complex by the viral Nsp3 protein, and its inhibition 
substantially reduces viral replication.  
Opaganib has also been shown to inhibit host inflammatory responses in vitro and 
in vivo by blocking the phosphorylation of sphingosine to sphingosine-1-
phosphate (S1P), preventing the pro-inflammatory effects of S1P in a number of 
disease models as well as in a radioprotection model. Opaganib has shown a 

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decrease in IL-6 levels, in TLR4 expression, NF-κB activation and TNFα-induced 
activation of NFκB pro-inflammatory cytokine/ chemokine (TNFα, IL-1β and 
CXCL-10) production; a decrease in monocyte/ macrophage and neutrophil tissue 
infiltration; blocking of CD4+ T cell infiltration and IFNγ production; abrogation 
of TNFα-induced expression of adhesion proteins and blockade of TNFα-induced 
PGE2 (as a measure of COX-2 activity).  
In an in vivo model of Pseudomonas aeruginosa pneumonia, opaganib has been 
shown to reduce TNF-alpha and IL-6 concentrations in bronchioloalveolar lavage 
fluid to near non-infected control levels. 
The decision to enroll patients into this study and, in some cases, add opaganib to 
other experimental medicines, will be at the discretion the study physician, based 
on the pharmacological action, existing data and dosage form described in this 
protocol.  Of note, in patients who are unable to swallow capsules, opaganib made 
into a suspension form may be administered via a nasogastric tube (administering 
opaganib suspension via nasogastric tube did not substantially alter the 
bioavailability of opaganib after a tube feed in a healthy volunteer study). 
Rationale- 
Clinical Studies 
to Date  
To date, three clinical trials have been completed with opaganib, a phase 1 food 
and administration route effect study in healthy volunteers, a phase 1b study in 
advanced solid tumor patients, and a phase 1b/2 study in patients with advanced 
multiple myeloma. Two additional studies are currently in progress, a phase 2 
study in patients with cholangiocarcinoma and a phase 2 study in patients with 
castration-resistant prostate cancer. In May 2020 the U.S. FDA approved a Phase 
2a clinical study evaluating opaganib in patients with confirmed moderate-to-
severe SARS-CoV-2 infection. 
Based on the Phase 1b studies, the dose of 500 mg of opaganib every 12 hours 
was determined as the maximum safe and tolerable dose in treatment in oncology 
patients. This same dose will be utilized in the COVID-19 studies. 
Of note, the dose and duration (exposure) proposed for COVID-19 patients is 
considerably shorter than that in oncology patients, who have received opaganib 
daily for more than 2 years. 
A Phase 2a Proof-of-Concept study has just been completed in the US, 
randomizing hospitalized, hypoxic patients suffering from COVID-19 pneumonia 
to be treated with either opaganib, 500 mg Q12 hours or placebo on the same 
schedule for 14 days (NCT04414618). The investigational product was given on 
top of standard of care therapy. The preliminary results demonstrated that 
opaganib as compared to placebo led to improved time to 50% reduction of 
supplemental oxygen requirement; a greater percentage of patients no longer 
needing supplemental oxygen by Day14 of treatment and less total oxygen 
requirements during the 14 days of treatment, as measured by Area under the 
curve (AUC). Further evaluations showed a greater percentage of patients on 
opaganib no longer needed supplemental oxygen by Day 7 and had improved 
time to discharge from hospital, compared to placebo. In addition, there was no 
substantial safety difference between opaganib and placebo treated patients. 

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Compassionate 
Use Experience 
in COVID-19 
Infection   
Under an compassionate exemption, 7 patients with severe COVID-19 infections 
were treated with opaganib. These results are uncontrolled, however provide 
important clinical data within the compassionate use context. 
One patient improved 36 hours after initiation of treatment to room air and was 
discharged from hospital.  Five other patients were treated with opaganib for up to 
14 days.  All patients had clinical improvement and were discharged from 
hospital. Patients treated with opaganib in the compassionate use program did not 
progress to requiring intubation and mechanical ventilation. 
Patients receiving opaganib via compassionate use were compared to a matched 
case-control group of 18 patients. Opaganib treated patients had faster 
improvement in lymphocyte counts, decreased CRP and faster time to being 
weaned off high flow oxygen. Of the 18 matched controls, 6/18 cases required 
intubation and mechanical ventilation.   
One patient started hydroxychloroquine, azithromycin and opaganib within 24 
hours and had diarrhea necessitating withdrawal of all three medications. This 
was the only adverse event thought to be at least possibly related to opaganib. 
Standard of 
Care 
Considerations 
 As the approval and/or guidance for treating COVID-19 are evolving, for this 
protocol, standard of care will be defined by the recommended schemes of 
treatment according to the severity of the disease, taking into consideration 
regulatory approvals in one or more regions. The proven effective therapies for 
the purpose of this protocol will be adjusted as new data emerges and will be 
documented in a stand-alone document entitled Approved COVID-19 Therapies, 
and shared with study personnel. 
All other treatments will be considered experimental, pending evaluation and 
potential future approval. Concomitant use of standard of care, and/or 
experimental treatments in patients enrolled in this study will be guided by the 
inclusion/exclusion criteria, prohibited medications and precautionary 
medications as outlined in the protocol and the study physician’s discretion. 
Justification for 
Opaganib, 
Population, 
Study Design, 
Primary 
Endpoint 
The population to be enrolled in this study will have severe COVID-19 infection, 
be hospitalized and require supplemental oxygen to treat hypoxemia, with or 
without an increased work of breathing. Data from the recently completed Phase 
2a study in the US suggest that opaganib may be beneficial in this population by 
reducing the need for supplemental oxygen and accelerating the time to discharge 
from the hospital.  
As the primary objective of opaganib therapy is to improve and/or stabilize the 
clinical status of the patient, the primary analysis is based on the proportion of 
patients who no longer need supplemental oxygen by Day 14 (end of treatment).  
This outcome will be considered a treatment success. The primary endpoint is 
consistent with achieving a score of 3 or better (0-3, inclusive) on the WHO 
Ordinal Scale for Clinical Improvement by Day 14 of treatment. 
The duration of treatment is 14 days, aligning with approved anti-viral treatment 
regimens for COVID-19, such as remdesivir. 

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Primary 
Objective 
To evaluate the proportion of patients no longer requiring supplemental oxygen 
for at least 24 hours by Day 14  
Secondary 
Objectives 
1) To evaluate change on the WHO Ordinal Scale for Clinical Improvement  
2) To evaluate the time to recovery defined by improvement to a score of 3 or 
less on the WHO Ordinal Scale for Clinical Improvement 
3) To evaluate the time to low oxygen flow via nasal cannula e.g. from high 
oxygen flow via nasal cannula or positive pressure ventilation at baseline 
4) To evaluate time to discharge from the hospital 
5) To evaluate the proportion of patients requiring intubation and mechanical 
ventilation by Day 42  
6) To evaluate the time to two consecutive negative swabs for SARS-CoV-2 by 
PCR  
7) To evaluate the proportion of patients with two consecutive negative swabs 
for SARS-CoV-2 by PCR at Day 14  
8) To evaluate the proportion of patients, with at least one measurement of fever 
at baseline (defined as temperature >38.0 C [100.4 F]), who are afebrile 
(defined as temperature <37.2C [99 F]) at Day 14   
9) To evaluate mortality 28 and 42 days post-baseline 
Exploratory 
Objectives 
1) To assess the change in systemic markers of inflammation (D-dimer, cardiac 
troponin, C-reactive protein [CRP], lactate dehydrogenase [LDH] and ferritin) 
over the treatment period of 14 days 
2) To assess the change in lymphocyte count over the treatment period of 14 
days 
3) To evaluate the time to recovery defined by improvement to a score of 1 or 
less on the WHO Ordinal Scale for Clinical Improvement 
4) To evaluate the proportion of patients no longer requiring supplemental 
oxygen for at least 24 hours by Day 7  
5) To evaluate time to 50% reduction of supplemental oxygen requirement for 
the subset of subjects who do not require positive pressure ventilation during 
the study 
Safety 
Objectives 
To assess the safety and tolerability of opaganib administered orally at 500 mg Q 
12 hours, for up to 14 days, in patients with severe COVID-19 pneumonia 
Study 
Population 
The study population will consist of patients diagnosed with COVID-19 infection 
that is defined as severe based on eligibility criteria to align with current WHO 
Ordinal Scale for Clinical Improvement level 5 (patients on a non-rebreather or 
reservoir face masks, which are capable of delivering high concentrations of 
oxygen, will be considered equivalent to high flow nasal cannulas). Specifically 
patients will at minimum have pneumonia secondary to SARS-CoV-2, 
radiographic evidence of pneumonia on chest X-ray or CT scan, and require 

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supplemental oxygen by high flow oxygen via nasal cannula or positive pressure 
ventilation. Patients must be hospitalized at least during screening and at Baseline 
(Day 1). 
Study Design 
and Description 
This is a phase 2/3 multi-center randomized, double-blind, parallel arm, placebo- 
controlled study with an adaptive design that will utilize a futility assessment. The 
study is planned to be performed worldwide in approximately up to 80 clinical sites. 
After informed consent is obtained, patients will enter a screening phase for no 
more than 3 days, to determine eligibility. Approximately 464 eligible patients will 
be randomized and receive either opaganib added to standard of care, or matching 
placebo added to standard of care, in a randomization ratio of 1:1. Treatment 
assignments will remain blinded to the patient, investigator and hospital staff, as 
well as the sponsor.   
Study participants will receive either opaganib 2 x 250 mg capsules (500 mg) every 
12 hours, or matching placebo, in addition to standard of care (pharmacological as 
defined above and/or supportive) at any given institution. Study drug will be 
administered every day for 14 days (Day 1 to Day 14). All participants will be 
followed up for 42 days from their first dose of study drug.  
Randomization 
and 
stratification 
Strategy 
Subjects will be randomized to receive either opaganib added to standard of care, 
or matching placebo added to standard of care, in a randomization ratio of 1:1.  
As the treatments in the recommended schemes of treatment according to the 
severity of the disease may differ, standard of care administered to patients may 
differ by institution.  
In order to ensure balance of standard treatment regimens in both treatment arms 
as well as with  
regard to patient risk status, randomization will be determined based upon two 
stratification factors: 
a)  Patients will be stratified on whether SoC treatment has established efficacy (yes 
versus no). The proven effective therapies for the purpose of this protocol will be 
adjusted as new data emerges and these updates will then be applied to this 
stratification. 
b) Patients will be stratified based on meeting three or more high risk (out of 
possible 8) clinical parameters for COVID-19 outcomes at baseline (yes versus no). 
 
The 8 parameters are: 1) age at screening, ≥60 years of age, (yes or no); 2) male, 
(yes or no); 3) HbA1c at screening,  ≥6.5 and/or on active treatment with insulin or 
oral hypoglycemics (yes or no); 4) hypoxemia without commensurate increased 
work of  breathing (defined as increased respiratory rate, nasal flaring and/or 
increase use of respiratory muscles including the diaphragm [yes or no]; 5) known 
underlying chronic lung disease (yes or no); 6) known cardiovascular disease or 
hypertension (yes or no); 7) BMI ≥ 28.0 kg/m2 (yes or no); 8) known renal disease 
(yes or no). 

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Adaptive 
Interim 
Analysis for 
Futility 
An unblinded futility interim analysis will be conducted when approximately 135 
subjects have had the Day 14 evaluation, in order to determine if it would be 
futile to continue the study. The futility criteria will be primarily based on the 
primary endpoint, and will further involve key clinical secondary endpoints such 
that futility can only be declared if the primary AND all key secondary endpoints 
cross the futility boundary. The exact futility boundaries will be prospectively 
determined and documented in the final version of the Statistical Analysis Plan 
(SAP) prior to the interim analysis. The analysis will be conducted by an 
independent statistician reporting only to members of the data safety monitoring 
board (DSMB). The DSMB members will be notified if the futility boundary has 
been crossed (yes/no) and will inform the sponsor.  Strict procedures will be 
employed to maintain the confidentiality of the interim results and will be 
documented in the SAP charter. 
Data Safety 
Monitoring 
Committee 
The DSMB will be convened for the safety oversight of the study in order to 
assure safety of the trial participants.  The DSMB meetings to review the safety 
data, will be planned after 25%, 50% and 75% or when approximately 70, 135, 
230 and 345 randomized patients, respectively, have reached Day 14.  The DSMB 
will also be responsible for conveying the results of the futility analysis conducted 
by an independent unblinded statistician to the sponsor (futile/non-futile).   
A DSMB charter will be provided as a separate document.   
Treatment and 
Administration 
Opaganib 500 mg Q12 hour or matching placebo 
Opaganib or placebo made into a suspension form may be administered by 
nasogastric tube. 
Study Duration Recruitment period is estimated at 6 months. 
The maximum duration of study participation will be up to 45 days (including up 
to 3 days screening; up to 14 days of double-blind treatment and completion of 
study at Day 42). 
Eligibility 
Criteria 
Inclusion: 
1) Adult male or female ≥18 to ≤80  years of age 
2) Proven COVID-19 infection per RT-PCR assay of a pharyngeal sample 
(nasopharyngeal or oropharyngeal) AND pneumonia defined as radiographic 
opacities on chest X-ray or CT scan that diagnosed COVID-19 pneumonia. 
Pharyngeal samples collected either at screening or within 7-days prior to 
screening for the same ongoing COVID-19 pneumonia illness are acceptable. 
3) The patient requires, at baseline, high flow supplemental oxygen or positive 
pressure ventilation, or is receiving oxygen via face mask, such as a non-
rebreather or reservoir mask, capable of delivering high concentrations of 
oxygen.  
4) Male participants with female partners of child-bearing potential agree to one of 
the following methods of contraception during the treatment period and for at 
least 1 month after the last dose of study drug:  

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• 
Abstinence from penile-vaginal intercourse and agree to remain abstinent.  
• 
Male condom, with female partner using a highly effective contraceptive 
method. (For further details regarding highly effective contraceptive methods 
refer to Section 11.3).  
 
In addition, male participants must refrain from donating sperm for the duration of 
the study and for 1 month after last dose of study drug.  
 
Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile penetration for at least 1 month after the last dose of study drug  
Female participants:  
A female participant is eligible to participate if she is:  
a) not pregnant 
b) not breastfeeding 
c) not a woman of child-bearing potential (WOCBP, as defined in Section 
11.3)  
d) a WOCBP who agrees to use a highly effective method of contraception 
consistently and correctly during the treatment period and for at least 1 
month after the last dose of study drug (refer to Section 11.3 for further 
details).  
5) The patient or legal representative has signed a written informed consent 
approved by the IRB/Ethics Committee 
 
Exclusion: 
1) Any co-morbidity that may add risk to the treatment in the judgment of the 
investigator, particularly patients with known cardiac conditions, or serious 
neuropsychiatric conditions such as psychosis or major depression.  
2) Requiring intubation and mechanical ventilation at baseline 
3) Patient has a ‘Do Not Intubate’ and/or ’Do Not Resuscitate’ order in place 
4) Oxygen saturation >95% on room air 
5) Any preexisting respiratory condition that requires intermittent or continuous 
ambulatory oxygen prior to hospitalization 
6) Patient is, in the investigator’s clinical judgement, unlikely to survive >72 
hours 
7) Pregnant (positive serum or urine test within 3 days prior to randomization) or 
nursing women . 
8) Unwillingness or inability to comply with procedures required in this 
protocol.  
9) Corrected QT (QTc) interval on electrocardiogram (ECG) >470 ms for 
females or >450 ms for males, calculated using Friedericia’s formula (QTcF) 
10) AST (SGOT) or ALT (SGPT)  > 2.0  x upper limit of normal (ULN) 
11) Total bilirubin >1.5 x ULN (except where bilirubin increase is due to 
Gilbert’s Syndrome) 

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12) Serum creatinine >2.0 X ULN  
13) Absolute neutrophil count <1000 cells/mm3  
14) Platelet count <75,000/mm3  
15) Hemoglobin <8.0 g/dL  
16) Medications that are sensitive substrates, or substrates with a narrow 
therapeutic range, for  CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 
CYP2D6 , CYP3A4, P-gP, BCRP and OATP1B1 should be avoided with 
opaganib Please see Appendix 2. 
17) Moderate or strong inhibitors of CYP1A2, CYP3A4, CYP2D6 or P-gP or 
moderate to strong inducers of CYP3A4 and CYP1A2 are prohibited.  Please 
see Appendix 2. 
18) Currently taking warfarin, apixaban, argatroban or rivaroxaban due to drug-
drug interaction based on CYP450 metabolism. For washout periods, refer to 
Section 13.1.4. 
19) Current drug or alcohol abuse 
20) Currently participating in a clinical study assessing pharmacological 
treatments, including anti-viral studies.  
21) Treatment with any medication that causes QT prolongation within seven 
days, or 5 half-lives, whichever is longest, prior to initiation of study drug, or 
intention to use them throughout the study, including but not limited to: 
amiodarone, amitriptyline, citalopram dose greater than 20 mg/day, 
dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, 
ibutilde, ondansetron or other 5-HT3 receptor antagonists, pimozide, 
procainamide, quinidine, quinine, quinolone, ranolazine, risperidone, 
sotaloland tolteridine. Investigators are directed to the following up-to-date 
web site listing QT-prolonging drugs: 
https://www.crediblemeds.org/index.php/drugsearch 
Number of 
Subjects 
Approximately up to 525 subjects will be screened to randomize approximately 
464 subjects  
Number of 
Investigator 
Sites 
Approximately up to 80 participating hospital centers 
Screening/Basel
ine Assessments 
• Signed informed consent by patient or legal representative 
• WHO Ordinal Scale for Clinical Improvement level 
• Eligibility determination 
• Complete medical history (including onset of COVID-19 symptoms, 
including date of positive PCR for SARS-CoV-2 prior to screening, where 
available) 
• Concomitant medication assessment 
• Baseline review of systems 

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• Physical examination 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and 
oxygen saturation by pulse oximeter)  
• Height and weight (most recent) 
• Oxygen requirement (L/min)- to be repeated prior to first dose as a baseline 
• FiO2 (estimate) 
• 12-lead electrocardiogram  
• Chest Xray or CT scan (performed up to 7 days prior to randomization) 
• Nasopharyngeal or oropharyngeal swab for SARS-CoV-2 PCR test (collected 
either at screening or up to 7 days prior to screening) 
• Serum chemistry 
• CRP, D-Dimer, LDH, ferritin, cardiac troponin (Troponin C, I or T, but must 
be consistent for each patient throughout the study) 
• HbA1c 
• CBC with differential  
• Urinalysis  
• Serum or urine pregnancy test (for WOCBP) within 3 days prior to treatment 
Study 
Assessments 
The following will be monitored and documented daily:  
• WHO Ordinal Scale for Clinical Improvement level 
• Concomitant medications 
• Adverse Events 
• Interim Physical exam, including specific assessment for signs of 
neuropsychiatric (e.g. anxiety, agitation, insomnia), and cardiopulmonary 
abnormalities (e.g. tachycardia, palpitations, chest pain, syncope)   
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and 
oxygen saturation by pulse oximeter)  
• Oxygen flow rate setting (L/min)  
• FiO2 (estimate or known if patient is ventilated) 
 
The following will be monitored less frequently: 
• Patients will have a 12-lead electrocardiogram prior to the first study drug 
administration on Day 1 and approximately 3 hours after the first dose.  If 
patients are on monitors (including telemetry or Holter monitors), 
investigators are encouraged to collect QT interval data 
• Nasopharyngeal or oropharyngeal viral swab for SARS-CoV-2 PCR test 
every 3 days ±1 day (confirmatory negative swab at least  24 hours after first 
negative swab) 
• Serum chemistry every 3 days ±1 day   
• Serum CRP, D-Dimer, LDH, ferritin, cardiac troponin (Troponin C, I or T, 
but must be consistent for each patient throughout the study) once weekly ±2 
days 

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• CBC with differential every 3 days ±1 day 
• Chest X-ray or CT scan as per physician decision 
Safety Follow-
Up Assessments 
 Day 42 unless the patient has died or withdraws consent 
• Concomitant medications 
• Adverse Events, (in case of a telephone visit: including specific assessment 
for signs of neuropsychiatric (e.g. anxiety, agitation, insomnia), and 
cardiopulmonary abnormalities (e.g. tachycardia, palpitations, chest pain, 
syncope)) 
• WHO Ordinal Scale for Clinical Improvement level 
• Physical exam, including specific assessment for signs of neuropsychiatric 
(e.g. anxiety, agitation, insomnia), and cardiopulmonary abnormalities (e.g. 
tachycardia, palpitations, chest pain, syncope)  
• Oxygen requirement (type and flow: L/min) 
Study 
Endpoints 
Primary  
The percentage of patients no longer requiring supplemental oxygen for at least 
24 hours by Day 14 for the opaganib arm as compared to the placebo arm  
 
Secondary 
1. The percentage of patients with ≥2 category improvement on the WHO 
Ordinal Scale for Clinical Improvement by Day 14 for the opaganib arm 
as compared to the placebo arm 
2. Time to recovery as defined by improvement to a score of 3 or less on the 
WHO Ordinal Scale for Clinical Improvement for the opaganib arm as 
compared to the placebo arm  
3. Time to low oxygen flow via nasal cannula e.g. from high oxygen flow 
via nasal cannula or positive pressure ventilation at baseline 
4. The time to discharge from the hospital for the opaganib arm as compared 
to the placebo arm 
5. The percentage of patients requiring intubation and mechanical ventilation 
by day 42 for the opaganib arm as compared to the placebo arm 
6. The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at 
least 24 hours apart for the opaganib arm as compared to the placebo arm 
7. The percentage of patients with at least two consecutive negative swabs 
for SARS-CoV-2 by PCR at Day 14  for the opaganib arm as compared to 
the placebo arm 
8. The percentage of patients with at least one measurement of fever at 
baseline (defined as temperature >38.0 C[100.4 F]), who are afebrile 
(defined as temperature <37.2C [99 F]) at Day 14 for the opaganib arm as 
compared to the placebo arm 
9. Mortality due to any cause by Days 28 and 42 after baseline for the 
opaganib arm as compared to the placebo arm 
 

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Exploratory 
1. The mean change in systemic markers of inflammation (D-dimer, cardiac 
troponin, C-reactive protein [CRP], lactate dehydrogenase [LDH] and 
ferritin) from baseline at Day 14 for the opaganib arm as compared to the 
placebo arm 
2. The mean change in lymphocyte count from baseline at Day 14 for the 
opaganib arm as compared to the placebo arm 
3. Time to recovery as defined by improvement to a score of 1 or less on the 
WHO Ordinal Scale for Clinical Improvement for the opaganib arm as 
compared to the placebo arm 
4. The percentage of patients no longer requiring supplemental oxygen for at 
least 24 hours by Day 7 for the opaganib arm as compared to the placebo 
arm 
5. The time to 50% reduction of supplemental oxygen requirement for the 
subset of subjects who do not receive positive pressure ventilation (non-
invasive or invasive) for opaganib arm as compared to the placebo arm 
Safety 
1. Incidence rates of all treatment-emergent AEs (TEAEs) and SAEs 
2. Evaluation of vital signs 
3. Evaluation of laboratory parameters (chemistry and hematology)  
4. Evaluation of electrocardiograms (ECG)  
Prohibited 
Medications 
during the 
Study 
The following medications are prohibited during the study, including the safety 
follow-up period: 
• Medications that are sensitive substrates and narrow therapeutic range 
drugs which are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19 CYP2D6 , CYP3A4, P-gP, BCRP and OATP1B1 should be 
avoided with opaganib. .Please see Appendix 2.   
• Moderate or strong inhibitors of CYP1A2, CYP3A4, CYP2D6 or P-gP are 
prohibited. Please see Appendix 2. Warfarin, apixaban, argatroban and 
rivaroxaban are prohibited due to drug-drug interaction based on CYP450 
metabolism. For washout periods, refer to Section 13.1.4.  
• Treatment with any medication that causes QT prolongation within seven 
days, or 5 half-lives, whichever is longest, prior to initiation of study drug, 
or intention to use them throughout the study, including but not limited to: 
amiodarone, amitriptyline, citalopram dose greater than 20 mg/day, 
dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, 
ibutilde, ondansetron or other 5-HT3 receptor antagonists, pimozide, 
procainamide, quinidine, quinine, quinolone, ranolazine, risperidone, 

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sotalol and tolteridine. Investigators are directed to the following up-to-
date web site listing QT-prolonging drugs: 
https://www.crediblemeds.org/index.php/drugsearch 
Precautionary 
Medications 
during the 
Study 
• Substrates for MATE1 and MATE2-K should be used with caution and 
monitored for safety due the potential for inhibition of this transporter 
protein. As the clinical relevance of these in-vitro interactions hasn’t been 
established, these should be decided in discussion with the Medical 
Monitor on a case-by-case basis. 
• Moderate to strong inducers of CYP3A4 and CYP1A2 may influence the 
exposure of opaganib. 
Adverse Events 
of Special 
Interest 
Opaganib may cause neuropsychiatric toxicity that may be due to increases in 
ceramides.  
In a Phase 1 healthy volunteer food effect study, these toxicities were found to be 
reduced by eating a light to moderate meal prior to each dose administration and 
this was likely due to delayed absorption and reduced Cmax.  
Neuropsychiatric events reported in clinical studies to date include: 
hallucinations, anxiety, insomnia, lethargy, agitation, distress and dysarthria.   
These neuropsychiatric adverse events occurred at higher frequencies at the 
highest dose administered, which is above the dose selected (maximum tolerated 
dose) for the current and future clinical studies.   
For further information, refer to Section 17.6.3. 
Stopping Rules At any time during the study, participants will stop study drug if it is determined 
that they have experienced any of the following adverse events (using Grading 
criteria as defined in the revised NCI Common Terminology for Adverse Events 
[CTCAE v.5.0])  
• Any neuropsychiatric adverse event of Grade 3 severity 
• Hallucinations of any severity (any Grade) 
• Nausea of Grade 3 severity 
• Vomiting of Grade 3 severity 
• Any Grade 3 or higher event or laboratory abnormality deemed possibly, 
probably, or definitely related to study drug 
Sample Size 
Estimation 
It is planned to enroll approximately 464 eligible patients into the double-blind 
treatment phase, to receive either opaganib added to standard of care (n=232), or 
matching placebo added to standard of care (n=232). The sample size calculation 
was based on powering the study with respect to the primary efficacy endpoint of 
proportions of patients no longer requiring supplemental oxygen for at least 24 
hours by 14 days. It was assumed that the treatment success rate at 14 days in the 
control arm would be 40% and that opaganib is expected to provide absolute 15% 
increase of this rate, to a success rate of 55%. A total of 464 subjects provides 

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90% power to detect the assumed difference in success rate, using chi square test, 
at a two-sided α=0.05 level of significance. 
Statistical 
Methods 
The primary efficacy endpoint will be based on a success (Yes/No) variable, 
indicating if a subject is no longer requiring supplemental oxygen, for at least 24 
hours by study Day 14 (patient death or subsequent requirement of supplemental 
oxygen or lost to follow-up through Day 42 will be regarded as failure for the 
primary efficacy endpoint). Any subject reported as not requiring supplemental 
oxygen on any given study day will be counted as a subject who has not required 
oxygen for at least 24 hours, based on the instructions to sites to enter the highest 
oxygen requirement for each study day. Subjects who are discharged from 
hospital on supplemental oxygen are expected to be followed up by the study site 
daily and will be considered a success only if for any given study day, the highest 
supplemental oxygen requirement is zero. By definition, death before day 14 will 
be regarded as a failure, even if prior room air has been achieved. If a patient 
initiates a new investigational therapy on a different formal clinical protocol for 
COVID-19 within 14 days of randomization, the patient will be followed for true 
outcomes in the primary analysis but be censored at the time that the new therapy 
was initiated in a sensitivity analysis. 
If a subject discontinues the study prematurely before reaching success, prior to 
Day 14, they will be counted as a failure for the primary analysis. Sensitivity 
analysis using time to event method will be performed censoring these cases at 
the latest informative time.  
The number and percentages of subjects achieving success (as defined above) will 
be tabulated per treatment group. A 95% confidence interval will be constructed 
for each proportion. A Cochran Mantel-Haenzel (CMH) test will compare the 
proportion of success between the two groups, using the study stratification 
factors used for randomization, and a corresponding stratified risk difference 
estimate will be presented with 95% confidence interval.   
The significance level for this test will be two-sided 5%. The primary analysis 
will be based on the modified Intent to treat population (mITT analysis set) which 
consists of all patients that were randomized and treated with at least one dose of 
study drug and who met entry criteria #3 (The patient requires, at baseline, high 
flow supplemental oxygen or positive pressure ventilation, or is receiving oxygen 
via non-rebreather mask or reservoir mask, capable of delivering high 
concentrations of oxygen. Patients who require mechanical ventilation or no 
longer require supplemental oxygen prior to receiving the first dose of study drug 
will not be included in the mITT analysis set.   

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4 
STUDY SCHEMATIC 
 
 
Opaganib Q12hours
Up to 3 days
screening
Double-blind treatment
Day 1 
RandomizaƟon
Day 14
Primary Endpoint
Placebo Q12hours
Safety follow-up
Day 42
End of Study

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5 
SCHEDULE OF ASSESSMENTS 
Table 1 Schedule of Assessments  
 
Assessments 
  
Study Days 
  
 -3 to -
113 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Early Term 
Day 42 
Safety 
F/U12 
ICF signed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics; 
medical and surgical 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review concomitant 
medication(s)2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
X 
X 
Review of adverse 
events2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
X 
X 
Physical 
examination2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO questionnaire3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
X 
X 
Vital signs2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen flow 
(L/min)2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
X 
X 
Height and Weight4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharyngeal viral 
sample5 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
12-lead ECG6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT 
scan7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry8 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Hematology (CBC 
with differential)9 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 

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Assessments 
  
Study Days 
  
 -3 to -
112 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Early Term 
Safety 
F/U12 
D-dimer, cardiac 
troponin, CRP, LDH, 
ferritin10 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine 
pregnancy test11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Protocol defined End of Treatment (EOT) occurs on Day 14. For subjects discharged from the hospital prior to Day 14, these 
assessments will be performed on a daily basis after discharge, via phone until Day 14.  
2daily assessments whilst patient is hospitalized; vital signs = temperature, blood pressure, pulse rate, respiratory rate and oxygen 
saturation by pulse oximeter and recording of supplemental oxygen requirement as oxygen flow (L/min) and FiO2 estimate; special 
attention to the possibility of neuropsychiatric (e.g. anxiety, agitation, insomnia), and cardiopulmonary abnormalities (e.g. tachycardia, 
palpitations, chest pain, syncope)    
3 For WHO questionnaire (WHO ordinal scale for clinical improvement) -refer to Appendix 1  
4record weight if even if just by patient estimate 
5 In screening, pharyngeal samples for SARS-CoV-2 PCR to be collected up to 7 days prior to screening. During treatment, samples are 
collected every 3 days±1 day, other than a confirmatory negative swab at least 24 hours after the first and a Day 14 swab if not 
confirmed negative prior.  Once two confirmed negative swabs are obtained, no further testing need be done. For patients having 
nasopharyngeal swabs, the same nostril must be used during the study. In countries where regulatory guidelines do not require a 
negative swab in order for a patient to be discharged from the hospital, reasonable efforts will be made to arrange for testing to be 
performed either at an external clinic or at the subject’s home. 
6 Screening ECG is required.  Additionally, all patients will have a 12-lead electrocardiogram prior to the first study drug administration 
on Day 1 and approximately 3 hours after the first dose.  If patients are on monitors (including telemetry or Holter monitors), 
investigators are encouraged to collect QT interval data 
7 In screening chest X-ray or CT scan (performed up to 7 days prior to randomization). Chest X-ray or CT scan, lab draws will be at the 
discretion of the Investigator depending on patient clinical condition 
8 Every 3 days ± 1 day. Serum Chemistries will include at a minimum albumin, alkaline phosphatase, ALT, AST, bicarbonate, total 
bilirubin, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, sodium, uric acid. 
9 CBC with differential once every 3 days ±1 day 
10  CRP=C-reactive protein, LDH=lactate dehydrogenase, cardiac troponin (Troponin C, I or T, but must be consistent for each patient 
throughout the study), D-dimer, ferritin, once weekly ±2 days 
11 women of childbearing potential; serum or urine pregnancy test must be negative within 3 days prior to randomization 
12 The Day 42 follow-up visit should be performed wherever possible but  
may be performed by telephone if returning to the hospital site is not feasible per Investigator and/or patient decision.  Only AEs, WHO 
questionnaire, concomitant medications and oxygen flow will be collected by telephone. 
13 Laboratory values and other diagnostic tests that have been obtained prior to the ICF being signed may be used if within the time 
allotted for the screening period. 

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6 
LIST OF ABBREVIATIONS  
 
Abbreviation 
Definition  
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvate transaminase) 
ARDS 
Adult Respiratory Distress Syndrome 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
Area under the curve 
COVID-19 
Coronavirus Disease of 2019 
CFR 
Code of Federal Regulations 
CRO 
Clinical Research Organization 
CYP 
Cytochrome P450 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
FDA 
United States Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
HBEC 
Human bronchial epithelial cells 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
NCI Common Terminology Criteria for Adverse Events 
NG 
Nasogastric 
PCR 
Polymerase Chain Reaction 
QTc 
Corrected QT 
QTcF 
Corrected QT using Friedericia’s formula 
RTC 
Replication transcription complex 
S1P 
Sphingosine-1-phosphate 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 

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SAP 
Statistical Analysis Plan 
SAE 
Serious adverse event 
SK2 
Sphingosine kinase 2 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper limit of the normal range 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 

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7 
BACKGROUND INFORMATION 
7.1 COVID-19 Disease 
COVID-19 is a newly recognized disease caused by a coronavirus virus, SARS-CoV-2.  A flu-like 
illness was first noted in December 2019, in Wuhan, China and was subsequently attributed to a virus 
similar to the SARS coronavirus, which is now designated as SARS-CoV-2.  While the clinical 
spectrum has not yet been well defined, early reports suggest that SAR-CoV-2 infection ranges from 
asymptomatic infection to pneumonia and Adult Respiratory Distress Syndrome (ARDS) with 
multiorgan failure that may lead to death (Zhou, 2020). In the Zhou study, the median duration of viral 
shedding was 20 days, with an interquartile range of 17-24 days and a maximum of 37 days. Common 
symptoms reported in the Zhou study for 191 patients were fever (94%), cough (79%), sputum 
production and fatigue (each 23%) and myalgia (15%).  Bilateral pulmonary infiltrates were noted in 
75% of patients on chest X-ray. Patients over 65 years and those with significant comorbidities, such 
as diabetes, cardiac or pulmonary disease, appeared to be more susceptible for developing severe 
infection and had a relatively higher mortality rate compared to younger, otherwise healthy patients.  
The incidence of symptomatic and severe infection, as a proportion of infected patients, is not yet 
known, as test availability, utilizing Polymerase Chan Reaction (PCR) performed on nasopharyngeal 
swabs or other body fluids, has been limited.   
For most individuals testing positive, COVID-19 currently appears to be self-limiting.  The major 
threat to this viral pandemic is spread through a nonimmune population, and to those most at risk of 
severe infection. SAR-CoV-2 is highly contagious, with spread by aerosol and surface contact (van 
Doremalen, 2020) and potential fecal spread (Chen, 2020).  As this is a newly identified disease, first 
noted in December 2019, and as testing and interpretation of data are in a very early stage, no specific 
therapy has demonstrated antiviral efficacy. 
7.2 Investigational Product 
Opaganib [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide, 
hydrochloride salt] is an orally available inhibitor of the enzyme sphingosine kinase-2 (SK2) (French, 
2010).  SK2 is an innovative molecular target due to its critical role in sphingolipid metabolism, which 
is known to regulate many cellular functions, including the replication-transcription complex (RTC) of 
+single-strand RNA viruses (Reid, 2015).  
7.3 Preclinical Rationale 
Recent pre-clinical studies in vitro data demonstrate that opaganib completely inhibits viral replication 
of SARS-CoV-2, at concentrations that are achievable in human serum. . Working in collaboration 
with the University of Louisville Center for Predictive Medicine and Biodefense, opaganib was 
studied in a 3D tissue model of human bronchial epithelial cells (EpiAirway™, HBEC) which 
morphologically and functionally resembles the human airway and is similar to the model used to 
discover SARS-CoV-2. This study was designed to evaluate the in vitro efficacy of opaganib in 
inhibiting SARS-CoV-2 infection and included a positive control of remdesivir, a drug with known 
antiviral activity. Results from this study showed a clear and compelling effect of opaganib resulting 

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in complete inhibition of SARS-CoV-2 viral replication (Figure 1). Treatment of cells infected with 
SARS-CoV-2 resulted in a dose-dependent inhibition of infectious virus production without 
compromising cell membrane integrity, a measure of cell viability and drug safety, demonstrating 
opaganib’s promising potential for treating patients with COVID-19 (Figure 2) 
 
   Figure 1. 
 
 
 
 
         Figure 2. 
 
 
Additionaly, preclinical studies demonstrate that opaganib both inhibits host inflammation and has 
anti-viral properties. Using SK2−/− mice and differential gene expression analysis, it was demonstrated 
that SK2/sphingosie-1-phosphate (S1P) signaling could play a key role in promoting pneumonia via 
promoting inflammation and suppressing other factors that inhibit inflammation and host defense 
(Ebenezer, 2019). The results suggested that inhibition of SK2 may both inhibit viral replication and 
decrease pulmonary inflammation, ameliorating lung  injury. Additional evidence for the anti-
inflammatory properties of opaganib is derived from murine inflammatory bowl disease (IBD) models 
of ulcerative colitis, Crohn’s disease and rodent models of inflammatory arthritis and liver ischemia 
reperfusion. Opaganib has been shown to suppress anti-inflammatory responses in-vitro and in-vivo, 
including:  
1) decreased IL-6 levels, TLR4 expression, NF-κB activation and TNFα-induced activation of 
NFκB pro-inflammatory cytokine/ chemokine (TNFα, IL-1β and CXCL-10) production 
(Liu, 2010, Maines, 2008, Maines, 2010) 
2) decreased infiltration of monocytes/ macrophages and neutrophils ( Liu, 2012) 
3) blocked CD4+ T cell infiltration and IFNγ production (Liu, 2012) 
4) abrogation of TNFα-induced expression of adhesion proteins and blockade of TNFα-
induced PGE2 as a measure of COX-2 activity (Maines, 2008).  
Several other studies have reported that SK2 regulates cellular gene expression during Chikungunya 
virus (CHIKV) infection (Reid, 2015) and can maintain viral latency for Kaposi’s sarcoma-associated 
herpesvirus (Dai, 2014). SK2 recruitment into the RTC has been demonstrated in CHIKV in the 
Togaviridae family of viruses which contains a non-segmented +single stranded RNA genome 
(COVID-19 is a +single stranded RNA genome). Treatment of infected HepG2 cells with opaganib 

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significantly reduced CHIKV infection (Reid, 2015).  Targeted knockdown of SK2 also inhibited 
hepatitis c virus (HCV) replication (Yamane, 2014).  
Inhibition of SK2 with opaganib has also demonstrated a decrease in viral titers of influenza virus in 
an in vitro model system (with an EC50 well within the achievable concentrations of opaganib in 
humans, based on the phase 1 human trial) as well as improved survival in a preclinical study of 
influenza infected mice receiving opaganib daily for two days (Xia, 2018). 
Opaganib has also demonstrated a substantial inhibitory effect in a dose dependent manner in a 
preliminary Ebola cell-based inhibition assay (RedHill Biopharma, unpublished data). The doses that 
displayed near complete inhibition of Ebola cellular infection are also achievable in humans. 
7.4 Prior Clinical Experience 
To date, four clinical trials have been completed with opaganib, a phase 1 food and administration 
route effect study in healthy volunteers, a phase 1b study in advanced solid tumor patients, a phase 
1b/2 study in patients with advanced multiple myeloma and a Phase 2a study evaluating opaganib in 
patients with moderate-to-severe SARS-CoV-2 infection.. Two additional studies are currently in 
progress, a phase 2 study in patients with cholangiocarcinoma and a phase 2 study in patients with 
castration-resistant prostate cancer. Based on the Phase 1b studies, described in Section 7.4.1.1 and 
Section 7.4.1.2, based on safety and tolerability, the dose of 500 mg of opaganib every 12 hours was 
selected for future studies. The duration of treatment in oncology patients has been considerably 
longer than that proposed for COVID-19 patients, with oncology patients receiving opaganib daily for 
more than  2 years. 
7.4.1 Completed Studies 
7.4.1.1 Phase 1b Study in patients with advanced solid tumors (Study No. ABC-101) 
Twenty-two patients were enrolled, of whom 21 were treated with doses from 250 mg QD through 750 
mg BID. All 21 patients were evaluable for pharmacokinetics, pharmacodynamics and safety. Sixteen 
were evaluable for efficacy per RECIST 1.1 criteria. Patients received treatment continuously in 28 
day cycles and treatment was given while fasting. Mean age of patients entered was 58 years. Seventy 
one percent were male, 67% white. All patients had received prior chemotherapy and approximately 
half had prior surgery and/or radiotherapy. Patients had a variety of concomitant medical conditions 
and were receiving a variety of medications in addition to their antitumor therapy.  
The administered oral dose of 500 mg Q12 hours was the maximum tolerated dose. There were no 
deaths reported during the administration of opaganib. There were no discontinuations due to adverse 
events (AEs), in 250 mg QD and 250 mg bid cohorts. Common adverse events were nausea (12 
patients, 57%), fatigue (12 patients, 57%), vomiting (8 patients, 38%) and neuropsychiatric effects (14 
patients, 67%) including anxiety, insomnia, agitation and dysarthria.  Of these, only fatigue appeared 
to be dose-related.  Nausea and vomiting were common but not dose-limiting and rarely required 
discontinuation of treatment. Neuropsychiatric effects were seen at all dose levels, though were more 
common and bothersome at the highest dose level, 750 mg Q12 hours, considered an intolerable dose.    

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There were no consistent trends toward increases or grade shifts in liver function tests, hematologic 
parameters, or other biochemical parameters except for creatinine and lymphocytes. No patient 
developed clinically significant ECG abnormalities on study. There were no treatment group 
differences noted for the changes from baseline of QTcF. For more detailed data refer to Investigator 
Brochure. 
7.4.1.2 Phase 1b Study in patients with advanced multiple myeloma (Study No. ABC-
103 
Thirteen patients received study drug:  3 at 250 mg Q12 hours, 4 at 500 mg Q12 hours and 6 at 750 mg 
Q12 hours.  Median age of patients was 69 years (range 57-89), 7 were males, 7 were white and 6 
black.  All patients had received multiple courses of therapy with a median of 7 prior lines of treatment 
(range 3-13) excluding stem cell transplantation.  Eight patients had autologous hematopoietic stem 
cell transplantation.  
The administered oral dose of 500 mg Q12 hours was the maximum tolerated dose. There were no 
deaths reported during the administration of opaganib. Common adverse events included dyspepsia, 
nausea and vomiting. Eight patients experienced neuropsychiatric effects including altered mental 
state, confusion, dizziness, hallucinations and insomnia. All patients experiencing neuropsychiatric 
effects were receiving concomitant narcotic analgesics and several patients were also receiving other 
psychotropic medications. In several patients, after adjustment of the narcotic analgesic dosing 
regimen, the symptoms subsided, with maintenance or improvement of pain control. For more detailed 
data refer to Investigator Brochure. 
7.4.1.3 Phase 1a Study of food and administration route effect study in healthy 
volunteers (Study No, ABC-109) 
A total of 23 subjects participated in the study, 19 each received the drug orally in the fed and fasted 
states, and 21 via nasogastric (NG) tube. Mean and median ages of the subjects were 48.2 and 50.0 
years, respectively (range 22-72 years). Of the subjects, 56.5% were males, 78.3% were white, and 
47.8% were Hispanic. Median weight was 75.2 kg (range 52.0-123.3).  
Subjects received a single 500 mg dose of opaganib (two 250 mg capsules) after a large standard meal, 
while fasting, and via nasogastric tube. Overall, 13 subjects (56.5%) experienced at least one 
treatment-emergent event (TEAE). Of these, 9/13 and 4/13 expereienced a Grade 1 and Grade 2 
TEAE, respectively.  
 
Overall, the most common TEAEs were nausea (3 subjects, 13%), diarrhea (3 subjects, 13%), 
dizziness (5 subjects, 21.7%) and headache (5 subjects, 21.7%). The drug was better tolerated after 
food as compared to the fasting state, with double the proportion of subjects experiencing TEAEs after 
fasted administration of opaganib  compared to the fed state. 
Administration with a large standard meal (fed state) resulted in prolongation of absorption, with an 
increase in time to maximum concentration by one hour and a 43% decrease in peak plasma 
concentration. Overall bioavailability (AUC0-inf) was reduced by 17% compared to fasted state. The 
change in bioavailability did not appear to affect pharmacologic activity, as S1P suppression, a 

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pharmacologic consequence of SK2 inhibition, was somewhat higher after administration of opaganib 
in the fed state.  
 
Administration of an opaganib suspension by nasogastric tube after tube feeding did not substantially 
alter bioavailability of the drug. Hence, subjects/patients who are unable to swallow capsules may take 
the drug in suspension form and via NG tube. For more detailed data refer to Investigator Brochure. 
7.4.1.4 A Phase 2a (Proof of Concept) Study in patients with moderate to severe COVID-
19 Pneumonia (Study No. ABC-110) 
A Phase 2a Proof of Concept study was completed in the US evaluating 40 patients (mITT population) 
with moderate to severe COVID-19 pneumonia (aligning with WHO Ordinal Scale of Improvement 
Scores of 4 and 5) (NCT04414618). The primary endpoint was a comparison of the AUC for 
supplemental oxygen requirements in opaganib treated vs. placebo control patients over the 14 day 
treatment period. All participants received 500 mg of investigational product Q12 hours for 14 days, 
unless they were discharged prior to 10 days, in which case they continued treatment to a total of 10 
days. The investigational product, either opaganib 500 mg Q12 hours or matching placebo, was given 
on top of standard of care therapy. Secondary endpoints included several metrics for supplemental 
oxygen requirement, intubation and mortality. The study was intended as a proof of concept study and 
was not powered to detect a difference in the efficacy measurements. 
 
The preliminary results demonstrated that opaganib as compared to placebo led to improved time to 
50% reduction of supplemental oxygen requirement; a greater percentage of patients no longer 
needing supplemental oxygen by Day14 of treatment and less total oxygen requirements during the 14 
days of treatment, as measured by Area under the curve (AUC). Further evaluations showed a greater 
percentage of patients on opaganib no longer needed supplemental oxygen by Day 7 and had improved 
time to discharge from hospital, compared to placebo.  
7.4.1.5 Compassionate Use Experience 
Under compassionate exemption, 7 patients with severe COVID-19 infections have been treated with 
opaganib. These results are uncontrolled however provide important clinical data within the 
compassionate use context. One patient improved 36 hours after initiation of treatment to room air and 
was discharged from hospital.  Five other patients were treated with opaganib for up to 14 days.  All 
patients had clinical improvement and were discharged from hospital. Patients treated with opaganib 
in the compassionate use program did not progress to requiring intubation and mechanical ventilation. 
Patients receiving opaganib via compassionate use were compared to a matched case-control group of 
18 patients (Kurd, 2020). Opaganib treated patients had faster improvement in lymphocyte counts, 
decreased CRP and faster time to being weaned off high flow oxygen. Of the 18 match controls, 6/18 
cases required intubation and mechanical ventilation.   
 
One patient started hydroxychloroquine, azithromycin and opaganib within 24 hours and had diarrhea 
necessitating withdrawal of all three medications. This was the only adverse event thought to be at 
least possibly related to opaganib. 

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8 
RATIONALE FOR OPAGANIB IN COVID-19 
Opaganib has demonstrated substantial anti-viral effects for RNA viruses in pre-clinical models.  
Opaganib has demonstrated the ability to completely inhibit SARS-CoV-2 infection in a bronchial 
epithelial in vitro model and has suggested several aspects of clinical benefit in the ABC-110 clinical 
trial described above. 
   
However, like all other experimental treatments at this time, opaganib has not been proven to be better 
or worse than the currently approved COVID-19 medicines. In this regard, its place among the 
existing experimental medicines will be at the discretion the study physician, based on the 
pharmacological action described above, existing data and dosage form.  Of note, in patients who are 
unable to swallow capsules, opaganib made into a suspension form (refer to Section 12.6) may be 
administered via a nasogastric tube (administering opaganib suspension via nasogastric tube did not 
substantially alter the bioavailability of opaganib after a tube fee in a healthy volunteer study). 
The population to be enrolled in this study will have severe COVID-19 infection, be hospitalized and 
require supplemental oxygen to treat hypoxemia, with or without an increased work of breathing. The 
effect of opaganib, as an anti-viral and anti-inflammatory medicine, if effective, is likely to provide the 
most measurable benefit at this clinical stage of severity.  
 
 
 
 
 
 

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9 
STUDY OBJECTIVES 
9.1 Primary 
To evaluate the proportion of patients no longer requiring supplemental oxygen for at least 24 hours 
by Day 14  
9.2 Secondary 
1) To evaluate change on the WHO Ordinal Scale for Clinical Improvement  
2) To evaluate the time to recovery defined by improvement to a score of 3 or less on the WHO 
Ordinal Scale for Clinical Improvement 
3) To evaluate the time to low oxygen flow via nasal cannula e.g. from high oxygen flow via nasal 
cannula or positive pressure ventilation at baseline 
4) To evaluate time to discharge from the hospital   
5) To evaluate the proportion of patients requiring intubation and mechanical ventilation by Day 42  
6) To evaluate the time to two consecutive negative swabs for SARS-CoV-2 by PCR  
7) To evaluate the proportion of patients with two consecutive negative swabs for SARS-CoV-2 by 
PCR at Day 14  
8) To evaluate the proportion of patients, with at least one measurement of fever at baseline (defined 
as temperature >38.0 C [100.4 F]), who are afebrile (defined as temperature <37.2C [99 F]) at Day 
14   
9) To evaluate mortality 28 and 42 days post-baseline 
9.3 Exploratory 
1) To assess the change in systemic markers of inflammation (D-dimer, cardiac troponin, C-reactive 
protein [CRP], lactate dehydrogenase [LDH] and ferritin) over the treatment period of 14 days  
2) To assess the change in lymphocyte count over the treatment period of 14 days 
3) To evaluate the time to recovery defined by improvement to a score of 1 or less on the WHO  
Ordinal Scale for Clinical Improvement 
4) To evaluate the proportion of patients no longer requiring supplemental oxygen for at least 24 
hours by Day 7  
5) To evaluate time to 50% reduction of supplemental oxygen requirement for the subset of subjects 
who do not require positive pressure ventilation during the study 
9.4 Safety 
To assess the safety and tolerability of opaganib administered orally at 500 mg Q 12 hours, for up to 
14 days, in patients with severe COVID-19 pneumonia. 

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10 STUDY POPULATION 
The study population will consist of patients diagnosed with COVID-19 infection that is defined as 
severe based on eligibility criteria to align with current region-specific diagnostic guidance.  
Specifically, patients will at minimum have pneumonia secondary to SARS-CoV-2, radiographic 
evidence of pneumonia on chest X-ray or CT scan, and require supplemental oxygen by high flow 
oxygen via nasal cannula or positive pressure ventilation or is receiving oxygen via non-rebreather or 
reservoir face mask, capable of delivering high concentrations of oxygen. The patients must be 
hospitalized at least during screening and at baseline (Day 1).   

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11 ELIGIBILITY CRITERIA 
11.1  Inclusion Criteria 
1) Adult male or female ≥18 to ≤80  years of age 
2) Proven COVID-19 infection per RT-PCR assay of a pharyngeal sample (nasopharyngeal or 
oropharyngeal) AND pneumonia defined as radiographic opacities on chest X-ray or CT scan that 
diagnosed COVID-19 pneumonia. Pharyngeal samples collected either at screening or within 7-
days prior to screening for the same ongoing COVID-19 pneumonia illness are acceptable. 
3) The patient requires, at baseline, high flow supplemental oxygen or positive pressure or is 
receiving oxygen via face mask, such as a non-rebreather or reservoir mask, capable of delivering 
high concentrations of oxygen.  
4) Male participants with female partners of child-bearing potential agree to one of the following 
methods of contraception during the treatment period and for at least 1 month after the last dose of 
study drug:  
• 
Abstinence from penile-vaginal intercourse and agree to remain abstinent.  
• 
Male condom, with female partner using a highly effective contraceptive method. (For further 
details regarding highly effective contraceptive methods refer to Section 11.3).  
 
In addition, male participants must refrain from donating sperm for the duration of the study and 
for 1 month after last dose of study drug.  
 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration for at 
least 1 month after the last dose of study drug  
 
Female participants:  
A female participant is eligible to participate if she is:  
a) not pregnant 
b) not breastfeeding 
c) not a woman of child-bearing potential (WOCBP, as defined in Section 11.3)  
d) a WOCBP who agrees to use a highly effective method of contraception consistently and 
correctly during the treatment period and for at least 1 month after the last dose of study drug 
(refer to Section 11.3 for further details).  
5) The patient or legal representative has signed a written informed consent approved by the 
IRB/Ethics Committee 
11.2  Exclusion Criteria  
1) Any co-morbidity that may add risk to the treatment in the judgment of the investigator, 
particularly patients with known cardiac conditions, and serious neuropsychiatric conditions such 
as psychosis or major depression.  
2) Requiring intubation and mechanical ventilation at baseline 

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3) has a ‘Do Not Intubate’ and/or ’Do Not Resuscitate’ order in place  
4) Oxygen saturation >95% on room air 
5) Any preexisting respiratory condition that requires intermittent or continuous ambulatory oxygen 
prior to hospitalization 
6) Patient is, in the investigator’s clinical judgement, unlikely to survive >72 hours 
7) Pregnant (positive serum or urine test within 3 days prior to randomization) or nursing women  
8) Unwillingness or inability to comply with procedures required in this protocol.  
9) Corrected QT (QTc) interval on electrocardiogram (ECG) >470 ms for females or >450 ms for 
males, calculated using Friedericia’s formula (QTcF) 
10) AST (SGOT) or ALT (SGPT)  > 2.0  x upper limit of normal (ULN) 
11) Total bilirubin >1.5 x ULN (except where bilirubin increase is due to Gilbert’s Syndrome) 
12) Serum creatinine >2.0 X ULN  
13) Absolute neutrophil count <1000 cells/mm3  
14) Platelet count <75,000/mm3  
15) Hemoglobin <8.0 g/dL  
16) Medications that are sensitive substrates, or substrates with a narrow therapeutic range, for  
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 CYP2D6 , CYP3A4, P-gP, BCRP and 
OATP1B1 should be avoided with opaganib. Please see Appendix 2  
17) Moderate or strong inhibitors of CYP1A2, CYP3A4, CYP2D6 or P-gP or moderate to strong 
inducers of CYP3A4 and CYP1A2 are prohibited. Please see Appendix 2 
18) Currently taking warfarin, apixaban, argatroban or rivaroxaban due to drug-drug interaction based 
on CYP450 metabolism. For washout periods, refer to Section 13.1.4. 
19) Current drug or alcohol abuse 
20) Currently participating in a clinical study assessing pharmacological treatments, including anti-
viral studies.  
21) Treatment with any medication that causes QT prolongation within seven days, or 5 half-lives, 
whichever is longest, prior to initiation of study drug, or intention to use them throughout the 
study, including but not limited to: amiodarone, amitriptyline, citalopram dose greater than 20 
mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilde, 
ondansetron or other 5-HT3 receptor antagonists, pimozide, procainamide, quinidine, quinine, 
quinolone, ranolazine, risperidone, sotaloland tolteridine. Investigators are directed to the 
following up-to-date web site listing QT-prolonging drugs: 
https://www.crediblemeds.org/index.php/drugsearch 
11.3  Women of Childbearing Potential Definition 
For the purpose of this protocol, a woman is considered of childbearing potential (WOCBP), 
i.e. fertile, following menarche and until becoming post-menopausal unless permanently 
sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
ligation and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women not using hormonal contraception or 

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hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Highly effective contraceptive measures for WOCBP include: 
a. intrauterine device 
b. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the 
WOCBP study participant and that the vasectomized partner has obtained medical assessment of 
surgical success for the procedure) 
c. and/or sexual abstinence. 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient. 
d. If combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, 
transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable), intrauterine 
hormone-releasing system associated with inhibition of ovulation is utilized then a back-up method of 
highly effective birth control is required, for example condom plus spermicide, cervical cap plus 
spermicide. 
Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods. 

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12 STUDY DESIGN 
12.1  Overall Investigation Plan 
This is a phase 2/3 multi-center randomized, double-blind, parallel arm, placebo-controlled study, with 
an adaptive design that will utilize a futility assessment. The study is planned to be performed 
worldwide in approximately up to 80 clinical sites.  
After informed consent is obtained, patients will enter a screening phase for no more than 3 days, to 
determine eligibility. Approximately 464 eligible patients will be randomized and receive either 
opaganib added to standard of care, or matching placebo added to standard of care, in a randomization 
ratio of 1:1.  Treatment assignments will remain blinded to the patient, investigator and hospital staff, 
as well as the sponsor.  
Study participants will receive either opaganib 2 x 250 mg capsules (500 mg) every 12 hours, or 
matching placebo, in addition to standard of care (pharmacological as defined above and/or 
supportive) at any given institution. Study drug will be administered every day for 14 days (Day 1 to 
Day 14).  
All participants will be followed up for 42 days after their first dose of study drug. The maximum 
duration of study participation will be up to 45 days (including up to 3 days screening; up to 14 days 
of double-blind treatment and completion of study at Day 42). 
12.2 Randomization Strategy 
Randomization will be done centrally, using pre-determined schedule, and will assign subjects in a 1:1 
ratio to opaganib added to standard of care or matching placebo added to standard of care. 
In order to ensure balance of standard treatment regimens in both treatment arms as well as with 
regard to patient risk status, randomization will be determined according to two stratification factors:  
a) Whether SoC treatment has established efficacy (yes versus no). The proven effective therapies 
for the purpose of this protocol will be adjusted as new data emerges and will be documented 
in a stand-alone document entitled Approved COVID-19 Therapies which will be updated and 
shared with study personnel regularly.  
b) Patients will further be stratified based on meeting three or more high risk clinical parameters 
for COVID-19 outcomes at baseline (yes or no). 
The parameters are: 1) age at screening, ≥60 years of age, (yes or no); 2) male, (yes or no); 3) HbA1c 
at screening,  ≥6.5 and/or on active treatment with insulin or oral hypoglycemics (yes or no); 4) 
hypoxemia without commensurate increased work of  breathing (defined as increased respiratory rate, 
nasal flaring and/or increase use of respiratory muscles including the diaphragm [yes or no]; 5) known 
underlying chronic lung disease (yes or no); 6) known cardiovascular disease or hypertension (yes or 
no); 7) BMI ≥ 28.0 kg/m2 (yes or no); 8) known renal disease (yes or no). 
 
Should clinical or laboratory changes occur between screening and randomization-or between 
randomization and first dose of study drug- that affect patient eligibility, the patient should not be 

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treated. In order to avoid this situation, screening, randomization and first treatment should preferably 
be accomplished in the shortest time interval possible. 
12.3  Study Assessments  
The assessments for this study are listed in Section 14.1 
12.4  Patient Discontinuation Criteria 
A patient may be withdrawn from the study treatment or the study for any of the following reasons: 
• Request of the patient or patient’s representative 
• AEs or adverse device effects (ADEs) based on the judgment of the Investigator 
• The patient has experienced an AE that meets protocol defined stopping criteria (refer to 
Section 12.6.2) 
• The Investigator decides that it is in the patient’s best interest 
• The patient is noncompliant with the protocol 
• Lost to follow-up 
• Death 
If a subject is withdrawn at any time, the reason(s) will be recorded in the relevant section of the 
eCRF. Patients who discontinue from study treatment and remain in the study, will continued to be 
monitored per the Schedule of Assessments until Day 14 and the safety follow-up phase to Day 42.  
Patients discontinued due to AEs or ADEs will be monitored until resolution or stability of the event 
based on the judgment of the investigator. 
12.5  Study Drug Information and Dosage  
12.5.1 Identification and Description of Investigational Drug 
Opaganib 250 mg capsules contain the milled active opaganib drug substance along with the 
excipients microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate vegetal and are 
encapsulated in gelatin, white opaque body and cap, coni-snap capsules.  
Opaganib will be supplied in bottles, each bottle containing 28 capsules  
Placebo will be supplied in bottles, each bottle containing 28 capsules 
 Treatments will be blinded 

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12.5.2 Packaging and Labeling 
The study medication will be packaged in bottles and labelled by the Sponsor. 
The labels may include:  
Protocol number 
Subject number 
Dispense Date 
Name and contact information for the Sponsor  
Route of administration: oral or nasogastric tube 
Quantity supplied: 28 per bottle 
Pharmaceutical dosage form: Capsules 250 mg  
Storage conditions: store drug at -20-25°C (68-77°F) with excursions permitted to 30°C (86°F) 
CAUTION: New Drug – Limited by Federal Law To Investigational Use 
Bottle number 
Lot number 
12.5.3 Storage and Handling of Investigational Drug 
Study drug should be stored at 20-25°C (68-77°F) with excursions permitted to 30°C (86°F). 
12.6 Study Drug Administration 
Study drug will be administered with food (after a light to moderate meal) and followed by 240 mL (8 
fluid ounces) of water. If the patient can only take opaganib through a nasogastric tube, the contents of 
the capsule will be suspended in 20 cc normal saline solution and pushed through the nasogastric tube 
and flushed adequately with sterile water. If the patient is being tube-fed, study drug should be 
administered shortly after (approximately 15-30 minutes) a tube feed.  
In cases where patients are discharged prior to completing their 14 days treatment, they will continue 
to take the study drug at the same dose and schedule as an outpatient and following the same 
instruction to take each dose after a light to moderate meal. 
12.6.1 Study Drug Dose Modification Plan for Study Drug Suspected Toxicities 
Study drug may be withheld for suspected toxicities. Once suspected toxicities resolve to baseline an 
attempt may be made to re-initiate the study drug, in consultation with the Medical Monitor. Should 
the suspected toxicities re-occur, the study drug should be withdrawn permanently. 
 

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12.6.2 Criteria for Stopping Study Drug 
At any time during the study, participants will stop of study drug if it is determined that they have 
experienced any of the following adverse events (refer to section 17.2 Table 4 for Adverse Event 
Grade Definitions):  
• Any neuropsychiatric adverse event of Grade 3 severity 
• Hallucinations of any severity (any Grade) 
• Nausea of Grade 3 severity 
• Vomiting of Grade 3 severity  
• Any Grade 3 or higher event or laboratory abnormality deemed possibly, probably, or definitely 
related to study drug. 

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13 PRIOR AND CONCOMITANT MEDICATIONS  
13.1.1 Standard of Care Considerations 
As the approval and/or guidance for treating COVID-19 are evolving, for the purpose of this protocol, 
standard of care will be continually redefined by the recommended schemes of treatment according to 
the severity of the disease, taking into consideration regulatory approvals in one or more regions. 
These will be documented in a stand-alone document entitled Approved COVID-19 Therapies which 
will be updated and shared with study personnel regularly. 
 
All other treatments will be considered experimental, pending evaluation and potential future 
approval. Concomitant use of standard of care, and/or experimental treatments in patients enrolled in 
this study will be guided by the inclusion/exclusion criteria, prohibited medications and precautionary 
medications as outlined in the protocol and the study physician’s discretion. 
13.1.2 Allowed Medications 
Necessary supportive measures for optimal medical care will be given throughout the study. 
Additional care may be administered as indicated by the treating physician and patient’s medical need, 
and after discussion with the medical monitor. Supportive medications that are not expected to interact 
with opaganib and are allowed (Table 2): 
Table 2.  Allowed Supportive Medications 
Class/Pharmacological Action 
Allowed medication 
Analgesia 
acetaminophen (paracetamol), naproxen, 
ibuprofen1 
Sleeping medications/anxiolytic 
lorazepam 
Anti-coagulant medications 
heparin, dalteparin, enoxaparin, tinazaparin and 
fondaparinux, bilvalrudin 
Monoclonal antibodies 
casirivimab, imdevimab, bamlanivimab, 
etesevimab 
Corticosteroids 
dexamethasone2 
Other 
baricitinib 
Antiviral 
remdesivir2 

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1Use with caution, opaganib was a borderline inhibitor of MATE-1 in vitro 
2While interactions with opaganib are theoretically possible, the is low potential and/or an expectation that any clinical sequelae can be 
managed at the point-of-care. 
The drugs listed in the table above are either weak substrates or not considered substrates for enzymes 
or transporters which are inhibited or induced by opaganib.  
Supportive therapies including supplemental oxygen, plasma treatment from convalescent patients and 
COVID-19 vaccines are allowed and not anticipated to interact with opaganib.  
13.1.3 Concomitant medications 
Concomitant medications will include all medications that started, or were continuing, during or after 
administration of the study drug. All concomitant medications and supportive therapy administered 
starting Day 1 and until the final off-study drug follow-up visit must be recorded on the appropriate 
eCRF page. 
13.1.4 Prohibited Medications 
The following medications are prohibited during the study, including the safety follow-up period: 
• Medications that are sensitive substrates and narrow therapeutic range drugs which are 
substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 CYP2D6, CYP3A4, P-gP, 
BCRP and OATP1B1 should be avoided with opaganib.  
• Moderate or strong inhibitors of CYP1A2, CYP3A4, CYP2D6 or P-gP are prohibited as they 
may increase the systemic exposure (plasma concentrations) of opaganib.  
• As azithromycin carries a risk of QTc prolongation and/or torsades de pointe, it should not be 
co-administered with opaganib. 
• Warfarin, apixaban, argatroban and rivaroxaban are prohibited due to drug-drug interaction 
based on CYP450 metabolism. The washout periods for these drugs: 
o Warfarin ~ 1 week 
o Apixaban- 2.5 days 
o Argatroban- 5 hours 
o Rivaroxaban- 2 days 
13.1.5 Precautionary Medications 
• Substrates for MATE1 and MATE2-K should be used with caution and monitored for safety 
due the potential for inhibition of this transporter protein. As the clinical relevance of these in-
vitro interactions hasn’t been established, these should be decided in discussion with the 
Medical Monitor on a case-by-case basis. 
Moderate to strong inducers of CYP3A4 and CYP1A2 may influence the exposure of 
opaganib.  

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14 SCHEDULE OF ASSESSMENTS 
14.1  Procedures and Assessments 
Please see “Schedule of Assessments” for a detailed study schedule (Section 5) presented in tabular 
form. 
14.1.1  Screening (Day -3 to Day 1)  
Prior to the initiation of study-specific screening assessments the Investigator or designee must 
provide the patient(s) a complete explanation of the purpose and evaluations (procedures and 
assessments) of the study. Subsequently, the patient, or legal representative, must sign and receive a 
copy of an Informed Consent Form and authorization of use and disclosure of protected health 
information (PHI) that was approved by the institutional review board (IRB). Once informed consent 
has been obtained, the eligibility of the patient will be determined, and Screening assessments will be 
performed. Screening may be performed prior to Baseline (Day -3 to -1) or on the same day as 
Baseline (Day 1). Patients who have had laboratory or diagnostic tests normally required for 
screening, but which were performed prior to the ICF being signed, may have those test results used in 
lieu of the screening tests, if these were part of standard of care, and performed within the same 
screening window prior to randomization. 
• Signed informed consent 
• Eligibility determination 
• WHO Ordinal Scale for Clinical Improvement level 
• Complete medical history (including onset of COVID-19 symptoms, including date of a 
positive PCR for SARS-CoV-2 prior to screening, where available 
• Concomitant medication assessment 
• Baseline review of systems 
• Physical examination, specifically assessing for baseline signs of neuropsychiatric (e.g. 
anxiety, agitation, insomnia), and cardiopulmonary abnormalities (e.g. tachycardia, 
palpitations, chest pain, syncope) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and oxygen saturation by 
pulse oximeter)  
• Height and weight (most recent) 
• Oxygen requirement (L/min)- to be repeated prior to first dose as a baseline  
• FiO2 estimate 
• 12-lead electrocardiogram   
• Chest Xray or CT scan (performed up to 7 days of randomization) 
• Nasopharyngeal or oropharyngeal swab for SARS-CoV-2 PCR test (collected either at 
screening or up to 7 days prior to screening)  
• Serum chemistry  

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• CRP, D-Dimer, LDH, ferritin, cardiac troponin (Troponin C, I or T, but must be consistent for 
each patient throughout the study) 
• HbA1c 
• CBC with differential  
• Urinalysis  
• Serum or urine pregnancy test (for women of childbearing potential) within 3 days prior to 
treatment 
14.1.2 The following will be monitored and documented daily for hospitalized subjects 
• WHO Ordinal Scale for Clinical Improvement level 
• Concomitant medications 
• Adverse Events  
• Interim Physical exam, including specific assessment for signs of neuropsychiatric (e.g. 
anxiety, agitation, insomnia), and cardiopulmonary abnormalities (e.g. tachycardia, 
palpitations, chest pain, syncope) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and oxygen saturation by 
pulse oximeter)  
• Oxygen requirement (L/min) 
• FiO2 (estimate or known if patient is ventilated) 
14.1.3 The following will be monitored and documented daily for discharged subjects (as 
collected from follow-up phone calls) or for subjects having terminated treatment 
early and who are continuing in the study 
• WHO Ordinal Scale for Clinical Improvement level  
• Concomitant medications 
• Adverse Events, including specific assessment for signs of neuropsychiatric (e.g. anxiety, 
agitation, insomnia), and cardiopulmonary abnormalities (e.g. tachycardia, palpitations, chest 
pain, syncope)  
• Oxygen requirement (L/min) 
• In countries where regulatory guidelines do not require a negative swab in order for a patient to 
be discharged from the hospital, reasonable efforts will be made to arrange for testing to be 
performed either at an external clinic or at the subject’s home. 
14.1.4 The following will be monitored less frequently  
• Patients will have a 12-lead electrocardiogram prior to the first treatment and approximately 3 
hours after the first study drug administration on Day 1.  If patients are on monitors (including 
telemetry or Holter monitors), investigators are encouraged to collect QT interval data  

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• Nasopharyngeal or oropharyngeal viral swab for SARS-CoV-2 PCR test every 3 days ±1 day 
(confirmatory negative swab at least 24 hours after first negative swab) and a Day 14 swab if 
not confirmed negative prior.  
• Serum chemistry every 3 days ± 1 day  
• Serum CRP, D-Dimer, LDH, ferritin, cardiac troponin (Troponin C, I or T, but must be 
consistent for each patient throughout the study) once weekly ±2 days 
• CBC with differential every 3 days ±1 day 
• Chest X-ray or CT scan as per physician decision 
14.1.5 Safety Follow-up (Day 42) 
Day 42  
• Concomitant medications 
• Adverse Events  
• WHO Ordinal Scale for Clinical Improvement level 
• Physical exam, specifically assessing neuropsychiatric and cardiopulmonary abnormalities 
• Oxygen requirement (L/min) 
The follow-up visits may be performed by telephone if returning to the hospital site is not feasible per 
Investigator and/or patient decision.  On Day 42, only AEs (including specific assessment for signs of 
neuropsychiatric (e.g. anxiety, agitation, insomnia), and cardiopulmonary abnormalities (e.g. 
tachycardia, palpitations, chest pain, syncope), WHO questionnaire, concomitant medications and 
oxygen flow will be collected by telephone. 

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15 STUDY ENDPOINTS 
15.1  Primary  
The percentage of patients no longer requiring supplemental oxygen for at least 24 hours by Day 14  
15.2 Secondary 
1) The percentage of patients with ≥2 category improvement on the WHO Ordinal Scale for Clinical 
Improvement by Day 14 for the opaganib arm as compared to the placebo arm 
2) Time to recovery as defined by improvement to a score of 3 or less on the WHO Ordinal Scale for 
Clinical Improvement for the opaganib arm as compared to the placebo arm 
3) Time to low oxygen flow via nasal cannula e.g. from high oxygen flow via nasal cannula or 
positive pressure ventilation at baseline 
4) The time to discharge from the hospital for the opaganib arm as compared to the placebo arm 
5) The percentage of patients requiring intubation and mechanical ventilation by day 42 for the 
opaganib arm as compared to the placebo arm 
6) The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 hours apart for 
the opaganib arm as compared to the placebo arm 
7) The percentage of patients with at least two consecutive negative swabs for SARS-CoV-2 by PCR 
at Day 14  for the opaganib arm as compared to the placebo arm 
8) The percentage of patients with at least one measurement of fever at baseline (defined as 
temperature >38.0 C[100.4 F]), who are afebrile (defined as temperature <37.2C [99 F]) at Day 14 
for the opaganib arm as compared to the placebo arm 
9) Mortality due to any cause at Days 28 and 42 after baseline for the opaganib arm as compared to 
the placebo arm 
15.3 Exploratory 
1) The change in systemic markers of inflammation (D-dimer, cardiac troponin, C-reactive protein 
[CRP], lactate dehydrogenase [LDH] and ferritin) from baseline at Day 14 
2) The mean change in lymphocyte count from baseline at Day 14 for the opaganib arm as compared 
to the placebo arm 
3) Time to recovery as defined by improvement to a score of 1 or less on the WHO Ordinal Scale for 
Clinical Improvement for the opaganib arm as compared to the placebo arm  
4) The percentage of patients no longer requiring supplemental oxygen for at least 24 hours by Day 7 
for the opaganib arm as compared to the placebo arm 
5) The time to 50% reduction of supplemental oxygen requirement for the subset of subjects who do 
not receive positive pressure ventilation (non-invasive or invasive) for opaganib arm as compared 
to the placebo arm 
 

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15.4 Safety 
1) Incidence rates of all treatment-emergent AEs (TEAEs) and SAEs 
2)  
3) Evaluation of vital signs 
4) Evaluation of laboratory parameters (chemistry and hematology)  
5) Evaluation of electrocardiograms (ECG)  

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16 SAFETY REPORTING   
CRO will notify the sponsor of any SAE and will perform follow-up activities with the concerned site. 
The sponsor will bear responsibility of expedited and periodic reporting to the Health Authorities 
according to national requirements. Procedure and timelines for safety reporting are provided in the 
Safety Management Plan as agreed by CRO and the sponsor. The investigator must comply with any 
applicable site-specific requirements related to the reporting of SAEs (particularly deaths and suspected 
unexpected serious adverse reactions) to the IEC/IRB that approved the study. Investigators should 
provide written documentation of IEC/IRB notification for each report to the CRO. In accordance with 
ICH GCP, CRO will inform the investigators of findings that could adversely affect the safety of 
participant, impact the conduct of the study, or alter the IEC’s/IRB’s approval/favourable opinion to 
continue the study, as assessed by the sponsor. In particular and in line with respective regulations, CRO 
will inform the investigators of suspected, unexpected, serious adverse reactions (SUSARs). The 
investigator should place copies of Safety Reports in the Investigator Site File. National regulations with 
regard to Safety Report notifications to investigators will be taken into account. When specifically 
required by regulations and guidelines, the CRO will provide appropriate Safety Reports directly to the 
concerned lead IEC/IRB and will maintain records of these notifications. When direct reporting is not 
clearly defined by national or site-specific regulations, the investigator will be responsible for promptly 
notifying the concerned IEC/IRB of any Safety Reports provided by the CRO and of filing copies of all 
related correspondence in the Investigator Site File. 
 
All adverse events should be reported to the sponsor on the provided data-capture forms. All serious 
adverse events should be reported within 24 hours of knowledge. If the serious adverse event results in 
a fatal or life threatening outcome, the sponsor and the medical monitor must be notified immediately. 
Complete and fax or email a Serious Adverse Event report form and provide any supporting 
documentation to the Medical Monitor. The relevant forms to be completed as well as all contact 
details, including fax number and email addresses, will be provided in a separate document.  
To discuss SAE with Medical Monitor, contact them directly by phone at the numbers provided in the 
separate document.   
Follow-up information to a serious AEs must be provided to the Medical Monitor within 24 hours of 
investigator awareness in the same manner detailed above. 
These serious adverse event reporting timelines must be followed in order for the sponsor to submit 
the safety information to the regulatory authority within the safety reporting time regulations. 

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17 ADVERSE EVENTS DEFINITIONS 
The following definitions of terms are guided by the United States Code of Federal Regulations (21 
CFR 312.32(a)) and are included here. 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  An AE (may also be referred to as an adverse 
experience) can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational or marketed) product, whether or not considered related to the medicinal 
(investigational or marketed) product and from any route of administration, formulation, or dose, 
including an overdose.  
Adverse events will be reported from the first study drug administration. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in any of 
the following outcomes:   
• death;  
• is a life-threatening adverse event (defined as an event in which the subject was at 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); 
• requires in-patient hospitalization or causes prolongation of existing hospitalization; 
• a persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
normal life functions; 
• a congenital anomaly/birth defect; 
• is an important medical event.  This is defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the other serious outcomes listed in the definition above.  
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization. 
If either the sponsor or investigator believes that the event is serious, the event must be considered 
serious and be evaluated by the Sponsor for expedited reporting. 
A suspected adverse reaction means any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed.    
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any (suspected) adverse reaction (any 
adverse event for which there is a reasonable possibility that the drug caused the adverse event) that is 
both serious and unexpected. 
17.1 Assessment of Casual Relationship 
The following categories and definitions for assessing the causal relationship of an event to the 
investigational product(s) are provided as a guide to be used for evaluating adverse events reported in 

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this study to determine “suspected adverse reactions” that require expedited reported to regulatory 
agencies if they are unexpected.  In addition to the assessment below, the aggregate number of 
occurrences will be considered to decide whether the event is a reportable event and requires an IND 
safety report. 
Table 3.  Relationship of Study Medication to Adverse Events 
Unrelated 
The study drug almost certainly (or certainly) did not cause the event.   
Guidelines: 
There is no reasonable temporal relationship of the event to the administration of drug; 
The pattern is inconsistent with that known for the drug; and/or 
There is another obvious etiology. 
Probably 
not related 
It is more likely that the event is due to another etiology than due to the study drug.   
Guidelines: 
There is no reasonable temporal relationship of the event to the administration of drug; 
The pattern is inconsistent with that known for the drug; and/or 
There is another more likely etiology. 
Possibly 
related 
It is approximately equally likely that the event is due to the study drug as it is due to another etiology.  
Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The drug seems as likely as other etiologies to have caused the effect 
Probably 
related 
It is more likely that the event is due to the study drug than due to another etiology.   
Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The event may be consistent with a known pattern of drug (or drug class) effects; 
The drug seems more likely than other etiologies to cause the effect; 
The adverse event diminished upon cessation of study drug exposure or reduction in dose; and/or 
The adverse event worsened or recurred upon unintentional re-exposure to the study drug (Intentional 
rechallenge for the purpose of assigning causality should not be performed.) 
Definitely 
related 
The evidence is compelling that the study drug caused the adverse event.   
Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The event is consistent with a known pattern of drug (or drug class) effects; 
The drug is far more likely than other etiologies to have caused the effect; 
The adverse event diminished upon cessation of study drug exposure or reduction in dose; 
The adverse event worsened or recurred upon unintentional re-exposure to the study drug (Intentional 
rechallenge for the purpose of assigning causality should not be performed.) 
 
17.2 Adverse Event Grading 
Adverse events will be graded according to the revised NCI Common Terminology Criteria for 
Adverse Events (NCI-CTCAE version 5.0).   

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If an AE is not listed in the NCI-CTCAE v.5.0, then the Physician will use the terms: mild, moderate, 
severe, life-threatening, or death to describe the maximum intensity of the AE. For purposes of 
consistency, these intensity grades are defined as follows: 
Table 4: Adverse Event Grade Definitions 
GRADE 
 
 
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL  
4 
 
Life-threatening 
Life-threatening consequences; urgent intervention indicated 
5 
Fatal 
Death related to AE 
17.3 
Handling of Serious Adverse Events 
Adverse events classified as serious must be recorded on the AE page of the eCRF and require 
expeditious handling and reporting to the CRO Safety Surveillance, who will notify Redhill 
Biopharma in order for Redhill Biopharma to comply with regulatory requirements.  These SAEs will 
include deaths, regardless of their causal relationship to investigational product.  All SAEs must be 
reported using the Serious Adverse Event Report form.  To the extent possible, the descriptive 
terminologies and other SAE attributes entered on the SAE report form should approximate similar 
information in the CRF.  The completed SAE report form with supporting documentation must be 
provided to the sponsor within 24 hours of the study site personnel’s initial notification/awareness of 
the event.  All telephone communication regarding SAE must be followed by a written report.  Duly 
authorized study site personnel may sign completed SAE report forms; however, it is recommended 
that the investigator sign each final SAE report. 
Collection of complete information concerning SAEs is extremely important.  Thus, follow-up 
information that becomes available as the SAE evolves, as well as supporting documentation (e.g. 
hospital discharge summaries, additional lab and test results, autopsy reports, etc.), should be collected 
subsequently, if not available at the time of the initial report, and immediately sent to the CRO using 
the same procedure as the initial SAE report. Information on the SAE must be in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of causality. 
For ease of analysis, worldwide standardization, and regulatory reporting, the sponsor will code each 
reported adverse event or symptom to its corresponding preferred term and body system/organ class in 
the MedDRA dictionary version adopted for the study. The principal investigator will be responsible 
for assessing severity based on the intensity of the event as it presented using the criteria listed in 
Section 17.2 Table 4. 

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All SAE reports must be sent to the CRO, who will notify the sponsor’s medical monitor and the 
sponsor’s regulatory/clinical affairs contact provided in a separate document. 
As required, all investigators will be notified of all AE reports that are determined to be serious, 
unexpected, and related (by the reporting investigator or sponsor) to the investigational product.  The 
notification will be in the form of a Safety Update (Dear Doctor Letter). 
The notification is considered an addendum to the current Investigator’s Brochure; therefore, upon 
receiving such notices, the investigator must review and immediately submit a copy to the IRB 
according to local regulations.  The notification must be retained within the Investigator’s Brochure.  
The investigator and IRB will determine if the informed consent requires revision. 
17.4 Pregnancy 
Pregnancy is not an adverse event but requires emergent reporting to the Sponsor. In case of a patient 
or patient’s partner becoming pregnant during study participation, the pregnancy will be followed up to 
confinement and for 6 months after delivery. Corresponding information will be filed with the source 
documents at the clinical site. Pregnancy should be reported in the same time period as SAE using the 
Pregnancy Form. If there are corresponding adverse events, these should be reported as separate AEs.  
17.5 
Laboratory Abnormalities 
All new abnormal laboratory findings and those abnormal at baseline which change significantly (e.g., 
by at least one toxicity grade as defined in the National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] v5.0) are considered AEs.  Laboratory AEs for which there 
is no clinical intervention will be recorded only on the laboratory data pages of the eCRF.  Laboratory 
AEs not listed in the NCI CTCAE v5.0 will be considered as grade 1 (mild) if there is no clinical 
effect or intervention.  Laboratory values outside the normal range for certain parameters will not be 
considered AEs if they are generally not considered as indicating an abnormality; this includes such 
parameters as liver enzymes which are below the normal range.  If there is a clinical sequela or 
intervention, the laboratory abnormality is to be graded according to the criteria used for clinical AEs, 
described above. 
The NCI CTCAE v5.0 can be downloaded in pdf format at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_8.5x11.pdf 
17.6 
Other Safety Considerations 
Patients will be followed for at least 28 days after discontinuation of study medication.  When possible, 
the patient will come to the clinic for an in-person assessment.  If not possible for logistic reasons, the 
assessment may be performed by phone contact with a study coordinator. 
All AEs must be recorded and followed until resolution or for at least 28 days after discontinuation of 
study medication, whichever comes first. 

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Any clinically significant changes noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded on the AE page of the eCRF. 
17.6.1 Serious Adverse Events 
A written report of all SAEs that occur after the administration of study drug and during the study 
(ending with the safety follow-up visit, 28 days off-study drug) must be submitted to the IRB/ethics 
committee (EC) and the sponsor. SAEs/SUSARs must be reported to the Sponsor within 24 hours for a 
determination of expedited reporting to applicable regulatory authorities. In all SAE reports, the 
investigator will advise whether or not the SAE is judged to be related to study drug administration. 
All SAEs that are judged by the investigator to be at least possibly related to study drug administration 
must be reported to the sponsor regardless of how much time has elapsed since the last exposure to 
study drug. All SAEs must be submitted to the IRB/EC in an annual report per local reporting 
guidelines. 
17.6.2 Overdoses 
Overdoses should be reported as a protocol violation. If an overdose results in an AE, the AE should 
be reported. If the overdose results in an SAE, then SAE reporting should be followed with overdose 
information entered in the narrative section. All available clinical information relevant to overdose, 
including signs and symptoms, laboratory findings, and therapeutic measures or treatments 
administered, should be summarized and discussed. 
17.6.3 Adverse Events of Special Interest 
Opaganib may cause neuropsychiatric toxicity that may be due to increases in ceramides.  
In a Phase 1 healthy volunteer food effect study, these toxicities were found to be reduced by eating a 
light to moderate meal prior to each dose administration and this was likely due to delayed absorption 
and reduced Cmax.  
Neuropsychiatric events reported in clinical studies to date include: hallucinations, anxiety, insomnia, 
lethargy, agitation, distress and dysarthria.   
These neuropsychiatric adverse events occurred at higher frequencies at the highest dose administered, 
which is above the dose selected (best tolerated dose) for the current and future clinical studies.   
The following adverse events are of special interest. 
Patients who experience either of the following, at the discretion of the investigator, the medical 
monitor must be notified immediately (by phone or email), as feasible, but no longer than 24 hours: 
• 
a sudden and clinically important increase in oxygen requirements 
• 
a rapid decline in clinical status leading to intubation and mechanical ventilation 
• 
clinically important increases in inflammatory markers  

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17.6.4 Emergency Unblinding 
Emergency treatment code breaks should only be undertaken when it is essential to treat the participant 
safely and efficaciously. Most often, investigational treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study participant who presents with an emergency 
condition. The investigator is encouraged to contact the medical monitor prior to code break. Emergency 
code breaks are performed using the Interactive Web Response System (IWRS). When the investigator 
contacts the system to break a treatment code for a participant, they must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for the 
participant. The investigator will then receive details of the investigational drug treatment for the 
specified participant via IWRS. The system will automatically inform the CRO site monitor and the 
Sponsor that the code has been broken, but no treatment assignment will be communicated. 
It is the investigator’s sole responsibility to break the treatment code in emergency situations and to 
ensure that there is a procedure in place to allow access to the IWRS in case of emergency. The 
investigator will inform the participant how to contact their backup in cases of emergency when they 
are unavailable. The investigator will provide the protocol number, investigational treatment name if 
available, participant number, and instructions for contacting the local entity which has responsibility 
for emergency code breaks to the participant in case an emergency treatment code break is required at a 
time when the investigator and backup are unavailable. 
17.6.5 Data Safety Monitoring Board 
A data safety monitoring board (DSMB) will be convened for the safety oversight of the study in order 
to assure safety of the trial participants.   
The DSMB meetings to review the safety data, will be planned after 25%, 50% and 75% or when 
approximately 70, 135, 230 and 345 randomized patients, respectively, have reached Day 14. 
 
Assessments will include but not be limited to: 
a) all adverse events  
b) all dose reductions in study drug  
Ad hoc DSMB meetings will convene when clinically significant events (adverse events of special 
interest Section 17.6.3), per physician discretion, may indicate a potential increase in systemically 
important inflammation in any one patient in the study, based on an increased and clinically significant 
oxygen requirement, or a precipitous clinical deterioration that leads to intubation and mechanical 
ventilation. 
At each review/meeting the DSMB will determine whether the study should proceed as planned or 
should be terminated.   
No formal efficacy analysis (early stopping for efficacy) will be performed at any DSMB review. 
 
An interim analysis to determine futility will be conducted by an independent statistician and reported 
to the DSMB. The DSMB will also be responsible for conveying the results of the futility analysis 
conducted by an independent unblinded statistician to the sponsor (futile/non-futile).  

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A DSMB charter will be provided as a separate document.   

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18 ETHICS 
18.1 Investigator Responsibilities 
18.1.1 Compliance with Declaration of Helsinki and Good Clinical Practices 
The study will be performed in accordance with the Declaration of Helsinki (1964) as revised, most 
recently in Seoul (2008), US FDA regulations and the ICH Guideline for Good Clinical Practice, 
E6(R1).  The investigator will ensure that all those concerned with conducting the study (such as 
pharmacists, research nurses and co-investigators) are provided with copies of the protocol and all 
safety information prior to the start of the study. 
18.1.2 Institutional Review Board (IRB)/Ethics Committee (EC) Review and Approval 
The investigator is responsible for obtaining IRB/EC approval to conduct this study (including 
IRB/EC approval of the Informed Consent form) and for ensuring continuing review as required by the 
IRB/EC.  Written confirmation of this approval and periodic review must be provided to the sponsor 
prior to the start of the study and at appropriate intervals. 
18.1.3 Informed Consent 
The investigator will inform patients as to the nature, expected duration and purpose of the study, the 
administration of the study medication, and the hazards involved, as well as the potential benefits that 
may come from treatment with this investigational drug.  Informed consent must be obtained in 
accordance with US Code of Federal Regulations (21 CFR Part 50), and other national regulations, if 
study is conducted at sites outside the US.   
The patient will be informed that his/her medical records will be subject to review by the sponsor and 
possibly by a representative of the Food and Drug Administration, as well as national regulatory 
authorities, for patients treated outside the US.  Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to them 
that they may withdraw from this study at any time without prejudicing further care.  Signed written 
informed consent must be obtained from every patient or legal representative prior to study entry.  The 
original will be kept by the investigator and will be subject to review by the sponsor; a copy will be 
given to the patient. 
18.1.4 Patient Anonymity 
The anonymity of participating patients must be maintained. Patients will be identified by a 
pseudonymization of patient initials and an assigned patient number on the datasheet, and other 
documents submitted to the sponsor, including but not limited to safety reports. Documents that will 
not be submitted to the sponsor and that identify the patient (e.g., the signed informed consent 
document), must be maintained in strict confidence by the Investigator, except to the extent necessary 

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to allow auditing by the appropriate regulatory authority, the study monitor, or sponsor 
representatives. 
18.1.5 Confidentiality 
All information provided to the investigator relevant to the study medication, as well as information 
obtained during the course of the study, will be regarded as confidential.  The investigator and 
members of his/her research team agree not to disclose or publish such information in any way to any 
third-party without prior written permission from the sponsor, except as required by law. 
18.1.6 Source Documentation 
The investigator will allow inspections of the study site and documentation by clinical research and 
audit personnel from the sponsor, external auditors or representatives of regulatory authorities.   The 
purpose of these inspections is to verify and corroborate the data collected on the case report forms.  In 
order to do this direct access to the subjects’ medical or clinic records is necessary.  The investigator 
will ensure that certain information is contained in the medical or clinic records of the subject and that 
the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical and 
medication histories 
• a note on the day the subject entered the study describing the study number, the drug being 
evaluated, the study number assigned to that subject and a statement that consent was obtained 
• a note of each subsequent study visit including any concerns about adverse events or abnormal 
laboratory data and their resolution 
• notes of all concomitant medication taken by the subject including start and stop dates 
• a note of when the subject terminated from the study, the reason for termination and the subject’s 
general condition at termination 
• a copy of the signed informed consent form should be kept in the medical records of each 
subject during the clinical phase of the study (thereafter it will be archived with the study file) 
18.1.7 Drug Accountability 
The investigator agrees to supervise the maintenance of records of the receipt, dispensing and return or 
destruction of study material supplied by the sponsor.  Destruction of any material must be witnessed 
and documented in writing.  The dispensing record must make it clear which subject received which 
material. 
18.1.8 Data Monitoring and Collection 
Suitably qualified and trained clinical research personnel of the sponsor will visit the study center at 
regular intervals during the study for monitoring purposes and to assist the research staff with any 
queries they may have. 

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18.1.9 Case Report Forms, Investigator’s Study File and Record Retention 
All case report forms and supporting source documentation must be available to the sponsor during 
monitoring visits. 
Prior to review of the case report forms by the sponsor’s representative and forwarding of the case 
report forms to the sponsor, they should be reviewed for completeness and legibility by the 
investigator or a member of the research team. 
The investigator will maintain all records relating to the study (including copies of case report forms) 
for at least 2 years after written notification by the sponsor that the investigational drug program has 
been either completed or terminated, or that a New Drug Application (NDA) has been approved by the 
FDA.  Should the investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept that responsibility, 
and the sponsor must be notified in writing of the name and address of said person. 
18.1.10  Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this study without the prior written permission of the subject, the sponsor and the IRB. 
18.2 Sponsor Responsibilities 
18.2.1 General 
The sponsor agrees to adhere to US FDA Guidelines on Good Clinical (Research) Practices and with 
the ICH Guideline for Good Clinical Practice, E6(R1).  The sponsor has a legal responsibility to report 
fully to regulatory authorities the results of this study.  It is the sponsor’s responsibility to obtain 
appropriate regulatory approval to perform the study. 
18.2.2 Case Report Forms 
Case report forms will be provided by the sponsor or, upon agreement with the sponsor, forms 
generated by the investigative site may be used.  If an electronic data collection system is used, the 
system will be compliant with applicable aspects of 21 CRF Part 11, ICH guidelines, GCP and 
HIPAA. 
18.2.3 Data Monitoring and Collection 
Suitably qualified and trained clinical research personnel of the sponsor will visit the study center at 
regular intervals during the study for monitoring purposes and to assist the research staff with any 
queries they may have. Case report forms and source documentation will be available for review 
during monitoring visits to the center.  The function of this monitoring is to ensure compliance with 
the protocol, adherence to regulatory and good clinical (research) practice obligations, proper 
maintenance of records including drug accountability records, correct administration of study 
medications including storage conditions and accurate reporting of adverse events.   

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18.2.4 Audit 
The sponsor has an obligation to audit a proportion of studies; this is usually undertaken by a 
department other than the clinical research department.  Therefore the sponsor, an independent auditor 
or a regulatory authority may wish to audit the study site and documentation and these audits may take 
place as the study is running or up to several years later. 
18.2.5 Confidentiality 
The sponsor will not keep any material on file bearing any subject’s name, and the subject’s 
confidentiality will be maintained at all times. 
18.2.6 Protocol Modifications 
If necessary, during the course of the study, the protocol may be modified by the sponsor in 
consultation with the investigator.  Except in the case of modifications to resolve an imminent safety 
issue, any protocol modification or revision must be reviewed and approved by the investigator’s 
IRB/EC prior to implementation. 
18.2.7 Publication 
RedHill Biopharma will provide unblinded data to a publications committee for publication of the 
results of this study once completed and all data have been cleaned and the blind broken.  The 
publications committee will be constituted according to the guidelines developed by the Company.  If 
deemed necessary by the Company for protection of proprietary information prior to patent filing, the 
investigator agrees to delay for 60 days before any presentation or publication is submitted. 
 
 
 

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19 STATISTICAL METHODS 
This section of the protocol describes the statistical analysis as it is foreseen at the time of planning the 
study. A fully detailed Statistical Analysis Plan (SAP) will be produced and finalized after finalizing 
the protocol and before breaking the blind of the study. A supplementary document will provide 
further details regarding the planned futility analysis. 
19.1 Sample Size Considerations 
It is planned to randomize approximately 464 eligible patients into the double-blind treatment phase, 
to receive either opaganib added to standard of care (n=232), or matching placebo added to standard of 
care (n=232). The sample size calculation was based on powering the study with respect to the primary 
analysis of the primary efficacy endpoint of proportions of patients no longer requiring supplemental 
oxygen for at least 24 hours by Day 14 (refer to Section 15.1). It was assumed that the treatment 
success rate at 14 days in the control arm would be 40% and that opaganib is expected to provide 
absolute 15% increase of this rate, to a success rate of 55%. A total of 464 subjects provides 90% 
power to detect the assumed difference in success rate, using chi square test, at a two-sided α=0.05 
level of significance. This sample size calculation takes into account a planned non-binding futility 
analysis to be performed after at least 135 patients in the study have been evaluated for the primary 
endpoint. 
19.2 Stratification 
Randomization will be done centrally, using pre-determined schedule, and will assign subjects in a 1:1 
ratio to opaganib added to standard of care or matching placebo added to standard of care.  
In order to ensure balance of standard treatment regimens in both treatment arms as well as with 
regard to patient risk status, randomization will be determined based upon two stratification factors:  
a) Whether SoC treatment has established efficacy (yes versus no). The proven effective therapies 
for the purpose of this protocol will be adjusted as new data emerges and will be documented 
in a stand-alone document entitled Approved COVID-19 Therapies which will be updated and 
shared with study personnel regularly.  
b) Patients will further be stratified based on meeting three or more high risk clinical parameters 
for COVID-19 outcomes at baseline (yes or no). 
Refer to Section 12.2 for further details. 
19.3 Populations for Analysis 
The primary analysis will be based on the modified Intent to treat population (mITT), which consists 
of all patients that were randomized and treated with at least one dose of study drug and who met entry 
criteria #3 (The patient requires, prior to first dose of study drug, high flow supplemental oxygen or 
positive pressure ventilation, or is receiving oxygen via a non-rebreather or reservoir mask, capable of 
delivering high concentrations of oxygen. Patients who require mechanical ventilation or no longer 

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require supplemental oxygen prior to receiving the first dose of study drug will not be included in the 
mITT analysis set.  
The primary analysis will also be analyzed using a Per-Protocol (PP) population that will be further 
defined in the SAP and the Intention-to-treat (ITT) population who consists of all randomized patients. 
In all efficacy analyses, treatment group will be assigned per randomization assignment. 
Safety analyses will be based on the safety analysis set, which consists of all patients who received at 
least one dose of study drug and analyzed based on the actual treatment the subject received. 
19.4 Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint will be based on a success (Yes/No) variable, indicating if a subject is 
no longer requiring supplemental oxygen, for at least 24 hours by study Day 14 (patient death or 
subsequent requirement of supplemental oxygen or lost to follow-up through Day 42 will be regarded 
as a failure for the primary efficacy endpoint). Any subject reported as not requiring supplemental 
oxygen on any given study day will be counted as a subject who has not required oxygen for at least 
24 hours, based on the instructions to sites to enter the highest oxygen requirement for each study day. 
Subjects who are discharged from hospital on supplemental oxygen are expected to be followed up by 
the study site daily and will be considered a success only if for any given study day, the highest 
supplemental oxygen requirement is zero.  
 
If a patient initiates a new investigational therapy on a different formal clinical protocol for COVID-19 
within 14 days of randomization, the patient will be followed for true outcomes in the primary analysis 
but in a sensitivity analysis the data under the new therapy will not be included. 
 
An early discontinuation of study before the subject has reached success (e.g. loss to follow up) thus 
preventing continued follow-up for success by Day 14, will be considered as missing data and  will be 
counted as failure for the primary analysis. Sensitivity analysis using time to event method will be 
performed censoring these cases at the latest informative time. 
 
The number and percentages of subjects achieving success (as defined above) will be tabulated per 
treatment group. A 95% confidence interval will be constructed for each proportion. A Cochran 
Mantel-Haenzel (CMH) test will compare the proportion of success between the two groups, using the 
study stratification factors used for randomization, and a corresponding stratified risk difference 
estimate will be presented with 95% confidence interval.   
 
The significance level for this test will be two-sided 5%. 
 
The primary analysis will be based on the modified Intent to treat population (mITT) as defined in 
Section 19.3. 
 
Sensitivity and supportive analyses for the primary endpoint analysis will be defined and detailed in 
the statistical analysis plan. These will address at least the following aspects:  

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• Negation of achieved Day 14 success by a post-day 14 failure event:  in a sensitivity analysis, 
events occurring after day 14 will not impact day 14 success. 
• Negation of achieved Day 14 success by any post-success failure: an analysis of endpoint 
targeting achieving any success will be performed. 
• Missing data due to early discontinuation of follow-up before achieving success (prior to day 
14):  the primary endpoint analysis imputed these cases as Failures, however in this sensitivity 
analysis, these cases will be handled via censoring, using time to event methodology. Kaplan-
Meier method will be used to estimate cumulative incidence of success at day 14. In this 
analysis death will be censored at 14 days. 
• Joining a different clinical trial prior to day 14 while patients do not withdraw consent from 
being followed up under ABC-201 protocol: a sensitivity analysis will be performed where 
data collected during the patient participation in another clinical trial are not included. 
• A sensitivity analysis of the primary analysis using the subset of patients in the mITT 
population regardless of meeting inclusion criteria #3 prior to first dose of study drug.  
• PP analysis: Criteria for PP protocol will be based on inclusion and exclusion criteria and 
protocol violations during the study and that confound the interpretation of analyses.  Patients 
who do not meet PP requirement will be defined blindly before database lock. 
• To account for the possibility of errors in values of stratification factors used for 
randomization, the primary analysis will supportively be repeated using the correct values. 
• Difference between the treatment and control groups when controlling for possible imbalance 
in important baseline factors will be analysed by evaluating a multiple logistic regression 
model. The list of baseline variables will be finalized in the SAP, prior to database lock. 
• To understand the possible impact of any initiation of allowed post-randomization effective 
anti-COVID 19 SOC treatments, descriptive statistics of such usage (frequency and timing of 
initiation) will be presented for each group.  
• The distribution of patient’s baseline SoC regimen will be summarized and presented by group. 
Further, opaganib treatment effect will be assessed to confirm comparability of effect across 
these strata. 
19.5 Analysis of the Secondary Efficacy Endpoints 
In general, unless otherwise specified in the SAP, binary endpoints where event of interest is of 
improvement/recovery type by a certain time frame (such as the percentage of patients with ≥2 
category improvement on the WHO Ordinal Scale for Clinical Improvement by Day 14, secondary 
endpoints #1) will be defined using the following rules: a binary success variable (Yes/No) will 
indicate if the subject achieved the success of interest within specified timeframe, or not.  A recorded 
failure (within timeframe) after success has been achieved, will be followed-up for re-achieving of 
success of interest - at the target timeframe. Comparison of these endpoints between treatment groups 
will employ similar methods as those specified for the primary endpoint. In case there are subjects 
who discontinue the study before achieving success and before timeframe ending, the cumulative 
incidence probabilities at desired time-point will be estimated using time to event analysis, censoring 
these subjects at last valid observation date . In this analysis, death before event of interest will be 
censored at timeframe end, thus taking the highest unfavorable possible outcome for the endpoint.  

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For the comparison of percent of patients requiring intubation and mechanical ventilation by day 42, 
this endpoint is aimed to be assessed as a binary endpoint analysis, unless there are subjects who 
discontinue the study before meeting event of interest. Otherwise, cumulative incidence probabilities 
at day 42 time-point will be estimated using time to event analysis, censoring these subjects at last 
valid observation date. Death prior to experiencing this progression-type of event will be handled via 
censoring at date of death.  As mortality is distinct secondary endpoint, this approach to handling 
death would allow assessing the effect of opaganib specifically on this event. Sensitivity analysis will 
estimate cumulative incidence using the nonparametric Aalen-Johansen estimator, where death is a 
competing event.  
Time to event endpoints will be calculated as the number of days from study day 1 until the event of 
interest or last valid observation time, whichever occurs first (within endpoint timeframe). A patient 
for whom event of interest will not be observed will be regarded as right censored. Unless otherwise 
specified in the SAP, the time frame for primary analysis of these endpoints is from Day 1 until Day 
14. Time to discharge from hospital will be using end of Day 14 of treatment as end-of-time frame. 
When event of interest is of Improvement/Recovery type (such as time to recovery), death within the 
timeframe for each endpoint, will be addressed corresponding to the highest unfavorable possible 
outcome for the endpoint, which is censoring at the end of time frame.  
 
Time to event endpoints will be compared using the stratified Log-rank test and the stratified Cox 
proportional hazards regression model will be used to estimate the hazard ratio (HR) along with 95% 
confidence interval, comparing opaganib versus control group. Kaplan-Meier plot by treatment arm 
will be presented and cumulative incidence of events of interest will be estimated along with 95% 
confidence interval for each group at several time points within timeframe.  
 
Mortality endpoints will be defined per subject as a binary variables indicating if a subject had died by 
target times (28 and 42) days from first dose date. These binary endpoints will be analyzed using the 
same methods specified for the binary endpoints above.  To note, in case of early discontinuation of 
follow-up, time to event analysis to derive the -days mortality rate will be applied, censoring such 
subjects at their last valid observation date. 
 
All secondary endpoints analyses will be based on mITT population and PP population and undergo 
the same sensitivity analyses as the primary analysis, as applicable. 
19.6 Safety Analyses 
The safety and tolerability of opaganib will be determined by reported treatment emergent adverse 
events (TEAEs), physical examinations, vital signs, and laboratory tests. Patients who receive at least 
one dose of study drug are considered evaluable for safety (Safety population).  
Detailed specification of the safety analyses will be provided in the SAP.  

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19.7 Type 1 error control 
The overall study-wise type I error will be 5%. The non-binding futility analysis does not increase type 
1 error probability and thus does not impact final analysis significance level (Guidance for Industry on 
Adaptive Designs for Clinical Trials of Drugs and Biologics, November 2019).  
To protect the study from type I error inflation, the secondary efficacy endpoints will be interpreted 
inferentially only if a statistically significant treatment effect (p-value ≤0.05) is detected in the primary 
endpoint. Type I error will be further controlled by employing Hierarchical Approach within the 
secondary efficacy endpoints: each endpoint will be formally analyzed only in case the previous 
endpoint will be statistically significant (p-value ≤0.05). 
19.8 Interim Analysis 
An unblinded futility interim analysis will be conducted when approximately 135 subjects have had 
the Day 14 evaluation, in order to determine if it would be futile to continue the study. The futility 
criteria will be primarily based on the primary endpoint and will further involve key clinical secondary 
endpoints such that futility can only be declared if the primary AND all key secondary endpoints cross 
the boundary. The exact futility boundaries will be prospectively determined and documented in the 
final version of the SAP prior to the interim analysis and in the DSMB charter. The analysis will be 
conducted by an independent unblinded statistician who will inform the DSMB of the futility outcome 
(futile/non-futile). Strict procedures will be employed to maintain the confidentiality of the interim 
results. To safeguard study integrity, the pre-defined details of the stopping rules are documented 
separately from the protocol and will be documented in the SAP. 
 
 

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20 INVESTIGATOR’S STATEMENT 
I have read the protocol entitled “Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 
Pneumonia: a Randomized, Double-blind, Placebo-Controlled Phase 2/3 Study, in Adult Subjects 
Hospitalized with Severe to Critical SARS-CoV-2 Positive Pneumonia” and agree that it contains all 
necessary details for carrying out the study as described. I will conduct this protocol as outlined therein 
and will make a reasonable effort to complete the study within the time designated. I will provide copies 
of the protocol and access to all information provided by Redhill Biopharma to study personnel under 
my supervision. I will discuss this material with them to ensure they are fully informed about the drug 
and the study. I understand that the study may be terminated or enrollment suspended at any time by 
Redhill Biopharma, with or without cause, or by me if it becomes necessary to protect the best interests 
of the study patients.  
 
Signature of Investigator 
 
Date (day/month/year) 
Printed Name of Investigator 
 
Site Number 

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21 REFERENCES 
 
Yifei Chen, Liangjun Chen, Qiaoling Deng, Guqin Zhang, Kaisong Wu, Lan Ni1, Yibin Yang, Bing 
Liu, Wei Wang, Chaojie Wei, Jiong Yang, Guangming Ye, Zhenshun Cheng, The Presence of SARS-
CoV-2 RNA in Feces of COVID-19, ORCID iD: 0000-0002-7387-496X  
 
Dai L, Plaisance-Bonstaff K, Voelkel-Johnson C, Smith CD, Ogretmen B, Qin Z, Parsons. 
Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells. PLoS 
One. 2014 Jul 10;9(7):e102314. 
 
Ebenezer DL, Berdyshev EV, Bronova IA, Liu Y, Tiruppathi C, Komarova Y, Benevolenskaya EV, 
Suryadevara V, Ha AW, Harijith A, Tuder RM, Natarajan V, Fu P. Pseudomonas aeruginosa 
stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory 
injury. Thorax. 2019 Jun;74(6):579-591. 
 
French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN,  
Smith CD. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine 
kinase-2. J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. 
 
Kurd R, Ben-Chetrit E, Karameh H, Bar-Meir M, Compassionate Use of Opaganib For Patients with 
Severe COVID-19. medRxiv 2020.06.20.20099010; doi: https://doi.org/10.1101/2020.06.20.20099010 
 
Liu Q, Rehman H, Shi Y, Krishnasamy Y, Lemasters JJ, Smith CD, Zhong Z. Inhibition of 
Sphingosine Kinase-2 Suppresses Inflammation and Attenuates Graft Injury after Liver 
Transplantation in Rats. PLoS One. 2012;7(7):e41834. 
 
Maines LW, Fitzpatrick LR, French KJ, et al. Suppression of ulcerative colitis in mice by orally-
available inhibitors of sphingosine kinase. Dig Dis Sci. 2008; 53(4):997-1012. 
 
Maines LW, Fitzpatrick LR, Green CL, Zhuang Y, Smith CD. Efficacy of a novel sphingosine kinase 
inhibitor in experimental Crohn’s disease. Inflammopharmacology. 2010 Apr; 18(2):73-85 
 
Reid, S.P.; Tritsch, S.R.; Kota, K.; Chiang, C.-Y.; Dong, L.; Kenny, T.; Brueggemann, E.E.; Ward, 
M.D.; Cazares, L.H.; Bavari, S. Sphingosine kinase 2 is a chikungunya virus host factor co-localized 
with the viral replication complex. Emerg. Microbes Infect. 2015, 4, e61 
 
van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, Tamin A, 
Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ. Aerosol and Surface 
Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17. 
 
Wilson KC, Chotirmall SH, Bai C, Rello J. COVID‐19: Interim Guidance on Management Pending 
Empirical Evidence. Last updated April 3, 2020. www.thoracic.org/professionals/clinicalresources/ 
disease‐related‐resources/covid‐19‐guidance.pdf.  

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World Health Organization.  WHO R&D Blueprint:  novel coronavirus.  2020.  Downloaded 3/20/20:  
https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf?ua=1 
 
Xia C, Seo YJ, Studstill CJ, Vijayan M, Wolf JJ, Hahm B. Transient inhibition of sphingosine kinases 
confers protection to influenza A virus infected mice. Antiviral Res. 2018 Oct;1 58:171-177. 
 
Yamane D, McGivern DR, Wauthier E, Yi M, Madden VJ, Welsch C, Antes I, Wen Y, Chugh PE, 
McGee CE, Widman DG, Misumi I, Bandyopadhyay S, Kim S, Shimakami T, Oikawa T, Whitmire 
JK, Heise MT, Dittmer DP, Kao CC, Pitson SM, Merrill AH Jr, Reid LM, Lemon SM. Regulation of 
the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med. 2014 Aug;20(8):927-
35. 
 
Zhou C, Gao C, Xie Y, Xu M. COVID-19 with spontaneous pneumomediastinum. Lancet Infect Dis. 
2020 Mar 9. 

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Appendix 1 WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT 
                                 
 
 
* For purposes of this protocol, subjects requiring face masks capable of high oxygen concentrations, 
such as non-rebreather or reservoir masks will be considered to be on high flow oxygen and WHO 
level 5. 
 
 
 
 
 

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Appendix 2 List of Prohibited Concomitant Medications that May Potentially 
Interact with Opaganib 
abiraterone  
ebastine  
mephenytoin  
rolapitant  
agomelatine  
edoxaban 
mephobarbital 
rosuvastatin 
alfentanil  
elagolix  
meloxicam  
selegiline  
aliskiren 
eletriptan 
metformin1 
sildenafil  
almorexant  
eliglustat 
metoprolol 
simvastatin  
alosetron 
encainide  
mexilitine 
sirolimus  
ambrisentan 
enoxacin  
 mibefradil 
St John's Wort extract  
apalutamide 
enclomiphene  
midazolam 
tacrolimus 
apixaban2  
enzalutamide 
 midostaurin 
tamoxifen  
aprepitant 
eplerenone  
 mifepristone 
talinolol  
atomoxetine  
eryhtomycin 
mirabegron 
tasimelteon 
Atorvastatin  
escitalopram 
 modafinil 
telotristat ethyl  
avanafil  
ethinyl estradiol 
 moclobemide 
terbinafine  
avasimibe 
everolimus  
montelukast 
thioridazine  
benzbromarone 
fedratinib 
nafcillin 
ticagrelor  
blonanserin 
felodipine 
naloxegol 
tilidine 
bosentan 
fexofenadine  
 nebivolol 
tizanidine  
budesonide 
fluconazole  
 nefazodone 
Tobacco smoking  
bupropion 
fluoxetine 
nisoldipine 
tolbutamide 
buspirone 
fluvoxamine 
nortriptyline 
tolterodine  
capravirine 
glimepiride  
omeprazole 
tolvaptan  
carbamazepine 
glipizide  
pantoprazole 
tramadol  
casopitant 
grapefruit juice  
paroxetine 
triazolam  
celecoxib 
glyburide (glibenclamide) 
 perospirone 
trimipramine 
celiprolol 
hexobarbital  
 perphenazine 
ubrogepant  
cenobamate  
hormonal contraceptives  
phenobarbital 
ulipristal  
cinacalcet  
ibuprofen  
phenytoin 
vardenafil  
ciprofloxacin 
idelalisib 
 pirfenidone 
venlafaxine  
clarithromycin 
isavuconazole 
piroxicam 
voclosporin  
cobicistat 
itraconazole 
 pridopidine 
voriconazole  
codeine 
ivabradine  
posaconazole 
warfarin  
conivaptan 
ivacaftor 
pravastatin 
yohimbine 
dabigatran  
ketoconazole 
propafenone 
 
daprodustat  
lansoprazole  
propoanolol 
 
darifenacin  
lefamulin 
quetiapine 
 
desipramine  
lesinurad 
quinidine 
 
deutetrabenazine  
levomethadyl (LAAM) 
ramelteon 
 
dexlansoprazole 
levothyroxine 
repaglinide  
 
dextromethorphan  
lomitapide 
ribociclib 
 
digoxin  
lorcaserin 
ridaforolimus  
 
diltiazem  
lornoxicam 
rifampin  
 
doxepin  
lovastatin 
rifapentine  
 
dronedarone  
lumacaftor 
risperidone  
 
duloxetine 
lumefantrine 
ritonavir 
 
duvelisib 
lurasidone 
rivaroxaban 
 
1 Use with caution