Clinical trial NCT04467840
Conditions: COVID-19 Lung Infection
Keywords: Therapeutic Use
Sponsor: RedHill Biopharma Limited
Start date: 2020-08-21; Completion date: 2021-07-18
Enrollment: 475 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A phase 2/3 multi-center randomized, double-blind, parallel arm, placebo- controlled study in Adult Subjects Hospitalized with Severe SARS-CoV-2 Positive Pneumonia to determine the potential of opaganib to improve and/or stabilize the clinical status of the patient.

Detailed 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 be performed worldwide in up to approximately 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. 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.

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 28 days after their last dose of study drug, which may occur at Day 14 or after premature study drug discontinuation, based upon patient or physician determination.

Arms: arm 1: In addition to standard of care, opaganib will be administered orally with 2 x 250 mg capsules (500 mg) every 12 hours. When required this may be made into a suspension form and may be administered by nasogastric tube. arm 2: In addition to standard of care, a matching placebo will be administered orally with 2 x 250 mg capsules (500 mg) every 12 hours. Where required this may be made into a suspension form and may be administered by nasogastric tube.
Interventions: intervention 1: Opaganib intervention 2: Placebo
Intervention descriptions: intervention 1: 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). intervention 2: 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).

Protocol documents:
Prot_000.pdf: 
 
 
 
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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CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
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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CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
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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Protocol ABC-201 Version 5.0 15 April 2021 
 
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CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
 
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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CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
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 

SAP_001.pdf: 
 
RedHill Biopharma Ltd. 
 
STATISTICAL ANALYSIS PLAN (SAP) 
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: 1 September 2021 
Version: 2.0 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
 
 
RedHill Biopharma Ltd. 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
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 
Phase: Phase 2/3 
 
Date: 1 September 2021 
Version: 2.0 
 
 
 
Prepared by: Michal Klein 
   
 
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. 
 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
Version Control Page 
 
Version: 
Version Date: 
Protocol Version 
Comments 
0.3 
9-SEP-2020 
version 2.0, 2 September 2020  
1.0 
24-JAN-2021 
version 4.0, 18 January 2021 
Changes following additional 
protocol amendment 
2.0 
01-SEP-2021 
Version 5.0, 15 April, 2021 
Changes following protocol 
amendment and FDA comments. 
Changes in numbering and hierarchy 
of secondary endpoints along with 
removal of the planned multiplicity 
adjustment for the secondary 
endpoints. Structural changes to the 
document to enhance consistency 
across endpoints, and adding 
supportive analyses. 
 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL FORM 
 
Study: ABC-201 
Date:  1 September 2021 
Version: 2.0 
 
I confirm that I have reviewed this document and agree with the content. 
APPROVALS 
  
Approved by: 
 
 
 
Mark L. Levitt, MD, PhD 
Medical Director, Oncology (Medical Monitor) 
RedHill Biopharma Ltd. 
 
Date (dd-Mmm-yyyy) 
Approved by: 
 
 
Ofra Barnett, PhD 
Biostatistics, Bioforum   
Bioforum, 3 Golda Meir St., 
Weizmann Science Park, 
Ness Ziona 7414001  Israel 
 
Date (dd-Mmm-yyyy) 
  
 
 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
TABLE OF CONTENTS 
1 
PREFACE ............................................................................................................. 1 
2 
STUDY OBJECTIVES ........................................................................................ 2 
 
Primary .................................................................................................................. 2 
 
Secondary .............................................................................................................. 2 
 
Exploratory ........................................................................................................... 2 
 
Safety ..................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................. 4 
 
General Design and Study Schema ..................................................................... 4 
 
Study Endpoints .................................................................................................... 8 
3.2.1 
General rules and definitions ............................................................................... 8 
3.2.1.1 
Definition of Sustained Success .......................................................................... 8 
3.2.1.2 
Biomarker-based endpoints ................................................................................. 9 
3.2.1.3 
Handling initiation of  a new investigational therapy on a different 
formal clinical protocol for COVID-19 .............................................................. 9 
3.2.2 
Primary efficacy endpoint .................................................................................. 10 
3.2.3 
Secondary Efficacy Endpoints ........................................................................... 11 
3.2.4 
Exploratory Endpoints ....................................................................................... 14 
3.2.5 
Safety Endpoints ................................................................................................. 16 
 
Sample Size and Power Considerations ............................................................ 16 
 
Randomization and Blinding ............................................................................. 17 
 
Sequence of Planned Analyses .......................................................................... 17 
3.5.1 
Interim Analyses ................................................................................................. 17 
3.5.2 
Final Analyses and Reporting ............................................................................ 17 
4 
ANALYSIS POPULATIONS ........................................................................... 18 
 
Screened .............................................................................................................. 18 
 
Intention to Treat (ITT) ...................................................................................... 18 
 
Modified ITT (mITT) ......................................................................................... 18 
 
Baseline High Flow Treated (BLHF Treated) .................................................. 18 
 
Per Protocol (PP) ................................................................................................ 18 
 
Safety ................................................................................................................... 18 
5 
GENERAL ASPECTS FOR DATA ANALYSIS............................................ 19 
 
General ................................................................................................................ 19 


Statistical Analysis Plan 
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Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
 
Specification of Baseline Values ....................................................................... 19 
 
Multiple Comparisons and Multiplicity ............................................................ 19 
 
Handling Withdrawals and Missing Data ......................................................... 20 
 
Study days and visit windows............................................................................ 20 
 
Futility analysis................................................................................................... 21 
5.6.1 
Outline ................................................................................................................. 21 
5.6.2 
Primary endpoint Futility boundary .................................................................. 22 
5.6.3 
Sensitivity analyses for the primary endpoint .................................................. 23 
5.6.4 
Results dissemination ......................................................................................... 24 
6 
STUDY POPULATION .................................................................................... 25 
 
General ................................................................................................................ 25 
 
Patient Disposition ............................................................................................. 25 
 
Demographics and Baseline Characteristics ..................................................... 25 
 
Covid-19 Disease Information ........................................................................... 26 
 
Medical and Surgical History ............................................................................ 27 
 
Prior Medications ............................................................................................... 27 
 
Electrocardiography ........................................................................................... 27 
 
Physical Examinations ....................................................................................... 27 
 
Chest X-Ray or CT scan .................................................................................... 28 
 
Protocol Violations ............................................................................................. 28 
7 
EFFICACY ANALYSIS.................................................................................... 28 
 
General Considerations for efficacy evaluation ............................................... 28 
7.1.1 
Populations for analysis ..................................................................................... 28 
7.1.2 
Stratification........................................................................................................ 28 
7.1.3 
Covariates ........................................................................................................... 28 
7.1.4 
Subgroups ........................................................................................................... 28 
7.1.5 
Use of effective anti-COVID 19 SOC treatments ............................................ 28 
 
Primary Efficacy Endpoint Analysis ................................................................. 29 
7.2.1 
Sensitivity and supportive analyses ................................................................... 29 
7.2.1.1 
Sensitivity analysis for the imputation of missing data due to early 
study discontinuation.......................................................................................... 29 
7.2.1.2 
Sensitivity analyses using other populations .................................................... 29 
7.2.1.3 
Sensitivity analysis account for stratification error .......................................... 29 


Statistical Analysis Plan 
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Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
7.2.1.4 
Sensitivity analysis to account for baseline characteristics adjustment .......... 29 
7.2.1.5 
Subgroup analysis to account for SoC regimen................................................ 30 
7.2.1.6 
Companion analysis: time to longer requiring supplemental oxygen 
for at least 24 hours, time frame of 14 days...................................................... 30 
 
Secondary Efficacy Endpoint Analysis ............................................................. 30 
 
Exploratory Endpoint analysis ........................................................................... 32 
8 
SAFETY ANALYSIS ........................................................................................ 34 
 
General ................................................................................................................ 34 
 
Study Drug Administration ................................................................................ 34 
8.2.1 
Exposure to study drug....................................................................................... 34 
8.2.2 
Treatment Compliance ....................................................................................... 34 
 
Adverse Events ................................................................................................... 34 
8.3.1 
Protocol Defined Adverse Events of Special interest ...................................... 35 
 
Clinical Laboratory Tests ................................................................................... 36 
 
Vital Signs ........................................................................................................... 36 
 
Supplemental oxygen requirement .................................................................... 37 
 
Electrocardiography ........................................................................................... 37 
 
Concomitant medications................................................................................... 37 
9 
OTHER ANALYSES ......................................................................................... 39 
 
Viral swab for SARS-CoV-2 PCR test ............................................................. 39 
 
WHO ordinal scale for clinical improvement assessment ............................... 39 
10 
CHANGE FROM LAST SAP VERSION AND FROM PROTOCOL .......... 39 
11 
STATISTICAL SOFTWARE ........................................................................... 41 
12 
LIST OF SUMMARIES AND LISTINGS ....................................................... 42 
13 
APPENDECIES.................................................................................................. 43 
 
APPENDIX 1: WHO ORDINAL SCALE FOR CLINICAL 
IMPROVEMENT ............................................................................................... 43 
 
APPENDIX 2: SAS CODES ............................................................................. 45 
 
 
LIST OF TABLES 
Table 1: Study Procedures and Assessments ..................................................................... 6 
 


Statistical Analysis Plan 
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Version: 2.0, Date: 1 September 2021 
Study ABC-201 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
BMI 
Body Mass Index 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
COVID-19 
Coronavirus Disease of 2019 
DB 
Double Blind 
ECG 
Electrocardiogram 
EOS 
End of Study 
FiO2 
Fraction of Inspired Oxygen 
ITT 
Intention to Treat 
LAV 
Last Available Value 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to Treat 
PT 
Preferred Term 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation  
SE 
Standard Error 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Serious Treatment Emergent Adverse Event  
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 1 - CONFIDENTIAL: PROPRIETARY INFORMATION 
1 PREFACE 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
RedHill Biopharma Ltd. study 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), and was written in accordance with SOP 100-60-02 (Statistical Analysis Plan 
Preparation, Review and Approval, Bioforum’s Procedure). 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): E9 Guidance on 
Statistical Principles in Clinical Trials. All work planned and reported for this SAP will 
follow internationally accepted guidelines, published by the American Statistical 
Association, and the Royal Statistical Society, for statistical practice. 
The following documents were reviewed in preparation of this SAP: 
• Clinical Study Protocol ABC-201, version 5.0, 15 May 2021. 
• Case report forms (CRFs) for Study ABC-201. 
• ICH E9 Guidance on Statistical Principles for Clinical Trials. 
• ICH E3 Structure and Content of Clinical Study Reports 
• COVID-19: Developing Drugs and Biological Products for Treatment or Prevention 
Guidance for Industry, May 2020. 
The reader of this SAP is encouraged to also read the clinical protocol for details on the 
conduct of this study, and the operational aspects of clinical assessments and timing for 
completing a patient in this study. When differences exist in descriptions or explanations 
provided in the protocol and this SAP, the SAP prevails.  Any deviations from the statistical 
analyses planned in the protocol will be documented in the SAP and any deviations from 
the statistical analyses planned in the SAP will be documented in the final clinical study 
report (CSR). 
This SAP describes the statistical analyses as foreseen at the time of early initiation of the 
study. The SAP may be updated during the study conduct and will be finalized before the 
final database lock and before breaking the blind of the study. 
 
 


Statistical Analysis Plan 
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Study ABC-201 
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2 STUDY OBJECTIVES 
 Primary  
To evaluate the proportion of patients no longer requiring supplemental oxygen for at 
least 24 hours by Day 14.  
 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 mortality 28 and 42 days post-baseline 
7. To evaluate the time to two consecutive negative swabs for SARS-CoV-2 by PCR  
8. To evaluate the proportion of patients with two consecutive negative swabs for SARS-
CoV-2 by PCR at Day 14  
9. 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  
 
 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 
 
  


Statistical Analysis Plan 
RedHill Biopharma 
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Study ABC-201 
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  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. 
 
 


Statistical Analysis Plan 
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Study ABC-201 
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3 STUDY DESIGN   
  General Design and Study Schema 
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 will be 
performed worldwide in up to approximately 60 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. Patients will be stratified based on patients meeting three or more high risk 
parameters for COVID-19 outcomes at baseline (yes or no) and whether SoC treatment has 
established efficacy (Yes or No), as specified in section 3.4. 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).  
Participants enrolled before the implementation of the 5th protocol amendment, were to be 
followed up for 28 days after their last dose of study drug, which may occur at Day 14 or 
after premature study drug discontinuation, based upon patient or physician determination. 
Starting with protocol v5.0 dated April 15, 2021, all participants enrolled will be followed 
up for 42 days after first dose of study drug. 
The maximum duration of study participation will be up to 45 days (including up to 3 days 
screening; 14 days of double-blind (DB) treatment and 28 days off-study drug follow-
up)/completion of study at Day 42, per final protocol version 5.0). 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
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Study ABC-201 
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The study schema is presented below and Visit-specific procedures and assessments are 
outlined in Table 1. 
 
 
 
 
  
 
 


Statistical Analysis Plan 
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Study ABC-201 
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Table 1: Study Procedures and Assessments 
 
Assessments 
  
Study Days 
  
 -3 
*to -
1 
1 
2 3 
4 
5 6 
7 
8 
9 10 11 12 13 14 
Early 
Term 
EOS12 
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 
X1 
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 
  
  


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Hematology (CBC 
with differential)9 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
Assessments 
  
Study Days 
  
 -3 to 
-1 
1 
2 3 
4 
5 6 
7 
8 
9 10 11 12 13 14 
Early 
Term 
Day 42 
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 that are discharged from the hospital prior 
to Day 14, these assessments will be performed at the day of discharge and on a daily basis 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 


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11 women of childbearing potential; serum or urine pregnancy test must be negative within 3 days prior to 
randomization 
12 The 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. For participants enrolled before the implementation of 
the 5th protocol amendment, EOS visit was scheduled 28 days after their last dose of study drug, which may occur at 
Day 14 or after premature study drug discontinuation. Starting with protocol v5.0 dated April 15, 2021, EOS was 
scheduled at 42 days after first dose of study drug. 
* 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. 
 
 Study Endpoints 
3.2.1 General rules and definitions 
3.2.1.1 Definition of Sustained Success 
This section describes the general strategy for deriving the set of study endpoints who focus 
on an improvement/desired health outcome event. These include the primary efficacy 
endpoint (percentage of patients no longer requiring supplemental oxygen for at least 24 
hours by Day 14) and the secondary endpoint #1 (percentage of patients with ≥2 category 
improvement on the WHO Ordinal Scale for Clinical Improvement by day 14), which aim 
to compare between study arms the proportion of subjects with favorable type of event 
(within Day 14 timeframe), and the secondary endpoints #2 (time to recovery), #3 (time to 
low oxygen flow) and #4 (time to discharge from the hospital), which involve comparison 
of the time to the occurrence of a favorable event (within specified timeframe). 
For the primary endpoint and the secondary endpoints listed above, we will denote the 
event of interest as ‘Success’, and correspondingly, a ‘Failure’ event will denote subject’s 
status that shows lack of Success.   
For all these endpoints, it is required that a Success event will be sustained throughout 
the study and therefore an initial Success followed by a Failure event occurring by 
EOS visit will be negated by this Failure and will not be considered Success anymore.  
Endpoint-specific Failure events will be listed at the subsequent relevant endpoint 
definition (section 3.2.1 and 3.2.2, for the primary endpoint and the secondary 
endpoints, respectively), and in addition, for all the considered endpoints:  
• Death during the study will be regarded as Failure event.  
• An Early discontinuation from the study (e.g. loss to follow-up, subject withdrawal) 
will be considered as missing data and subject’s ultimate Sustained Success/Failure 
status will be imputed as follows: the primary analysis of each endpoint will employ 
worst-case imputation in which subject’s ultimate status is Failure. A sensitivity 
analysis will employ a different imputation strategy where subject’s ultimate status will 
be determined based on Observed data while on study (LOCF approach). With this 
approach, a subject who achieved an initial success by the required timeframe and 
subsequently never experienced a Failure event before early termination of  the study 


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Study ABC-201 
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will be considered as Failure in the primary analysis of these endpoints, but as 
Sustained Success in the sensitivity analysis. A subject whose status just before early 
termination was already that failed to achieve the required Sustained success, will be 
imputed as Failure in both the primary and the sensitivity analyses. 
For the binary endpoints requiring deriving subject’s ultimate Success/Failure response at 
the end of a specific time-frame (primary endpoint and secondary endpoint #1), a subject 
will be counted as Success if achieved Success by the required timeframe which was also 
sustained until the end of study visit, and Failure otherwise. 
A time to Success endpoint will be defined as the time (in days) from study Day 1 to the 
earliest day at which a subject achieves a Success that meets the rules defined above. Those 
subjects who failed to achieve this will be assigned a censored time at the end of the time-
frame. For example, for a hypothetical scenario as displayed below, of a subject who had 
initial success on Day 3 (blue + sign) followed by failure event on Day 7 (red triangle) and 
later achieved success on Day 14: as no additional failure events were recorded and EOS 
was performed as planned showing Success as well, we will define this subject as achieved 
the required Success (maintained through EOS) on Day 14. 
 
 
 
 
3.2.1.2 Biomarker-based endpoints 
For the PCR-based secondary and exploratory endpoints and exploratory temperature-
based endpoint, Success is not required to be maintained by EOS visit and analysis will be 
based on observed data while on study only, without imputations. It is acknowledged that 
as subjects rarely perform laboratory or temperature testing after discharge, these endpoints 
are expected to provide only limited information. Endpoint-specific derivations will be 
provided in the relevant sections below (sections 3.2.33.2.4). 
 
3.2.1.3 Handling initiation of  a new investigational therapy on a different 
formal clinical protocol for COVID-19 
For all endpoints derivation, If a subject initiates a new investigational therapy on a 
different formal clinical protocol for COVID-19 during participation in this study, the 
subject will be followed for true outcomes so that data under the new therapy will be 
included. 
 
EOS 
Day 14 
Day 3 
Day 7 


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3.2.2 Primary efficacy endpoint 
The primary efficacy objective of the study is to evaluate the percentage of patients no 
longer requiring supplemental oxygen for at least 24 hours by Day 14. 
The primary efficacy endpoint will be defined per patient as a binary (“Success”/”Failure”) 
variable, indicating if a subject is no longer requiring supplemental oxygen, for at least 24 
hours (the ‘Success’ event) by treatment Day 14. 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. Discharge from hospital without supplemental 
oxygen requirement before or at Day 14 is also considered Success event  (note, when 
discharge occurs exactly on Day 14 and subject is reported requiring supplemental oxygen 
on day 13, then information on being oxygen-free through the entire discharge date is 
required to meet Success definition). To note, subjects who are discharged from hospital 
on supplemental oxygen are expected to be followed up by the study site daily and thus 
can  be considered a success only if for any given study day (prior to Day 14), the highest 
supplemental oxygen requirement is none.  
According to the general approach and rules set in Section 3.2.1.1, a subject is required to 
achieve a Success by Day 14, that will be maintained throughout EOS (Sustained 
Success), in order to be counted as Success for the primary endpoint analysis.  
The applicable Failure events that can negate initial success events are: 
• Resumption of any type of supplemental oxygen.  
• Re-admission after discharge from hospital, for supplemental oxygen, for covid-19 
related reason.  
•  Death (occurring by EOS visit). 
A blinded review of the adverse event data will be performed to identify re-admissions 
satisfying failure event per bullet 2 above. If it cannot be determined if AE involved 
supplemental oxygen for covid-19 related reason or not, a worst-case assumption will be 
employed, of a Failure event.   
Handling of Missing data in determination of Success status will be in accordance to  
section 3.2.1.1 above. 
In addition to the primary endpoint, in order to assess when Sustained Success event 
occurred, an endpoint of time to no longer requiring supplemental oxygen for at least 24 
hours by Day 14 will be calculated as well. This time to event endpoint will be defined in 
accordance to the approach set in section 3.2.1.1, as the number of days from Day 1 until 
the earliest day at which a subject reaches Sustained Success, and all subjects with 
“Failure” status will be assigned a censored time at 14 days.  As an example, if a subject 
reached Sustained Success at Day 4 (that is no failure events occurred between day 4 and 
EOS visit), time to success will be calculated as 4 days. To note, when partial data in 
supplemental oxygen records inform that subject is discharged without supplemental 
oxygen yet the oxygenation status throughout this day up to discharge hour is unknown, 


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and subject was reported to require supplemental on the previous day, the Success date 
will be taken as the discharge succeeding day (as only then the 24 hours confirmation can 
be fulfilled). 
 
3.2.3 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
1. 
The percentage of patients with ≥2 category improvement on the WHO 
Ordinal Scale for Clinical Improvement by day 14.  
 
This endpoint will be defined per subject as a binary ("Success" / "Failure") variable with 
"Success" indicating that a subject has an improvement of  2 or more on the WHO Ordinal 
Scale compared to baseline. Patients who have been discharged alive, will be counted as 
Success, depending on baselines score, as discharge is associated with score<3 (to note, 
baseline WHO score of 5 is study inclusion criteria). The time frame for this end point is 
from day 1 until day 14.  
The WHO questionnaire (WHO ordinal scale for clinical improvement) –is provided in 
Appendix 1 
According to the general approach and rules set in Section 3.2.1.1, a subject is required to 
achieve a Success by Day 14, that will be sustained by EOS, in order to be counted as 
Success for the primary analysis of this endpoint. The applicable Failure events that can 
negate initial success events are: 
• Death (occurring by EOS visit). 
• Regression in WHO improvement to less than 2 levels.  
Refer to 13.1APPENDIX 1: WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT for the scoring 
definitions and conventions for inferring WHO improvement in the absence of explicit 
score. 
Handling of Missing data in determination of Success status will be in accordance to  
section 3.2.1.1 above. 
 
2. 
Time to recovery as defined by improvement to a score of 3 or less on the 
WHO Ordinal Scale for Clinical Improvement  
 
This time to event endpoint is defined within the time frame of 14 days and will be 
calculated as the number of days from Day 1 of study medication until the earliest date of 
score 3 or less on WHO scale – the success event, or Day 14.  
For this time to Success endpoint, in accordance with the general approach and rules set in 
Section 3.2.1.1, a subject is required to achieve a Success by Day 14, that will be sustained 
by EOS, in order to be counted as Success for the primary analysis of this endpoint. The 
applicable Failure events that can negate initial success events are: 


Statistical Analysis Plan 
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• Death (occurring by EOS visit). 
• Worsening of WHO score to a score of 4 or higher. 
 
Those subjects who will fail to achieve Success within Day 14 will be assigned a 
censored time at Day 14. 
 
Refer to 13.1APPENDIX 1: WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT for the scoring 
definitions and conventions for inferring WHO score of 3 (or less) in the absence of 
explicit score. 
Handling of Missing data in determination of Success status will be in accordance to  
section 3.2.1.1 above. 
 
3. Time to low oxygen flow via low flow nasal cannula or simple face mask from 
high oxygen flow via high flow nasal cannula, non-rebreather (reservoir) face 
mask or positive pressure ventilation at baseline 
 
This time to event endpoint, where event of interest is a desired outcome is defined within 
the time frame of 14 days and will be defined similarly to secondary endpoint #2, where 
now the event of interest is recording of a low oxygen flow via low flow nasal cannula or 
simple face mask received before Day 14.  
The applicable Failure events to determine Sustained Success status for this endpoint are: 
• Re-need of high-flow oxygen, positive pressure ventilation or mechanical ventilation, 
• Re-admission after discharge from hospital, for high-flow oxygen, positive pressure 
ventilation or mechanical ventilation (as will be captured as an SAE), 
• Death (occurring by EOS visit). 
Identification of a low flow oxygenation will be made through the type of apparatus used. 
As an inclusion criteria into the study required high flow oxygenation at baseline, all 
patients will be included in this analysis unless there was a protocol violation of this 
inclusion criteria and the patient was on low flow nasal cannulas or a simple face mask at 
the time of randomization (or, conversely, was intubated prior to the first treatment). 
Specifically, subjects enrolled prior to version 5 of the protocol receiving oxygen via face 
mask with an oxygen flow of >5L/min, will not be included in this endpoint analysis. 
 
4. Time to discharge from the hospital. 
 
This time to event endpoint where discharge from hospital, the event of interest, is a desired 
outcome, will be defined similarly to secondary endpoint #2, yet with a time frame of 42 
days. To note, the time frame for describing the data is Day 42, however as by 42 days 
most subjects from both arms are expected to be discharged, treatment effect estimation 
will be primarily focused within day 14 timeframe. 
The applicable Failure events to determine Sustained Success status for this endpoint are: 


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• Re-admission after discharge from hospital (as captured in AE log) for COVID-19-
related reasons. If reason cannot be determined, it will be regarded as COVID-19 
related. 
• Death (occurring by EOS visit). 
 
 
5. The percentage of patients requiring intubation and mechanical ventilation by 
day 42. 
 
This endpoint will be defined per subject as a binary ("Failure" / "Success") variable 
indicating “Failure” if a subject required intubation and mechanical ventilation or died 
before End of safety follow-up period (Day 28 post-last dose of therapy/Day 42 from the 
first dose, as applicable for the subject, per the protocol amendment under which 
informed consent was signed).  
An early discontinuation from the study (e.g. loss to follow-up, subject withdrawal) or 
failure to complete the EOS visit, will be considered as missing data and will be handled 
as follows:  
In the primary analysis, a worst-case imputation will be employed so that subject will be 
considered as Failure.  
A sensitivity analysis will employ a different strategy, in which the percentage of patients 
requiring intubation and mechanical ventilation or death by day 42 will be estimated using 
time to event analysis, in which subjects early terminating the study before experiencing 
intubation/failure will be assigned a right-censored Failure time at their last valid 
observation date (e.g. last oxygen observation date). In addition, for this analysis:  
• Patients who experienced intubation/death will be assigned a Failure time equal to 
the treatment days between Day 1 and their Failure time (“Failure”),  
•  Patients who successfully completed the study without experiencing 
intubation/death will be assigned a Right-censored failure time at their End of 
Study contact date (“Censored”). 
 
 
6. 
Mortality due to any cause at Days 28 and 42 after baseline 
 
These binary endpoints will be defined per subject as a binary ("Failure" / "Success") 
variables with "Failure" indicating that a subject had died within 28 treatment days from 
first dose date or by EOS visit (namely  Day 28 post-last dose of therapy/Day 42 from the 
first dose, as applicable), respectively. “Success” will be assigned for patients known alive 
at the target time. 
Derivation for these mortality endpoints for both the primary and sensitivity analysis will 
be performed according to the same approach defined for endpoint # 5 above, now with 
Death as event of interest.    
 
 


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7. 
Time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart. 
 
This endpoint will be defined only for patients who were positive for SARS-Cov-2 by PCR 
at screening or 7 days prior to screening. According with the note on biomarker-driven 
endpoints given in Section 1, due to the rarity of PCR testings post discharge, an observed 
data approach will be utilized in derivation this time to event endpoint where event of 
interest is a desired outcome which is recording of two consecutive negative swabs for 
SARS-CoV-2 by PCR by Day 14. Time will be calculated as the number of days from Day 
1 of study medication until the first time Success is recorded (the earliest date of the two 
swabs), and  if no success will be recorded, subjects will be censored at the latest PCR test 
before  day 14 date. 
 
8. 
The percentage of patients with at least two consecutive negative swabs for 
SARS-CoV-2 by PCR at Day 14. 
 
This endpoint will be defined only for patients who were positive for SARS-Cov-2 by PCR 
at screening or 7 days prior to screening. This PCR-based binary success endpoint will be 
defined according to Section 1 using the observed data approach. For this purpose, only 
those patients with at least two post-baseline PCR tests will be analyzed, and subjects will 
be classified based on testings performed by Day 14 if the results of the latest PCR testing 
by Day 14 will be classified as Success/Failure, where success  is recording of two 
consecutive negative swabs for SARS-CoV-2 by PCR by Day 14, or not.  
 
9. 
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. 
 
This endpoint will be defined only for patients who had fever at baseline (i.e at least one 
measurement of temperature >38.0C [100.4F]), with at least one temperature testing post-
baseline.  In accordance to Section 1, this binary endpoint will be calculated based on 
observed data approach This binary endpoint where event of interest is a desired outcome 
will be defined as Success/Failure based on subject’s latest temperature measurement by 
Day 14, and Success will be assigned if subject was afebrile on this test and Failure 
otherwise. Death by Day 14 will not be considered Success despite possible previous 
success.  
 
 
3.2.4 Exploratory Endpoints 
Exploratory endpoints will include: 
 


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1. 
The changes 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 change in lymphocyte count from baseline at Day 14 for the opaganib arm as 
compared to the placebo arm. 
 
The biomarkers above were planned to be collected at Screening visit and then once 
every 3 days and Day 14 visits. As was noted  in Section 1,3.2.1.2 these assessments 
are mostly available only up to patient’s discharge, often before Day 14 visit, and an 
observed data approach will be utilized. Therefore,  a Last Available Value up to and 
including day 14 (LAVD14) will be calculated and analyzed.  
 
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  
This time to event endpoint is defined within the time frame of 14 days and will be 
calculated as the number of days from Day 1 of study medication until the earliest date of 
score 1 or less on WHO scale – the success event, or Day 14.  
For this time to Success endpoint, in accordance with the general approach and rules set in 
Section 3.2.1.1, a subject is required to achieve a Success by Day 14, that will be sustained 
by EOS, in order to be counted as Success for the primary analysis of this endpoint.  
The applicable Failure events that can negate initial success events are: 
• Death (occurring by EOS visit). 
• Worsening of WHO score to a score of 2 or higher. 
 
Those subjects who will fail to achieve Success within Day 14 will be assigned a 
censored time at Day 14. 
Because the reality is that follow-up data collected at the EOS visit do not capture the 
difference between WHO 1 and 2 with regard to all Covid-19 impacted aspects of daily 
life  (i.e. not just need for supplemental oxygen), determining initial success or 
sustainability of this endpoint for any patient who did not achieve a score of 1 prior to 
discharge may be impossible, resulting in large amount of missing data. Therefore missing 
data due to discharge from hospital will be right censored at discharge date and not defined 
as Failure event. Those subjects who have missing data for identifying discharge will be 
considered as Failures.  
 
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. 
This end point will be defined similar to the primary end point within the time frame of 7 
days. 


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5. 
Time to 50% reduction of supplemental oxygen requirement for the subset of 
subjects who do not receive positive pressure ventilation (non-invasive or 
invasive) at baseline for opaganib arm as compared to the placebo arm. 
This time to event endpoint, where event of interest is a desired outcome is defined within 
the time frame of 14 days and will be defined similarly to secondary endpoint #2, where 
now the event of interest is reaching a value of supplemental oxygen, which is at least 50% 
lower than the baseline value.  
The applicable Failure events to determine Sustained Success status for this endpoint are: 
• Requirement of  supplemental oxygen value which is does not show 50% increase 
relative to baseline, or, positive pressure ventilation or intubation and mechanical 
ventilation, 
• Re-admission after discharge from hospital, for high-flow oxygen, positive pressure 
ventilation or intubation and mechanical ventilation (as will be captured as an SAE), 
• Death (occurring by EOS visit). 
 
This time to event endpoint is defined for a subset of patients who do not receive positive 
pressure ventilation (non-invasive or invasive, and met inclusion criteria  #3 according to 
Version 5 of the protocol) at baseline.  
 
 
3.2.5 Safety Endpoints 
The safety and tolerability endpoints will include: 
• Treatment Emergent Adverse Events (TEAEs) and serious Adverse events (SAEs) 
• Laboratory tests 
• vital signs  
• ECG  
 Sample Size and Power 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. 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 


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planned non-binding futility analysis to be performed after at least 135 patients in the 
study have been evaluated for the primary endpoint. 
 Randomization and Blinding 
A total of 464 patients will be randomized, using 1:1 assignment ratio and receive either 
Opaganib added to standard of care (232 patients), or matching placebo added to standard 
of care (232 patients). 
Stratification will be done based on: 
 1) whether the patients meet three or more high risk parameters for COVID-19 outcomes 
at baseline (yes or no).  
This will be determined by: age at screening ≥60 years, (yes or no); male, (yes or no); 
HbA1c at screening ≥6.5 or on active treatment with insulin or oral hypoglycemics (yes 
or no); hypoxemia without commensurate increased work of breathing (yes or no); 
known underlying chronic lung disease (yes or no); known cardiovascular disease or 
hypertension (yes or no); BMI ≥ 28.0 kg/m2 (yes or no); known renal disease (yes or no). 
2) Whether SoC treatment has established efficacy (yes or no) 
Treatment assignments will remain blinded to the patient, investigator and hospital staff, 
as well as the sponsor. 
  
 Sequence of Planned Analyses 
3.5.1 Interim Analyses 
One futility analysis when a total of 135 subjects have had day 14 evaluation is planned.  
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 analysis will be 
conducted by an independent unblinded statistician who is charged to reporting to the 
DMC, who will inform the DMC of the futility outcome: a single statement saying if 
boundary has or has not been crossed. No unblinded data will be shared in any outcome 
case. Strict procedures will be employed to maintain the confidentiality of the interim 
results.. The futility analysis is further detailed in section 5.6. 
3.5.2 Final Analyses and Reporting 
All final, planned analyses identified in this SAP will be performed only after the last 
patient has completed the study and database have been locked.   The randomization codes 
will not be unblinded until this SAP has been signed and approved. Any exploratory 
analyses completed to support study analyses, which were not identified in this SAP, will 
be documented and reported in appendices to the CSR.  
 


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4 ANALYSIS POPULATIONS 
This section describes the analysis populations defined for the study. 
 Screened  
The Screened population will include all subjects who underwent screening, defined by 
date of informed consent. 
 Intention to Treat (ITT)  
The ITT population will include all randomized subjects.  In this population, treatment 
will be assigned based upon the treatment to which patients were randomized regardless 
of which treatment they actually received.  
 Modified ITT (mITT) 
This population consists of all patients that were randomized and treated with at least one 
dose (even partial) of study drug.   
 Baseline High Flow Treated (BLHF Treated) 
This population consists of subset of mITT population  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 non-rebreather or reservoir mask, 
capable of delivering high concentrations of oxygen). Patients who require mechanical 
ventilation or no longer require at least high flow supplemental oxygen (as defined in 
entry criterion #3) prior to receiving the first dose of study drug will not be included in 
this analysis set.  
 Per Protocol (PP) 
This Population will consist of subjects that were randomized, treated with at least one 
dose of study drug who further meet PP Criteria. These criteria will be based on inclusion 
and exclusion criteria and major protocol violations during the study that may confound 
the interpretation of the analyses as determined on blinded review by the medical monitor 
or his designate. A blinded review before database lock will be applied to define this 
population. 
 Safety  
The safety population will include all randomized patients who receive at least one dose 
of study medication.   
 
In the ITT, mITT, BLHF Treated and the PP populations, treatment will be assigned based 
upon the treatment to which subjects were randomized regardless of which treatment they 
actually received. In the Safety population, treatment will be assigned based upon the 
treatment patients actually receive regardless of the treatment to which they were 
randomized.  


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5 GENERAL ASPECTS FOR DATA ANALYSIS 
 General 
The following is a list of general reporting conventions:  
1. Descriptive statistics for continuous variables include n (number of non-missing 
observations), mean, standard deviation (SD), standard error of the mean (SE), 
median, minimum, and maximum.  
2. Means and medians will be reported with 1 more digit than the precision of the 
captured data.  Standard deviations and confidence intervals will be reported at 2 
more digits than the precision of the data. Minimum and maximum will be reported 
to the same level of precision as the original observations.  
3. Descriptive statistics for categorical variables will include counts (n) and 
percentages (%) and will be presented in the form of n (%).  
4. Percentages will be reported with 1 decimal place.  
5. No preliminary rounding should be performed; rounding should only occur after 
analysis.  To round, consider digit to right of last significant digit:  if < 5, then round 
down; if ≥ 5, then round up. 
6. Unless otherwise noted, all statistical analyses will be conducted with a significance 
level (α) of 0.05 and utilize two-sided testing. 
7. All data collected will be presented in the by-subject data listings, sorted by subject 
and by time point, where appropriate. 
If departures from these general conventions are present in the specific evaluation sections 
of this SAP, then those will take precedence over the above general conventions. 
 Specification of Baseline Values 
In general, Baseline will be defined for each subject as the last available, valid, non-
missing assessment before first study drug dose. 
 Multiple Comparisons and Multiplicity 
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).  
The primary endpoint will utilize the overall allowed type 1 error. There is no planned 
adjustment for multiple comparisons in any secondary or exploratory endpoints analyses 
and their evaluation will aim at further enhancing the understanding of  the beneficial 
effect of Opaganib. 
 


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 Handling Withdrawals and Missing Data 
The primary endpoint, the binary secondary efficacy endpoint #1 and  the time to event  
secondary endpoint #2, #3 and #4 are all involving the identification of a Sustained 
improvement/beneficial event. Early termination from study is considered missing data 
with regard to determining ultimate Success status in these endpoints and the general 
strategy for handling it is detailed in section 3.2.1.1, employing a worst-case Failure 
imputation in the primary analysis along with a ‘while on study’ observed data approach 
as a sensitivity analysis. To note, death by EOS visit in the above listed endpoints is not 
considered Missing data and is counted as Failure event by definition.   
Efficacy Secondary endpoints # 5 and #6 are binary endpoints concerning the occurrence 
of a severe negative-impact health event of interest, by a certain time-point. In both, early 
termination of study follow-up alive before a Failure event had a chance to occur will be 
handled via worst-case imputation in the primary analysis along with a sensitivity analysis 
estimating the cumulative incidence of Failure by a certain time point using time to event 
methods, where early termination is regarded as right censored Failure time, as defined in 
Section5 
It should be noted that End of Study follow up visit has been defined as 28 days after last 
dose for subjects enrolled prior to version 5 of the protocol (‘Day 28’ visit) and as Day 42 
after the first dose – following protocol amendment 5. Therefore, subjects should not be 
considered to have missing day 42 assessment if performed their scheduled ‘Day 28’ visit 
as planned.  
In this relative short-period study, because the EOS visit is the only scheduled visit after 
Day 14 visit, it is expected that all completing subjects will have EOS visit, while missing 
EOS visit will be associated with an Early termination status. It is noted though that missing 
EOS visit (or missing information in this visit) will bear same application as early 
termination. 
PCR-based and temperature-based secondary efficacy and exploratory endpoints are 
expected to have high rates of missing data due to discharge from hospital and a strategy 
to employ ‘while on study’ observed data will be employed as explained in section 
3.2.1.2. 
Missing data for exploratory endpoints not covered above (i.e not PCR-based) are 
defined and handled within the endpoint-specific definition in Section 3.2.4. 
Generally, no imputation will be performed for safety endpoints unless stated otherwise 
in the specific endpoint analysis.  
 Study days and visit windows 
Throughout this SAP, the following terms and conventions will be applied for this 
protocol scheduled for of 14 treatment days (each includes morning and evening takes) 
and an overall up to 42 study days. Scheduled Visit names are named using the relevant 
planned Study day. 
 


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Derived study days will be calculated relative to the Study day 1 date whereas 
treatment days will be derived relative to the Treatment day 1 date. 
Whereas Study day 1 refers to  the date of the 1st dose, for deriving the first  treatment 
day (Treatment day 1), refers to the date of when uptake of both 1st morning & evening 
doses is due, which depends if 1st study dose was a Morning or an Evening 
administration.  The Study day 1 and Treatment day 1 will be equivalent for those 
subjects enrolled to take their 1 study dose at the Morning but differs for those subjects 
who due to the pandemic constraints were enrolled to take their first study dose only at 
the Evening administration, leading to expected completion of 1st treatment day at study 
day 2. In this later case, Treatment Day 1 date will be equivalent to Study day 2 date. For 
those randomized subjects who never started study treatment, both study day 1 and 
treatment day 1 will be referring to the Randomization date. 
The efficacy endpoints are based on endpoint-specific Timeframes, (detailed in Section 
3.2). These timeframes will be defined using Treatment days, as defined above. It 
should be noted that vital signs assessments were also to be taken on study day 15 (the 
14’th treatment day), for those subjects who started treatment only at Evening. Summary 
By-Treatment day tables of  the efficacy measurements  data will be provided .  
Listings will include all collected data, and will provide both Study day and Treatment 
day information. For by-visit summaries, assessments at ‘Day 1’ visit refer to time before 
first dose of study drug (baseline), and assessments performed on ‘Day 2’ visit and 
subsequent visits refer to days after first dose date.    
When the EOS visit is included in by-visit summaries, no distinction will be made between 
those visits completed as scheduled under Version 5 of the protocol and those performed 
per version 5 protocol. 
In case assessments are done at the Early Termination visit, these assessments will be used 
as data for the scheduled assessment day closest to the early termination time point and as 
relevant per end point, in case the corresponding data are missing from this assessment 
day. Generally, measurement taken at unscheduled visits will not be included in by-visit 
descriptive analyses, however will be otherwise included in ‘any time post baseline’ 
analyses and will be included in data listings. 
 Futility analysis 
One futility analysis when about a total of 135 subjects have had day 14 evaluations is 
planned.  
5.6.1 Outline 
The futility analysis will be performed in two steps: 
Step 1: primary endpoint analysis 
For the primary endpoint, the futility rule is based on performing a statistical test to 
compare the proportion of success, for opaganib versus placebo. The stopping rule 
boundary for the primary endpoint is present in section 5.6.2 below. 


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In the case that this futility boundary is crossed, sensitivity analyses will be performed on 
the primary endpoint to ensure that this result is robust, according to specifications 
provided in Section 5.6.3 below.  
If the sensitivity analyses substantiate the futility conclusion with respect to the primary 
endpoint, then the following step 2 will be performed. 
Step 2: key secondary outcomes analysis 
In the face of the unpredicted nature of the disease and pandemic situation, it is required 
that in the case that futility conclusion is reached with regard to the primary endpoint, the 
final conclusion of study futility will be declared after inspecting key secondary outcomes, 
as listed below: 
1. Time to no longer requiring supplemental oxygen for at least 24 hours (timeframe 
Day 14) 
2. Time to ≥2 category improvement on the WHO Ordinal Scale (timeframe:  day 14); 
3. Proportion need intubation and mechanical ventilation (timeframe: 14 days) 
4. Time to low oxygen flow via nasal cannula e.g. from high oxygen flow via nasal 
cannula or positive pressure ventilation, if high oxygen flow is not an available 
option (timeframe Day 14) 
Assessed hierarchically, If ANY of the observed treatment effects on these endpoints 
comparing opaganib to placebo is in the right direction (beneficial), then study will be 
concluded as NOT futile. If on the other hand all effects are trending in the wrong direction, 
then the study will be concluded as Futile.  
To note, observed effect is regarded as trending in the right direction when HR>1 for 
endpoints #1, #2 and #4and when observed % in Opaganib – % in placebo <0 (opaganib 
numerically need less), for endpoint #2 .  
5.6.2 Primary endpoint Futility boundary 
The stopping rule for the primary endpoint was chosen so that futility will be recommended 
if the interim result is trending in the wrong direction, and is such that the conditional 
probability of statistically significant result if continue to the end of the study, given 
interim data so far, and assuming that the future patients will follow the design 40% and 
55% success rates for control and opaganib, respectively, is lower than 30%.  
The futility stopping rule can be expressed equivalently in terms of: 
1. Observed success rate difference:  futility boundary will be crossed if placebo has 
excess of 12.3% success rate over opaganib. 
2. The statistical test Z value: futility boundary will be crossed if Z<-1.428.    
3. To note, if interim result is such that the futility rule is crossed, the probability for study 
to turn out to be successful (significant) should continue to the end if the future 
results will follow the observed rates (rather than those hypothesized at design), is 
almost 0.  
The equivalent stopping rules for the primary endpoint are summarized in the following 
table: 


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Futility stopping rule (equivalent forms):  
stop if  
Information at 
interim 
Number 
of 
patients 
success rate 
difference 
(opaganib-
placebo) 
 
Conditional power 
(CP) assuming the 
design effect 
Z value 
135/464=29% 
135 
Diff<-12.3% 
CP <30% 
Z<-1.428 
 
The operating characteristics of the plan are presented in terms of false-stopping (risk), and 
correct-stopping (that is power to stop a futile treatment) probabilities. 
Probability to stop at interim 
under H1 
(false-stopping) 
under H0 
(correct-stopping) 
<0.01% 
~8% 
 
5.6.3 Sensitivity analyses for the primary endpoint 
Per the protocol and SAP, The primary analysis for the primary endpoint is the Cochran 
Mantel-Haenzel (CMH) test to compare the proportion of success between the two groups, 
a stratified test using the study stratification factors as used for randomization, applied on 
the mITT population. Treatment effect is estimated by the corresponding stratified risk 
difference. Thus, step 1 of the futility analysis plan will employ the primary analysis 
specified above. In accordance rules set above if the CMH Z statistic <-1.428 and stratified 
risk difference<-12.3%, this analysis will indicate futility. 
To note, this rule will be employed even if different number than 135 patients are included 
in analysis. 
If the boundary has been crossed then the following sensitivity analyses for the primary 
endpoint will be performed: 
•Repeat the stratified analysis using strata values according to baseline (instead of those 
known at time of randomization) 
•Perform crude analysis: simple risk difference test 
•If important baseline imbalance appear, perform adjusted analysis (using logistic 
regression).. 
•Impute missing data as ‘NOT failures’ and repeat the stratified and crude analyses above 
•Repeat the stratified and crude analysis without potential outlier site 115 data. 
In case in ALL the sensitivity analyses the futility boundary is crossed for the primary 
endpoint, then it will be regarded as substantiated futility outcome and Step two of outline 
should be performed, as defined in the outline.  
 


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5.6.4 Results dissemination  
The independent statistician reporting to the DMC will perform the futility analysis as 
outlined above. Only a futile/non-futile statement (without unblinded results) will be 
included in the closed report, that can be passed on as a recommendation to the Sponsor.  
Important note: the futility analysis is non-binding such that if boundary is crossed yet 
other consideration lead to continuation of the trial, it will not impact the study type 1 error. 
 
 


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6 STUDY POPULATION  
 General 
Study population summaries will be presented by treatment group and overall unless 
otherwise noted.  
 Patient Disposition 
The subject disposition will be summarized as follows and presented for each treatment 
group and overall, unless otherwise specified. Summary will include all screened 
subjects. The percentages will be calculated from the ITT population, unless otherwise 
specified. 
• The number of all screened subjects (i.e. the number of subjects in the Screened 
population), presented only for overall group 
• The number (%) of subjects who were not eligible for the study (% calculated from the 
Screened population), including the distribution of reasons for not eligible for the study, 
presented only for overall group 
• The number (%) of subjects screened but not randomized, if applicable (% calculated 
from the Screened population), presented only for overall group 
• The number of randomized subjects (i.e. the number of subjects in the ITT population) 
• The number (%) of randomized but not treated subjects, if applicable 
• The number (%) of subjects in the Safety population (i.e. treated subjects) 
• The number (%) of subjects in the mITT population 
• The number (%) of subjects in the BLHF Treated population 
• The number (%) of subjects in the PP population 
• The number (%) of subjects who completed the study treatment according to protocol  
• The number (%) of subjects who discontinued the study treatment prematurely, 
including the distribution of reasons for premature discontinuation  
• The number (%) of subjects who completed the study 
• The number (%) of subjects who discontinued the study prematurely, including the 
distribution of reasons for premature discontinuation 
 Demographics and Baseline Characteristics 
Demographics and baseline characteristics including the stratification factors will be 
summarized by treatment group and overall using ITT, mITT and Safety populations. 
Summaries will be presented with the appropriate descriptive statistics as specified in 
section 5.1 above. 
The following will be provided: 
Demographics: 
• Age (years) (continuous) 
• Sex: Male, Female, Not Specified (categorical) 
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Unknown, (categorical) 


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• Race: White, American Indian or Alaska native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, Other (categorical) 
 
Baseline characteristics: 
• Smoking status: Never, Former, Current (categorical)  
• Weight  
• BMI 
• Height 
• Vital signs including supplemental oxygen requirement 
• HBA1C 
 
Stratification factors (categorical): 
• Whether SoC treatment has established efficacy (Yes versus No). For both stratification 
factors, both values used for randomization and those recorded in the eCRF at baseline 
(possibly corrected/updated) values will be presented.  
• High or low risk (i.e meet three or more high risk factors for COVID-19 outcomes) 
(Yes versus No) 
COVID-19 Risk Factors (only values as recorded at eCRF at baseline will be presented): 
• age at screening, ≥60 years of age, (yes or no);  
• male, (yes or no);  
• Diabetes Mellitus status at screening: HbA1c at screening≥6.5 or on active 
treatment with insulin or oral hypoglycemics (yes or no));  
• hypoxemia without commensurate increased work of breathing (yes or no);  
• known underlying chronic lung disease (yes or no);  
• known cardiovascular disease or hypertension (yes or no);  
• BMI ≥ 28.0 kg/m2 (yes or no); 
• known renal disease (yes or no). 
 
 Covid-19 Disease Information  
Disease information will be summarized by treatment group and overall using ITT, mITT, 
and Safety populations. Summaries will be presented with descriptive statistics as specified 
in section 5.1 above 
• Time from onset of symptoms to Hospitalization (Days) 
• Time from onset of symptoms to diagnosis (Days) 
• Time from onset of symptoms to randomization (Days) 
• Time from diagnosis to hospitalization (Days) 
• Time from diagnosis to supplemental oxygen (Days) 
• Time from diagnosis to randomization (Days) 
• Time from hospitalization to supplemental oxygen (Days) 


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 Medical and Surgical History 
Medical history data will be summarized by treatment group and overall using mITT and 
Safety populations. All medical history terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). The number and percentage of subjects with at least 
one medical history term will be summarized by System Organ Class (SOC) and by 
Preferred Term (PT) within SOC for each treatment group and overall. The table will be 
sorted by overall descending frequency of SOC and then, within a SOC, by overall 
descending frequency of PT.  
All medical and surgical history data will be listed. 
 Prior Medications 
Prior medications will include all recorded medications and supplements a patient was 
taking during the screening period that were stopped prior to administration of the study 
drug.   
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) 
classification codes and preferred terms (PT) from the World Health Organization Drug 
Dictionary (WHO-DD).  Prior medications data will be summarized by treatment group 
and overall using mITT and Safety populations. The number and percentage of subjects 
with at least one medication term will be summarized by ATC Level 4 category and by PT 
within an ATC Level 4 for each treatment group and overall. The table will be sorted by 
overall descending frequency of ATC Level 4 and then, within an ATC Level 4, by overall 
descending frequency of PT. 
Distribution of SoC medications, as identified by on a blinded review, at baseline will be 
presented by group. Number and percentage of subjects with at least one SoC medication 
per each category will be calculated and sorted by overall descending frequency of the SoC 
category. 
In addition, all prior medications data will be listed. 
 Electrocardiography 
Electrocardiogram findings (normal, abnormal, and missing) at screening will be 
summarized using appropriate descriptive statistics, and will be presented for the Safety 
population. 
In addition, all screening ECG results data will be listed. 
 Physical Examinations 
Physical examination findings (normal, abnormal, and missing) at baseline will be 
summarized by treatment group and overall using Safety population. Summaries will be 
presented using appropriate descriptive statistics. 


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 Chest X-Ray or CT scan 
Screening Chest X-ray or CT scan findings (normal, abnormal, and missing) will be 
summarized by treatment group and overall using Safety population. Summaries will be 
presented using appropriate descriptive statistics. 
In addition, all screening chest X-ray and CT scan data will be listed. 
 Protocol Violations  
All protocol violations will be tabulated presenting incidence (count and percentage) of 
subjects with deviation category for each group, and data will be listed as well. 
7 EFFICACY ANALYSIS 
 General Considerations for efficacy evaluation 
7.1.1 Populations for analysis 
The analysis of the primary efficacy endpoints will be performed on the ITT, mITT, BLHF 
Treated and PP populations, with the mITT population serving as the primary analysis 
population. The secondary efficacy endpoints will be analyzed using the mITT, BLHF 
Treated and PP populations, unless otherwise noted for a specific endpoint. 
Summaries will be presented by treatment group to which subjects were randomized. 
7.1.2 Stratification 
Stratified analysis will employ values of stratification factors used for randomization,  
where sensitivity analysis will be conducted using the updated/corrected values known at 
baseline. 
7.1.3 Covariates 
The comparability of the baseline risk factors for COVID-19 (listed on section 6.3) 
between groups will be assessed during the Final analysis and statistical procedures (as 
appropriate for Binary or time-to-event endpoint), to control for the possible impact of 
factors that appear to be imbalanced, will be performed as a robustness analysis.  
7.1.4 Subgroups 
Opaganib treatment effect for specific endpoint will be assessed to confirm comparability 
of effect across baseline SoC regimen strata. As strata may involve small number of 
subjects, crude analysis (no further stratification) will be performed, as adequate.  
7.1.5 Use of effective anti-COVID 19 SOC treatments 
Descriptive statistics including frequency and timing (relative to study day 1) of initiation 
of each type of effective anti-COVID-19 SoC treatment, will be presented by each group. 
Subjects already exposed to specific treatment before or on Day 1 will be counted as 
users as well with associated time to initiation of 0 days. 


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 Primary Efficacy Endpoint Analysis 
The primary endpoint aims at comparing the percentage of patients no longer requiring 
supplemental oxygen, for at least 24 hours by treatment Day 14 as defined in section 3.2.1, 
between Opaganib and placebo. The primary analysis will be based on the Modified Intent 
to Treat population (mITT) as defined in section 4.3.  
This binary endpoint will be analyzed as follows: the number of subjects having “Success” 
event will be summarized using counts and percentages for each group.  
A 95% confidence interval will be constructed for the proportion of success in each group. 
A Cochran Mantel-Haenzel (CMH) test will compare the proportion of success between 
the two groups, using the study stratification factors as used for randomization, and 
corresponding stratified risk difference estimate will be presented with 95% confidence 
interval.  
The significance level for this test will be two-sided 5%. 
The SAS syntax for the above calculations is provided in appendix 1. 
A listing providing details on derivation of the primary endpoint will be provided. 
7.2.1 Sensitivity and supportive analyses 
Sensitivity and supportive analyses for the primary endpoint analysis will address the 
following aspects:  
7.2.1.1 Sensitivity analysis for the imputation of missing data due to early 
study discontinuation. 
The primary endpoint analysis imputed all early discontinuation from the study (or  
missing EOS visit/data) as Failures, even if a Sustained Success has been observed prior 
to termination. However in this sensitivity analysis an imputation using Observed data 
while on study (LOCF approach) will be used, as explained in Section 3.2.1. 
7.2.1.2 Sensitivity analyses using other populations  
As described in Section 7.1.1. 
7.2.1.3 Sensitivity analysis account for stratification error  
As described in Section 7.1.2. 
7.2.1.4 Sensitivity analysis to account for baseline characteristics adjustment 
In accordance with Section 7.1.3, difference between the treatment and control groups 
(the treatment effect for the primary endpoint) when controlling for possible imbalance in 
baseline risk factors will be analyzed by evaluating the odds ratio for Success obtained 
from estimating a multiple logistic regression model that include treatment effect along 
with the factors appear to be imbalanced as explanatory variables.. 


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7.2.1.5 Subgroup analysis to account for SoC regimen 
 opaganib treatment effect will be assessed to confirm comparability of effect across these 
strata, according to Section7.1.4. Post-hoc subgroup analysis by treatments that started 
before or after Day 1 may be performed as deemed applicable. 
7.2.1.6 Companion analysis: time to longer requiring supplemental oxygen 
for at least 24 hours, time frame of 14 days 
Kaplan-Meier plot by treatment arm will be presented along with corresponding median 
estimates. The stratified Cox proportional hazards regression model estimate of the hazard 
ratio (HR) along with 95% confidence interval, comparing Opaganib versus control group 
will be provided.  
To note, both the primary analysis and the sensitivity analysis for missing data will undergo 
the analyses in section 7.2.1.2 to 7.2.1.6. 
 
 Secondary Efficacy Endpoint Analysis 
This section describes the analyses to be performed on the secondary efficacy endpoints, 
based on endpoints definition provided in section 3.2.3. 
The secondary efficacy endpoints will be primarily analyzed using the mITT as primary 
analysis and will undergo sensitivity analyses for Missing data as applicable in endpoint–
specific definition, and both the primary derivation and the sensitivity for missing data 
derivation will undergo the sensitivity analyses for Populations, Covariates and 
Subgroups (per sections 7.1), as applicable. 
 
1. The percentage of patients with ≥2 category improvement on the WHO Ordinal 
Scale for Clinical Improvement by day 14.  
This binary endpoint (“success”/”failure”) will be analyzed as follows: the number of 
subjects with “success” and “failure” will be summarized using counts and percentages 
for each group. A 95% confidence interval will be constructed for the proportion of event 
of interest (“success”) in each group. 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 corresponding stratified risk difference estimate will 
be presented with 95% confidence interval.  
   
2.  Time to recovery as defined by improvement to a score of 3 or less on the WHO 
Ordinal Scale for Clinical Improvement  
 
This time to event endpoint will be analyzed using the stratified Log-rank test as well as 
the stratified Cox proportional hazards regression model estimates the hazard ratio (HR) 
along with 95% confidence interval, comparing opaganib versus control group. Kaplan-
Meier plot by treatment arm will be presented and based on it the cumulative incidence of 
event of interest will be estimated for each group and the for their difference along with 


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95% confidence interval for each group at day 7 and at day 14. Median time and 95% 
confidence interval will be estimated using the KM curve for each group. 
 
3. The time to low oxygen flow via nasal cannula e.g. from high oxygen flow via 
nasal cannula, non-rebreather (reservoir) face mask or positive pressure 
ventilation, if high oxygen flow is not an available option. 
 
This time to event end point will be analyzed using the same analytical methods as the 
secondary end point #2, where the event of interest now is time to low oxygen flow via 
nasal cannula. 
 
4. Time to discharge from the hospital. 
Kaplan-Meier plot by treatment arm will be presented and based on it the cumulative 
incidence of discharge from hospital will be estimated along with 95% confidence 
interval for each group and the for their difference at day 7, day 14, day 28 and day 42 
time points. Median time and 95% confidence interval will be estimated using the KM 
curve for each group. 
Stratified Log-rank test as well as the stratified Cox proportional hazards regression 
model estimates the hazard ratio (HR) along with 95% confidence interval, will be used 
to compare opaganib with the control group, only through 14 days. For this purpose, any 
discharge time beyond 14 days will be censored at day=14. Restricted means at day 14 
will also be provided for each group. 
 
5. The percentage of patients requiring  intubation and mechanical ventilation by 
day 42 
According to section 3.2.3, the primary analysis will employ binary variable 
(“Failure”/”Success”), where event of interest is any intubation and mechanical 
ventilation or death or early termination from study. This binary variable  will be 
analyzed using the same analytical methods for binary outcome as the first secondary 
endpoint, where now the event of interest is any Failure. 
As a sensitivity analysis for missing data, the Kaplan-Meier method will be used to 
estimate the cumulative incidence of a composite failure of intubation and mechanical 
ventilation/death at day 42,  when early termination and subjects completing the study 
successfully without failure are censored at their last contact date, as explained in Section 
3.2.3 for this endpoint. The Cumulative Incidence of failure at day 42 and their difference 
will be provided, along with a 95% confidence interval for the between-group 
comparison. Additional time points will also be described (e.g. day 14, day 28) and 
Kaplan Meier curves of time to event through Day 42 will also be provided 
A table will be provided presenting the number (%) of each of the failure events 
comprising the composite intubation/death/early termination binary variable used for the 
primary analysis of this endpoint. Subjects with Failure event will be classified into one 


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of 3 mutually exclusive categories: any intubation and mechanical ventilation, death 
without intubation and early termination. 
 
6. Mortality due to any cause at Days 28 and 42 after baseline 
These mortality endpoints will be analyzed according to the same approach defined for 
endpoint # 5 above, now with Death as event of interest.   Kaplan Meier curves of time to 
death through Day 42 will also be provided. 
 
7. Time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart 
This time to event end point will be analyzed using the same analytical methods as the 
secondary end point #2, where the event of interest now is time to two consecutive 
negative swabs for SARS-CoV-2 by PCR. No sensitivity analyses will be performed for 
this endpoint. 
 
8. The percentage of patients with at least two consecutive negative swabs for 
SARS-CoV-2 by PCR at Day 14 
This binary end point ("Success" / "Failure") will be analyzed using similar methods as 
those specified for the first secondary endpoint and according to the endpoint definitions 
in section 3.2.2. As noted in endpoint definition, death at any time prior to day 14 will be 
counted as Failure. No sensitivity analyses will be performed for this endpoint.  
 
9. 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. 
 
This binary end point ("Success" / "Failure") will be analyzed using similar methods as 
those specified for the 7th  secondary endpoint and according to the endpoint definitions 
in section 3.2.2. No sensitivity analyses will be performed for this endpoint. 
 
 Exploratory Endpoint analysis 
This section describes the analyses to be performed on the Exploratory efficacy 
endpoints, based on endpoints definition provided in section 3.2.4. All analyses will be 
based on the mITT population unless otherwise specified in endpoint definition. There 
are no planned sensitivity analyses for these endpoints. 
 


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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 for the opaganib arm as compared to the placebo arm 
Descriptive statistics for raw values and changes from baseline will be provided for Day 
7, Day 14 and Last Available Value up to and including day 14 (LAVD14). The non-
parametric  Wilcoxon rank sum test will be used to compare the defined latest timepoint.  
 
2. The change in lymphocyte count from baseline at Day 14 for the opaganib arm as 
compared to the placebo arm 
This endpoint will be analyzed as specified above  (exploratory endpoint #1). 
 
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 
This time to event end point will be analyzed using the same analytical methods as the 
secondary end point #2 where the event of interest now refer to a score of 1 or less 
(instead of 3 or less). Sensitivity analysis will not be applied here. 
 
 
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 
This end point will be analyzed using the same analytical methods applied for the primary 
end point but within the time frame of 7 days. Sensitivity analysis will not be applied here. 
 
 
5. 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 
This time to event end point will be analyzed using the same analytical methods as the 
secondary end point #2, where the event of interest now is time to 50% reduction in 
supplemental oxygen requirement. Sensitivity analysis will not be applied here. 
 
 


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8 SAFETY ANALYSIS 
 General 
The safety population will be used for all safety analyses.  Summaries will be presented 
by treatment group as actually received unless otherwise specified.  
 Study Drug Administration 
8.2.1 Exposure to study drug 
The following information will be summarized by treatment group: 
• Duration of treatment (days treated) will be calculated as the number of days on 
treatment based on the first and last days of treatment with the study drug (last day of 
study drug – first day of study drug + 1).  Duration of treatment (days) will be 
summarized using appropriate descriptive statistics for continuous variable (section 5.1 
above). 
• The number and proportion of subjects with at least one dose reduction, and the total 
number of dose reduction will be tabulated.  
8.2.2 Treatment Compliance   
Compliance with the prescribed study treatment will be assessed per subject, continuously 
from treatment initiation to end of treatment. The drug accountability log of returned study 
bottles will be used to evaluate the number of capsules used, unused and lost (recorded by 
site personnel). In addition, the Dose Missed/Reduced Log, which captures on a daily basis 
all missed or modified doses and reasons for modification, will be used to more accurately 
assess compliance. 
Compliance rates will be presented as percentages, and subject-level compliance rates will 
be computed as follows:  ([actual number of twice-daily doses taken minus reduced or 
missed] ÷ [expected number of twice-daily doses taken]) x 100. 
Compliance rates will be summarized using appropriate descriptive statistics for 
continuous variable (section 5.1 above). 
Compliance will also be categorized as ≤80% or >80% and will be summarized using 
counts and percentages. 
Subject-level compliance details will be presented in a single data listing, incorporating 
count of dispensed (28 capsules) and returned capsules, number of expected vs. actual 
doses taken, occurrence of and reasons for missed and reduced doses, computed 
compliance rates and AEs leading to change in dose. 
 Adverse Events 
All adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Adverse events will be graded according to the revised NCI 
Common Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0).  If an AE 
is not listed in the NCI-CTCAE v.5.0, then the Physician will use the terms: mild/Grade 1, 
moderate/Grade 2, severe/grade 3, life-threatening or disabling/Grade 4, or death 


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related/Grade 5 to describe the maximum intensity of the AE, as specified in the protocol 
(section 17.2). 
Only Treatment Emergent Adverse Events (TEAEs) will be summarized. TEAEs are 
defined as all AEs that start on or after the date of first dose.  
The following summaries will be provided: 
• An overall summary that will include the number and percentage of subjects with: 
o any TEAEs; any serious TEAE (TESAE); 
o TEAEs will be presented by grade; 
o any treatment related (treatment related is defined as Possibly, Probably and 
related) related TEAEs, also missing relationship will be regarded as 
treatment related); any treatment related TESAE; 
o any TEAE resulting in dose reduced; any TEAE resulting in drug withdrawn 
(drug withdrawn or stopped) 
o any TEAE with an outcome of death 
• Summaries by System Organ Class (SOC) and by Preferred Term (PT) within SOC 
will present the number and percentages of patients: experiencing any TEAEs; any 
TESAE; any grade 3 or above TEAE; any grade 3 or above TESAE; any treatment 
related TEAE; any treatment related TESAE; any TEAE resulting in dose reduced; 
any TEAE resulting in drug withdrawn or stopped; any AE with an outcome of 
death. 
• Summary of TEAEs by SOC and PT and by maximum severity 
• Summary of TEAEs by SOC and PT by maximal Relationship to Treatment 
In summaries by SOC and PT, subjects are counted only once in each SOC category, and 
only once in each preferred term category.   
In addition, characteristics of all TEAEs and TESAEs for all subjects will be presented in 
detail across multiple subject-level data listings. All AEs will be listed, regardless of 
whether they were treatment emergent. Listings for deaths, serious adverse events, adverse 
events leading to treatment withdrawal.  
8.3.1 Protocol Defined Adverse Events of Special interest 
The following adverse events are defined as of special interest. 
• 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 
• Neuropsychiatric AEs 
Adverse events of interest will be summarized using counts and percentages and a Listing 
will be provided. 


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 Clinical Laboratory Tests 
Laboratory assessments, providing indication of safety, include serum chemistry (Glucose, 
Blood Urea Nitrogen, Sodium, Chloride, Creatinine, Potassium, Calcium, Uric Acid, Total 
Protein, Albumin, Total Bilirubin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Bicarbonate) and and hematology (Red blood cell count, 
Hemoglobin, Hematocrit, Platelets, White blood cell count, Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils) will be collected. Scheduled visits for serum 
chemistry parameters were screening and then once weekly (at Day 7 and at Day 14), and 
from version 3 of the protocol were changed to every 3 days. Hematology parameters 
scheduled visits are: Screening visit and then every 3 days. Urinalysis is scheduled to be 
collected only in Screening visit.  
Laboratory results will be assessed versus normal ranges (provided locally for each site) 
and abnormal results will be further classified as clinically significant (Yes/No). In 
addition, results will be graded using the NCI CTCAE v5.0 criteria. 
Hematology and chemistry laboratory tests will be presented at baseline, and every 3 days 
up to Day 14.  Laboratory tests results and changes from baseline to each visit including 
Last available value up to and including day 14 (LAVD14) will be summarized using 
descriptive statistics for continuous variables.  
The incidence of abnormal results and of clinically significant abnormal results will be 
summarized for laboratory data using frequencies and percentages, per analyte, time-point, 
including LAVD14 and ‘any time post-baseline’ time point. 
Shifts (below, within, and above the normal range) from baseline to each visit, LAVD14 - 
and ‘any time post-baseline’ will be summarized using patient counts. Similarly, shifts in 
interpreted result (normal, abnormal high clinically significant result, and abnormal low 
clinically significant) will be provided. In shift analysis to any time during study, the worst 
outcome in both directions (Low, High) will be considered (A subject may be counted both 
as a shift to High and as a shift to Low, if experienced both events during the study). 
In addition, laboratory tests will be summarized by maximal toxicity grade.   
 
Denominators for percentages will equal the number of subjects in the safety population 
providing data for specific time point.  
Listings for clinically significant abnormal laboratory data will be presented. 
 Vital Signs 
Vital signs (temperature, blood pressure, pulse rate, respiratory rate, oxygen saturation, 
FiO2) will be collected during screening visit, at Day 1, and daily whilst the subject is 
hospitalized, at End of treatment visit and at Safety follow-up visit. 
Summary statistics for vital signs values and changes from baseline will be presented at 
baseline (Day 1), and at each scheduled visits (Day 2-13, LAVD14, end of treatment, safety 
follow up).  The incidence of clinically significant abnormal values will be summarized for 
selected vital signs using descriptive statistics.   
A listing for clinically significant abnormal vital signs will be presented. 


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 Supplemental oxygen requirement 
Supplemental oxygen requirement  will be collected during screening visit, at Day 1, and 
on daily basis. For subjects discharged from the hospital prior to Day 14, this assessment 
will be performed on a daily basis after discharge, via phone until Day 14. It is expected 
though, based on a previously completed study, that towards end of treatment period, 
available data will be predominantly from the more severe patients, still hospitalized. 
Therefore we will also be evaluating outcomes at the last available observation (LAVD14, 
up to and including day 14) time point. Lastly, data will be collected as well at the 
scheduled EOS visit. Descriptive statistics of required supplemental oxygen, type, type of 
positive ventilation, flow rate and percent oxygen in the gas mixture by scheduled visit per 
above including change from baseline for oxygen flow rate will be provided.  The number 
and percentage of subjects with no requirement will be provided for each visit as well. 
Listings of all supplemental oxygen requirement evaluation will also be provided.. 
 Electrocardiography  
12-lead electrocardiogram will be performed for all subjects during screening visit, day 1  
and at Day 14 visit. For patients on concomitant chloroquine /hydroxychloroquine 
/mefloquine (for subjects enrolled before protocol amendment #5 and for all patients 
following this amendment, the 12-lead ECG will be repeated after 3 hours (±30mins) of 
initial dose, on Day 2 and Day 4).  
Incidence of abnormal result and of abnormal clinically significant results any time during 
the study will be summarized using appropriate descriptive statistics. Summaries may be 
provided 
separately 
for 
the 
subjects 
on 
concomitant 
chloroquine/hydroxychloroquine/mefloquine/ azithromycin. 
A listing for clinically significant abnormal results will be presented. 
 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 will be recorded on the appropriate eCRF page. In the case of partial or missing dates 
such that it is not possible to determine if medication is concomitant, it will be regarded as 
such. 
All concomitant medications will be coded using the WHO Drug.  The number and 
percentage of subjects with at least one medication term will be summarized by ATC Level 
4 category and by PT within an ATC Level 4 for each treatment group.  Patients are counted 
only once in each ATC Level 4, and only once in each preferred term category. 
The distribution of patient’s baseline SoC regimen for COVID-19 will be summarized 
and presented by group. 


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Distribution of post baseline use of   COVID -19 SoC treatment will be presented by 
each group, providing the  number and percentage of subjects with at least one use by 
SoC group, where patients will be counted only once per SoC category. 
Descriptive statistics of the days from the study first dose date to the initiation of post-
baseline SoC treatment  will be presented for each SoC COVID-19 treatment category, 
were the first SoC medication start time will be used for the analysis.  
Similar analysis including the distribution and the time to initiation will be performed for 
any time use (before or post the study first dose) of SoC COVID-19 treatment (as 
described on 7.2.1.5) . 
 Identification and categorization of SoC for COVID-19 medications will be done by 
blinded review of medications prior to data base lock. 
   
 


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9 OTHER ANALYSES 
 Viral swab for SARS-CoV-2 PCR test 
Pharyngeal samples for SARS-CoV-2 PCR will be collected up to 7 days prior to screening 
and every 3 days until 2 negatives are obtained otherwise another one on day 14 will be 
done. Efficacy analysis of this outcome is described in Section 3.2.2. Listings of results 
will also be provided. 
 WHO ordinal scale for clinical improvement assessment 
WHO ordinal scale for clinical improvement assessment will be done on Screening visit, 
and on days 1-14 including at Safety follow-up visit. Efficacy analysis of this outcome is 
described in Section 3.2.2. Descriptive statistics of the continuous values including change 
from baseline and distribution of the categorical values will be presented by treatment day 
(including the Last Available Observation before day 14). Listing of the questionnaire will 
be provided.   
10 Change from last SAP version and from protocol  
The list below describes the known changes in this SAP relative to the statistical methods 
provisioned in the protocol: 
Endpoints hierarchy:  
The protocol specified an hierarchical approach for the control of type I error will due to 
the secondary endpoints, who were to be tested in an hierarchal manner  according to 
their protocol defined order, following success in the primary endpoint. The SAP defines 
that no type 1 error control will be applied for the secondary endpoints, and their 
numbering has been changed (see section 5.3). 
Approach to addressing early termination of study in derivation of secondary 
endpoints:  
In the protocol,  it has been read as a different approach will be used for the secondary 
endpoints versus the primary endpoint, where Failure imputation (worst-case) will be 
applied for the primary endpoint and censoring at time of study termination along with 
application of time to event methodology for estimating cumulative incidence was to 
applied fo the various secondary endpoints. In the SAP, a unified conservative approach 
was applied, where for the clinical secondary endpoints, early termination would now be 
imputed as Failure (worst-case) as well. The analytical methods has been updated 
accordingly in the SAP.   
Analysis of endpoint percent of patients requiring intubation and mechanical 
ventilation by day 42: 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 40 - CONFIDENTIAL: PROPRIETARY INFORMATION 
In the protocol, death was to be handled as censoring event for the primary analysis of 
this endpoint and as competing risk event for the sensitivity analysis. In the SAP, death 
was incorporated as a Failure event, leading to the composite endpoint of intubation and 
ventilation/death (refer to section 3.2.3 for more details). 
Populations:   
The mITT population now includes the broader population of all subjects who were 
randomized and treated with at least one study dose , whereas the population 
definition included the additional requirement of meeting study entry criteria #3 and 
exclusion of patients who require mechanical ventilation or no longer require 
supplemental oxygen prior to receiving the first dose of study drug 
The BLHF treated population has been added. 
Primary endpoint sensitivity analysis:  
The following sensitivity analyses were cancelled: 
• Negation of achieved Day 14 success by a post-day 14 failure event. 
• Negation of achieved Day 14 success by any post-success failure 
• Missing data due to early discontinuation of follow-up before achieving success 
(prior to day 14). 
• 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 treating missing data due to early study termination using an ‘while 
on study’ approach has been added, consistent across  all endpoints, as defined in the 
SAP. 
The above list of changes from protocol also applies to the Changes from previous SAP 
version, and in addition, the updated SAP has been re-structured to enhance consistency 
in approaches across endpoints derivation and analysis. 
In addition, the term treatment day versus study day has been clarified and it has been 
established that all efficacy endpoints will be defined in terms of Treatment day (please 
refer to section 5.5). 
A derived additional timepoint has been defined for by-visit descriptive summaries and 
for biomarker analyses, the Last Available Value by day 14.  
 
 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 41 - CONFIDENTIAL: PROPRIETARY INFORMATION 
11 STATISTICAL SOFTWARE 
All summary tables, figures, listings and statistical analyses will be generated using 
SAS® software, version 9.3 or later. 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 42 - CONFIDENTIAL: PROPRIETARY INFORMATION 
12 LIST OF SUMMARIES AND LISTINGS 
The list of summary tables, figures and listings, along with further details will be 
provided in a separate document. 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
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13 APPENDECIES 
  APPENDIX 1: WHO ORDINAL SCALE FOR CLINICAL 
IMPROVEMENT 
 
 
Note: While there is a designated  form to collect  the WHO score per the Scheduled 
activities table (Table 1),  the  link between  the patient’s clinical status  and scores 
definition allows inferring patient’s score at a certain day  even when score is not 
provided explicitly. These include:    


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 44 - CONFIDENTIAL: PROPRIETARY INFORMATION 
• From the day after the subject is discharged alive from hospital, unless  there is 
adverse event indicating otherwise, the patient is regarded ambulatory , and thus 
scored <=2. 
• Any  report on requirement of supplemental oxygen while patient is still 
hospitalized indicate that patient’s status is  score 4 or more, depending on 
procedure used  low or high flow oxygenation, etc). 
• As long as the patient is hospitalized, and as  a conservative measure also at day 
of discharge, the patient can be regarded as  having score of 3 or more, depending 
on oxygenation used on that specific date. 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 45 - CONFIDENTIAL: PROPRIETARY INFORMATION 
 APPENDIX 2: SAS CODES 
 
• 
The following is a generic SAS syntax for binary endpoint analysis. It performs the 
stratified  CMH test and provides the associated adjusted risk difference. 
 
 
ods output CMH =cmh(where=(Statistic=2))  
CommonPdiff =COMMONRISKDIFF(where=(Method='Mantel-Haenszel')); 
proc freq data=data ; 
   tables strata1*strata2*group10*outcome01 /nopct nocol cmh  
COMMONRISKDIFF(col=2)  ; 
run; 
** COMMONRISKDIFF requests the common (stratified) risk difference,  
where the risk difference is the difference between  
the row 1 proportion and the row 2 proportion in a  table.  
 
• The following is a generic SAS syntax for estimating and comparing the cumulative 
incidence of event at a certain time-point based on Kaplan-Meier method (applicable 
for the sensitivity analysis of endpoint #5 and endpoint #6): 
 
(a) Estimate per group, with confidence interval 
 
ods output ProductLimitEstimates   = ProductLimitEstimates; 
Proc lifetest data=data timelist=14 28 42 reduceout outsurv=outsurv ; 
 time TIME*CNSR(1); 
 strata  trt01p; 
quit; 
 
data outsurv; 
set outsurv; 
CI=1-survival; 
CI_low=1-sdf_ucl; 
CI_high=1-sdf_lcl; 
run; 
 
(b) Estimate difference between groups, with confidence interval (testing no difference). 
 
data ProductLimitEstimates; 
set ProductLimitEstimates; 
VAR=(STDERR*STDERR); 
run; 
proc transpose data=ProductLimitEstimates out=tFAILURE prefix=FAIL; 
var Failure  ; 
id trt01; 
by timelist; 
run; 
 
data tFAILURE; 
set tFAILURE; 
FAILDif=FailTRT-FailPBO; 
label FAILDif="Difference in FAILURE rate"; 
run; 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 2.0, Date: 1 September 2021 
Study ABC-201 
Page 46 - CONFIDENTIAL: PROPRIETARY INFORMATION 
proc transpose data=ProductLimitEstimates out=tVAR prefix=VAR; 
var  VAR ; 
id trt01; 
by timelist; 
run; 
 
data SEdiff; 
set tVAR; 
VarDiff=VARTRT+VARPBO; 
SEDiff=sqrt(VarDiff); 
label SEDiff="SE of Difference in FAILURE rate"; 
run; 
 
data diffs; 
merge tFAILURE SEdiff; 
by timelist; 
za=probit(0.975); 
D=SEDiff*za; 
Diff_Low=FAILDif-D; 
Diff_Upper=FAILDif+D; 
run;