Clinical trial NCT04414618
Conditions: Coronavirus Infections
Sponsor: RedHill Biopharma Limited
Start date: 2020-07-02; Completion date: 2020-12-23
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This proof of concept study will take place in the US and other countries in approximately 15 clinical sites and will enroll about 40 hospitalized patients diagnosed with COVID-19 infection who have developed pneumonia and require supplemental oxygen. 20 patients will receive opaganib in addition to standard of care twice each day for 14 days. 20 will receive matching placebo in addition to standard of care unless the patient has been discharged from the hospital without requiring supplemental oxygen, in which case study drug will only be administered for 10 days. All participants will be followed up for 4 weeks after their last dose of study drug.

Detailed description:
Opaganib, a sphingosine kinase-2 (SphK2) inhibitor, has been broadly tested in Phase I/II studies. Extensive nonclinical data indicates both anti-viral and anti-inflammatory activity via selective SphK2 inhibition which may prove beneficial for treating COVID-19 infection and resulting pneumonia. This proof of concept study will take place in the US and other countries and will enroll about 40 hospitalized patients diagnosed with COVID-19 infection who have developed pneumonia and require supplemental oxygen. Half of the patients, i.e. 20 patients, will receive opaganib in addition to standard of care for 14 days. The other 20 will receive matching placebo (capsules that do not contain the medication) in addition to standard of care. Study drug will be administered every day for 14 days, twice each day, unless the patient has been discharged from the hospital without requiring supplemental oxygen, in which case study drug will only be administered for 10 days. All participants will be followed up for 4 weeks after their last dose of study drug.

Arms: arm 1: Study participants will receive opaganib 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours arm 2: Study participants will receive placebo 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours
Interventions: intervention 1: Opaganib intervention 2: Placebo
Intervention descriptions: intervention 1: Study participants received opaganib 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive). intervention 2: Study participants received placebo 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive).

Protocol documents:
Prot_000.pdf: 
Confidentiality Statement 
The information contained herein is confidential and/or proprietary property of 
 
RedHill Biopharma Ltd. and may not be used, disclosed, copied, 
published or transferred to any third party without the prior written authorization 
of 
 
RedHill Biopharma Ltd.  
COVER PAGE for ABC-110 STUDY PROTOCOL 
 
The following document is the study protocol of: 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, 
Placebo-Controlled Phase 2a Study in Adult Subjects Hospitalized with SARS-CoV-2 Positive Pneumonia 
Dated 30 Aug 2020 
NCT04414618 


RedHill Biopharma Ltd 
Protocol ABC-110  Version 1.2 30 August 2020 
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CONFIDENTIAL: PROPRIETARY INFORMATION 
 
CLINICAL STUDY PROTOCOL: ABC-110 
Title: 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 
Pneumonia: a Randomized, Double-blind, Placebo-Controlled 
Phase 2a Study, in Adult Subjects Hospitalized with SARS-CoV-
2 Positive Pneumonia 
Name of Investigational 
Product: 
Opaganib (ABC294640) 
Phase of Development: 
Phase 2a/Proof of Concept 
IND number: 
148560 
Protocol Identification: 
ABC-110 
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. 
Date of Protocol 
Amendment: 
Version 1.2, 30 August 2020 
Version 1.1, 6 May 2020 
Version 1.0, 16 April 2020 
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-110 .............................................................................1 
1 
Table of Contents ...........................................................................................................2 
APPROVALS .................................................................................................................................4 
2 
PROTOCOL SYNOPSIS...............................................................................................5 
3 
STUDY SCHEMATIC ................................................................................................13 
4 
SCHEDULE OF assessments ......................................................................................14 
5 
List of Abbreviations ...................................................................................................15 
ALANINE AMINOTRANSFERASE (SERUM GLUTAMIC PYRUVATE 
TRANSAMINASE) ..............................................................................................................15 
ADULT RESPIRATORY DISTRESS SYNDROME ...............................................................15 
ASPARTATE AMINOTRANSFERASE (SERUM GLUTAMIC OXALOACETIC 
TRANSAMINASE) ..............................................................................................................15 
CORONAVIRUS DISEASE OF 2019 ........................................................................................15 
6 
BACKGROUND INFORMATION ............................................................................17 
6.1 
COVID-19 Disease .........................................................................................17 
6.2 
Investigational Product ...................................................................................17 
6.3 
Rationale .........................................................................................................17 
6.4 
Prior Clinical Experience ...............................................................................18 
7 
STUDY OBJECTIVES ................................................................................................21 
7.1 
Primary ...........................................................................................................21 
7.2 
Secondary .......................................................................................................21 
7.3 
Exploratory .....................................................................................................21 
7.4 
Safety ..............................................................................................................21 
8 
study population ...........................................................................................................22 
9 
ELIGIBILITY CRITERIA ...........................................................................................23 
9.1 
Inclusion Criteria ............................................................................................23 
9.2 
Exclusion Criteria ...........................................................................................23 
9.3 
Women of Childbearing Potential Definition .................................................24 
10 
STUDY DESIGN.........................................................................................................26 
10.1 
Overall Investigation Plan ..............................................................................26 
10.2 
Study Assessments .........................................................................................26 
10.3 
Patient Discontinuation Criteria .....................................................................26 
10.4 
Study Drug Information and Dosage ..............................................................27 


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10.5 
Study Drug Administration ............................................................................28 
11 
Prior and Concomitant Medications ............................................................................30 
12 
Schedule of Events .......................................................................................................31 
13 
STUDY ENDPOINTS .................................................................................................33 
13.1 
Primary ...........................................................................................................33 
13.2 
Secondary .......................................................................................................33 
13.3 
Exploratory .....................................................................................................33 
13.4 
Safety ..............................................................................................................33 
14 
safety reporting ............................................................................................................34 
15 
Adverse Events Definitions .........................................................................................35 
15.1 
Assessment of Casual Relationship ................................................................36 
15.2 
Adverse Event Grading ..................................................................................37 
15.3 
Handling of Serious Adverse Events ..............................................................37 
15.4 
Laboratory Abnormalities ..............................................................................38 
15.5 
Other Safety Considerations ...........................................................................39 
16 
ethics ............................................................................................................................41 
16.1 
Investigator Responsibilities ..........................................................................41 
16.2 
Sponsor Responsibilities ................................................................................43 
17 
Statistical Methods .......................................................................................................45 
17.1 
Sample Size Considerations ...........................................................................45 
17.2 
Stratification ...................................................................................................45 
17.3 
Analysis of the primary efficacy endpoint .....................................................45 
17.4 
Safety Analyses ..............................................................................................46 
18 
INVESTIGATOR’S STATEMENT ............................................................................47 
19 
REFERENCES ............................................................................................................48 
 
 
 
 
 
 


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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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2 
PROTOCOL SYNOPSIS 
Study Title 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a 
Randomized, Double-blind, Placebo-Controlled Phase 2a Study, in Adult 
Subjects Hospitalized with SARS-CoV-2 Positive Pneumonia 
Protocol 
Number 
ABC-110 
Sponsor 
RedHill Biopharma Ltd. 
Investigational 
Product 
Opaganib (ABC294640) 
Primary 
Objective 
To evaluate the total oxygen requirement (area under the curve) using daily  
supplemental oxygen flow (L/min) over 14 days (Day 1 to Day 14)  
Secondary 
Objectives 
1) To evaluate the time to 50% reduction from baseline in supplemental oxygen 
based on oxygen flow in L/min 
2) To evaluate the proportion of patients no longer requiring supplemental 
oxygen for at least 24 hours by Day 14 
3) To evaluate the proportion of afebrile patients at Day 14  
4) To evaluate the time to negative swabs for SARS-CoV-2 by PCR  
5) To evaluate the proportion of patients with negative swabs for SARS-CoV-2 
by PCR at Day 14 
6) To evaluate the need for intubation and mechanical ventilation by Day 14 
7) To evaluate the time to mechanical ventilation 
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 30 days post-baseline 
Exploratory 
Objectives 
To assess the change in systemic markers of inflammation (D-dimer, cardiac 
troponin, C-reactive protein [CRP], lactate dehydrogenase [LDH] and ferritin) 


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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 COVID-19 pneumonia 
Study 
Population 
The study population will consist of patients diagnosed with COVID-19 infection 
who have developed pneumonia defined as radiographic opacities on chest X-ray 
and require supplemental oxygen. The patients must be hospitalized at least 
during screening and at baseline (Day 1).  
Study Design 
and Description 
This is a phase 2a, proof of concept, multi-center randomized double-blind, 
parallel arm, placebo-controlled study. The study is planned be performed in US 
and in other countries, in approximately 15 clinical sites. 
After informed consent is obtained, patients will enter a screening phase for no 
more than 3 days, to determine eligibility. Approximately 40 eligible patients 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.  Treatment 
assignments will remain blinded to the patient, investigator and hospital staff, as 
well as  the sponsor. As there is currently no consensus for a definitive treatment 
specifically targeting the SARS-CoV-2 virus causing COVID-19 (Wilson, 2020), 
standard of care will refer to regional, institutional or physician directed therapies, 
that may be implemented during the COVID-19 pandemic.   
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 and/or supportive). Study drug will be administered every day 
for 14 days (Day 1 to Day 14), unless the patient has been discharged from the 
hospital without requiring supplemental oxygen, in which case study drug will 
only be administered to Day 10. 
All participants will be followed up for 4 weeks after their last dose of study drug, 
which may occur at the end of the 2-week double-blind treatment phase or after 
premature study drug discontinuation, based upon patient or physician 
determination.  
Stratification 
Patients will be stratified based on a minimization algorithm taking the following 
three parameters into account: age at screening, ≥70 years of age, (yes or no); 
HbA1c at screening,  ≥6.5, (yes or no); oxygen requirement at baseline, requiring 
non-invasive positive pressure ventilation (e.g. via BIPAP, CPAP), (yes or no) 
Treatment 
Opaganib 500 mg Q12 hour or matching placebo 


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Study Duration Recruitment period is estimated at 3 months  
The maximum duration of study participation will be up to 45 days (including up 
to 3 days screening; 2 weeks double-blind (DB) treatment phase and 4-weeks off-
study drug follow-up) 
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  
3) The patient requires supplemental oxygen at baseline  
4) The patient, guardian or legal representative has signed a written IRB-
approved informed consent 
5) 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 
please see section 9.3.)  
 
In addition, male participants must refrain from donating sperm for the duration of 
the study and for 1 months 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 months 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 
9.3)  
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 
months after the last dose of study drug (please see further details on Section 
9.3). 
Exclusion: 


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1. Any co-morbidity that may add risk to the treatment in the judgement of the 
investigator.  
2. Requiring intubation and mechanical ventilation 
3. Patient having a do not intubate or do not resuscitate order 
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 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)  > 5.0 x upper limit of normal (ULN) 
11. Bilirubin >2.0 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. Currently taking medications that are sensitive CYP3A4, CYP1A2, CYP2C9,  
CYP2C19 or CYP2D6 substrates and have a narrow therapeutic index. These 
should be decided in discussion with the Medical Monitor on a case-by-case 
basis. 
17. Currently taking medications that are strong inducers or inhibitors of CYP2D6 
and CYP3A4. These should be decided in discussion with the Medical 
Monitor on a case-by-case basis. 
18. Currently taking warfarin, apixaban, argatroban or rivaroxaban.  
19. Current  drug or  alcohol abuse 


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20. Currently participating in a clinical study assessing pharmacological treatments, 
including anti-viral studies  
Number of 
Subjects 
Up to approximately 40 subjects will be randomized 
Number of 
Investigator 
Sites 
Approximately 15 participating hospital centers 
Screening/Basel
ine Assessments 
• Signed informed consent 
• Eligibility determination 
• Complete medical history (including onset of COVID-19 symptoms) 
• Concomitant medication assessment 
• Baseline review of systems 
• Physical examination 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and 
oxygen saturation by pulse oximeter)  
• Weight if the patient is ambulatory 
• Oxygen requirement (L/min) 
• 12-lead electrocardiogram   
• Chest Xray  
• Nasopharyngeal or oropharyngeal swab for SARS-CoV-2 PCR test 
• Serum chemistry 
• CRP, D-Dimer, LDH, ferritin, cardiac troponin  
• HbA1c 
• CBC with differential  
• Urinalysis  


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• Serum pregnancy test (for women of childbearing potential) within 3 days 
prior to treatment 
Study 
Assessments 
The following will be monitored and documented daily as part of the standard of 
care:  
• Concomitant medications 
• Adverse Events 
• Interim Physical exam  
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and 
oxygen saturation by pulse oximeter)  
• Oxygen requirement (L/min) 
The following will be monitored less frequently as part of standard of care and 
wherever possible: 
• For patients on concomitant hydroxychloroquine, a 12-lead electrocardiogram 
(if allowed by hospital treatment guidelines under COVID-19) approximately 
3 hours after the first study drug administration on Day 1, anytime on Days 2 
and 4, and again at end-of-treatment (either Day 10, 14 or at premature study 
drug discontinuation).  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 1-3 days 
• Serum chemistry once weekly   
• Serum CRP, D-Dimer, LDH, ferritin, cardiac troponin once weekly  
• CBC with differential once weekly   
• Chest X-ray as per physician decision 
Study 
Endpoints 
Primary  
The total oxygen requirement (area under the curve) using the daily supplemental 
oxygen flow (L/min) over 14 days (Day 1 to Day 14) 
Secondary 
1) Time to 50% reduction from baseline in supplemental oxygen based on 
oxygen flow in L/min 


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2) The percentage of patients no longer receiving supplemental oxygen for at 
least 24 hours by Day 14 
3) The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at 
least 24 hours apart 
4) The percentage of patients with at least two consecutive negative swabs, 
followed by continued negative swabs, for SARS-CoV-2 by PCR at Day 14 
5) The percentage of patients requiring intubation and mechanical ventilation by 
the end of the 2-week off-study-drug follow-up 
6) The time to intubation and mechanical ventilation  
7) 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  
8) Mortality due to any cause at Day 30  
Exploratory 
1) The mean change in systemic markers of inflammation (D-dimer, cardiac 
troponin, C-reactive protein [CRP], procalcitonin [PCT], lactate 
dehydrogenase [LDH] and ferritin) from baseline at Day 14 
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)  
Sample Size 
Estimation 
The sample size for this Proof of Concept study was not chosen for statistical 
consideration, as there are no formal statistical inferences planned. The size of the 
study is judged adequate for the preliminary evaluation objectives.  
Statistical 
Methods 
The primary efficacy objective of the study is to evaluate the effect of Opaganib 
on total supplemental oxygen requirement (area under the curve) using daily 
oxygen flow (L/min) measurements for 14 days (Day 1 to Day 14). The primary 
efficacy endpoint will calculate for each patient the area under the curve of the 
supplemental oxygen requirement through day 14, using the trapezoidal rule after 
subtracting the baseline oxygen requirement at each day. Days where no 
supplementary oxygen was needed, will be recorded as 0. If several values of 


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oxygen requirement (L/min) are recorded in a certain day, for the primary 
analysis the highest of these values will be taken. In the primary analysis, for 
patients who die before Day 14, or require intubation and mechanical ventilation, 
missing daily values will be assigned the maximal supplemental oxygen flow 
requirement of 8L/min. For patients discharged from hospital on supplemental 
oxygen prior to Day 14, if no values are collected by the site after discharge, the 
oxygen requirement (L/min) on the day of discharge will be assigned thereafter 
for each day to Day 14.  The primary analysis will be based on the modified 
Intent to treat population (mITT), which consist of all patients that were 
randomized and treated with at least one dose of study drug, Descriptive statistics 
of the baseline-adjusted AUC will be presented by group along with 95% 
confidence interval for each group and for the difference in means between the 
groups. It is planned to collect supplemental oxygen requirement up to Day 14 
even if a patient discontinues treatment prior to Day 14 but continues in the study 
to  Day 14. Further, it is assumed that loss to follow up such that vital status up to 
Day 14 will be missing is unlikely. Therefore, the primary analysis will assume 
that in case that all supplemental oxygen values are missing after treatment 
discontinuation, the last value is carried forward - until Day 14, or death, if 
occurred before. A sensitivity analysis to the above missing data handling 
approach will be performed using an AUC summary statistics approach, in which 
groups AUC is calculated from the estimated parameters of a Repeated-Measures 
model. 
 


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3 
STUDY SCHEMATIC 
 
 


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4 
SCHEDULE OF ASSESSMENTS 
Table 1 Schedule of Assessments for the Study 
Assessments 
Screening 
Randomization 
DB Phase 
Early 
termination 
Safety follow-
up 
Days -3 - 1 
Day 1 
Day 7 
Day 14 
ICF signed 
X 
 
 
 
 
 
Inclusion/exclusio
n criteria  
X 
 
 
 
 
 
Demographics; 
medical and 
surgical history 
X 
 
 
 
 
 
Review 
concomitant 
medication(s)1 
X 
X 
X 
X 
X 
X 
Review of adverse 
events1 
 
X 
X 
X 
X 
X 
Physical 
examination1  
X 
 
X 
X 
X 
X 
Vital signs1  
X 
X 
X 
X 
X 
X 
Oxygen flow 
(L/min)1 
X 
X 
X 
X 
X 
X 
Weight2 
X 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
Pharyngeal viral 
sample3 
X 
X 
X 
X 
X 
X 
12-lead ECG4 
X 
 
 
X 
 
 
Chest X-ray5 
X 
 
 
 
 
 
Serum chemistry 
X 
 
X 
X 
 
 
Hematology (CBC 
with differential) 
X 
 
X 
X 
 
 
D-dimer, cardiac 
troponin, CRP, 
LDH, ferritin6 
X 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
Serum pregnancy 
test7 
X 
 
 
 
 
 
1 daily 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) 
2 record weight if patient is ambulatory 
3 pharyngeal samples for SARS-CoV-2 PCR are collected daily, per standard of care.  For patients having nasopharyngeal swabs, the 
same nostril must be used during the study  
4 for patients on concomitant hydroxychloroquine, the 12-lead ECG will be repeated after 3 hours (±30mins) of initial dose, on Day 2 
and Day 4 
5 Chest X-ray, lab draws will be at the discretion of the Investigator depending on patient clinical condition 
6  CRP=C-reactive protein, LDH=lactate dehydrogenase 
7 women of childbearing potential; serum pregnancy test must be negative within 3 days prior to randomization 


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5 
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) 
COVID-19 
Coronavirus Disease of 2019 
CFR 
Code of Federal Regulations 
CHKV 
Chikungunya virus 
CRO 
Clinical Research Organization 
CYP 
Cytochrome P450 
DB 
Double-blind 
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 
GCP 
Good Clinical Practice 
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 
SAP 
Statistical Analysis Plan 
SAE 
Serious adverse event 
SK2 
Sphingosine kinase 2 


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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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6 
BACKGROUND INFORMATION 
6.1 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. 
6.2 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).  
6.3 Rationale 
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-


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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 
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 remarkable 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. 
6.4 Prior Clinical Experience 
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.  
6.4.1 Completed Studies 
6.4.1.1 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 


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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.    
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. 
6.4.1.2 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. 
 
 
 


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6.4.1.3 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 
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. 


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7 
STUDY OBJECTIVES 
7.1 Primary 
 To evaluate the total oxygen requirement (area under the curve) using daily  supplemental oxygen 
flow (L/min) over 14 days (Day 1 to Day 14) 
7.2 Secondary 
1) To evaluate the time to 50% reduction from baseline in supplemental oxygen based on oxygen flow in 
L/min 
2) To evaluate the proportion of patients no longer requiring supplemental oxygen for at least 24 hours by Day 
14 
3) To evaluate the proportion of afebrile patients at Day 14  
4) To evaluate the time to negative swabs for SARS-CoV-2 by PCR  
5) To evaluate the proportion of patients with negative swabs for SARS-CoV-2 by PCR at Day 14 
6) To evaluate the need for intubation and mechanical ventilation by Day 14 
7) To evaluate the time to mechanical ventilation 
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 30 days post-baseline 
7.3 Exploratory 
To assess the change in systemic markers of inflammation (D-dimer, cardiac troponin, C-reactive 
protein [CRP], lactate dehydrogenase [LDH] and ferritin) 
7.4 Safety 
To assess the safety and tolerability of opaganib administered orally at 500 mg Q 12 hours, for up to 4 
weeks, in patients with COVID-19 pneumonia. 


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8 
STUDY POPULATION 
The study population will consist of patients diagnosed with COVID-19 infection who have developed 
pneumonia defined as radiographic opacities on chest X-ray, and require supplemental oxygen. The 
patients must be hospitalized at least during screening and at baseline (Day 1).  


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9 
ELIGIBILITY CRITERIA 
9.1 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  
3) The patient requires supplemental oxygen at baseline  
4) The patient, guardian or legal representative has signed a written IRB-approved informed consent 
5) 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 please see section 9.3.)  
 
In addition male participants must refrain from donating sperm for the duration of the study and for 1 
months 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 
months after the last dose of study drug  
Female participants:  
A female participant is eligible to participate if she is:  
d) not pregnant 
e) not breastfeeding 
f) not a woman of child-bearing potential (as defined in Section 9.3)  
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 months after the last dose of study drug 
(please see further details on Section 9.3). 
9.2 Exclusion Criteria 
1) Any co-morbidity that may add risk to the treatment in the judgement of the investigator.  
 
2) Requiring intubation and mechanical ventilation 
3) Patient having a do not intubate or do not resuscitate order 
 
4) Oxygen saturation >95% on room air 


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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 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)  > 5 x upper limit of normal (ULN) 
11) Bilirubin >2x 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) Currently taking medications that are sensitive CYP3A4, CYP1A2, CYP2C9, CYP2C19 or 
CYP2D6 substrates and have a narrow therapeutic index. These should be decided in discussion 
with the Medical Monitor on a case-by-case basis. 
17) Currently taking medications that are strong inducers or inhibitors of CYP2D6 and CYP3A4. 
These should be decided in discussion with the Medical Monitor on a case-by-case basis. 
18) Currently taking warfarin, apixaban, argatroban or rivaroxaban  
19) Current  drug or  alcohol abuse 
20) Currently participating in a clinical study assessing pharmacological treatments, including anti-
viral studies  
9.3 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, tubal ligation 
and bilateral oophorectomy. 


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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 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, multiple FSH 
measurement are required to confirm postmenopausal state. 
Highly effective contraceptive measures, with a failure rate of less than 1% per year, 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 secondary method 
of highly effective birth control is required, for example condom plus spermicide, or 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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10 STUDY DESIGN 
10.1 Overall Investigation Plan 
This is a phase 2a, proof of concept, multi-center randomized double-blind, parallel arm, placebo 
controlled study. The study is planned be performed in the US and in other countries, in approximately 
15 clinical sites. 
After informed consent is obtained, patients will enter a screening phase for no more than 3 days, to 
determine eligibility. Approximately 40 eligible patients 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.  Treatment assignments will remain blinded to the patient, investigator and hospital staff, as well 
as  the sponsor. As there is currently no consensus for a definitive treatment specifically targeting the 
SARS-CoV-2 virus causing COVID-19 (K. Wilson, 2020), standard of care will refer to regional, 
institutional or physician directed therapies, that may be implemented during the COVID-19 
pandemic.   
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 and/or supportive). Study drug will 
be administered every day for 14 days (Day 1 to Day 14), unless the patient has been discharged from 
the hospital without requiring supplemental oxygen, in which case study drug will only be 
administered to Day 10.  
All participants will be followed up for 4 weeks after their last dose of study drug, which may occur at 
the end of the 2-week double-blind treatment phase or after premature study drug discontinuation, 
based upon patient or physician determination.  
The maximum duration of study participation will be 45 days (including up to 3 days screening; 2 weeks 
double-blind (DB) phase and 4-weeks off-study drug follow-up).  
10.2 Study Assessments  
The assessments for this study are listed in Section 12.0 
10.3 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 
• The patient has experienced an AE that meets protocol defined stopping criteria (refer to 
Section 10.5.2) 
• AEs or adverse device effects (ADEs) based on the judgment of the InvestigatorThe 
Investigator decides that it is in the patient’s best interest 
• The patient is noncompliant with the protocol 


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• 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.  
Patients discontinued due to AEs or ADEs will be monitored until resolution or stability of the event 
based on the judgment of the investigator. 
10.4 Study Drug Information and Dosage  
10.4.1 Identification and Description of Investigational Drug 
Opaganib is supplied as Capsules 250 mg, containing 250 mg opaganib along with excipients in white 
opaque hard gelatin capsules.   
Opaganib will be supplied in bottles, each bottle containing 28 capsules 
Placebo will be supplied in bottles, each bottle containing 28 capsules 
For the treatment phase of the study, treatments will be blinded. 
10.4.2 Packaging and Labeling 
The study medication will be packaged in bottles and labelled by the Sponsor. 
The labels will include:  
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 room temperature 15-30C (59-86F) 
CAUTION: New Drug – Limited by Federal Law To Investigational Use 
Lot number 
Manufacturing date in day/month/year format. 


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10.4.3 Storage and Handling of Investigational Drug 
Study drug should be stored at room temperature 15-30C (59-86F) 
10.5 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 feeding.  
10.5.1 Study Drug Dose Modification Plan for Study Drug Suspected Toxicities 
Patients may undergo step-wise dose reduction to one capsule Q12 hours, as shown below.  Patients 
who develop study drug related toxicity of ≥ Grade 2 at one capsule Q12 hours will not be permitted 
further dose reduction, and treatment will be discontinued.  These patients will then enter a 2-week 
off-study drug safety follow-up period 
 
 
NCI CTC 5.0 Criteria 
Study Drug Modification Instructions 
Any Grade 1 toxicity  
For all Grade 1 toxicities, the Investigator may 
continue with study drug per the Investigator’s 
discretion, without discussion with the sponsor  
Any ≥ Grade 2 toxicity  
The physician should discuss with the sponsor 
opaganib-related Grade 2 or greater toxicities that 
are likely to result in study drug discontinuation.  
A dose reduction may be considered as an 
alternative for continued treatment, after 
consultation with and approval by the sponsor.  
The physician should discuss with the sponsor 
opaganib-related Grade 2 or greater toxicities that 
are likely to result in study drug discontinuation.  
Please see criteria for stopping study drug in 
section 10.5.2). 
Any ≥ Grade 2 toxicity 
(specifically 
neuropsychiatric) 
The physician should discuss with the sponsor 
opaganib-related Grade 2 or greater toxicities that 
are likely to result in study drug discontinuation.  
Please see criteria for stopping study drug in 
section 10.5.2). 


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Dose Level 
Dose (mg AM/PM) 
1 (planned) 
2 capsules/2 capsules 
-1 
1capsule/1 capsules 
10.5.2 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 15.2 Table 3 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 
 


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11 PRIOR AND CONCOMITANT MEDICATIONS 
11.1.1 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.  These should be 
recorded in the eCRF. 
11.1.2 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. 
11.1.3 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. 
11.1.4 Prohibited Medications 
Medications that are sensitive CYP3A4, CYP1A2 CYP2C9, CYP2C19 or CYP2D6 substrates and 
have a narrow therapeutic index are prohibited. These should be decided in discussion with the 
Medical Monitor on a case-by-case basis. 
Strong inducers or inhibitors of CYP2D6 and 3A4 are prohibited. These should be decided in 
discussion with the Medical Monitor on a case-by-case basis. 
Warfarin, apixaban, argatroban and rivaroxaban are prohibited 


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12 SCHEDULE OF EVENTS 
12.1.1 Procedures and Assessments 
Please see “Schedule of Assessments” for a detailed study schedule (Section 4) presented in tabular 
form. 
12.1.2 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 -7 to -1) or on the same day as 
Baseline (Day 1) 
• Signed informed consent 
• Eligibility determination 
• Complete medical history (including onset of COVID-19 symptoms) 
• Concomitant medication assessment 
• Baseline review of systems 
• Physical examination 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and oxygen saturation by 
pulse oximeter)  
• Weight if the patient is ambulatory 
• Oxygen requirement (L/min) 
• 12-lead electrocardiogram   
• Chest Xray  
• Nasopharyngeal or pharyngeal swab for SARS-CoV-2-PRC   
• Serum chemistry  
• CRP, D-Dimer, LDH, ferritin, cardiac troponin 
• CBC with differential  
• Urinalysis  
• Serum pregnancy test (for women of childbearing potential) within 3 days prior to treatment 
12.1.3 The following will be monitored and documented daily as part of the standard of 
care  
• Concomitant medications 
• Adverse Events 
• Interim Physical exam  


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• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and oxygen saturation by 
pulse oximeter)  
• Oxygen requirement (L/min) 
12.1.4 The following will be monitored less frequently as part of standard of care and 
wherever possible 
• For patients on concomitant hydroxychloroquine, a 12-lead electrocardiogram (if allowed by 
hospital treatment guidelines under COVID-19) approximately 3 hours after the first study 
drug administration on Day 1, anytime on Days 2 and 4, and again at end-of-treatment (either 
Day 14, 28 or at premature study drug discontinuation).  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 1-3 days 
• Serum chemistry once weekly   
• Serum CRP, D-Dimer, LDH, ferritin, cardiac troponin once weekly  
• CBC with differential once weekly 
• Chest X-ray as per physician decision 
12.1.5 Safety Follow-up (28 days after last dose of study drug) 
• Concomitant medications 
• Adverse Events 
• Physical exam  
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate and oxygen saturation by 
pulse oximeter)  
• Oxygen requirement (L/min) 
 


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13 STUDY ENDPOINTS 
13.1  Primary  
The total oxygen requirement (area under the curve) using the daily oxygen flow (L/min) over 14 days 
(Day 1 to Day 14) 
13.2 Secondary 
1) Time to 50% reduction from baseline in supplemental oxygen based on oxygen flow in L/min 
2) The percentage of patients no longer receiving supplemental oxygen for at least 24 hours by Day 
14 
3) The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 hours apart 
4) The percentage of patients with at least two consecutive negative swabs, followed by continued 
negative swabs, for SARS-CoV-2 by PCR at Day 14 
5) The percentage of patients requiring intubation and mechanical ventilation by the end of the 2-
week off-study-drug follow-up 
6) The time to intubation and mechanical ventilation  
7) 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  
8) Mortality due to any cause at Day 30  
13.3 Exploratory 
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 
13.4 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)  


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14 SAFETY REPORTING 
All adverse events should be reported from first dose 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 a Serious Adverse Event report form and provide any supporting documentation to 
the Medical Monitor at the Fax number or email provided above. 
To discuss SAE with Medical Monitor, contact him directly by phone at the numbers provided above.   
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 FDA within the safety reporting time regulations. 
The medical monitor will notify all sites of any suspected, unexpected, serious adverse reactions 
(SUSARs). It is each Investigator’s responsibility to forward all SUSAR reports that are provided by 
the sponsor to their local IRB/EC. The sponsor will forward all SUSAR reports to central IRBs.  


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15 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.  
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. 


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15.1 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 
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 2.  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.) 
Unknown 
The data are inadequate to assign any of the above causal relationship categories to the study drug. 
 


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15.2 Adverse Event Grading 
Adverse events will be graded according to the revised NCI Common Terminology Criteria for Adverse Events 
(NCI-CTCAE version 5.0).   
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 3.: 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 
15.3 
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 


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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 15.2, above. 
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: 
CRO Medical Monitor: 
Raphael Ryan Zantua, MD 
Phone: +1 267 645 3494, +1 857 296 2093 
e-mail: RaphaelRyan.Zantua@iconplc.com 
 
Sponsor Medical Monitor:    
 
 
 
Name: Mark L. Levitt, MD PhD 
Phone:  +972-(0)58-760-1010 (Israel), +1-914-294-3988 (US) 
e-mail:  mark@redhillbio.com 
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. 
15.4 
Laboratory Abnormalities 
All new abnormal laboratory findings and those abnormal at baseline which change significantly (i.e., 
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 


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15.5 
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 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. 
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. 
15.5.1 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, 2 weeks 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 FDA. 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. 
15.5.2 Adverse Events of Special Interest 
The following adverse events are of special interest. 
Patients who experience either of the following, at the discretion of the investigator, must be notified 
to the medical monitor immediately, 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  
15.5.3 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. 


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15.5.4 Data Safety Monitoring Board 
A data safety monitoring board (DSMB) will be convened for the safety oversight of the study.  A 
DSMB charter will be provided as a separate document.   
The DSMB meetings to review the safety data, will be planned after 30% and 60%, or when 
approximately 12 or 24 randomized patients, respectively, have reached Day 7, and then 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 15.5.2), 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 will be performed at any DSMB review, as the sample size is not 
sufficient to determine futility conclusions. 


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16 ETHICS 
16.1 Investigator Responsibilities 
16.1.1 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. 
16.1.2 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. 
16.1.3 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. 
16.1.4 Patient Anonymity 
The anonymity of participating patients must be maintained. Patients will be identified by their 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 to allow auditing by the appropriate 
regulatory authority, the study monitor, or sponsor representatives. 


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16.1.5 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. 
16.1.6 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) 
16.1.7 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. 
16.1.8 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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16.1.9 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. 
16.1.10 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. 
16.2 Sponsor Responsibilities 
16.2.1 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. 
16.2.2 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. 
16.2.3 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 


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maintenance of records including drug accountability records, correct administration of study 
medications including storage conditions and accurate reporting of adverse events.   
16.2.4 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. 
16.2.5 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. 
16.2.6 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. 
16.2.7 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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17 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. 
17.1 Sample Size Considerations 
It is planned to enroll approximately 40 eligible patients into the double-blind treatment phase, to 
receive either opaganib added to standard of care (n=20), or matching placebo added to standard of 
care (n=20). The sample size for this Proof of Concept study was not chosen for statistical 
consideration, as there are no formal statistical inferences planned. The size of the study is judged 
adequate for the preliminary evaluation objectives. 
17.2 Stratification 
Patients will be stratified based on a minimization algorithm taking the following three parameters into 
account: age at screening, ≥70 years of age, (yes or no); HbA1c at screening,  ≥6.5, (yes or no); 
oxygen requirement at baseline, requiring non-invasive positive pressure ventilation (e.g. via BIPAP, 
CPAP), (yes or no) 
17.3 Analysis of the primary efficacy endpoint 
The primary efficacy objective of the study is to evaluate the effect of Opaganib on total supplemental 
oxygen requirement (area under the curve) using daily oxygen flow (L/min) measurements for 14 days 
(Day 1 to Day 14). The primary efficacy endpoint will calculate for each patient the area under the 
curve of the supplemental oxygen requirement through day 14, using the trapezoidal rule after 
subtracting the baseline oxygen requirement at each day. Days where no supplementary oxygen was 
needed, will be recorded as 0. If several values of oxygen requirement (L/min) are recorded in a 
certain day, for the primary analysis the highest of these values will be taken. In the primary analysis, 
for patients who die before Day 14, or require intubation and mechanical ventilation, missing values 
will be assigned the maximal supplemental oxygen flow requirement of 8L/min. For patients 
discharged from hospital on supplemental oxygen prior to Day 14, if no values are collected by the site 
after discharge, the oxygen requirement (L/min) on the day of discharge will be assigned thereafter for 
each day to Day 14.  
The primary analysis will be based on the modified Intent to treat population (mITT), which consist of 
all patients that were randomized and treated with at least one dose of study drug,  
Descriptive statistics of the baseline-adjusted AUC will be presented by group along with 95% 
confidence interval for the difference in means between the groups.  
It is planned to collect supplemental oxygen requirement up to Day 14 even if a patient discontinues 
treatment prior to Day 14 but continues in the study to  Day 14. Further, it is assumed that loss to 
follow up such that vital status up to Day 14 will be missing is unlikely. Therefore, the primary 


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analysis will assume that in case that all supplemental oxygen values are missing after treatment 
discontinuation, the individual AUC will be calculated  where the last value is carried forward - until 
Day 14, or death, if occurred before. A sensitivity analysis to the above missing data handling 
approach will be performed using an AUC summary statistics approach, in which groups AUC is 
calculated from the estimated parameters of a Repeated-Measures model. 
17.4 Safety Analyses 
The safety and tolerability of opaganib will be determined by reported AEs, physical examinations, vital 
signs, and laboratory tests. Patients who receive at least one dose of study drug are considered evaluable 
for safety (Safety analysis set). Detailed specification of the safety analyses will be provided in the SAP.  
 


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18 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 2a Study, in Adult Subjects 
Hospitalized with 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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19 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. 
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Suryadevara V, Ha AW, Harijith A, Tuder RM, Natarajan V, Fu P. Pseudomonas aeruginosa 
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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 
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Maines LW, Fitzpatrick LR, French KJ, et al. Suppression of ulcerative colitis in mice by orally-
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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.  
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 
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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-
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Zhou C, Gao C, Xie Y, Xu M. COVID-19 with spontaneous pneumomediastinum. Lancet Infect Dis. 
2020 Mar 9. 
 
 
 

SAP_001.pdf: 
Confidentiality Statement 
The information contained herein is confidential and/or proprietary property of 
 
RedHill Biopharma Ltd. and may not be used, disclosed, copied, 
published or transferred to any third party without the prior written authorization 
of 
 
RedHill Biopharma Ltd.  
COVER PAGE for ABC-110 STATISTICAL ANALYSIS PLAN (SAP) 
 
The following document is the SAP of study ABC-110: 
Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, 
Placebo-Controlled Phase 2a Study in Adult Subjects Hospitalized with SARS-CoV-2 Positive Pneumonia 
Dated 13 Dec 2020 
NCT04414618 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
 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 2a Study, in Adult 
Subjects Hospitalized with SARS-CoV-2 Positive Pneumonia 
 
 
 
Study: ABC-110 
Phase: Phase 2a/Proof of Concept 
 
Date: 13-December-2020 
Version: 3 
 
 
 
Prepared by: Ofra Barnett-Griness, Ph.D 
   
 
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: 3, Date: 13-DEC-2020  
Study ABC-110 
 CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
Version Control Page 
 
Version: 
Version Date: 
Comments 
1 
12-MAY-2020 
Initial version 
2 
16-JULY-2020 
Amendment following FDA recommendations 
3 
25-Oct-2020 
Amendment following sponsor request for subgroup 
additions 
4
13-DEC-2020
Final clarification prior to unblinding for primary 
outcomes results (early unblinding) 
 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
 CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL FORM 
 
Study: ABC-110 
SAP Date: 13-December-2020 
SAP Version:  
 
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: 
 
 
Nissim Sasson 
VP, Biostatistics, Bioforum   
Bioforum, 3 Golda Meir St., 
Weizmann Science Park, 
Ness Ziona 7414001  Israel 
 
Date (dd-Mmm-yyyy) 
  
 
 
 
 
13/DEC/2020
13/DEC/2020
SIGN


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
TABLE OF CONTENTS 
1 
PREFACE .........................................................................................................1 
2 
STUDY OBJECTIVES ....................................................................................2 
2.1 
Primary .............................................................................................................2 
2.2 
Secondary .........................................................................................................2 
2.3 
Exploratory .......................................................................................................2 
2.4 
Safety ................................................................................................................2 
3 
STUDY DESIGN .............................................................................................3 
3.1 
General Design and Study Schema...................................................................3 
3.2 
Study Endpoints ................................................................................................6 
3.2.1 
Primary efficacy endpoint .................................................................................6 
3.2.2 
Secondary Efficacy Endpoints ..........................................................................6 
3.2.3 
Exploratory Endpoints ......................................................................................8 
3.2.4 
Safety Endpoints ...............................................................................................9 
3.3 
Sample Size and Power Considerations ...........................................................9 
3.4 
Randomization and Blinding ............................................................................9 
3.5 
Sequence of Planned Analyses .........................................................................9 
3.5.1 
Interim Analyses ...............................................................................................9 
3.5.2 
Final Analyses and Reporting .........................................................................10 
4 
ANALYSIS POPULATIONS ........................................................................10 
4.1 
Screened ..........................................................................................................10 
4.2 
Intention to Treat (ITT) ..................................................................................10 
4.3 
Safety ..............................................................................................................10 
4.4 
Modified ITT (mITT) .....................................................................................10 
4.5 
Per protocol (PP) .............................................................................................10 
5 
GENERAL ASPECTS FOR DATA ANALYSIS ..........................................12 
5.1 
General ............................................................................................................12 
5.2 
Specification of Baseline Values ....................................................................12 
5.3 
Multiple Comparisons and Multiplicity..........................................................12 
5.4 
Handling Withdrawals and Missing Data .......................................................12 
5.5 
Study days and visit windows .........................................................................12 
5.6 
Subgroups .......................................................................................................12 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
6 
STUDY POPULATION .................................................................................14 
6.1 
General ............................................................................................................14 
6.2 
Patient Disposition ..........................................................................................14 
6.3 
Demographics and Baseline Characteristics ...................................................14 
6.4 
Covid-19 Disease Information ........................................................................15 
6.5 
Medical History ..............................................................................................15 
6.6 
Prior Medications ............................................................................................15 
6.7 
Electrocardiography ........................................................................................16 
6.8 
Physical Examinations ....................................................................................16 
6.9 
Chest X-Ray ....................................................................................................16 
6.10 
Protocol Violations .........................................................................................16 
7 
EFFICACY ANALYSIS ................................................................................17 
7.1 
General ............................................................................................................17 
7.2 
Primary Efficacy Endpoint Analysis ..............................................................17 
7.2.1 
Sensitivity and supportive analyses ................................................................17 
7.2.1.1 
Missing data ....................................................................................................17 
7.2.1.2 
Baseline characteristics adjustment ................................................................18 
7.2.1.3 
Per protocol analysis .......................................................................................18 
7.2.1.4 
Robustness for outliers ...................................................................................18 
7.3 
Secondary Efficacy Endpoint analysis ...........................................................18 
7.4 
Exploratory Endpoint analysis ........................................................................19 
7.5 
Subgroup analysis ...........................................................................................20 
8 
SAFETY ANALYSIS ....................................................................................21 
8.1 
General ............................................................................................................21 
8.2 
Study Drug Administration.............................................................................21 
8.2.1 
Exposure to study drug ...................................................................................21 
8.2.2 
Treatment Compliance ....................................................................................21 
8.3 
Adverse Events ...............................................................................................22 
8.3.1 
Protocol Defined Adverse Events of Special interest .....................................22 
8.4 
Clinical Laboratory Tests ...............................................................................23 
8.5 
Vital Signs ......................................................................................................23 
8.6 
Supplemental oxygen requirement .................................................................24 
8.7 
Electrocardiography ........................................................................................24 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
 
CONFIDENTIAL: PROPRIETARY INFORMATION 
8.8 
Physical Examinations ....................................................................................24 
8.9 
Chest X-ray .....................................................................................................24 
8.10 
Concomitant medications ...............................................................................24 
8.11 
Hospitalization ................................................................................................25 
8.12 
Viral swab for SARS-CoV-2 PCR test ...........................................................25 
9 
STATISTICAL SOFTWARE ........................................................................26 
10 
SUMMARY OF CHANGES FROM LAST SAP VERSION AND 
PROTOCOL SPECIFIED ANALYSES.........................................................26 
11 
REFERENCES ...............................................................................................28 
12 
LIST OF SUMMARIES AND LISTINGS.....................................................29 
 
 
LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ..................................................................5 
Table 2:  
Summary of changes in Version 2 ..................................................................26 
Table 3:  
Summary of changes in Version 3 ..................................................................27 
 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
 
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 
DB 
Double Blind 
DM 
Data Management 
HFNC 
High flow nasal canula 
ITT 
Intention to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to Treat 
PEEP 
Positive End Expiratory Pressure 
PT 
Preferred Term 
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: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 1 - CONFIDENTIAL: PROPRIETARY INFORMATION 
1 PREFACE 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
RedHill Biopharma Ltd. study ABC-110 (Opaganib, a Sphingosine Kinase-2 (SK2) 
Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, Placebo-Controlled 
Phase 2a Study, in Adult Subjects Hospitalized with 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-110, version 1.2,30 August 2020. 
 Case report forms (CRFs) for Study ABC-110. 
 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. 
 Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency, Guidance for Industry, June 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). 
Version 1 of the SAP describes the statistical analyses as foreseen at the time of planning 
the study and version 2 incorporates an amendment responding to FDA recommendations 
received prior to study initiation, including additional clarifications and edits made early 
during initiation of study. Version 3 of the SAP include final clarifications and updates  
based on blinded data review and is finalized before the first database lock and before 
breaking the blind of the study. Any changes made after this event will be documented in 
the final CSR. First database lock refers to the event of locking all data up to and including 
Day 14 visit, enabling the final analysis of the Primary endpoint and those Secondary 
endpoints with timeframe of 14 days. 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 2 - CONFIDENTIAL: PROPRIETARY INFORMATION 
2 STUDY OBJECTIVES 
2.1 Primary  
To evaluate the total oxygen requirement (area under the curve) using daily supplemental 
oxygen flow (L/min) over 14 days (Day 1 to Day 14) 
2.2 Secondary 
1. To evaluate the time to 50% reduction from baseline in supplemental oxygen based 
on oxygen flow in L/min 
2. To evaluate the proportion of patients no longer requiring supplemental oxygen for at 
least 24 hours by Day 14 
3. To evaluate the proportion of afebrile patients at Day 14  
4. To evaluate the time to negative swabs for SARS-CoV-2 by PCR  
5. To evaluate the proportion of patients with negative swabs for SARS-CoV-2 by PCR 
at Day 14 
6. To evaluate the need for intubation and mechanical ventilation by Day 14 
7. To evaluate the time to mechanical ventilation 
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 30 days post-baseline 
2.3  Exploratory 
To assess the change in systemic markers of inflammation (D-dimer, cardiac troponin, C-
reactive protein [CRP], lactate dehydrogenase [LDH] and ferritin) 
2.4  Safety 
To assess the safety and tolerability of opaganib administered orally at 500 mg Q 12 hours, 
for up to 2 weeks, in patients with COVID-19 pneumonia. 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 3 - CONFIDENTIAL: PROPRIETARY INFORMATION 
3 STUDY DESIGN   
3.1  General Design and Study Schema 
This is a phase 2a, proof of concept, multi-center randomized double-blind, parallel arm, 
placebo controlled study.  
After informed consent is obtained, patients will enter a screening phase for no more than 
3 days, to determine eligibility.  
Approximately 40 eligible patients 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.  Patients will be stratified based on a minimization algorithm, as specified in 
section 3.4. Treatment assignments will remain blinded to the patient, investigator and 
hospital staff, as well as the sponsor. As there is currently no consensus for a definitive 
treatment specifically targeting the SARS-CoV-2 virus causing COVID-19 (K. Wilson, 
2020), standard of care will refer to regional, institutional or physician directed therapies, 
that may be implemented during the COVID-19 pandemic.   
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 and/or 
supportive). Study drug will be administered every day for 14 days (Day 1 to Day 14), 
unless the patient has been discharged from the hospital without requiring supplemental 
oxygen, in which case study drug will only be administered to Day 10.  
All participants will be followed up for 4 weeks after their last dose of study drug, which 
may occur at the end of the 2-week double-blind treatment phase or after premature study 
drug discontinuation, based upon patient or physician determination.  
The maximum duration of study participation will be 45 days (including up to 3 days 
screening; 2 weeks double-blind (DB) phase and 4-weeks off-study drug follow-up). 
The study schema is presented below and Visit-specific procedures and assessments are 
outlined in Table 1. 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 4 - CONFIDENTIAL: PROPRIETARY INFORMATION 
 
 
 
 
  
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 5 - CONFIDENTIAL: PROPRIETARY INFORMATION 
 
Table 1: 
Study Procedures and Assessments 
Assessments 
Screening 
Randomizatio
n 
DB Phase 
Early 
termination 
Safety 
follow-up 
Days -3 - 1 
Day 1 
Day 7 
Day 14 
ICF signed 
X 
 
 
 
 
 
Inclusion/exclu
sion criteria  
X 
 
 
 
 
 
Demographics; 
medical and 
surgical 
history 
X 
 
 
 
 
 
Review 
concomitant 
medication(s)1 
X 
X 
X 
X 
X 
X 
Review of 
adverse events1 
 
X 
X 
X 
X 
X 
Physical 
examination1  
X 
 
X 
X 
X 
X 
Vital signs1  
X 
X 
X 
X 
X 
X 
Oxygen flow 
(L/min)1 
X 
X 
X 
X 
X 
X 
Weight2 
X 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
Pharyngeal 
viral sample3 
X 
X 
X 
X 
X 
X 
12-lead ECG4 
X 
 
 
X 
 
 
Chest X-ray5 
X 
 
 
 
 
 
Serum 
chemistry 
X 
 
X 
X 
 
 
Hematology 
(CBC with 
differential) 
X 
 
X 
X 
 
 
D-dimer, 
cardiac 
troponin, CRP, 
LDH, ferritin6 
X 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
Serum 
pregnancy test7 
X 
 
 
 
 
 
1 daily 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) 
2 record weight if patient is ambulatory 
3 pharyngeal samples for SARS-CoV-2 PCR are collected daily, per standard of care.  For patients having 
nasopharyngeal swabs, the same nostril must be used during the study  
4 for patients on concomitant hydroxychloroquine, the 12-lead ECG will be repeated after 3 hours (±30mins) of initial 
dose, on Day 2 and Day 4 
5 Chest X-ray, lab draws will be at the discretion of the Investigator depending on patient clinical condition 
6  CRP=C-reactive protein, LDH=lactate dehydrogenase 
7 women of childbearing potential; serum pregnancy test must be negative within 3 days prior to randomization.


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 6 - CONFIDENTIAL: PROPRIETARY INFORMATION 
3.2 Study Endpoints 
3.2.1 Primary efficacy endpoint 
The primary efficacy objective of the study is to evaluate the effect of Opaganib on total 
supplemental oxygen requirement (area under the curve) using daily oxygen flow (L/min) 
measurements for 14 days (Day 1 to Day 14).  
The primary efficacy endpoint will calculate for each patient the area under the curve of 
the supplemental oxygen requirement through day 14, using the trapezoidal rule after 
subtracting the baseline oxygen requirement at each day.  
The following rules will be applied: 
 If several values of oxygen requirement (L/min) are recorded in a certain day, then for 
the primary analysis the highest of these values will be taken. 
 Days where no supplementary oxygen was needed, will be recorded as 0.  
 Subjects who require intubation and mechanical ventilation, at these days will be 
assigned the maximal supplemental oxygen flow requirement of 8L/min (or if higher, 
the maximal value observed in the study). 
 For subjects discharged from hospital without requiring supplemental oxygen prior to 
Day 14, the oxygen requirement (L/min) will be assigned thereafter as 0 for each day 
to Day 14 (in the rare case that subject will re-hospitalize before Day 14, the new 
supplemental oxygen data will be collected and used, until day 14). 
 For the primary analysis, if a patient dies any time before Day 14), all his/her values 
(D1-D14) will be assigned at the maximal supplemental oxygen flow requirement of 
8L/min, or if higher, the maximal value observed in the study.  
For patients discharged from hospital with supplemental oxygen prior to Day 14, or early 
terminate the treatment before Day 14 while still requiring supplemental oxygen, data on 
the supplemental oxygen up to Day 14 is expected to be collected. However, in the rare 
case that all supplemental oxygen values are missing after discharge/treatment 
discontinuation, the individual AUC will be calculated where the last value is carried 
forward - until Day 14, or death, if occurred before (note, death event is analyzed as 
specified above). This approach will be employed also if a patient initiates new 
investigational therapy for COVID-19 within 14 days, in which case the primary analysis 
will include only measurement taken under study treatment while the rest of the days will 
be imputed as noted above. Sensitivity analysis will address this scenario as well. To note, 
according to blinded data review prior to database lock, no cases of such prohibited 
investigational therapy was recorded. 
3.2.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
1. Time to 50% reduction from baseline in supplemental oxygen based on oxygen 
flow in L/min 
This endpoint will be based on the oxygen flow values used for the primary efficacy 
endpoint. It will be calculated as the number of days from baseline (Day 1) of study 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 7 - CONFIDENTIAL: PROPRIETARY INFORMATION 
medication until the first day when the subject reached a value, which is at least 50% lower 
than the baseline value (the event of interest). Patients who early terminate the study before 
reaching this reduction will have their time censored at the last valid observation time point. 
Patients who will die within the followup timeframe will be censored at the time of the end 
of the follow-up period, thus taking the highly unfavorable possible outcome for this 
endpoint. The time frame for this endpoint is from Day 1 until end of off-study-drug follow-
up. Additional analysis will be performed in the time frame of the 14-day-treatment DB 
Phase period (sensitivity analysis).  
To note, in order to focus this endpoint on sustained success, it implies increase in 
supplemental oxygen negating initial success would be followed for re-achievement of 
success. Further note, a patient who reached success but did not have any further data 
supporting this success (i.e. discharged from hospital still requiring oxygen and no further 
data supporting success afterwards), may be subject to sensitivity analysis where  regarded 
censored at last evaluable time.  
 
2. The percentage of patients no longer receiving supplemental oxygen for at least 24 
hours by Day 14 
This endpoint will be defined per subject as a binary ("Success" / "Failure") variable with 
"Success" indicating that a subject no longer receiving supplemental oxygen for at least 24 
hours by Day 14, and “Failure” otherwise. Patients who will die within 14-days will be 
regarded as “Failure”, corresponding to the highly unfavorable possible outcome. 
To note, in order to focus this endpoint on sustained success, it implies need in 
supplemental oxygen negating initial success would be followed for re-achievement of 
success. 
3. The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart 
This time to event endpoint will be calculated as the number of days from baseline (Day 
1) of study medication until  the first occurrence of two consecutive negative swabs for 
SARS-CoV-2 by PCR, at least 24 hours apart (the event of interest). Patients who early 
terminate the study before reaching this event will have their time censored at the last valid 
observation time point. Patients who will die within the follow-up timeframe will be 
censored at the time of the end of the follow-up period, thus taking the highly unfavorable 
possible outcome for this endpoint. The time frame for this endpoint is from Day 1 until 
end of off-study-drug follow-up. Additional analysis will be performed in the time frame 
of the 14-day-treatment DB Phase period (sensitivity analysis).  
4. The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart, followed by continued negative swabs 
This time to event endpoint will be defined similarly to the  3rd secondary efficacy endpoint, 
where the event of interest is the first occurrence of two consecutive negative swabs for 
SARS-CoV-2 by PCR , at least 24 hours apart, followed by continued negative swabs.  The 
time frame for this endpoint is from Day 1 until end of off-study-drug follow-up. 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 8 - CONFIDENTIAL: PROPRIETARY INFORMATION 
Additional analysis will be performed in the time frame of the 14-day-treatment DB Phase 
period (sensitivity analysis). 
5. The percentage of patients requiring intubation and mechanical ventilation  
The percentage of patients requiring intubation and mechanical ventilation by Day 30 will  
will be defined per subject as a binary ("Failure" / "Success") variable with "Failure" 
indicating that a subject had a reported requirement of intubation and mechanical 
ventilation any time before 30-days following first study dose, and “Success” otherwise. 
Death during this time frame will be regarded as “Failure” as well. 
The percentage of patients requiring intubation and mechanical ventilation by Day 14 will 
also be estimated in a similar way. Death before day 14 will be regarded as “Failure” as 
well. 
 
6. The time to intubation and mechanical ventilation. 
This time to event endpoint will be calculated as the number of days from baseline (Day 1 
of study medication) until the earliest date of a reported requirement of intubation and 
mechanical ventilation, or death. Subjects who early terminate the study alive and without 
such requirement will have their time censored at the last valid observation time point. The 
time frame for this endpoint is from Day 1 until Day 30 from first dose. Additional analysis 
will be performed in the time frame of the 14-day-treatment DB Phase period (sensitivity 
analysis).  
7. 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 per subject as a binary ("Success" / "Failure") variable with 
"Success" indicating that a subject with fever at baseline is reported as afebrile on Day 14. 
“Failure” will be assigned otherwise.  
This endpoint will be calculated only to the population of subject having fever at baseline. 
Additionally, to address objective # 3 (To evaluate the proportion of afebrile patients at 
Day 14), endpoint and analysis will be applied to the entire mITT analysis set.  
8. Mortality due to any cause at Day 30. 
This binary endpoint will be defined per subject as a binary ("Failure" / "Success") variable 
with "Failure" indicating that a subject had died within 30 days from first dose. “Success” 
will be assigned for patients known alive at day 30. 
3.2.3 Exploratory Endpoints 
Exploratory endpoints will include changes from baseline in the systemic markers of 
inflammation: D-dimer, cardiac troponin, C-reactive protein [CRP], lactate dehydrogenase 
[LDH] and ferritin. 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 9 - CONFIDENTIAL: PROPRIETARY INFORMATION 
3.2.4 Safety Endpoints 
The safety and tolerability endpoints will include reported AEs, laboratory tests, vital signs, 
ECG, physical examinations, concomitant medications and hospitalization. 
Hospitalization endpoints will include days of hospitalization and status of supplementary 
oxygen requirement at discharge (No/Yes). When calculating days of hospitalization, if a 
subject dies while hospitalized, the number of days of hospitalization will be imputed 
as the worst maximal duration of 42 days. 
3.3 Sample Size and Power Considerations 
It is planned to enroll approximately 40 eligible patients into the double-blind treatment 
phase, to receive either opaganib added to standard of care (n=20), or matching placebo 
added to standard of care (n=20). The sample size for this Proof of Concept study was not 
chosen for statistical consideration, as there are no formal statistical inferences planned. 
The size of the study is judged adequate for the preliminary evaluation objectives. 
3.4 Randomization and Blinding 
A total of 40 subjects 18 to 80 years old, inclusive will be randomized, using a 1:1 
assignment ratio, to treatment with either Opaganib 500 mg Q12 hour (20 subjects) or 
Placebo (20 subjects), respectively. 
A dynamic randomization using the minimization method will be used in this study by 
Bioforum’s DM vendor. Three stratification factors will be used for the minimization 
algorithm:   
1. Age at screening, ≥70 years of age, (yes or no)  
2. HbA1c at screening,  ≥6.5, (yes or no); 
3. Oxygen requirement at baseline, requiring non-invasive positive pressure 
ventilation (e.g. via PEEP, BIPAP, CPAP, HFNC), (yes or no) 
The minimization algorithm will be programmed by Bioforum Ltd using Viedoc system 
and will employ the Pocock and Simon (Pocock S.J. and Simon R. 1975) methodology 
with biased coin probability of 0.8 and ‘Range’ as the variation method. All stratification 
factors will use the same weight of importance. If the subject meets the eligibility criteria, 
he or she will be allocated to Opaganib 500 mg Q12 hour or Placebo at 1:1 ratio 
respectively. Once the enrollment of the subject is approved, the investigator will assign 
the subject an ID number (subject number) provided by the Viedoc system after running 
the algorithm on the subject’s stratification information. 
Treatment assignments will remain blinded to the patient, investigator and hospital staff, 
as well as the sponsor. 
3.5 Sequence of Planned Analyses 
3.5.1 Interim Analyses 
No formal interim analysis to stop the study early is planned for this proof of concept study. 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 10 - CONFIDENTIAL: PROPRIETARY INFORMATION 
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. 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. The analysis of the primary endpoint and supporting efficacy 
secondary analyses can be started once this SAP has been signed, all data up to day 14 
(including) has been locked and unblinded. Study personnel involved in data management 
activities and those engaged in study conduct will remain blinded until the few remaining 
safety follow-up visits will be performed and all remaining unlocked data (after Day 14) 
have been cleaned and locked. Only then, formal final analysis for the CSR will be 
performed. No difference is expected in results of the primary endpoint (and supporting 
efficacy secondary endpoints noted above), however in case of any difference occur, it will 
be documented and presented in the CSR as well. Procedures and firewalls have been 
defined and documented in study files to maintain study integrity during the partial team 
unbinding. 
4 ANALYSIS POPULATIONS 
This section describes the analysis populations defined for the study. 
4.1 Screened  
The Screened population will include all subjects who underwent screening. 
4.2 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. 
4.3 Safety  
The safety population will include all randomized patients who receive at least one dose 
of study medication.  In this population, treatment will be assigned based upon the 
treatment patients actually receive regardless of the treatment to which they were 
randomized.  
4.4 Modified ITT (mITT) 
This population consists of all subjects that were randomized and treated with at least one 
dose of study drug. In this population, treatment will be assigned based upon the treatment 
to which subjects were randomized regardless of which treatment they actually received. 
4.5 Per protocol (PP) 
A per protocol population will include those subjects in the mITT population who had no 
major protocol violation. Criteria for PP protocol will be mainly based on inclusion and 
exclusion criteria and will be defined before database lock. The list of protocol deviations 


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precluding patients from PP population has been prepared using blinded review and 
documented in study files. 
 


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5 GENERAL ASPECTS FOR DATA ANALYSIS 
5.1 General 
Descriptive statistics for continuous variables include n, mean, standard deviation, 
standard error of the mean, median, minimum, and maximum. 
Descriptive statistics for categorical variables include patient counts and percentages.  
Summaries of clinically significant abnormal values will include all post baseline values 
(including scheduled, unscheduled, and early termination visits). 
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. 
5.2 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. 
5.3 Multiple Comparisons and Multiplicity 
This is a proof of concept study for which no formal statistical hypotheses were defined.  
When presented, nominal p-values will not be interpreted inferentially. The results of the 
study will be interpreted by the overall pattern of benefits of opaganib.   
5.4 Handling Withdrawals and Missing Data 
Missing data in the primary endpoint are handled as described in sections 3.2.1 and 7.2. 
Sections 3.2.2 and 7.3 provides details on handling missing data for the secondary efficacy 
endpoints. Generally, no imputation will be performed for safety endpoints unless stated 
otherwise in the specific endpoint analysis. For time to event analysis, early withdrawal (or 
death before event of interest) will be addressed via right censoring, as described in 
Sections 3.2.2.  
5.5 Study days and visit windows 
The study data will be summarized as collected at the scheduled study day during DB and 
follow-up phases. 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, in case the corresponding data are missing from this assessment 
day. 
5.6 Subgroups 
The subgroup of low-flow vs. high-flow oxygen will be define based on the baseline 
oxygen required type. Subject will be classified with ’High-Flow’ if baseline oxygen 


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required was positive pressure or high flow nasal cannulas and ‘Low-Flow’ if baseline 
oxygen required was regular.  
 


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6 STUDY POPULATION  
6.1 General 
Study population summaries will be presented by treatment group and overall unless 
otherwise noted.  
6.2 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 who completed the study treatment according to protocol 
(i.e. on day 14 or on day 10 if discharged from the hospital without requiring 
supplemental oxygen before day 14) 
 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 
6.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics 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) 
 Gender: Male, Female (categorical) 
 Childbearing Potential: Yes, No (categorical, females only)  
 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) 
 Smoking status: Never, Former, Current (categorical), and packyears 
 Stratification factors (categorical): 
 Age (years): <70, ≥70 
 HbA1c at screening: <6.5, ≥6.5o)  
 Oxygen requirement at baseline requiring non-invasive positive pressure 
ventilation (e.g. via PEEP, BIPAP, CPAP): yes or no 
 Vital signs at baseline, including supplemental oxygen requirement 
6.4 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 
 Reason for hospitalization 
 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) 
6.5 Medical History 
Medical history data will be summarized by treatment group and overall using ITT and 
Safety population. 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 history data will be listed. 
6.6 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 ITT 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 


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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. 
In addition, all prior medications data will be listed. 
6.7 Electrocardiography 
Electrocardiogram findings (normal, abnormal, and missing) at baseline will be 
summarized using appropriate descriptive statistics, and will be presented for the Safety 
population. 
6.8 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. 
6.9 Chest X-Ray 
Chest X-ray 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. 
 
6.10 Protocol Violations  
All protocol violations will be listed. 
 
 
 


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7 EFFICACY ANALYSIS 
7.1 General 
The analysis of the primary efficacy endpoints will be performed on the mITT, ITT and 
safety populations, with the mITT population serving as the primary analysis population. 
The secondary efficacy endpoints will be analyzed using the mITT populations, unless 
otherwise noted for a specific endpoint. 
Summaries will be presented by treatment group, unless otherwise noted. 
 
7.2 Primary Efficacy Endpoint Analysis 
The primary analysis will be based on the modified Intent to treat population (mITT), 
which consist of all patients that were randomized and treated with at least one dose of 
study drug,  
The primary analysis will be based on the baseline-adjusted AUC calculated individually 
for each subject, as defined in section 3.2.1. Descriptive statistics of the baseline-adjusted 
AUC will be presented by group and group means will be presented along with 95% 
confidence interval. The difference in means between the groups will be estimated and 
presented with 95% confidence interval. Plots presenting individual baseline-adjusted 
AUC will be presented. Difference between group medians with confidence interval will 
also be estimated using the Hodges-Lehmann statistics and will be presented along with 
the non-parametric Wilcoxon rank sum test. 
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 Missing data 
The primary analysis above is based on individual AUC calculation, where in case that all 
supplemental oxygen values are missing after discharge or early treatment discontinuation 
that occur while subject still requires supplemental oxygen (before day 14), the last value 
is carried forward - until Day 14, or death, if occurred before. In addition, worst case 
imputation is applied for subjects who died any time within 14 days and on days of 
intubation.  
A sensitivity analysis to the above missing data handling approach will be performed using 
an AUC summary statistics approach, in which groups AUC is calculated from the 
estimated parameters of a Repeated-Measures model. More specifically, taking as the 
dependent variable the observed daily oxygen requirement per each subject (change from 
baseline), a model incorporating factors for group, day (categorical) and group by day 
interaction will allow estimation of the mean oxygen requirement at each day, for each 
group. The model will be implemented using the MIXED procedure in SAS software with 
subject taken as random factor. To confirm that correlation among observations from the 
same subject are adequately modeled in this MIXED model application, the following 
correlation structures will be fitted as well: Unspecified (UN) and  Autoregressive(1) 


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(AR(1)).  The denominator degrees of freedom will be computed using the Kenward-Roger 
method. Each group mean AUC will be estimated using a linear combination of the 
parameter estimates after a model has been fit. Group AUCs and their difference will be 
presented along with 95% confidence interval. 
7.2.1.2 Baseline characteristics adjustment 
Estimation of difference between the treatment groups when controlling for the 
stratification factors and baseline oxygen requirement will be performed, using regression 
analysis, both for the individual subjects AUC (via Analysis of Covariance) and the group 
AUC modeling via Repeated measures approach sensitivity analysis. 
 
7.2.1.3 Per protocol analysis 
Analysis using the per-protocol population will be performed as supportive analysis. 
 
7.2.1.4 Robustness for outliers 
Analysis based on ranked observations will be performed to confirm robustness of the 
estimated effect for potential outliers. 
 
7.3 Secondary Efficacy Endpoint analysis 
This section describes the analyses to be performed on the secondary efficacy endpoints, 
as defined in section 3.2.2. 
The secondary efficacy endpoints will be analysed using the mITT populations unless 
otherwise noted for a specific endpoint. 
1. Time to 50% reduction from baseline in supplemental oxygen based on oxygen 
flow in L/min 
This time to event will be analyzed as follows: Cox proportional hazards regression model 
will be used to estimate the hazard ratio (HR) along with 95% confidence interval, 
comparing Opaganib versus control group. The model will include treatment group as 
explanatory variable and supplemental oxygen at baseline as covariates. If possible, the 
stratification factors will also be included as covariates. Kaplan-Meier plot will be provided 
for illustration of effect (along with median estimates). Cumulative incidence function of 
the time to 50% reduction from baseline in supplemental oxygen   will be estimated using 
the Kaplan-Meier estimator and will be used to estimate the 14-days cumulative incidence 
of 50% reduction event for each group, along with 95% confidence interval. 
2. The percentage of patients no longer receiving supplemental oxygen for at least 24 
hours 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. Difference in proportions will be estimated and 
presented along with 95% confidence interval. Exact confidence intervals will be used as 
needed (otherwise Wilson (Score) limits will be used). In case loss to follow-up before 


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event will be recorded, the Cumulative Incidence probabilities at 14-days from the starting 
of treatment will be estimated using time to event analysis (Kaplan-Meier estimator), 
censoring loss-to follow up patients at last valid observation date. This analysis will censor 
death on Day 14. 
3. The time to two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart  
This time to event endpoint will be analyzed using the same methods specified for the first 
secondary efficacy endpoint (without adjustment for the supplemental oxygen at baseline). 
4. The time to  two consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart, followed by continued negative swabs 
This time to event endpoint will be analyzed using the same methods specified for the first 
secondary efficacy endpoint (without adjustment for the supplemental oxygen at baseline). 
5. The percentage of patients requiring intubation and mechanical ventilation  
This binary endpoint will be analyzed using the same methods specified for the second 
secondary efficacy endpoint. The event of interest is defined as “Failure”. As defined in 
section 3.2.2. death will be analyzed as “Failure”. 
The percentage of patients requiring intubation and mechanical ventilation by Day 14 will 
be analyzed similarly. 
6. The time to intubation and mechanical ventilation. 
This time to event endpoint will be analyzed using the same methods specified for the 1st 
secondary efficacy endpoint (without adjustment for the supplemental oxygen at baseline). 
7. 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 endpoint will be analyzed using the same methods specified for the second 
secondary efficacy endpoint.  This analysis will be based on observed case analysis using 
patients with Day 14 measurement. 
8. Mortality due to any cause at Day 30. 
This binary endpoint will be analyzed using the same methods specified for the second 
secondary efficacy endpoint. The event of interest is defined as “Failure”.  To note, in case 
that loss to follow up, the associated time to event analysis to derive the 30-days mortality 
rate will not encounter any competing event. Kaplan Meier curves of time to death through 
Day 30 will also be provided. 
7.4 Exploratory Endpoint analysis 
 The systemic markers of inflammation (D-dimer, cardiac troponin, C-reactive protein 
[CRP], lactate dehydrogenase [LDH] and ferritin) will be collected at Screening visit and 
then once weekly at Day 7 and Day 14 visits. These tests will be evaluated versus local site 


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normal ranges and assessed by the investigator as Clinically Significant (Yes/No). Changes 
from baseline analysis and other analyses similar to those planned for the 
Chemistry/Hematology laboratory tests (section 8.4) will be applied. 
7.5  Subgroup analysis 
The primary and secondary endpoints will be summarized using the low vs. high oxygen 
flow subgroup as defined on section 5.6 above. The efficacy primary endpoint and ‘Time 
to event’ secondary endpoints will be analyzed by subgroup using the methods described 
in Section 7. Safety analysis may be provided as well, as deemed relevant. 
 
 


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8 SAFETY ANALYSIS 
8.1 General 
The safety population will be used for all safety analyses.  Summaries will be presented 
by treatment group as actually received unless otherwise specified. 
Rules to address safety data analysis of single patient who may have received a flipped 
treatment due to bottle switches are documented in study files, in which if the patient was 
initially on placebo but then mistakenly received opaganib, his/her data before and after 
the switch will be assigned as Placebo and opaganib, respectively, and thus may be 
counted twice.   
8.2 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). 
 Days on treatment will also be categorized as ≤10days or >10days and will be 
summarized using counts and percentages. 
 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] ÷ [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, and computed 
compliance rates. 


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8.3 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/Grade 4, or death/Grade 5 to describe 
the maximum intensity of the AE, as specified in the protocol (section 15.2). 
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 any grade 3 or above TEAE; any grade 3 or above TESAE;  
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 treatment related TEAE grade 3 or above;  
o any TEAE resulting in dose reduced; any TEAE resulting in drug withdrawn 
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; 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 


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 Neuropsychiatric AEs 
Adverse events of interest will be summarized using counts and percentages and a Listing 
will be provided. 
8.4 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 hematology (Red blood cell count, 
Hemoglobin, Hematocrit, Platelets, White blood cell count, Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils), and will be collected during Screening visit and then 
once weekly at Day 7 and Day 14 visits. 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. 
Chemistry and Hematology laboratory tests will be presented at baseline, Day 7 and Day 
14 visits.  Laboratory tests results and changes from baseline to each visit 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 and time-
point, including ‘any time post-baseline’ time point. 
Shifts (below, within, and above the normal range) from baseline to each visit 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. 
8.5 Vital Signs 
Vital signs (temperature, blood pressure, pulse rate, respiratory rate and oxygen saturation 
by pulse oximeter) 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, end of treatment, safety follow 
up).  The incidence of clinically significant abnormal values will be summarized for 
selected vital signs using descriptive statistics.   


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A listing for clinically significant abnormal vital signs will be presented. 
8.6 Supplemental oxygen requirement 
Supplemental oxygen requirement outcome is the target of the primary efficacy endpoint 
(refer to section 3.2.1. Listings of all supplemental oxygen requirement evaluation will also 
be provided. Figures will be provided as possible. 
8.7 Electrocardiography  
12-lead electrocardiogram will be performed for all subjects during screening visit and at 
Day 14 visit. For patients on concomitant hydroxychloroquine, 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 will be 
summarized using appropriate descriptive statistics. Summaries may be provided 
separately for the subjects on concomitant hydroxychloroquine. 
8.8 Physical Examinations 
Physical examinations will be conducted at screening visit and then daily while subject is 
hospitalized, at End of treatment visit and at Safety follow-up visit. Any physical 
examination finding that is judged by the investigator as abnormal (worsening) compared 
to a baseline value will be considered an adverse event and reported as such. Therefore, no 
specific summary tables will be provided. Listings of abnormal physical examination will 
be provided. 
8.9 Chest X-ray 
Chest X-ray will be performed at Screening visit and subsequently at the discretion of the 
Investigator depending on subject’s clinical condition. Any post baseline finding that is 
judged by the investigator as abnormal (worsening) compared to a baseline value will be 
considered an adverse event and reported as such. Listings of abnormal chest X-ray will be 
provided. 
8.10 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.   


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8.11 Hospitalization 
Summary statistics on subject’s hospitalization information will be provided. These will 
include duration of hospitalization and whether the subject is taking supplemental oxygen 
at discharge.  
8.12 Viral swab for SARS-CoV-2 PCR test 
Pharyngeal samples for SARS-CoV-2 PCR will be collected per standard of care, every 1-
3 days. Efficacy analysis of this outcome is described in Section 7.3. Listings of results 
will also be provided. 
 


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9 STATISTICAL SOFTWARE 
All summary tables, figures, listings and statistical analyses will be generated using 
SAS® software, version 9.3 or later. 
10 SUMMARY OF CHANGES FROM LAST SAP VERSION AND 
PROTOCOL SPECIFIED ANALYSES 
Version 2 of the SAP incorporates edits to the previous version of the SAP and some 
deviations in text from the latest version of the Clinical Study Protocol. 
These edits/deviations, however, were made in response to the FDA recommendations, and 
attempts to insert greater detail and provide further clarifications. The most significant 
changes made to the text in this document are summarized in the table below: 
Table 2: Summary of changes in Version 2 
Topic  
Change description and rationale 
Analysis 
Populations 
Per-protocol population was defined to address major protocol 
deviations that may occur, mainly relating to inclusion/exclusion criteria
Primary 
efficacy 
endpoint and 
analysis  
 In Section 3.2.1: Originally, it was thought that multiple units will be 
used for reporting oxygen flow, and thus a placeholder for algorithm to 
address that was given. Yet, it was confirmed that all oxygen flow values 
will be reported using the same, L/min unit, therefore referral for further 
addendum is no longer needed. 
Imputation rules have been edited as follows: 
 Following FDA recommendation, any death during study will be 
imputed using maximal supplemental oxygen flow requirement of 
8L/min from Day 1 to Day 14 for the primary efficacy endpoint. 
 In case that higher values than 8L/min will be recorded, the SAP 
now define that 8L/min or if higher, the maximal value observed in 
the study will be used. 
 The SAP now address the scenario that a patient initiates new 
investigational therapy for COVID-19 within 14 days, in which case 
the primary analysis will include only measurement taken under 
study treatment and the rest of the days will be imputed according to 
imputation rules.  
In the sensitivity analysis (section 7.2.1.1): it was clarified that Change 
from baseline will be analyzed in the model. 
 
A supportive per-protocol analysis was added. 
Secondary 
Efficacy 
Endpoints 
#1,#2,#5 
Following FDA recommendation and in accordance with the newly 
released COVID-19 guidance to address death as the highly unfavorable 
possible outcome for efficacy endpoints, the secondary endpoints and 
associated analyses have been updated accordingly. 


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Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 27 - CONFIDENTIAL: PROPRIETARY INFORMATION 
Topic  
Change description and rationale 
Secondary 
Efficacy 
endpoint #4 
The endpoint was changed based on FDA recommendation, and analysis 
was subsequently fitted to analyze the resulting time to event endpoint. 
 
Secondary 
Efficacy 
endpoint #7 
Assessment of Afebrile status at day 14 will be performed also for the 
entire mITT patients, in addition to the subgroup of patients with fever 
at baseline, in order to address study objective #3. 
Version 3 of the SAP incorporates the below changes relative to the previous version: 
Table 3: Summary of changes in Version 3 
Topic  
Change description and rationale 
Primary Efficacy 
endpoint (Section 
3.2.1) 
Derivation of endpoint was updated in accordance with FDA 
earlier recommendation, that death imputation will trigger worst 
case imputation if occurring any time within the 14 days period 
rather than any time during study. In addition, it was updated that 
based on blinded data review, no cases of, and therefore no need 
to handle, new investigational COVID-19 therapy. 
Secondary Efficacy 
Endpoints #1,#2 
(Section 3.2.2) 
Text was added to endpoint definition to clarify that endpoint 
focus on sustained success, rather than success that may be 
negated by subsequent failure within the time-frame 
Secondary efficacy 
endpoint #5,#6 
(Section 3.2.2) 
To align with the protocol, endpoint to estimate cumulative 
incidence of event by 14 days was added, and, the long term time 
frame was defined as 30-days post first dose. Time frame for the 
time to event #6 endpoint was correspondingly aligned. 
Secondary efficacy 
endpoint #8 (Section 
3.2.2) 
In order to align with other endpoints, origin of timeframe was 
changed to first dose instead of date of randomization. 
Sequence of 
planned analyses 
(Section 3.5.2) 
Details have been provided on database lock and unbinding 
process. 
Subgroup analysis 
(Sections 5.6 and 
7.5) 
Pre-definition of subgroup by baseline type of oxygen 
requirement: low-flow vs. high-flow oxygen. 
Primary efficacy 
endpoint analysis 
(Section 7.2) 
Non-parametric analysis of the individual subjects AUC was 
added.  
Additional robustness analysis was added, in which analysis will 
be repeated on ranked transformed data.  
 
Text was added to clarify that various robustness analysis will be 
performed for both individual subjects AUC analysis and the 
group AUC modeling via Repeated measures approach 
sensitivity analysis.  
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 28 - CONFIDENTIAL: PROPRIETARY INFORMATION 
Topic  
Change description and rationale 
In the group AUC modeling via Repeated measures approach 
sensitivity analysis, analyses to confirm that correlation among 
observations from the same subject are adequately modeled was 
added. 
Secondary Efficacy 
endpoint #7 (Section 
7.3) 
Clarification that analysis of this endpoint will be based on 
observed case analysis using patients with Day 14 measurement.
Safety analysis 
general (Section 8.1) 
A note on addressing case of patients who may have received a 
flipped treatment due to bottle switches. 
 
11 REFERENCES  
Pocock S.J. and Simon R. (1975) Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics 31:103-115. 
 
 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
Page 29 - CONFIDENTIAL: PROPRIETARY INFORMATION 
12 LIST OF SUMMARIES AND LISTINGS 
The list of summary tables, figures and listings as foreseen at study onset is provided 
below. The final updated list is maintained and recorded at study files. 
Summary 
number 
Title 
Population 
Study Population Summaries 
 
14.1.1 
Patient Disposition 
All Screened 
Patients 
14.1.2.1-3 
Demographics and Baseline Characteristics (by treatment group and 
overall) 
ITT,  mITT and 
Safety  
14.1.2.4-6  
Stratification factors at time of Randomization and on eCRF (by 
treatment group and overall) 
ITT,  mITT  
14.1.3.1-3 
Covid-19 Disease Information (by treatment group an overall) 
ITT,  mITT and 
Safety  
14.1.4.1-2 
Medical and Surgical History (by treatment group an overall) 
ITT and Safety  
14.1.5.1-3 
Prior Medications 
ITT,  mITT and 
Safety  
14.1.6 
Baseline ECG Findings (by treatment group and overall)  
Safety  
14.1.7 
Baseline Physical Examination Findings (by treatment group and 
overall) 
Safety  
14.1.8 
Baseline X-Ray Findings (Normal/Abnormal/Missing) 
Safety  
Primary Efficacy Endpoint 
 
14.2.1.1 
Primary Endpoint Analysis: Total Supplemental Oxygen 
Requirement (area under the curve) using Daily Oxygen Flow 
(L/min) Measurements for 14 Days (Day 1 to Day 14).  
mITT  
14.2.1.2 
Primary Endpoint: Total Supplemental Oxygen Requirement (area 
under the curve) using Daily Oxygen Flow (L/min) Measurements 
for 14 Days (Day 1 to Day 14) - Sensitivity Analysis for missing 
data 
mITT  
14.2.1.3 
Primary Endpoint: Total Supplemental Oxygen Requirement (area 
under the curve) using Daily Oxygen Flow (L/min) Measurements 
for 14 Days (Day 1 to Day 14) - Sensitivity Analysis for Baseline 
Characteristics Adjustment 
mITT  
14.2.1.4 
Daily Oxygen Flow (L/min) Requirement Values and Change from 
Baseline, by Treatment Group 
mITT  
Secondary Efficacy endpoints 
 
14.2.2.1-2 
Time to 50% reduction from baseline in supplemental oxygen based 
on oxygen flow in L/min (two time frames: up to end of follow up; 
up to Day 14) 
mITT  
14.2.3 
Percentage of patients no longer receiving supplemental oxygen for 
at least 24 hours by Day 14 
mITT 


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RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
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Summary 
number 
Title 
Population 
14.2.4.1-2 
The time to two consecutive negative swabs for SARS-CoV-2 by 
PCR, at least 24 hours apart (two time frames: up to end of follow up; 
up to Day 14) 
mITT  
14.2.5.1-2 
The time to two consecutive negative swabs for SARS-CoV-2 by 
PCR, at least 24 hours apart followed by continued negative swabs 
(two time frames: up to end of follow up; up to Day 14) 
mITT 
14.2.6 
Percentage of patients requiring intubation and mechanical 
ventilation by the end of the 4-week off-study-drug follow-up 
mITT 
14.2.7.1-2 
Time to intubation and mechanical ventilation 
(two time frames: up to end of follow up; up to Day 14) 
mITT 
14.2.8 
The percentage of patients with at least one measurement of fever at 
baseline, who are afebrile at Day 14  
mITT (with 
Fever at 
baseline) 
14.2.9 
The percentage of patients who are afebrile at Day 14  
mITT 
14.2.10 
Mortality due to any cause at Day 30 
mITT 
Exploratory Efficacy endpoints 
 
14.2.11.1 
Summary of Systemic Markers of Inflammation and Change from 
Baseline by Visit and Treatment Groups 
mITT  
14.2.11.2 
Systemic Markers of Inflammation Normal/Abnormal and Clinically 
Interpretations Results by Visit and at Any Post Baseline Time Point 
and by treatment Group 
mITT 
14.2.11.3 
Shift from baseline to each Visit and 'Any Time Post Baseline' of 
Systemic Markers of Inflammation Abnormal Values by Treatment 
Group 
mITT 
14.2.11.4 
Shift from baseline to each Visit and 'Any Time Post Baseline' of 
Systemic Markers of Inflammation Clinically Interpreted Test 
Results by Treatment Group  
mITT 
Exposure and Safety 
 
14.3.1.1 
Study Drug Exposure by Treatment Group 
Safety  
14.3.1.2 
Treatment Compliance by Treatment Group  
Safety  
14.3.2.1 
Summary of Treatment Emergent Adverse Events by Treatment 
Group  
Safety  
14.3.2.2 
TEAEs by SoC and PT by Treatment Group  
Safety  
14.3.2.3 
TE-SAE by SoC and PT by Treatment Group  
Safety  
14.3.2.4 
Grade 3 or Above TEAE by SoC and PT by Treatment Group  
Safety  
14.3.2.5 
Grade 3 or above TESAE by SoC and PT by Treatment Group  
Safety  
14.3.2.6 
Treatment related TEAE by SoC and PT by Treatment Group  
Safety  
14.3.2.7 
Treatment related TESAE by SoC and PT by Treatment Group  
Safety  
14.3.2.8 
TEAE resulting in dose reduced by SoC and PT by Treatment Group 
Safety  
14.3.2.9 
TEAE resulting in drug withdrawn by SoC and PT by Treatment 
Group  
Safety  


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
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Summary 
number 
Title 
Population 
14.3.2.10 
Any TEAE with an outcome of death by SoC and PT by Treatment 
Group  
Safety  
14.3.2.11 
TEAEs by SOC, PT and Maximum severity by Treatment Group  
Safety  
14.3.2.12 
TEAEs by SOC and PT by maximal Relationship to Treatment by 
Treatment Group  
Safety  
14.3.2.13 
TEAEs of Special Interest by Treatment Group  
Safety  
14.3.3.1.1 
Chemistry Results and Change from Baseline by Visit and by 
Treatment Group  
Safety  
14.3.3.1.2 
Chemistry Normal/Abnormal and Clinically Interpretations Results 
by Visit and at ‘Any Post Baseline Time by Treatment Group  
Safety  
14.3.3.1.3 
Shift from baseline to each Visit and 'any time post baseline' for 
Chemistry Abnormal Values by Treatment Group and Overall 
Safety  
14.3.3.1.4 
Shift From Baseline to each Visit and 'any time post baseline'  for 
Chemistry Clinically Interpreted Test Results, by Treatment Group  
Safety  
14.3.3.2.1 
Hematology Results and Change from Baseline by Visit and by 
Treatment Group  
Safety  
14.3.3.2.2 
Hematology Normal/Abnormal and Clinically Interpretations 
Results by Visit and at ‘Any Post Baseline Time Point’ and by 
Treatment Group  
Safety  
14.3.3.2.3 
Shift from baseline to each Visit and 'any time post baseline' for 
Hematology Abnormal Values by Treatment Group and Overall 
Safety  
14.3.3.2.4 
Shift From Baseline to each Visit and 'any time post baseline'  for 
Hematology Clinically Interpreted Test Results, by Treatment Group 
Safety  
14.3.3.3 
Incidence of  laboratory toxicity by maximal toxicity grade during 
study by Treatment Group 
Safety  
14.3.4.1 
Vital signs Results and Change from Baseline by Visit and Treatment 
Group  
Safety  
14.3.4.2 
Vital Signs Clinically Interpretations Results at any time during study 
by Treatment Group  
Safety  
14.3.5.1 
ECG Normal/ ABNORMAL and Clinically Interpretations Results 
by visit and time point by Treatment Group  
Safety  
14.3.5.2 
ECG Normal/ ABNORMAL and Clinically Interpretations Results 
by visit and time point by Treatment Group for Subjects on 
concomitant Hydroxychloroquine 
Safety: subjects 
on concomitant 
Hydroxychloroq
uine 
14.3.6 
Concomitant medications by WHO Dictionary ATC Level 4 and PT 
by Treatment Group  
Safety  
14.3.7 
Hospitalization by Treatment Group  
Safety  
 
Individual Patient Data Listings 
Listing 
Number 
Title 
Population 
16.2.1.1 
Patients Disposition 
All Screened 
Patients 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
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Listing 
Number 
Title 
Population 
16.2.1.2 
Patients Not Eligible for the Study 
All Screened 
Patients 
16.2.1.3 
Patient Disposition with reasons for early termination of treatment 
and early termination of study 
ITT  
16.2.2 
Demographic and Baseline Characteristics 
ITT  
16.2.3 
Covid-19 Disease History 
ITT 
16.2.4 
Medical History 
ITT 
16.2.5 
Prior Medication 
ITT 
16.2.6 
ECG 
Safety  
16.2.7 
Abnormal Physical Examinations 
Safety  
16.2.8 
Protocol Violations 
All Screened 
Patients 
16.2.9 
Supplemental oxygen requirement and AUC 
mITT
16.2.10 
Viral swab for SARS-CoV-2 PCR test 
mITT
16.2.11.1 
Systemic markers of inflammation results 
mITT 
16.2.11.2 
Abnormal systemic markers of inflammation 
mITT 
16.2.12 
Secondary End Points by Subject Derivations 
mITT 
16.2.13.1 
Study Drug Exposure 
Safety  
16.2.13.2 
Study Drug Compliance 
Safety 
16.2.14.1 
All Adverse Events 
Safety 
16.2.14.2 
Adverse Events Resulted in Death 
Safety 
16.2.14.3 
Serious Adverse Events 
Safety 
16.2.14.4 
Adverse Events Leading to Treatment Withdrawal 
Safety 
16.2.14.5 
Special Interest Adverse Events 
Safety 
16.2.15.1 
Chemistry Results 
Safety  
16.2.15.2 
Abnormal Clinically Significant Chemistry Results 
Safety  
16.2.15.3 
Hematology Results 
Safety  
16.2.15.4 
Abnormal Clinically Significant Hematology Results 
Safety  
16.2.16.1 
Vital Signs Results 
Safety  
16.2.16.2 
Clinically Significant Vital Signs 
Safety 
16.2.17.1 
ECG Results 
Safety  
16.2.17.2 
Abnormal ECG Results 
Safety 
16.2.18 
Abnormal Physical Examination 
Safety 
16.2.19 
Abnormal X-Ray Results 
Safety 


Statistical Analysis Plan 
RedHill Biopharma 
Version: 3, Date: 13-DEC-2020  
Study ABC-110 
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Listing 
Number 
Title 
Population 
16.2.20 
Concomitant medications 
Safety 
16.2.21 
Hospitalization 
Safety  
 
Graphs 
Graph 
Number 
Title 
Population 
17.1.1 
Dot plot of total oxygen requirement (baseline adjusted AUC) by 
treatment 
mITT 
17.1.2 
Overlaid individual oxygen requirement -time profiles by 
treatment 
mITT 
17.1.3 
Boxplots of oxygen requirement by time and treatment 
mITT 
17.2 
Kaplan-Meier Curves of Cumulative Incidence for Time to 50% 
reduction from baseline in supplemental oxygen based on oxygen 
flow in L/min 
mITT
17.3.1 
Kaplan-Meier Curves of Cumulative Incidence for Time to two 
consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart 
mITT
17.3.2 
Kaplan-Meier Curves of Cumulative Incidence for Time to two 
consecutive negative swabs for SARS-CoV-2 by PCR, at least 24 
hours apart, followed by continued negative swabs 
mITT
17.4 
Kaplan-Meier Curves of Cumulative Incidence for Time to 
intubation and mechanical ventilation 
mITT
17.5 
Kaplan-Meier Curves of Time to Death through Day 30  
mITT