Clinical trial NCT04382924
Conditions: COVID
Sponsor: Algernon Pharmaceuticals
Start date: 2020-08-05; Completion date: 2021-01-26
Enrollment: 168 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this adaptive trial is to determine the clinical efficacy of Ifenprodil in the treatment of patients infected with COVID-19. This Protocol is largely based on the recommendations of the World Health Organization (WHO) R\&D Blueprint Clinical Trials Expert Group COVID-19 Therapeutic Trial Synopsis, and associated Master Protocol.

The choice of the primary outcome measure will be determined by a pilot study of the first 150 subjects. Subject clinical status (on a 7-point ordinal scale) at day 15 in treatment versus the control group is the default primary endpoint.

Detailed description:
NP-120 (Ifenprodil) is an N-methyl-D-Aspartate (NDMA) inhibitor that is specific for the NR2B subunit of the NMDA Receptor. The NMDA receptor, and specifically the NR2B subunit, is involved in glutamate signaling, and is expressed on both neutrophils and T cells. In the case of neutrophils, activation of the NMDA receptor can (1) result in expression of CD11b which targets neutrophils via ICAM-1 to areas of inflammation, and (2) trigger the autocrine release of glutamate. In the case of T-cells, activation of T cells via glutamate can cause (1) T cell proliferation and, (2) the release of cytokines. The activation of T cells and cytokine release can be blocked in vitro by the addition of Ifenprodil. As such it could be a potent anti-inflammatory agent.

Ifenprodil was discovered by a genome wide RNAi assay to uncover gene targets associated with cytoprotective activity against highly pathogenic H5N1 influenza, specifically by preserving cell viability in vitro. When tested in a murine model of H5N1, the drug at clinically relevant doses: (1) improved survivability from 0% at day 6 to 40% day 14 post-infection, (2) the drug significantly reduced edema and lung injury score and (3) reduced infiltrating T cells, neutrophils and NK cells and attenuated the 'cytokine storm'. The mortality rate of H5N1 in humans is \>50%, whereas the mortality rate of COVID-19 infected patients is \< 5%, and both viruses cause acute lung injury and share similar pulmonary pathologies. NP-120 has also been shown to mediate anti-inflammatory responses and reduce pulmonary fibrosis in a murine model of idiopathic pulmonary fibrosis, a complication which can occur after a respiratory virus infection.

Based on the fact that H5N1 has a significantly higher mortality rate than COVID-19 but still shares similar lung pathologies, Algernon Pharmaceuticals believes Ifenprodil could reduce lung injury associated with COVID-19 infection, thereby improving lung function and accelerating patient recovery.

The purpose of this Phase 2b/3 trial is to determine the safety and efficacy of NP-120 in the treatment of COVID-19 infection.

Arms: arm 1: NP-120 (Ifenprodil) 20 mg TID + Standard of Care arm 2: Standard of Care only arm 3: NP-120 (Ifenprodil) 40 mg TID + Standard of Care
Interventions: intervention 1: NP-120 (Ifenprodil)
Intervention descriptions: intervention 1: Ifenprodil, 20 mg TID Ifenprodil, 40 mg TID

Protocol documents:
Prot_000.pdf: 
Ifenprodil  
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Clinical Trial Protocol AGN120-3 
 
 
1 
 
 
 
A RANDOMIZED OPEN LABEL PHASE 2B/3 STUDY OF THE 
SAFETY AND EFFICACY OF NP-120 (IFENPRODIL) FOR THE 
TREATMENT OF HOSPITALIZED PATIENTS WITH 
CONFIRMED COVID-19 DISEASE 
 
INVESTIGTIONAL PRODUCT: 
Ifenprodil tartrate (NP-120) 
 
IND/CTA NUMBER: 
EUDRACT NUMBER: 
148484/238605 
2020-002746-16 
 
PROTOCOL NUMBER: 
AGN120-3 
 
PHASE: 
 
2b/3 
 
PROTOCOL VERSION AND DATE: 
 
Version 2.0 
2020-11-16 
 
SPONSOR ADDRESS 
 
Algernon Pharmaceuticals 
915 – 700 West Pender Street 
Vancouver, BC, Canada  
V6C 1G8 
 
CONFIDENTIAL 
 
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board. The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent 
may not be disclosed to another party unless such disclosure is required by law or regulations. 
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 
 


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CLINICAL STUDY PROTOCOL 
 
Title:  A Randomized Open Label Phase 2b/3 Study of the Safety and Efficacy of NP-120 (Ifenprodil) 
for the Treatment of Hospitalized Patients with Confirmed COVID-19 Disease  
 
Protocol Number:  
 
IND/CTA Number: 
EudraCT Number: 
 
AGN120-3 
 
148484/238605 
2020-002746-16 
Investigational Product: 
Ifenprodil tartrate (NP-120) 
 
Version and Date: 
 
 
v. 2.0 (2020-11-16) 
 
 
Product Sponsor: 
Algernon Pharmaceuticals 
915 – 700 West Pender Street 
Vancouver, BC, Canada  
V6C 1G8 
 
 
 
Authorized Signatory: 
Mark Williams, Ph.D. 
Chief Scientific Officer, Algernon 
Pharmaceuticals 
Suite 915-700 West Pender Street 
Vancouver, BC, Canada V6C 1G8 
 
Study Contact: 
Nancy Stewart, Ph.D. 
Senior Scientific Manager, CDS 
4-1250 Waverley Street 
Winnipeg, MB, Canada R3T 6P6 
204-928-7905 
nstewart@gvicds.com 
 
 
 
 
 
 
 




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INVESTIGATOR AGREEMENT 
 
I have read the protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of the study. I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study. 
 
I will use only the informed consent form approved by Algernon Pharmaceuticals or their 
designee and the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
and will fulfill all responsibilities for submitting pertinent information to the IRB or IEC 
responsible for this study. 
 
I further agree that Algernon Pharmaceuticals or their designee shall have access to any 
source documents from which CRF information may have been generated. 
 
 
 
 
_______________________________________ 
Printed Name of Investigator 
 
 
_______________________________________ 
Title of Investigator 
 
 
_____________________________________________________________ 
Signature of Principal Investigator 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Leader 
Mark Williams, 
Ph.D. 
Chief Scientific Officer,  
Algernon Pharmaceuticals 
Suite 915-700 West Pender Street 
Vancouver, BC, Canada V6C 1G8 
431-777-7759 
Drug Safety 
Physician/Emergency 
Contact (Global) 
Carolynne Darby 
Medical Monitor 
Novotech 
PO Box: 244 Pyrmont NSW 2009 | Level 3, 235 
Pyrmont St Pyrmont NSW 2009 Australia 
+61 2 9199 9506 
Drug Safety 
Physician/Emergency 
Contact (North America) 
Ahmad Khalil 
Medical Director 
Clinical Development Solutions 
4-1250 Waverley Street 
Winnipeg, Manitoba, Canada R3T 6P6 
204-807-2777 
 
 
 


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1. PROTOCOL SYNOPSIS 
 
TITLE:  
A Randomized Open Label Phase 2b/3 Study of the Safety and Efficacy of NP-120 
(Ifenprodil) for the Treatment of Hospitalized Patients with Confirmed COVID-19 Disease 
TRIAL DESIGN: Open-label, multi-center, randomized, parallel group study 
This protocol is largely based on the recommendations of the WHO R&D Blueprint Clinical Trials Expert 
Group COVID-19 Therapeutic Trial Synopsis, and associated Master Protocol. 
NUMBER OF STUDY CENTERS: Approximately 10 
STUDY LOCATION: Canada, US, Australia, Philippines, Romania 
PHASE OF DEVELOPMENT: 2b/3 
INDICATION: Treatment of SARS-CoV-2 Infected Patients  
INVESTIGATIONAL PRODUCT: NP-120 (Ifenprodil tartrate) 
STUDY RATIONALE: NP-120 (Ifenprodil) is an N-methyl-D-Aspartate (NDMA) inhibitor that is 
specific for the NR2B subunit of the NMDA Receptor. The NMDA receptor, and specifically the NR2B 
subunit, is involved in glutamate signaling, and is expressed on both neutrophils and T cells. In the case of 
neutrophils, activation of the NMDA receptor can (1) result in expression of CD11b which targets 
neutrophils via ICAM-1 to areas of inflammation, and (2) trigger the autocrine release of glutamate. In the 
case of T-cells, activation of T cells via glutamate can cause (1) T cell proliferation and, (2) the release of 
cytokines. The activation of T cells and cytokine release can be blocked in vitro by the addition of 
Ifenprodil. As such it could be a potent anti-inflammatory agent. 
Ifenprodil was discovered by a genome wide RNAi assay to uncover gene targets associated with 
cytoprotective activity against highly pathogenic H5N1 influenza, specifically by preserving cell viability 
in vitro. When tested in a murine model of H5N1, the drug at clinically relevant doses: (1) improved 
survivability from 0% at day 6 to 40% day 14 post-infection, (2) the drug significantly reduced edema and 
lung injury score and (3) reduced infiltrating T cells, neutrophils and NK cells and attenuated the 
‘cytokine storm’. The mortality rate of H5N1 in humans is >50%, whereas the mortality rate of SARS-
CoV-2 infected patients is < 5%, and both viruses cause acute lung injury and share similar pulmonary 
pathologies.   NP-120 has also been shown to mediate anti-inflammatory responses and reduce pulmonary 
fibrosis in a murine model of idiopathic pulmonary fibrosis, a complication which can occur after a 
respiratory virus infection.  
Based on the fact that H5N1 has a significantly higher mortality rate than SARS-CoV-2 but still shares 
similar lung pathologies, Algernon Pharmaceuticals believes Ifenprodil could reduce lung injury 
associated with COVID-19 disease, thereby improving lung function and accelerating patient recovery. 
The purpose of this Phase 2b/3 trial is to determine the safety and efficacy of NP-120 in the treatment of 
COVID-19 disease.  
PRIMARY OBJECTIVES: To investigate the clinical efficacy and safety of NP-120 (20 and 40 mg 
TID) compared to standard of care in patients hospitalized with COVID-19 disease. 
• 
The choice of the primary outcome measure for Phase 3 will be determined by a pilot Phase 2b 
study of the first 150 subjects. 


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• 
Subject clinical status (on the WHO7-point ordinal scale) at day 15 is the default primary 
endpoint 
 
SECONDARY OBJECTIVES: To investigate the clinical efficacy of NP-120 (20 and 40 mg TID) as 
compared to the control arm as assessed by: 
 
• 
Ordinal scale: 
o Time to an improvement of one category from baseline on an ordinal scale. 
o Subject clinical status on an ordinal scale at days 3, 5, 8, 11, and 29. 
o Mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 15 and 
29 from baseline 
• 
National Early Warning Score (NEWS): 
o The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever 
occurs first. 
o Change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS 
• 
Oxygenation: 
o Oxygenation free days in the first 28 days (to day 29) 
o Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio 
taken at baseline and measured once daily up to 2 weeks of treatment in IP versus control 
group patients 
• 
Mechanical Ventilation: 
o Ventilator free days in the first 28 days (to day 29) 
o Incidence and duration of new mechanical ventilation use during the trial 
• 
Hospitalization: 
o Duration of hospitalization (days) 
o Time to discharge (days) 
• 
Mortality: 
o 15-day mortality 
o 28-day mortality 
 
EXPLORATORY OBJECTIVES: To investigate the effects of NP-120 (20 and 40 mg TID) on lung 
function, health status, and SARS-CoV-2 RNA status in hospitalized patients with COVID-19 disease.  
SAFETY OBJECTIVES: To study the safety of NP-120 (20 and 40 mg TID) in hospitalized patients 
with COVID-19 disease. 
PATIENT POPULATION: Individuals with COVID-19 disease that are currently hospitalized, and 
either requiring supplemental oxygen, or non-invasive ventilation or high flow oxygen devices. This 
corresponds to a score of 4 or 5 (moderate and severe disease) on the WHO proposed ordinal scale for 
clinical improvement. 
STUDY CONDUCT: The trial will be conducted in two stages: 
1. A Pilot Stage (Phase 2b) and, 
2. A Pivotal stage (Phase 3) 
 
 


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NUMBER OF SUBJECTS FOR THE PILOT STAGE OF THE STUDY: Approximately 150: 
Treatment Arm A:  
Ifenprodil (20 mg TID) on top of Standard of Care (N=50) 
Treatment Arm B: 
Ifenprodil (40 mg TID) on top of Standard of Care (N=50) 
Control Arm:   
Standard of Care (N=50) 
 
For the pilot phase, a sample of approximately 150 patients (50 in Arm A, Arm B and SOC) will be 
recruited. To account for drop out of 10%, a total of 168 patients will be enrolled. 
 
NUMBER OF SUBJECTS FOR THE PIVOTAL PHASE 3 STAGE OF THE STUDY: 
 
For the pivotal phase, a sample of 462 patients (231 in the SOC group and 231 in the active treatment 
group/s) achieves 90% power to detect a change in the log odds ratio of 0.5596 when the significance 
level (alpha) is 0.05 using a two-sided test. A log odds ratio of 0.5596 corresponds to an odds ratio of 1.75 
comparing treatment to SOC. To account for drop out of 10%, a total of 514 patients will be enrolled. 
 
Phase 2b Interim analysis and increasing the patient number: An interim analysis will be conducted on 
the ITT population when 75 patients complete the clinical status assessment at day 15 (the primary 
endpoint).  A preliminary full analysis report of 150 patients with up to Day 29 entered will also be 
presented.  An interim analysis that allows stopping for futility or efficacy will be considered for Phase 3. 
Details for the Phase 3 futility or efficacy analysis will be specified in the Phase 3 Statistical Analysis 
Plan and DSMB Charter as appropriate. 
 
PRIMARY EFFICACY PARAMETER: Patient clinical status (on the WHO 7-point ordinal scale) at 
day 15 in IP versus SOC control group patients:  
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
 
SECONDARY EFFICACY PARAMETERS:  
• 
Status on an ordinal scale assessed daily while hospitalized and on days 15 and 28 in IP versus 
control group patients 
• 
NEWS assessed days 3, 5, 8 ,11 while hospitalized and on days 15 and 29 in IP versus control 
group patients 
• 
Rate of mechanical ventilation in IP versus control group patients 
• 
Duration of mechanical ventilation (if applicable) in IP versus control group patients 
• 
Duration of supplemental oxygen in IP versus control group patients 
• 
Time to return to SpO2 > 94% on room air 
• 
Duration in ICU (if applicable) in IP versus control group patients 
• 
Rate of Mortality in IP versus control group patients 
• 
Duration of hospitalization in IP versus control group patients 
• 
Time to discharge in IP versus control group patients 


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• 
Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio taken at 
baseline and measured once daily up to 2 weeks of treatment in IP versus control group patients 
EXPLORATORY EFFICACY PARAMETERS: 
• 
Changes in the extent of dyspnea from baseline, using a Likert scale, at Days 2, 4, 8, and 14 in IP 
versus control group   
[Likert scale: The patient grades his/her current breathing compared to when he/she first started 
the study (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" 
=markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse].  For 
the first questionnaire (at baseline), the patient compares their current shortness of breath to their 
shortness of breath when they are well. 
• 
Rate of change to patient’s experience of cough (Visual analog scale [VAS]) at Days 2, 4, 8,  and 
14 in IP versus control group 
VAS: The patient draws a vertical line on an axial graph (from 0 to 100) to show the degree of 
how he/she feels about coughing. The number "100" equals the worst coughing the patient has 
ever felt and the number "0" equals the best he/she has felt since baseline. 
• 
Changes in D-dimer in IP versus control group 
• 
Qualitative PCR for SARS-CoV-2 at baseline, days 5 (while hospitalized, and days 15 and 29 (if 
able to return to clinic or still hospitalized) 
• 
Quantitative PCR (if available) for SARS-CoV-2 at baseline, days 5 (while hospitalized, and days 
15 and 29 (if able to return to clinic or still hospitalized) 
 
 
SAFETY PARAMETERS: 
• 
Type, frequency, severity, and relationship of AEs to investigational product (IP)  
• 
Number of patients who discontinue IP due to any AE 
• 
Frequency of clinically significant changes in vital signs and/or laboratory findings 
 
TREATMENT: Test Product:  NP-120, 20 or 40 mg TID for up to 2 weeks (either to hospital discharge, 
or Day 14, whichever comes first). Patients who find it difficult to swallow pills can be administered 
crushed pills of NP-120 and fed via a naso-gastric tube. 
 
Duration of subject participation: Up to 60 days (from screening to follow up on day 60 ± 3 days) 
 
INCLUSION CRITERIA: 
1. Male and female subjects aged ≥18 years of age  
2. Confirmed coronavirus infection 
a) Positive real-time fluorescence polymerase chain reaction of the patient’s respiratory or 
blood specimens for SARS-CoV-2 nucleic acid 
b) Viral gene sequences in respiratory or blood specimens that are highly homologous to 
SARS-CoV-2 
c) Any other diagnostic test accepted by local regulatory authorities 
3. Must be hospitalized and requiring supplemental oxygen, or on non-invasive ventilation or high 
flow oxygen devices (Score of 4 or 5 on WHO Ordinal Clinical Scale) 
4. Female subjects of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least 1 highly effective method of contraception (e.g. oral contraceptives, 


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intrauterine device, diaphragm plus spermicide) from the time of screening and must agree to 
continue using such precautions for 90 days after the final dose of study drug(s) 
5. Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use condom plus spermicide from day 1 through 90 days after receipt of the last dose of study 
drug(s) 
6. Subjects (or legal designate) must have the capacity to understand, sign and date a written, 
informed consent form and any required authorization prior to initiation of any study procedures 
 
EXCLUSION CRITERIA: 
1. Patients with vasodilatory shock, orthostatic hypotension, hypotension, or tachycardia at 
screening/baseline 
2. Patients experiencing cerebral hemorrhage or cerebral infarction at baseline 
3. ALT/AST > 5 times the upper limit of normal; Child-Pugh Score 10 to 15. 
4. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30) 
5. Patients on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 
6. Patients taking droxidopa 
7. Pregnant and lactating women and those planning to get pregnant 
8. Known or suspected allergy to the trial drug or the relevant drugs given in the trial 
9. Presence of other disease that may interfere with testing procedures or in the judgement of the 
Investigator may interfere with trial participation or may put the patient at risk when participating 
in this trial 
10. Know inability of patient to comply with the protocol for the duration of the study 
11. Involvement in a clinical research study within 4 weeks prior to screening and/or prior enrollment 
in the study or plan to participate in another interventional clinical trial during the study period. 
Participation in observational registry studies is permitted. 
 
Schedule of Events: 
Visit 
Procedures 
Visit 1 (Screening/Baseline/ 
Randomization, Days -1 to 1) 
Informed Consent 
Inclusion/Exclusion Criteria 
SARS-CoV-2 RNA status testing 
Pregnancy test  
Demographics/medical history 
Vital signs (including SpO2) 
Physical Exam 
Clinical support data collection 
Safety laboratory testing 
Child-Pugh Score 
Cytokine MarkersPaO2 and PaO2/FiO2 ratio 
ECG 
VAS 
Extent of Dyspnea (Likert Scale) 
Concomitant medications 
Randomization 
Administer IP 
Daily until hospital discharge or Visit 
2 (Day 15) 
Vital signs (including SpO2) 
Clinical support data collection 


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SARS-CoV-2 RNA status testing (Day 5 or discharge, 
whichever comes first) 
Safety laboratory testing (Days 3, 5, 8, 11 if hospitalized) 
Child-Pugh Score (Days 3, 5, 8, 11 if hospitalized) 
Cytokine Markers 
PaO2 and PaO2/FiO2 ratio 
VAS (Days 2, 4, 8, and 14 if hospitalized) 
Extent of Dyspnea (Likert Scale, Days 2, 4, 8, and 14 if 
hospitalized) 
AEs recorded 
Concomitant medications 
IP administration (daily to discharge or Day 14) 
Visit 2 – Day 15 (± 2 days) 
Vital signs (including SpO2) 
Clinical support data collection 
SARS-CoV-2 RNA status testing 
Cytokine Markers 
Safety laboratory testing 
PaO2 and PaO2/FiO2 ratio 
VAS 
Extent of Dyspnea (Likert Scale) 
AEs recorded 
Concomitant medications 
Visit 3 – Day 29 (± 2 days) 
Safety Follow Up Visit 
Vital signs (including SpO2) 
Clinical support data collection 
SARS-CoV-2 RNA status testing (if viral RNA still detected 
on Day 15) 
Safety laboratory testing 
PaO2 and PaO2/FiO2 ratio 
VAS 
Extent of Dyspnea (Likert Scale) 
AEs recorded  
Concomitant medications 
Visit 4 – Day 60 (± 3 days) 
Vital Status 
AEs recorded 
 
STATISTICAL CONSIDERATIONS:  
Primary Efficacy Analysis: The SOC and treatment arms under WHO7 ordinal scale will be compared 
with respect to the primary endpoint using proportional odds models (ordinal logistic regression) adjusted 
for site and age. Treatment will be compared to SOC by testing whether the common odds ratio differs 
from 1.0 at day 15 using two-sided test at 2.5% level of significance under the ITT population set, 
followed by PP population set. All modeling assumptions will be verified. 
Separate 95% CI and p-values will be computed across each of the ordinal scale between SOC and 
treatment arms for both ITT and PP population sets. Multiple comparison techniques (to be detailed in the 
SAP) will be employed to ensure type I error is controlled to 5% for these comparisons. 
If, following the second interim analysis, the primary endpoint changes, details will be written in the SAP, 
and a protocol amendment will be created. 


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Sample size determination:  
For the pilot Phase 2b phase, a sample of 150 patients (50 in Arm A, Arm B and SOC) will be recruited. 
To account for drop out of 10%, a total of 168 patients will be enrolled. 
 
For the pivotal Phase 3 phase, A sample of 462 patients (231 in the SOC group and 231 in the active 
treatment group) achieves 90% power to detect a change in the log odds ratio of 0.5596 when the 
significance level (alpha) is 0.05 using a two-sided test. A log odds ratio of 0.5596 corresponds to an odds 
ratio of 1.75 comparing treatment to SOC. The sample size was estimated using the Tests for Two 
Ordered Categorical Variables module in PASS 14. To account for drop out of 10%, a total of 514 
patients will be enrolled. 
The sample size assumes that the distribution of patients on day 15 will be as shown in Table 2, which is 
scenario 4 in the WHO master protocol (2020) for enrolled patients with moderate to severe disease under 
an odds ratio of 1.75.  
Table 2 Distribution of Patients Across Outcome Categories at Day 15: SOC (WHO MP Scenario 4) 
and Treatment (Assuming OR of 1.75)  
 
Percent of Patients 
Outcome 
SOC 
Treatment 
7. Death 
2 
1.0 
6. Hospitalized & on mechanical ventilation or 
ECMO 
1 
0.6 
5. Hospitalized & on non-invasive ventilation or 
high flow O2 
2 
1.2 
4. Hospitalized & requires supplemental O2 
5 
3.03 
3. Hospitalized not requiring supplemental O2 
17 
11.45 
2. Not hospitalized but limitations on activities 
36 
31.90 
1. Not hospitalized & no limitations on activities 
37 
50.70 
 
PREMATURE WITHDRAWAL/DISCONTIUNATION CRITERIA: 
1. Patients who suffer vasodilative shock. However, physicians can use rescue therapy such as 
vasopressin to restore blood pressure and allow patients to continue in the study, at the discretion of 
the attending physician. 
2. Patients whose ALT/AST rise to >5x upper limit of normal or Child-Pugh of 10-15. 
3. Patients who experience a cerebral hemorrhage or cerebral infarction 


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TRIAL STOPPING RULES: The Medical Monitor team will review AE / SAE data every 2 weeks. If 
there are a concerning number of unexpected AEs, the DSMB will be asked to review safety data in an ad 
hoc meeting. 
The DSMB will review safety data after every 25 subjects are entered into the trial up to 100 subjects, and 
then at every 50 subjects ad hoc reviews will be undertaken if there are other specific safety concerns. The 
study will not stop enrolment awaiting these DSMB reviews, though the DSMB may recommend 
temporary or permanent cessation of enrolment based on their safety reviews. Based on the 
recommendations of the WHO R&D Blueprint Clinical Trials Expert Group and given the severity of 
illness in COVID-19, there are no pre-specified study stopping rules for safety. 
For Phase 2b, an interim analysis will also be performed when 75 patients completed Day 15 assessments 
for the primary endpoint. For this interim analysis with first 75 patients with Day 15 efficacy data, in 
addition to standard DSMB outputs, the following descriptive statistics efficacy analysis will also be 
presented: 
 
1. WHO-7 efficacy with Day 15 assessment 
2. Status on an ordinal scale assessed daily while hospitalized and on days 15 
3. NEWS assessed days 3, 5, 8 ,11 while hospitalized and on days 15 in IP versus control group 
patients 
4. Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio taken at 
baseline and measured once daily up to 2 weeks of treatment in IP versus control group patients 
5. Rate of mechanical ventilation in IP versus control group patients (Patients who received 
Invasive/non-invasive Mechanical Ventilation by Day 15)  
 
For item 5, if a patient did not experience mechanical ventilation by Day 15, he/she will be marked as a 
negative response even if the patient did experience mechanical ventilation past Day 15. This is different 
to the final analysis described above. 
 
ANTICIPATED NUMBER OF PATIENTS PER SITE: TBD 
ANTICIPATE START DATE/COMPLETION DATE: Q3 2020/Q1 2022 
 
 


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TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL ................................................................................................................ 2 
PROTOCOL APPROVAL ............................................................................................................................ 3 
INVESTIGATOR AGREEMENT ................................................................................................................ 4 
PROCEDURES IN CASE OF EMERGENCY ............................................................................................. 5 
1. PROTOCOL SYNOPSIS .......................................................................................................................... 6 
TABLE OF CONTENTS ............................................................................................................................ 14 
LIST OF TABLES ...................................................................................................................................... 18 
LIST OF FIGURES ..................................................................................................................................... 18 
LIST OF ABBREVIATIONS ..................................................................................................................... 19 
2. INTRODUCTION ................................................................................................................................... 21 
2.1 
Background ................................................................................................................................. 21 
2.2 
Study rationale ............................................................................................................................. 21 
2.3 
Risk/Benefit analysis ................................................................................................................... 23 
3. OBJECTIVES AND ENDPOINTS ......................................................................................................... 25 
3.1 
Objectives .................................................................................................................................... 25 
3.2  
Endpoints ..................................................................................................................................... 26 
4. STUDY DESIGN .................................................................................................................................... 28 
4.1 
Overall Design ............................................................................................................................. 28 
4.2 
Planned Number of Patients ........................................................................................................ 30 
4.3 
Data Safety Monitoring Board .................................................................................................... 30 
4.4 
Design Justification ..................................................................................................................... 30 
4.5 
Dose Justification ........................................................................................................................ 31 
4.6 
Trial Schedule and End-of-Trial .................................................................................................. 32 
4.7  
Trial Stopping Rules and Safety .................................................................................................. 32 
5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ................................... 32 
5.1 
Inclusion Criteria ......................................................................................................................... 32 
5.2 
Exclusion Criteria ........................................................................................................................ 33 
5.3 
Screening/Baseline/Randomization ............................................................................................. 33 
5.4 
Premature Withdrawal and Discontinuation Criteria .................................................................. 33 


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5.5 
Rescue Medication and Risk Management Plans ........................................................................ 35 
5.6 
Appropriate Methods of Contraception for Study ....................................................................... 35 
6. STUDY TREATMENT .......................................................................................................................... 37 
6.1 
Description of the Investigational Product .................................................................................. 37 
6.2 
Treatment Administration and Schedule ..................................................................................... 37 
6.3 
Packaging and Labelling ............................................................................................................. 37 
6.4 
Accountability ............................................................................................................................. 37 
6.5 
Compliance with Study Treatment Administration ..................................................................... 38 
7. STUDY ASSESSMENTS AND PROCEDURES .................................................................................. 39 
7.1 
Informed Consent ........................................................................................................................ 39 
7.2 
Trial Flowchart ............................................................................................................................ 39 
7.3 
Visits ............................................................................................................................................ 42 
7.3.1 Visit 1 (Screening/Baseline/Enrollment) ................................................................................. 42 
7.3.2 Daily Assessments (Days 2 - 14; Treatment Period) ............................................................... 43 
7.3.3 Visit 2 (Day 15 ±2; End of Treatment Period) ........................................................................ 43 
7.3.4 Visit 3 (Day 29 ±2; Safety Follow Up Visit) ........................................................................... 44 
7.3.5 Visit 4 (Day 60±2; Vital Status Follow Up Visit) ................................................................... 45 
7.4 
Assessments ................................................................................................................................ 45 
7.4.1 Vital Signs ............................................................................................................................... 45 
7.4.2 Safety Laboratory Parameters ................................................................................................. 45 
7.4.3 Cytokine Markers .................................................................................................................... 46 
7.4.4 Clinical support status ............................................................................................................. 46 
7.4.5 National Early Warning Score (NEWS) .................................................................................. 46 
7.4.6 Demography ............................................................................................................................ 47 
7.4.7 Medical and Surgical History .................................................................................................. 47 
7.4.8 Physical Exam ......................................................................................................................... 47 
7.4.9 Prior and Concomitant Therapies ............................................................................................ 47 
7.4.10 Lung Function Test ................................................................................................................. 47 
7.4.11 Prohibited Therapy .................................................................................................................. 48 
7.4.12 Safety Evaluations ................................................................................................................... 48 
7.4.13 SARS-CoV-2 RNA Testing .................................................................................................... 48 
8. ADVERSE EVENTS .............................................................................................................................. 49 


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8.1 
Adverse Event Definition ............................................................................................................ 49 
8.1.1  Treatment Emergent Adverse Events ...................................................................................... 49 
8.2 
Collection and Reporting of Adverse Events .............................................................................. 49 
8.2.1 Collection of Treatment Emergent Adverse Events ................................................................ 49 
8.2.2 Reporting of Treatment Emergent Adverse Events ................................................................. 50 
8.3 
Abnormal Laboratory Values ...................................................................................................... 52 
8.4 
Adverse Events of Special Interest .............................................................................................. 52 
8.5 
Pregnancy .................................................................................................................................... 52 
8.6 
Serious Adverse Events ............................................................................................................... 52 
8.6.1 SAE Definition ........................................................................................................................ 52 
8.6.2 Reporting of Treatment Emergent SAEs ................................................................................. 53 
8.7 
Follow-up of Treatment Emergent Adverse Events and Serious Adverse Events ...................... 53 
9. DATA HANDLING ................................................................................................................................ 54 
9.1 
Data and Documents ................................................................................................................... 54 
9.2 
Electronic Case Record Form ...................................................................................................... 54 
9.3 
Data Management........................................................................................................................ 54 
9.4 
Records Retention ....................................................................................................................... 54 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ........................................................ 56 
10.1 
Overview ..................................................................................................................................... 56 
10.2 
Study Population Definitions ...................................................................................................... 56 
10.3 
Sample Size and Power Considerations ...................................................................................... 56 
10.4 
Statistical Methods ...................................................................................................................... 57 
10.4.1 General Conventions ................................................................................................................ 57 
10.5 
Patient Disposition ...................................................................................................................... 57 
10.6 
Background and Demographic Characteristics ........................................................................... 57 
10.7 
Prior and Concomitant Medication ............................................................................................. 58 
10.8 
Treatment Exposure and Compliance ......................................................................................... 58 
10.9 
Efficacy ....................................................................................................................................... 58 
10.9.1 Primary Efficacy Analysis ........................................................................................................ 58 
10.9.2 Secondary Efficacy Analyses ................................................................................................... 58 
10.10 Safety Analysis ............................................................................................................................ 58 
10.11 Missing Data................................................................................................................................ 59 


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11. CHANGES IN THE CONDUCT OF THE TRIAL .............................................................................. 60 
11.1 
Protocol Amendments ................................................................................................................. 60 
11.2 
Deviations from the Protocol....................................................................................................... 60 
11.3 
Premature Trial Termination ....................................................................................................... 60 
12. MONITORING PROCEDURES .......................................................................................................... 61 
12.1 
Study Monitoring and Source Data Verification ......................................................................... 61 
12.2 
Audits and Inspections ................................................................................................................ 61 
13. REPORTING AND PUBLICATION ................................................................................................... 63 
13.1 
Clinical Trial Report .................................................................................................................... 63 
13.2 
Confidentiality and Ownership of Trial Data .............................................................................. 63 
13.3 
Publications and Public Disclosure ............................................................................................. 63 
13.3.1 Publication Policy .................................................................................................................... 63 
13.3.2 Public Disclosure ..................................................................................................................... 63 
14. REGULATORY AND ETHICAL ASPECTS ...................................................................................... 64 
14.1 
Good Clinical Practice ................................................................................................................. 64 
14.2 
Investigator Responsibilities ....................................................................................................... 64 
14.3 
Patient Information and Informed Consent ................................................................................. 64 
14.4 
Confidentiality ............................................................................................................................. 65 
14.5 
Institutional Review Board/Independent Ethics Committee ....................................................... 65 
14.6 
End-of-Trial and End-of-Trial Notification ................................................................................. 65 
15. REFERENCES ...................................................................................................................................... 66 
16. APPENDICES ....................................................................................................................................... 68 
16.1 National Early Warning (NEW) Score ............................................................................................ 68 
16.2 Extent of Dyspnea (Likert Scale) .................................................................................................... 69 
16.3 Cough Severity Visual Analogue Scale .......................................................................................... 70 
 
 
 
 


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LIST OF TABLES 
 
Table 1 Emergency Contact Information ................................................................................................... 5 
Table 2  Distribution of Patients Across Outcome Categories at Day 15: SOC (WHO MP Scenario 4) 
and Treatment (Assuming OR of 1.75) ....................................................................................................... 12 
Table 3 Schedule of Events ...................................................................................................................... 40 
 
LIST OF FIGURES  
 
Figure 1  
Putative Mechanism of Ifenprodil on Glutamate Signalling in Neutrophils and T cells ......... 22 
Figure 2 
Survival Rates of H5N1 Infected Mice after Treatment with Ifenprodil ................................. 23 
Figure 3  
Overview of Trial Design ........................................................................................................ 29 
 
 
 


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LIST OF ABBREVIATIONS 
 
°C 
 
degrees Celsius 
AE 
 
adverse event 
AM 
 
before noon 
ALT 
 
alanine transaminase 
APTT  
activated partial thromboplastin time 
AST 
 
aspartate transaminase 
BP 
 
blood pressure 
BUN 
 
blood urea nitrogen 
CFR 
 
code of federal regulations 
cm 
 
centimetres 
CRO 
 
contract research organization 
d 
 
day 
DSMB  
data and safety monitoring board 
ECG 
 
electrocardiogram 
ECMO  
extracorporeal membrane oxygenation 
e-CRF  
electronic case report form 
g 
 
gram(s) 
GCP 
 
good clinical practice 
GGT 
 
gamma-glutamyltransferase 
GMP 
 
good manufacturing practice 
HED 
 
human equivalent dose 
ICF 
 
informed consent form 
ICH 
 
international conference on harmonization 
ICMJE  
international committee of medical journal editors 
IEC 
 
Independent Ethics Committee 
INR 
 
international normalized ratio 
IP 
 
Investigational Product 
IRB 
 
Institutional Review Board 
ITT 
 
intent-to-treat 
IV 
 
intravenous 
L 
 
liter 
LOCF  
last-observation-carried-forward 
MedDRA 
medical dictionary for regulatory activities 
mg 
 
milligram(s) 
min 
 
minute(s) 
mL 
 
millilitre(s) 
mmHg  
millimetres mercury 
MMRM 
mixed model repeated measures 
NEWS  
National Early Warning Score 
ng 
 
nanogram 
NOAEL 
no-observed-adverse-effect level 
pdf 
 
portable document format 
PM 
 
after noon 
PO 
 
by mouth 
PP 
 
per-protocol 
PTT 
 
partial thromboplastin time 
RBC 
 
red blood cell(s) 
SAE 
 
serious adverse event 


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SAP 
 
statistical analysis plan 
SOC 
 
standard of care 
SOP 
 
standard operating procedure 
SRM 
 
study reference manual 
SUSAR 
suspected, unexpected serious adverse reaction 
TEAE  
treatment emergent adverse event 
TID 
 
three times per day 
ULN 
 
upper limit of normal 
WBC  
white blood cell(s) 
wk 
 
week(s) 
 
 
 
 


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2. INTRODUCTION 
2.1 
Background 
COVID-19 is a severe respiratory infection caused by the SARS-CoV-2 virus. The disease occurs was 
first detected in China’s Wuhan province in 2019 and spread globally over several months, in spite of 
efforts to quarantine infected patients. The disease is characterized by fever, dry cough, and fatigue. A 
minority of patients have symptoms such as nasal congestion, nasal discharge, sore throat, muscle pain, 
and diarrhea. Severe patients often suffer from dyspnea and/or hypoxemia one week after symptom onset, 
and severe patients can rapidly progress to acute respiratory distress syndrome, septic shock, difficult to 
correct metabolic acidosis, coagulation dysfunction and multiple organ failure. Most patients have a good 
prognosis and a minority are in critical condition; however, the prognosis of the elderly and those with 
chronic underlying diseases is more poor (Novel Coronavirus Pneumonia Diagnosis and Treatment Plan).  
The mortality rate of the disease has yet to be determined but is generally estimated at <5%. An early 
published study showed that fatalities are often attributed to respiratory failure, and there is evidence that 
suggests that COVID-19 mortality might be due to a virus-activated “cytokine storm syndrome” (Ruan et. 
al., 2020).  
2.2 
Study rationale 
Ifenprodil, an NMDA antagonist, specifically targeting the NR2B subunit, with a piperidinoalkanol 
structure, was first approved in Japan in 1971. It was developed as a vasodilator and has been used in 
Japan in the treatment of dizziness and vertigo, as well as in France in the treatment of Peripheral Arterial 
Obstructive Disease (Williams, 2001). Due to the widespread use of Ifenprodil in Japan and France, the 
safety, tolerability and pharmacokinetics of the drug are well established. The drug was also approved in 
South Korea in 2003. 
The N-methyl-D-aspartate receptor (NMDAr) is historically regarded as a neurological target, but its 
functional expression has been reported in pulmonary tissue. The NMDAr is activated by glutamate (Glu), 
the main excitatory neurotransmitter which acts on receptors in the central nervous system (CNS). But 
overactivation of these receptors can cause several damages to neural cells including death. However, the 
target is also important for immunological function. The NMDA receptor, and specifically the NR2B 
subunit is expressed on both neutrophils (Del Arroyo, 2019) and T cells (Kahlifuss, 2014). In the case of 
neutrophils, activation of the NMDA receptor can (1) result in expression of CD11b which targets 
neutrophils via ICAM-1 to areas of inflammation (Li, 2015), and (2) trigger the autocrine release of 
glutamate. In the case of T-cells, activation of T cells via glutamate can cause (1) T cell proliferation and, 
(2) the release of cytokines. The activation of T cells and cytokine release can be blocked in vitro by the 
addition of Ifenprodil. Recent studies have also shown that the glutamate agonist N-methyl-D-aspartate 
can trigger acute lung injury (ALI). 
 
 


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Figure 1  Putative Mechanism of Ifenprodil on Glutamate Signaling in Neutrophils and T 
cells 
 
 
ALI is a direct and indirect injury to alveolar epithelial cells and capillary endothelial cell, causing diffuse 
pulmonary interstitial and alveolar edema and acute hypoxic respiration failure (Zhe et. al., 2018). ALI is 
characterized by reduced lung volume and compliance, and imbalance of the ventilation/perfusion ratio, 
inducing hypoxemia and respiratory distress and its severe stage (oxygen index <200) known as acute 
respiratory distress syndrome (ARDS). ARDS is a common, devastating clinical syndrome of acute lung 
injury with high mortality ranging from 40% to 60%. Furthermore, pathological findings show that 64% 
of ARDS patients may have pulmonary fibrosis (PF) during convalescence (Qiao et. al., 2009). 
Antagonism of glutamate signaling could therefore ameliorate some of the complications of ALI and 
thereby also prevent the development of PF. 
A recent paper from an independent group in China, found that repurposing ifenprodil could be useful for 
preventing virus-induced acute lung injury (Zhang et. al., 2019). A genome wide RNA interference 
(RNAi) screen was performed to identify gene targets that could rescue lung cell viability from H5N1 
infection in vitro. Drug bank searches for compounds that could affect the same gene targets as were 
identified by the RNAi screen selected ifenprodil as a lead for further testing in an in vivo mouse model of 
H5N1 infection. The H5N1 is a highly lethal infection in humans with a >50% mortality rate, far larger 
than the estimated overall mortality rate of COVID-19 disease at <5%.  
Notably, treatment with ifenprodil was able to significantly increase the survival of H5N1-infected mice: 
after 6 days, survival was 60% in the treatment group vs. 0% in the control group, and after 14 days, 
survival was 40% of ifenprodil-treated animals (see figure inline; No.42 refers to ifenprodil). In addition, 
several markers of lung function improved significantly including the lung injury score, the lung wet/dry 
ratio and the infiltrating cell count, in particular T cells and neutrophils. Multiple proinflammatory 
cytokines/chemokines which are elevated in the “cytokine storm” associated with viral infection were also 
significantly reduced.  
 
 


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Figure 2 
Survival Rates of H5N1 Infected Mice after Treatment with Ifenprodil  
 
 
(Zhang et al., 2019). 
Early clinical reports suggest that the COVID-19 mortality might be due to virus activated “cytokine 
storm syndrome” or fulminant myocarditis, the latter of which could be addressed by Ifenprodil treatment 
(Ruan et al., 2020). 
The ability of Ifenprodil to reduce pulmonary fibrosis was demonstrated using a murine bleomycin-
induced IPF model (see Investigator’s Brochure for details). In this experiment, disease severity as 
measured histologically was significantly reduced in animals treated with Ifenprodil versus control 
animals who received vehicle treatment. Ifenprodil was also tested in a guinea pig citric acid tussive 
model using Gefapixant as a positive control. Ifenprodil was found to significantly reduce both coughing 
frequency and onset of first cough. Pulmonary fibrosis also correlates with outcome in adult respiratory 
distress syndrome (Martin et. al., 1995). 
The purpose of this trial is to determine the clinical efficacy of Ifenprodil in the treatment of patients with 
COVID-19 disease.  This Protocol is largely based on the recommendations of the WHO R&D Blueprint 
Clinical Trials Expert Group COVID-19 Therapeutic Trial Synopsis, and associated Master Protocol. 
The choice of the primary outcome measure for Phase 3 will be determined by a pilot Phase 2b study of 
the first 150 subjects. Subject clinical status (on a 7-point ordinal scale) at day 15 in treatment versus the 
control group is the default primary endpoint. 
2.3 
Risk/Benefit analysis 
Currently, neither a vaccination nor a cure is available for COVID-19 disease. Treatment is performed on 
the basis of symptom management, prevention and management of complications, treatment of underlying 
diseases, prevention of secondary infections, and prompt support of organ functions. Respiratory support 
(including oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation) is 
indicated in severe cases. The use of antiviral therapy (interferon-α, lopinavir/ritonavir, ribavirin, 
chloroquine phosphate, and umifenovir) has been proposed, but data on the effectiveness of these agents 
are not yet available. Use of tocilizumab has been suggested for patients with extensive and bilateral lung 
disease and severely ill patients with elevated IL-6 levels; however, this agent is contraindicated in 
patients with active infections. For patients with progressively deteriorating oxygenation index, rapid 


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imaging progression, and overactive inflammatory responses, short-term (3-5 days) glucocorticoid 
treatment may be used; however, the immunosuppressive function of high-dose glucocorticoid may delay 
the clearance of coronavirus from the system. There remains an unmet need for a therapy which can 
reduce levels proinflammatory cytokines and ameliorate lung injury without inhibiting the immune 
system. 
Ifenprodil has a well-established safety record, having been used in Japan and France for almost 50 years.  
In addition, a review of 8 years of post-marketing surveillance in over 15,000 patients revealed no serious 
side effects.  
Overall, based on the medical need and on the available Ifenprodil safety, tolerability, and efficacy data, 
the proposed Phase 2b/3 clinical trial design is considered appropriate and potential benefits of evaluating 
Ifenprodil in the study outweigh the perceived risks. 
 
 


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3. OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
 
Primary objective: 
• 
To investigate the clinical efficacy and safety of NP-120 (20 and 40 mg TID) compared to 
standard of care in patients hospitalized with COVID-19 disease. 
o The choice of the primary outcome measure for Phase 3 will be determined by a pilot 
Phase 2b study of the first 150 subjects. 
o Subject clinical status (on the WHO 7-point ordinal scale) at day 15 is the default primary 
endpoint  
Secondary objectives:  
• 
To investigate the clinical efficacy of NP-120 (20 and 40 mg TID) as compared to the control arm 
as assessed by: 
o Ordinal scale: 
 
Time to an improvement of one category from baseline on an ordinal scale. 
 
Subject clinical status on an ordinal scale at days 3, 5, 8, 11, and 29. 
 
Mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 
15 and 29 from baseline. 
o National Early Warning Score (NEWS): 
 
The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, 
whichever occurs first. 
 
Change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS. 
o Oxygenation: 
 
Oxygenation free days in the first 28 days (to day 29). 
 
Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 
ratio taken at baseline and measured once daily up to 2 weeks of treatment in IP 
versus control group patients 
o Mechanical Ventilation: 
 
Ventilator free days in the first 28 days (to day 29). 
 
Incidence and duration of new mechanical ventilation use during the trial. 
o Hospitalization 
 
Duration of hospitalization (days). 
Time to discharge (days) 
o Mortality 
 
15-day mortality. 
 
28-day mortality. 
Exploratory objectives: 
• 
To investigate the effects of NP-120 (20 and 40 mg TID) on lung function, health status, and 
SARS-CoV-2 RNA status in hospitalized patients with COVID-19 disease. 
Safety objectives: 
• 
To study the safety of NP-120 (20 and 40 mg TID) in hospitalized patients with COVID-19 
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3.2  
Endpoints 
 
Primary efficacy endpoint: 
Patient clinical status (on the WHO 7-point ordinal scale) at day 15 in IP versus control group patients 
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
Secondary efficacy endpoints: 
• 
Status on an ordinal scale assessed daily while hospitalized and on days 15 and 28 in IP versus 
control group patients 
• 
NEWS assessed day 3, 5, 8 ,11 while hospitalized and on days 15 and 29 in IP versus control 
group patients 
• 
Rate of mechanical ventilation in IP versus control group patients 
• 
Duration of mechanical ventilation (if applicable) in IP versus control group patients 
• 
Duration of supplemental oxygen in IP versus control group patients 
• 
Time to return to room pressure (SpO2 > 94%) 
• 
Duration in ICU (if applicable) in IP versus control group patients 
• 
Rate of Mortality in IP versus control group patients 
• 
Duration of hospitalization in IP versus control group patients 
• 
Time to discharge in IP versus control group patients 
• 
Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio taken at 
baseline and measured once daily up to 2 weeks of treatment in IP versus control group patients 
Secondary safety endpoints: 
The following safety parameters will be evaluated for the duration of the study: 
• 
Type, frequency, severity, and relationship of AEs to investigational product (IP). 
• 
Number of patients who discontinue IP due to any AE. 
• 
Frequency of clinically significant changes in vital signs and/or laboratory findings. 
 
Exploratory efficacy endpoints: 
• 
Changes in the extent of dyspnea from baseline, using a Likert scale, at Days 2, 4, 8, and 14 in IP 
versus control group. [Likert scale: The patient grades his/her current breathing compared to 
when he/she first started the IP (from -3 to 3). "0" = no change, "1" =minimally better, "2" 
=moderately better, "3" =markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" 
=markedly worse]. For the first questionnaire (at baseline), the patient compares their current 
shortness of breath to their shortness of breath when they are well. 
• 
Rate of change to patient’s experience of cough (Visual analog scale [VAS]) at Days 2, 4, 8, and 
14 in IP versus control group. VAS: The patient draws a vertical line on an axial graph (from 0 to 
100) to show the degree of how he/she feels about coughing. The number "100" equals the worst 


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coughing the patient has ever felt and the number "0" equals the best he/she has felt since 
baseline. 
• 
Changes in D-dimer in IP versus control group 
• 
Qualitative PCR for SARS-CoV-2 at baseline, days 5 (while hospitalized, and days 15 and 29 (if 
able to return to clinic or still hospitalized) 
• 
Quantitative PCR (if available) for SARS-CoV-2 at baseline, days 5 (while hospitalized, and days 
15 and 29 (if able to return to clinic or still hospitalized) 
 
 
 


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4. STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2b/3, multicenter, open label, randomized, parallel group study to evaluate the efficacy of 
Ifenprodil in patients with COVID-19 disease. 
In the Phase 2b phase, patients will be randomized in a ratio of 1:1:1 to either a) 20 mg TID IP plus 
Standard of Care group, b) 40 mg TID IP plus Standard of Care or c) Standard of Care only group. 
Investigators will collectively enroll approximately 50 evaluable patients in each treatment group, for a 
total of 150 patients. Patients receive either oral Ifenprodil (20 or 40 mg TID) for up to 14 days in addition 
to Standard of Care, or Standard of Care only.  The Standard of Care for each patient will be captured in 
the eCRF. 
Randomization will be stratified by site, and age (<65 versus ≥65).  
For Phase 2b, One interim statistical analysis will be performed on the primary endpoint of each arm after 
the first 75 patients have completed up to 2 weeks of treatment (Day 15).   This analysis is being done to 
allow safety assessment and some snapshots of efficacy assessments as the trial progresses. 
 
The Phase 2b study will also evaluate the different constructs of the ordinal scale (different days and 
different number of categories) by severity (severe vs. mild-moderate). Data from the Phase 2b study will 
be used to down select and prioritize the secondary endpoints.  . The protocol would then be amended for 
the Phase 3 study to include the additional required number of patients to be recruited for the study to 
meet statistical significance in its primary endpoint. 
An additional placebo arm will be added in the Phase 3 portion of the study. The number of participants to 
be enrolled in Phase 3 pivotal stage will be determined based upon the outcome of pilot Phase 2b stage of 
the study. Participants will be randomized to receive IP plus SOC, or Placebo plus SOC. Details will be 
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Figure 3  
Overview of Trial Design 
 
 
 
 
 
 
 
 
 
Week 1 
Week 2 
Visit 1 
Day 1(-1) 
Ifenprodil (20 or 40 mg 
TID) + Standard of Care 
Treatment 
Follow-up 
Screening/Baseline 
 
Visit 2 
Day 15±2 
Week 3 
Week 4 
Visit 3 
Day 29±2 
Visit 4 
Day 60±2 
Standard of Care 


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4.2 
Planned Number of Patients 
In total, approximately 682 patients with COVID-19 disease at sites in Canada, the US, Australia, the 
Philippines, and Romania will be enrolled competitively. Addition countries may be added depending on 
enrolment.  Adjustments to sample size may be made depending on the results of the final analysis from 
Phase2b. 
4.3 
Data Safety Monitoring Board 
An Independent Data and Safety Monitoring Board (DSMB) will be established. The DSMB is an expert 
advisory group commissioned and charged with the responsibility of evaluating, primarily, cumulative 
safety data at regular intervals. The DSMB will review blinded data and provide recommendations to the 
Sponsor based on their evaluation.  All DSMB members will be independent of the Sponsor and study. 
Membership in the independent DSMB will consist of at least a medical monitor, a physician, a 
statistician, and a pharmacologist. All members have experience and expertise in their field of practice, 
and will not have scientific, financial or conflict of interest related to the trial. 
A DSMB Charter will be prepared and signed prior to initiation of the first DSMB meeting. The charter 
will outline the specific purpose and functions of the DSMB in monitoring the safety of patients in the 
trial. This charter will also describe the procedures for data extraction and data delivery conventions to 
and from the DSMB members for review purposes, and decision criteria to recommend changes to study 
parameters like the primary endpoint, eligibility requirements, and sample size. 
The first DSMB meeting to review safety data, other than the orientation meeting, will occur when 25 
subjects have completed Visit 2 (Day 15) of the study. A subsequent DSMB meeting will occur after each 
25 subjects have completed Visit 2 (Day 15) up to 100 subjects; subsequent to 100 subjects, review will 
occur after every 50 subjects have completed Visit 2 (Day 15).  The study will not stop enrolment 
awaiting these DSMB reviews, although the DSMB may recommend temporary or permanent cessation 
of enrolment based on their safety reviews. 
Should initial enrollment be slower than expected, the DSMB will have the option of reviewing data prior 
to the 25 subject/Visit 2 event if the DSMB believes such a review would be of value. An earlier review 
would be in addition to the planned 25 subject/Visit 2 review. Should any untoward safety issue be 
observed, the DSMB will schedule an immediate meeting to review the relevant safety data.  
Additional data may be requested by the DSMB, and interim statistical reports may be generated as 
deemed necessary and appropriate by the DSMB. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates of the 
AEs in an unblinded fashion and may request the treatment assignment be unblinded for an individual 
subject if required for safety assessment. The DSMB will review grouped and unblinded data in the 
closed session only. As an outcome of each review/meeting, the DSMB will make a recommendation as 
to the advisability of proceeding with study interventions (as applicable), and to continue, modify, or 
terminate this trial. 
4.4 
Design Justification 
This study represents one of the first repurposed investigations of Ifenprodil in patients with COVID-19 
disease. This study will provide information on the safety and clinical efficacy in the SARS-CoV-2 
infected population prior to advancing to larger clinical trials, as well as provide critical information for 
the design of future studies in this population.  


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The purpose of this study is to determine whether Ifenprodil is effective and safe in the treatment of 
patients with COVID-19 disease. The primary measure of efficacy will be patient clinical status (on a 7-
point ordinal scale) at day 15 in IP versus control group patients.  This protocol is based on the 
recommendations of the WHO R&D Blueprint Clinical Trials Expert Group.   
The Phase 2b stage will be an open label study with patients, investigator, site and CRO staff aware of 
treatment received.  The Phase 3 stage of the protocol will also include a placebo arm to allow for double-
blinding. 
4.5 
Dose Justification 
 
20 mg TID: 
20 mg TID of Ifenprodil is within the recommended dosing guidelines for other indications as per the 
manufacturer’s package insert. 
Assuming a 60 kg person, a single 20 mg dose would yield a 0.333 mg/kg weight adjusted dose. To 
convert to a mouse dose, a factor of 12 is applied to the human equivalent dose (Nair and Jacob, 2016), 
which results in approximately 4 mg/kg for mice.  
A 4 mg/kg dose given three times daily (12 mg/kg total daily dose) was found to be efficacious in 
reducing pulmonary fibrosis, and better than a single 30 mg/kg daily dose in reducing fibrosis in mice. 
The independent study involving H5N1 infection in mice also used a single daily dose of 20 mg/kg.  
Similarly, the single 1.5 mg/kg dose selected in the acute cough model in the guinea pig was also 
equivalent to the single 20 mg/kg human dose on a body surface area adjusted basis based on an 
adjustment factor of 4.6.  
Thus, the current 20 mg TID human dose is proposed to be a reasonable dose for this initial exploratory 
study. Please refer to the Investigator’s Brochure for additional details on the aforementioned pre-clinical 
studies. 
40 mg TID: 
40 mg TID of Ifenprodil is also expected to be a reasonable dose for this exploratory study.  Long term 
pre-clinical toxicological studies suggest dosing up to 16 mg/kg/day should produce no adverse effects. 
Specifically, the no-observed-adverse-effect level (NOAEL) observed were 50 mg/kg/day (HED of 8 
mg/kg/day) in repeat oral dose studies in the rat of up to 52 weeks (Kawai et al, 1975a; Kawai et al, 
197b), 30 mg/kg day (HED of 17 mg/kg/day) in dogs of up to 6 months (Nagata et al, 1997), and 50 
mg/kg/day (HED 16 mg/kg/day) in rabbit of 30 days (Kawai et al, 1976). 
Furthermore, high doses of Ifenprodil (60-300 mg/day) have been used for analgesic purposes in humans. 
In addition, a trial using 120 mg/day of Ifenprodil for methamphetamine dependence is underway in 
Japan (UMIM clinical trial registry UMIN000030849; Kotajima-Murakami et al, 2019) for 84 days. 
Assuming a 60 kg subject, the proposed 40 mg TID dose in this study is 2 mg/kg/day dose level and 
limited to 14 days exposure, well within previously used dosing regimens.  
 


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4.6 
Trial Schedule and End-of-Trial 
First patient first visit is planned for the Third Quarter of 2020 and last patient last visit is planned for the 
First Quarter 2022. The expected total duration of the trial is approximately 18 months. 
The End of Trial is defined as the date of the last visit of the last patient to complete the study. 
At the end of the trial patients will be treated for their COVID-19 disease at the discretion of the 
Investigator. 
4.7  
Trial Stopping Rules and Safety 
The Medical Monitor will review AE / SAE data every 2 weeks. If there are a concerning number of 
unexpected AEs, the DSMB will be asked to review safety data in an ad hoc meeting. 
The DSMB will review safety data after every 25 subjects are entered into the trial up to 100 subjects, and 
then at every 50 subjects; ad hoc reviews will be undertaken if there are other specific safety concerns. 
The study will not stop enrolment awaiting these DSMB reviews, though the DSMB may recommend 
temporary or permanent cessation of enrolment based on their safety reviews. Following the 
recommendations of the of the WHO R&D Blueprint Clinical Trials Expert Group and given the severity 
of illness in COVID-19, there are no pre-specified study stopping rules for safety. 
   
5. SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA 
 
Deviations from inclusion and exclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or patient safety. Therefore, adherence to the 
criteria as specified in the protocol is essential. 
5.1 
Inclusion Criteria 
1. Male and female subjects aged ≥18 years of age  
2. Confirmed coronavirus infection 
a) Positive real-time fluorescence polymerase chain reaction of the patient’s respiratory or 
blood specimens for SARS-CoV-2 nucleic acid 
b) Viral gene sequences in respiratory or blood specimens that are highly homologous to 
SARS-CoV-2 
c) Any other diagnostic test accepted by local regulatory authorities 
3. Must be hospitalized and requiring supplemental oxygen, or on non-invasive ventilation or high 
flow oxygen devices (Score of 4 or 5 on WHO Ordinal Clinical Scale) 
4. Female subjects of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least 1 highly effective method of contraception (e.g. oral contraceptives, 
intrauterine device, diaphragm plus spermicide) from the time of screening and must agree to 
continue using such precautions for 90 days after the final dose of study drug(s) 


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5. Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use condom plus spermicide from day 1 through 90 days after receipt of the last dose of study 
drug(s) 
6. Subjects (or legal designate) must have the capacity to understand, sign and date a written, 
informed consent form and any required authorization prior to initiation of any study procedures 
5.2 
Exclusion Criteria 
1. Patients with vasodilatory shock, orthostatic hypotension, hypotension, or tachycardia at 
screening/baseline 
2. Patients experiencing cerebral hemorrhage or cerebral infarction at baseline 
3. ALT/AST > 5 times the upper limit of normal; Child-Pugh Score 10 to 15. 
4. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30) 
5. Patients on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 
6. Patients taking droxidopa 
7. Pregnant and lactating women and those planning to get pregnant 
8. Known or suspected allergy to the trial drug or the relevant drugs given in the trial 
9. Presence of other disease that may interfere with testing procedures or in the judgement of the 
Investigator may interfere with trial participation or may put the patient at risk when participating 
in this trial 
10. Know inability of patient to comply with the protocol for the duration of the study 
11. Involvement in a clinical research study within 4 weeks prior to screening and/or prior enrollment 
in the study or plan to participate in another interventional clinical trial during the study period. 
Participation in observational registry studies is permitted. 
5.3 
Screening/Baseline/Randomization 
Screen failures are defined as patients who consent to participate in the clinical trial but are never 
subsequently enrolled. In this study, a patient can become a screen failure at any time during the 
screening visit (Visit 1), prior to randomization. In order to ensure transparent reporting of screen failure 
patients, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen failure information is required 
including Demography, Screen Failure details, and Eligibility Criteria. 
When a patient meets all eligibility requirements, study site personnel will consult the study database to 
obtain the patient’s randomization number and treatment assignment.  
Under no circumstances will patients randomized in the trial be permitted to be re-screened and 
randomized for a second time in this trial.  
5.4 
Premature Withdrawal and Discontinuation Criteria 
 
5.4.1  Withdrawal from Randomized Treatment or from the Study by Patient 
The patients have the right to withdraw from the trial at any time for any reason, without the need to 
justify their decision. However, the Investigator should record the reason for the patient’s withdrawal, if 


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possible. Every effort should be made to encourage patients to remain in the study for the duration of their 
planned outcome assessment.   
In case the patient has withdrawn consent, no new data can be entered into the e-CRF and data will be 
recorded in the medical records only. Correction of previous data entries and/or entering of data related to 
visits/procedures done prior to but made available after withdrawal of consent (e.g. laboratory results) 
will be allowed unless the patient disapproves it. 
5.4.2 
Discontinuation of Study Drug 
A patient in this clinical study may discontinue study drug for any of the following reasons: 
• 
An adverse event which, in the opinion of the Investigator necessitates withdrawal of study 
drug 
• 
A patient’s substantial non-compliance (e.g. visits non-compliance)  
• 
The Investigator’s opinion that continuing the patient in the trial is not appropriate. The 
Investigator may withdraw a patient at any time if it is considered to be in the patient’s best 
interest. 
• 
Patient requests to discontinue study drug 
• 
Patients who suffer vasodilative shock. However, physicians can use rescue therapy such as 
vasopressin to restore blood pressure and allow patients to continue in the study, at the 
discretion of the attending physician. 
• 
Patients whose ALT/AST rise to >5x upper limit of normal or Child Pugh score of 10-15. 
• 
Patients who experience a cerebral hemorrhage or cerebral infarction 
Patients discontinued from study treatment should remain in the study and complete all remaining study 
assessments.  If not possible, at a minimum, they should be invited to a Safety Follow-up Visit 7 days 
after the last dose of IP as soon as possible after a decision of discontinuation has been taken. At these 
visits, the Investigator will obtain all the required details and document the date of the premature 
termination and the main reason in the e-CRF.  If the reason for study drug discontinuation is an adverse 
event, the specific event will be recorded in the e-CRF. 
NOTE:  patients that progress to mechanical ventilation during the study may remain on study drug and 
should not be withdrawn. 
Definition of Dose Limiting Toxicity: 
The occurrence of any of the following toxicities from the initial dose of Ifenprodil administration (in 
combination with Standard of Care (SOC)) which results in: 
a. The necessity to delay ifenprodil administration in the participant, OR 
b. To reduce the dose of ifenprodil administered, either for the participant, or for subsequent 
participants, 
will be considered a DLT, if judged by the investigator to have a reasonable possibility of being related to 
the ifenprodil administration.   
Severity is graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0 equivalents of mild, moderate or severe: 
1. Grade 3 or higher toxicity, except elevations in gamma-glutamyltransferase (GGT) 


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2. Grade ≥ 3 AST/ALT elevation 
3. Grade ≥ 2 AST/ALT elevation with Grade ≥ 2 bilirubin elevation 
5.4.3 
Withdrawal of Patients from the Study 
The Investigator also has the right to withdraw patients from the study post initial dosing. Whenever 
possible the patient should be followed for all assessments per protocol.  Patients will be withdrawn in the 
following circumstances: 
• 
Patients withdraws consent or requests discontinuation from the study for any reason 
• 
Death of the patient 
• 
Termination of the study 
• 
Loss to follow-up (every effort must be made to contact the patient; phone calls on three separate 
days must be made, and a certified letter must be sent to the patient’s most recent address) 
Any withdrawal must be fully documented in the e-CRF and source documents, registered in the e-CRF 
as discontinued, and followed by the Investigator/Investigative Staff.   Patients who withdraw from the 
study or are lost to follow-up after signing the informed consent form and randomization will not be 
replaced. 
5.5 
Rescue Medication and Risk Management Plans  
Cautions from the manufacturer of Ifenprodil include monitoring for hypotension, palpitations/increased 
heart rate, and risk of bleeding (including those patients on drugs with a risk of bleeding).  Investigators 
should monitor their patients for occurrence of these adverse events and proceed as follows: 
Vasopressin can be used as a rescue therapy for patients who suffer vasodilative shock. If low blood 
pressure occurs, use of vasopressor medication may also be considered. This may or may be coincident 
with an increased heart rate, in which case a vasopressor may correct both events. In the event of an 
increased heart rate in the absence of coincident hypotension, use of a positive inotropic agent may be 
considered. In the event of an increased risk of bleeding, antifibrinolytic therapy may be considered. 
Please consult with the Medical Monitor regarding the best course of treatment should any of these events 
occur.   
In addition, patients should be monitored for elevation in liver enzymes.  Those patients whose ALT/AST 
rise to >5x the upper limit of normal and/or Child Pugh score of 10-15 should be discontinued from study 
medication (ifenprodil). In addition, the Medical Monitor and DSMB will monitor for the occurrence of 
these adverse events as part of their normal safety review.  Additional guidance or updates to the protocol 
will be provided if necessary. 
The DSMB will review the adverse events profile after 25, 50, 75 and 100 patients enrolled in the study, 
then every 50 patients thereafter. Particular attention will also be paid to patients over 65 for the 
frequency and severity of serious adverse events (e.g. ALT/AST, creatinine) as the manufacturer has 
mentioned caution should be taken in this particular age group.  If, based on the DSMB’s opinion, there is 
a significant concern in any of the identified risk groups, additional restrictions may be added to the 
inclusion/exclusion criteria.  
5.6 
Appropriate Methods of Contraception for Study 
Females of childbearing potential:  Women who are sexually active with a non-sterilized male partner 
must use at least 1 highly effective method of contraception, such as oral contraceptives, intrauterine 


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device, or diaphragm plus spermicide from the time of screening and must agree to continue using such 
precautions for 90 days after the final dose of study drug(s) 
Non-sterilized males:  Men who are sexually active with a female partner of childbearing potential must 
use condom plus spermicide from day 1 through 90 days after receipt of the last dose of study drug(s) 
     
 


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6. STUDY TREATMENT 
6.1 
Description of the Investigational Product 
The chemical name of Ifenprodil tartrate is (1RS,2SR)-4-[2-(4-Benzylpiperidin-1-yl)-1-hydroxypropyl] 
phenol hemi-(2R,3R)-tartrate. The drug is more commonly referred to as ifenprodil. Ifenprodil will be 
provided as white, round, biconvex, film-coated tablets containing 20 mg of the active ingredient.  All IP 
is provided by the sponsor and is produced and handled according to the principles of Good 
Manufacturing Practice (GMP). 
6.2 
Treatment Administration and Schedule 
Tablet/s (20 mg TID arm = 1 tablet; 40 mg TID arm = 2 tablets) will be taken by mouth TID after food (if 
possible) in the in the morning (AM, upon rising), in the afternoon (PM, 6-10 hours following first dose), 
and evening (PM, 6-10 hours before the next day’s anticipated first dose). Best efforts should be made to 
keep the three doses approximately 8 hours apart.  The length of dosing for the study is up to 2 weeks 
(either to hospital discharge, or Day 14, whichever comes first). 
The first dose of study medication will be taken on day 1 at the first visit, following randomization. 
In cases where the patient is unable to swallow tablets the use of a nasogastric/stomach tube is permitted. 
Crushing and administration of tablets should follow local practices/SOPs. 
Study drug administration should continue until the end of Day 14, or hospital discharge, whichever 
comes first.  
6.3 
Packaging and Labelling 
The contents of the label will be in accordance with all applicable regulatory requirements. 
Description of Product: White, round, biconvex, film-coated tablets containing 20 mg of the active 
ingredient. 
Investigational Drug Packaging and Labeling: The study drug (Ifenprodil) will be supplied by 
Algernon Pharmaceuticals, in cartons containing blister packs (50 tablets contained in 5blister packs (10 
tablets per blister pack)). 
 
The study drug will be provided to the sites by Algernon Pharmaceuticals.  Separate labels, as per the 
GMP regulations and requirements will also be provided for site staff to apply to the packages and blister 
packs, as provided by the local laws.  All investigational labels for the study drug will meet applicable 
country specific regulatory requirements. 
 
Storage: Store in a dry dark place at temperatures no higher than 25°C, keep protected from moisture. 
Dispensing: Study treatment must be stored in a secure area under the appropriate physical conditions for 
the product. Access to and administration of the study treatment will be limited to the investigator and 
authorized site staff. 
Drug Return/Destruction: The clinical site, upon confirmation with Sponsor, should follow their local 
regulations for final disposition of unused study treatment. 
6.4 
Accountability 
Only patients enrolled in the study may receive study treatment.  


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The investigator, institution, or the head of the medical institution (where applicable) is responsible for 
study treatment accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation and 
final disposition records). Study treatment must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of the study treatment will be limited to the 
investigator and authorized site staff. 
Under normal conditions of handling and administration, study treatment is not expected to pose 
significant safety risks to site staff. 
The Sponsor (or designee) will review with the Investigator and relevant site personnel the process for IP 
return, disposal, and/or destruction, including responsibilities for the site versus the Sponsor (or 
designee).  Further details can be found in the Pharmacy Manual. 
6.5 
Compliance with Study Treatment Administration 
Study personnel will review the instructions printed on the package with the study patients prior to 
dispensing the IP. The IP will be dispensed as noted in Table 3.  
 
 


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7. STUDY ASSESSMENTS AND PROCEDURES 
7.1 
Informed Consent 
Voluntary written informed consent must be obtained before any study-related procedures are performed 
in accordance with the International Conference on Harmonization (ICH) E6 Guidelines for Good 
Clinical Practise (GCP) and the regulatory requirements of informed consent for each jurisdiction (e.g. 
US Title 21 Code of Federal Regulations (CFR) Part 50, Canadian Food and Drug Regulations, Part C 
Division 5). Consent must be documented by the use of a written consent form approved by Algernon 
Pharmaceuticals and the IEC/IRB. A copy of the signed informed consent will be provided to the 
patient/parent/guardian/legal representative signing the form and the original retained in the source 
documents of the study participant. Documentation of the consent process must be collected with the 
source documents at the site. 
7.2 
Trial Flowchart 
The trial includes a Screening/Baseline visit, a 2-week open label Treatment Period, and a 6-week Safety 
Follow-up Period to Day 60. All periods are associated with evaluations and procedures that must be 
performed at specific time points, as described in Section 7.3. The Schedule of Events (Table 3) 
summarises the frequency and timing of trial events. 


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Table 3 
Schedule of Events 
Trial Activity 
Screening/Baseline/ 
Enrolment visit 
Daily until 
hospital 
discharge 
End of 
treatment  
Follow-up period 
Day 
1 
2-14 
15 
29 
60 
Allowed window for visit (±) 
-1a 
 
2 
2 
3 
Visit 
1 
 
2b 
3 
4 
Informed consent 
● 
 
 
 
 
Inclusion/exclusion criteria 
including confirmation of 
COVID-19 diagnosis 
● 
 
 
 
 
Confirmation SARS-CoV-2h 
● 
● 
● 
● 
 
Pregnancy test 
● 
 
 
 
 
Demographics/Medical History 
● 
 
 
 
 
Physical Exam 
● 
 
 
 
 
Vital signsc 
● 
● 
● 
● 
 
Clinical support data collectionf 
● 
● 
● 
● 
 
Safety Laboratory Testingd 
● 
● 
● 
● 
 
Cytokine Markersk 
● 
● 
● 
 
 
Child-Pugh Scorei 
● 
● 
 
 
 
PaO2 and PaO2/FiO2 ratioj 
● 
● 
● 
● 
 
ECG 
● 
 
 
 
 
Cough Severity (VAS)e 
● 
● 
● 
● 
 
Extent of Dyspnea (Likert 
Scale)e 
● 
● 
● 
● 
 
Adverse Events documented 
● 
● 
● 
● 
● 
Concomitant Medications 
● 
● 
● 
● 
 
Randomization 
● 
 
 
 
 
Administer IP 
● 
● 
 
 
 
Vital Status 
 
 
 
 
●g 
a Screening/baseline may occur up to 24 hours prior to randomization 
bTreatment can be given up to 14 days post randomization, or until hospital discharge, whichever comes first. If patient is 
discharged prior to Day 14, the next visit should be Visit 2. 
c Includes blood pressure (measured after the patient has been in a seated position (if possible) for ≥3 minutes of rest), pulse, 
respiratory rate, body temperature, and SpO2.  Body weight and height will be measured at the screening visit only. 


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d Baseline, Days 3, 5, 8, 11 if hospitalized, Day 15, Day 29 
e Baseline, Days 2, 4, 8, and 14 if hospitalized, Day 15 (if not done Day 14), Day 29 
f Includes NEW Score, on Baseline, Days 3, 5, 8, 11 if hospitalized, Day 15, Day 29 
g Vital status (is patient alive) 
h Baseline, Days 5 (or discharge, whichever comes first) and 15.  Day 29 for subjects with viral RNA detected at Day 15. 
Qualitative (mandatory) and Quantitative (if available) testing done all days. 
i Baseline, Days 3, 5, 8, 11 if hospitalized  
j Minimum complete baseline, Days 3, 5, 8, 11, 15 and 29.  If PaO2 not able to be taken, SpO2 should be obtained using a 
forehead sensor.  Fingertip probes may be used if forehead sensors are not available. Remain consistent with the method of 
testing for the patient over the course of the study.   
k Cytokine markers at Baseline, Day 5, Day 15 (if available per local lab):  IFN-γ, GM-CSF, IL-6, IL-12, TNF-α  


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7.3 
Visits 
7.3.1 
Visit 1 (Screening/Baseline/Enrollment) 
At Visit 1, information will be collected for evaluation of trial eligibility by provided information as 
follows and patients will be randomized and dosed after confirmation of eligibility: 
• 
Signing ICF (prior to any trial-related activities) 
• 
Inclusion criteria and exclusion criteria 
• 
Demographics (gender, date of birth, race and ethnic origin) and relevant medical and surgical 
history 
• 
Confirmation of COVID-19 diagnosis (SARS-CoV-2 RNA confirmation).  Include dates of onset 
of symptoms (if available) and initiation of treatment. 
• 
Pregnancy test (females of reproductive age; Romania: Serum beta-human chorionic 
gonadotropin [β-HCG]; Rest of World: Serum beta-human chorionic gonadotropin [β-HCG] or 
urine test is acceptable) 
• 
Vital signs measurements (including pulse, respiration rate, body temperature, systolic and 
diastolic blood pressure measured with the patient in a seated position [if possible] after ≥3 
minutes of rest), and SpO2. Body weight and height will be included for the screening visit only 
• 
Limited Physical Exam 
• 
Assess baseline measures of clinical support 
o Hospitalized 
o Oxygen requirement 
o Non-invasive mechanical ventilation (via mask) 
o Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) 
o ECMO requirement 
o Ordinal Scale Assessment 
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
o For the purposes of eligibility/baseline the worse score from the previous day (Day -1) 
will be used 
o NEW Score 
• 
Safety laboratory testing 
• 
Child-Pugh Score 
• 
Cytokine Markers 
• 
PaO2 and PaO2/FiO2 ratio 
• 
ECG 
• 
VAS (if possible) 
• 
Extent of Dyspnea (if possible).  For the first questionnaire (at baseline), the patient compares 
their current shortness of breath to their shortness of breath when they are well.) 
• 
Concomitant medications documented 
• 
Randomization* after eligibility confirmation.  All screening/baseline procedures must be 
completed prior to randomization and administration of study medication. 


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• 
Begin administration of study medication after randomization (within 24 hours of screening 
procedures).   
*Randomization should occur within 24 hours of screening procedures. 
7.3.2 
Daily Assessments (Days 2 - 14; Treatment Period) 
At each study day while hospitalized, the following data will be collected: 
• 
Vital signs (including pulse, respirations rate, body temperature, systolic and diastolic blood 
pressure, SpO2) 
• 
Assess measures of clinical support 
o Hospitalized 
o Oxygen requirement 
o Non-invasive mechanical ventilation (via mask) 
o Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) 
o ECMO requirement 
o Ordinal Scale Assessment 
o The ordinal scale is an assessment of the clinical status at the first assessment of a given 
study day. Each day, the worse score for the previous day will be recorded. i.e. on Day 3, 
Day 2 score is obtained and recorded as Day 2. The scale is as follows: 
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
o NEW Score (Days 3, 5, 8 ,11 if still hospitalized) 
• 
SARS-CoV-2 RNA status testing (Day 5, or discharge, whichever comes first) 
• 
Safety laboratory testing (Days 3, 5, 8, 11 if still hospitalized) 
• 
Child-Pugh Score (Days 3, 5, 8, 11 if still hospitalized) 
• 
Cytokine Markers (Day 5) 
• 
PaO2 and PaO2/FiO2 ratio  
• 
VAS score questionnaire (Days 2, 4, 8, and 14 if still hospitalized) 
• 
Extent of Dyspnea (Likert Scale, Days 2, 4, 8, and 14 if still hospitalized) 
• 
Adverse Events recorded 
• 
Concomitant medications 
• 
IP administration (daily until discharge or Day 14) 
7.3.3 
Visit 2 (Day 15 ±2; End of Treatment Period) 
During this visit the following data will be collected: 
• 
Vital signs (including pulse, respirations rate, body temperature, systolic and diastolic blood 
pressure, SpO2) 
• 
Assess measures of clinical support 
o Hospitalized 
o Oxygen requirement 
o Non-invasive mechanical ventilation (via mask) 


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o Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) 
o ECMO requirement 
o Ordinal Scale Assessment 
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
o NEW Score 
• 
SARS-CoV-2 RNA status testing 
• 
Cytokine Markers 
• 
Safety laboratory Testing 
• 
PaO2 and PaO2/FiO2 ratio 
• 
VAS (if not performed on Day 14; if possible) 
• 
Extent of Dyspnea (if not performed on Day 14; if possible) 
• 
Adverse Events recorded 
• 
Concomitant medications 
It is understood that restrictions on the return of study patients to the clinical site may be in place after 
their discharge from hospital.  If not possible for the patient to return, the site may use remote methods 
(for example Telehealth, remote or nurse for hire, remote laboratories) to obtain the visit specific 
measurements/samples for both Visits 2 (Day 15; End of Treatment) and 3 (Day 29; Safety Follow Up 
Visit). 
7.3.4 
Visit 3 (Day 29 ±2; Safety Follow Up Visit) 
For all continuing patients, a Safety Follow-up Visit will be scheduled on Day 29 (Week 4).   For patients 
that have discontinued from the study, they will be invited to attend a Safety Follow up visit 7 days after 
their last dose of IP   and following the same schedule of events as Visit 3.   
The following data will be collected: 
• 
Vital signs (including pulse, respirations rate, body temperature, systolic and diastolic blood 
pressure, SpO2) 
• 
Assess measures of clinical support 
o Hospitalized 
o Oxygen requirement 
o Non-invasive mechanical ventilation (via mask) 
o Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) 
o ECMO requirement 
o Ordinal Scale Assessment 
8. Not hospitalized, no limitations on activities 
9. Not hospitalized, limitation on activities 
10. Hospitalized, not requiring supplemental oxygen 
11. Hospitalized, requiring supplemental oxygen 
12. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
13. Hospitalized, on invasive mechanical ventilation or ECMO 


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14. Death 
o NEW Score 
• 
SARS-CoV-2 RNA status testing (if still positive on Day 15) 
• 
Safety laboratory Testing 
• 
PaO2 and PaO2/FiO2 ratio 
• 
VAS (if possible) 
• 
Extent of Dyspnea (if possible) 
• 
Adverse Events recorded 
• 
Concomitant medications 
7.3.5 
Visit 4 (Day 60±2; Vital Status Follow Up Visit) 
At the Safety Follow-up Visit, the following data will be collected: 
• 
Vital Status (alive, deceased) 
• 
Adverse Events recorded 
 
Note: This visit may be conducted via phone call. 
 
7.4 
Assessments 
7.4.1 
Vital Signs 
Vital signs will be measured as indicated in Section 7.3 and Table 3 and will include blood pressure 
(measured after the patient has been in a seated position, if possible, for ≥3 minutes of rest), pulse, 
respiration rate, body temperature, SpO2, and weight and height (screening visit only). Standard of care 
measurements can be used if they fall within the protocol specific windows. 
The Investigator should evaluate the clinical significance of the results. Clinically significant abnormal 
findings will be reported as adverse events. 
7.4.2 
Safety Laboratory Parameters 
Samples for laboratory analysis in local laboratories will be collected during the study at time point 
specified in the schedule of events (See Table 3 and Section 7.3). All safety laboratory tests will be 
analyzed at the local laboratory, unless specified in the protocol. Standard of care measurements can be 
used if they fall within the protocol specific windows. 
The Investigator will review the laboratory results and evaluate and document whether the results are 
normal or abnormal and whether abnormal results are non-clinically significant or clinically significant. 
Pre-existing clinically significant conditions diagnosed as a result of the screening procedures must be 
recorded as medical history. If any clinically significant abnormal findings are discovered after informed 
consent or any pre-existing conditions worsen during the trial, these must be recorded as adverse events. 
The laboratory report will be signed and dated by the Investigator. 
7.4.2.1 Hematology 
Hemoglobin, hematocrit, white blood cell counts, including differential, platelet count, red blood 
cell count, myoglobin 
 


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7.4.2.2  Chemistry 
Glucose, blood urea nitrogen (BUN), serum creatinine, sodium, potassium, chloride, bicarbonate, 
ALT, AST, GGT, alkaline phosphatase, total bilirubin, calcium, phosphorus, albumin, total 
protein, uric acid 
7.4.2.3 Coagulation 
APTT, PT, INR, D-dimer. 
7.4.2.4 Urinalysis 
Specific gravity, hydrogen ion concentration (pH), protein, glucose, bilirubin, ketone, 
urobilinogen, blood, leukocytes, casts, bacteria. 
7.4.3 
Cytokine Markers 
The following cytokines should be collected if available at local laboratory:  IFN-γ, GM-CSF, IL-6, IL-
12, TNF-α  
Cytokine markers to be collected at Baseline, Day 5, Day 15. 
7.4.4 
Clinical support status  
Patients will be assessed for their measures of clinical support, including: 
• 
Hospitalized 
• 
Oxygen requirement 
• 
Non-invasive mechanical ventilation (via mask) 
• 
Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) 
• 
ECMO requirement 
• 
Ordinal Scale Assessment 
o The ordinal scale is an assessment of the clinical status at the first assessment of a given study 
day. Each day, the worse score for the previous day will be recorded. i.e. on Day 3, Day 2 
score is obtained and recorded as Day 2.  
o For the purposes of baseline the worse score from the previous day (Day -1) will be used 
o The scale is as follows: 
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
7.4.5 
National Early Warning Score (NEWS) 
The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes (WHO 
R&D Blueprint Master Protocol; Royal College of Physicians 2012 and 2017). This score is based on 7 
clinical parameters. The NEW Score is being used as an efficacy measure. 
This should be evaluated at the first assessment of a given study day. These parameters can be obtained 
from the hospital chart using the last measurement prior to the time of assessment. This is recorded for the 
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A copy of the Table for determining NEW Score can be found in Appendix 16.1. 
7.4.6 
Demography 
Demographic data will be collected at the Screening Visit, including gender, date of birth, race, and ethnic 
origin (to the extent allowed by local regulations). 
7.4.7 
Medical and Surgical History 
Information on clinically significant previous and concomitant illnesses, or any clinically significant signs 
or symptoms that are present before informed consent, or pre-existing conditions identified through 
findings from assessments and examinations done during the Screening Visit will be recorded as medical 
and surgical history at Screening. For planned procedures/hospitalisations during the trial, documentation 
should be completed at the time of the Screening. 
7.4.8 
Physical Exam 
A limited physical examination will be performed at screening. 
Assessments for the physical examination should include those systems affected by the SARS-CoV-2 
infection.  These can include: General appearance, Eyes, Ears/Nose/Throat, Respiratory 
(Chest/Pulmonary), Heart, Abdomen, Vascular, Neurological, Musculoskeletal, Lymphatic (Lymph 
nodes), Skin. 
Standard of care measurements can be used if they fall within the protocol specific windows. 
If during routine clinical care during the study the physician notes any physical findings of interest these 
should be noted in the eCRF. 
7.4.9 
Prior and Concomitant Therapies 
All medications (prescription and non-prescription), treatments, and therapies taken by the patient from 
screening throughout their entire participation in the study, including those initiated prior to the start of 
the study, must be recorded on the patient’s source document and on the appropriate page of the eCRF. 
The dose, unit, frequency, route, indication, date the medication was started, and date the medication was 
stopped (if not ongoing) must be recorded. 
All Investigational COVID-19 therapeutic agents used both prior to, and current to randomization and 
participation in the study should be captured in the CRF. 
7.4.10 Lung Function Test 
Lung function will be assessed by PaO2 and PaO2/FiO2 ratio analyses, and two patient questionnaires. 
These assessments should be completed following the time points specified in the schedule of events (See 
Table 3 and Section 7.3). Standard of care measurements can be used for PaO2 and PaO2/FiO2 ratio 
analyses if they fall within the protocol specific windows. 
7.4.10.1 PaO2 and PaO2/FiO2 Measurement Considerations 
It is recognized that the performing of PaO2 and PaO2/FiO2 measurements can cause significant 
discomfort to patients.  All efforts should be made in obtaining each PaO2 sample as per protocol.  
However, if not possible (e.g. patient refuses) at a minimum complete PaO2 measurements at 
baseline, Days 3, 5, 8, 11, 15 and 29.   
For those days where PaO2 measurements are not able to be taken, SpO2 should be obtained.  
First preference is for these measurements to be taken using a forehead sensor.  Fingertip probes 
may be used if forehead sensors are not available. The site should remain consistent with the 


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method of testing for the patient over the course of the study, e.g. all SpO2 measurements are 
taken with only forehead sensors.   
7.4.10.1 Extent of Dyspnea (Likert scale) 
The patient should grade his current breathing compared to when he first started the study (from -
3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" =markedly better, "-
1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse 
For the first questionnaire (at baseline), the patient compares their current shortness of breath to 
their shortness of breath when they are well. 
A copy of the Extent of Dyspnea (Likert Scale) can be found in Appendix 16.2.  
7.4.10.2 VAS Questionnaire 
Cough severity will be measured using a 0-100mm Visual Analog Scale (VAS) from “no cough” 
to “worst cough ever.” 
A copy of the VAS Questionnaire can be found in Appendix 16.3. 
Note: the site should hand out the Visual Analogue Scale (VAS) to the subject for completion. If 
this is not possible, any alternative administration of the VAS must be documented clearly in the 
source. Reasons for an alternative method may include e.g. site policy to avoid document 
contamination, or a visually impaired subject. The following alternative options are accepted: 
• 
Subject pointing to the VAS with some device and another person adding the line for 
them.  
• 
If this is not possible, the subject can rank the score 0 – 100 (as the VAS line is 100mm). 
Site should hold up the VAS in front of the subject and/or describing this to try and retain some 
visual aspect. 
 
7.4.11 Prohibited Therapy 
Patient should not be taking droxidopa. Single use of ketamine is permitted.  Use of unapproved/off label 
medications for COVID-19 treatment is permitted if they fall under the established local standard of care. 
7.4.12 Safety Evaluations 
Adverse events reporting, including clinically significant laboratory abnormalities, physical examinations 
and vital signs. AE event collection will be performed from signing of ICF, until end of study. 
7.4.13 SARS-CoV-2 RNA Testing 
Confirmation of SARS-CoV-2 RNA using one of the methods outlined in the Inclusion criteria should be 
performed at baseline, Day 5 (or at discharge if sooner), and at Day 15.  Additional testing should be done 
at Day 29 if the patient still has detectable viral RNA at Day 15. 
If possible, testing should be done using both qualitative (e.g. positive/negative) and quantitative (e.g. 
viral RNA load) methods, but at a minimum qualitative testing should be used.  The route of testing 
(nasopharyngeal, oropharyngeal, blood, etc.) should be captured in the CRF. 
 
 


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8. ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
Events MEETING the definition of an AE include the following: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including an increase in 
frequency and/or intensity of the condition 
• 
Any abnormal laboratory test results (urinalysis, haematology, or clinical chemistry) or other 
safety assessments (e.g. ECGs, vital signs measurements), including those that worsen from 
baseline, and are felt to be clinically significant in the medical and scientific judgement of the 
investigator 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for any 
medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical 
procedures 
• 
Overdoses and medication errors of the IP or concomitant medication with and without clinical 
consequences 
Events NOT meeting the definition of an AE include the following: 
• 
The disease being studied or expected progression, signs, or symptoms of the disease being 
studied, unless judged by the investigator to be more severe than expected for the patient’s 
condition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless more severe than expected for the 
patient’s condition 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen 
8.1.1  Treatment Emergent Adverse Events 
Treatment emergent adverse events (TEAE) are undesirable events do not present prior to medical 
treatment, or an already present event that worsens either in intensity or frequency following the treatment 
up to and including the follow up period. 
8.2 
Collection and Reporting of Adverse Events 
8.2.1 
Collection of Treatment Emergent Adverse Events 
The Investigator must monitor the condition of the patient throughout the trial from signing the ICF until 
the last visit. 
The sources of treatment emergent adverse events cover: 
• 
The patient’s response to questions about his/her health (a standard non-leading question such as 
“How have you been feeling since your last visit?” is asked at each visit). 
• 
Symptoms spontaneously reported by the patient. 


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• 
Investigations and examinations where the findings are assessed by the Investigator to be 
clinically significant changes or abnormalities. 
• 
Other information relating to the patient’s health becoming known to the Investigator (e.g. 
hospitalisation). 
When an TEAE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., 
hospital progress notes, laboratory, and diagnostics reports) relative to the event. The investigator will 
then record all relevant information regarding an TEAE/SAE in the e-CRF. It is not acceptable for the 
investigator to send photocopies of the patient’s medical records in lieu of completion of the TEAE/SAE 
e-CRF page. 
8.2.2 
Reporting of Treatment Emergent Adverse Events 
 
A qualified Investigator will evaluate all TEAEs as to: 
8.2.2.1 Adverse Event 
• 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and 
symptoms should be recorded. One diagnosis/symptom should be entered per record. 
• 
If a patient suffers from the same adverse event more than once and the patient recovers 
in between the events, the adverse events should be recorded separately.  
• 
Note the following: A procedure is not an adverse event; the reason for conducting the 
procedure is. Hospitalisation is not an adverse event; the reason for hospitalisation is. 
Death is not an adverse event, but the cause of death is (an exception is sudden death of 
unknown cause, which is an adverse event). 
8.2.2.2 Intensity 
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event and assign 
to one of the following categories (NCI CTCAE): 
 
Mild 
• 
Asymptomatic or mild symptoms; clinical or diagnostic observations only 
• 
Everyday activities minimally or not affected 
• 
Intervention not indicated; no or minimal therapy required 
Moderate 
• 
Symptom(s) cause moderate discomfort  
• 
Some interference with normal everyday activities 
• 
Local or non-invasive intervention indicated; drug therapy may be required 
Severe 
• 
Symptoms causing severe discomfort/pain 
• 
Inability to perform daily social and functional activities (e.g. absenteeism and/or bed 
rest) 
• 
Symptoms requiring medical/surgical attention/intervention; drug therapy is required 


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• 
An event is categorized as “serious” when it meets one of the pre-defined criteria for 
seriousness; an event may be severe in intensity but be of relatively minor medical 
importance (e.g. a severe headache). An event that is categorized as severe will not be 
confused with an SAE. 
Life Threatening 
• 
Life threatening consequences 
• 
Urgent intervention required 
Death 
8.2.2.3 Causality 
The possibility of whether the IP caused the adverse event must be classified as one of the 
following: 
Reasonable possibility 
The term “reasonable possibility” conveys that there is evidence or argument to suggest a 
causal relationship between the IP and the adverse event, rather than to imply that a 
relationship cannot be ruled out. The adverse event may occur as part of the pharmacological 
action of the IP or may be unpredictable in its occurrence 
 
No reasonable possibility 
A causal relationship of the AE to IP administration is unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event 
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed as necessary and provided as additional information 
becomes available. 
8.2.2.4 Duration 
The investigator will record the start and stop dates of the event. The date of onset is the date 
when the first sign(s) or symptom(s) were first noted. If the adverse event is an abnormal 
clinically significant laboratory test or outcome of an examination, the onset date is the date the 
sample was taken, or the examination was performed. For pre-existing clinically significant 
conditions (diagnosed or observed as a result of the screening procedures) becoming worse after 
IP administration, the date of onset is the date the worsening began. The date of outcome is the 
date the patient recovered or died, or that the disease condition worsened. 
8.2.2.5 Action Taken 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(i.e. discontinuation, interruption, or reduction of IP, as appropriate), and report if concomitant 
and/or additional treatments were given for the event. 
 


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8.2.2.6 Outcome 
The Investigator will report the outcome of the event for both AEs and SAEs. The Investigator is 
responsible for following all SAEs until the event has resolved or has stabilized. 
8.3 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
Results in discontinuation from the study. 
• 
Requires treatment, modification/interruption of IP dose, or any other therapeutic intervention; or 
• 
Is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion need to be 
documented as an SAE. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page/screen of the e-CRF. If the abnormality was not a part of a 
diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If possible, the 
laboratory abnormality should be recorded as a medical term and not as an abnormal laboratory result 
(e.g., record thrombocytopenia rather than decreased platelets). 
8.4 
Adverse Events of Special Interest 
Adverse events of special interest include known side effects of Ifenprodil. Nausea, dry mouth, loss of 
appetite, heartburn, diarrhea, constipation, headache, dizziness, allergic reactions, and heart palpitations 
are known to occur in between 0.1 – 5% of patients. Elevated ALT/AST levels have been observed in 
<1% of patients. 
8.5 
Pregnancy 
All pregnancies or suspected pregnancies occurring in either a female patient or partner of a male patient 
must be reported immediately. The IP should be discontinued, and the patient withdrawn from the trial. 
The Investigator will follow the female patient until completion of the pregnancy and collect the outcome 
of the pregnancy (either normal or abnormal outcome). 
If the outcome of the pregnancy was abnormal, the Investigator should report the abnormal outcome as an 
AE. If the abnormal outcome meets any of the serious criteria, it must be reported as an SAE within 24 
hours of the Investigator’s knowledge of the event. All neonatal deaths that occur within 28 days of birth 
should be reported, without regard to causality, as SAEs. In addition, any infant death after 28 days that 
the Investigator suspects is related to the in-utero exposure to the IP should also be reported within 24 
hours of the Investigator’s knowledge of the event. 
8.6 
Serious Adverse Events 
8.6.1 
SAE Definition 
An SAE is an adverse event at any dosage that: 
• 
Results in death; 
• 
Is life threatening (in the opinion of the Investigator, at the time of the event; 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
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• 
Is a congenital anomaly/birth defect; or 
• 
Is an important medical event 
Important medical events are defined as those that that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. Medical and scientific judgement 
should be exercised in deciding whether events qualify as medically important. 
8.6.2 
Reporting of Treatment Emergent SAEs 
In order to meet the requirements for expedited reporting of SAEs meeting specific requirements to 
applicable regulatory authorities and IRB/IEC, all SAEs, must be reported to the Sponsor within 24 hours 
from the time the site investigational team first become aware of the event using the appropriate method 
as outlined in the Safety Reporting Guidelines.  
As further information regarding the SAE becomes available, such follow-up information should be 
documented on a new SAE report form, marked as a follow-up report, and reported using the appropriate 
method as outlined in the Safety Reporting Guidelines.  
Withdrawal from the study in the event of an SAE and therapeutic measures taken shall be at the 
discretion of the Investigator. A full explanation for the discontinuation from the study should be made in 
the patient’s medical records and in the eCRF.  
A planned hospitalization will not be a requirement of SAE reporting. 
The Investigator is required to ensure that the data on these forms is accurate and consistent. 
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study (from 
the time the patient signs informed consent until 7 days after the last dose of IP) or any SAE made known 
to the Investigator at any time thereafter that is suspected of being related to IP.  
The SAE report should provide a detailed description of the SAE and include a concise summary of 
hospital records and other relevant documents. If a patient died and an autopsy has been performed, 
copies of the autopsy report and death certificate are to be sent to the Investigator as soon as these become 
available.  
Where required by local legislation, the Investigator is responsible for informing the IRB/IEC of the SAE 
and providing them with all relevant initial and follow-up information about the event. The Investigator 
must keep copies of all SAE information on file, including correspondence with the IRB/IEC. 
8.7 
Follow-up of Treatment Emergent Adverse Events and Serious Adverse Events 
During the trial, the Investigator must follow-up on each adverse event until it is resolved or until the 
medical condition of the patient is stable.  
After the patient’s last visit, the Investigator must follow-up on any adverse event classified as serious or 
considered to have a reasonable possible causality to the IP until it is resolved or until the medical 
condition of the patient is stable. The Sponsor’s Safety Surveillance Contact will follow all SAEs with 
outcomes pending until the last subject enrolled has completed the study. 
 
 


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9. DATA HANDLING 
9.1 
Data and Documents 
The Investigator must ensure that the records and documents pertaining to the conduct of the study and 
the distribution of the investigational product are complete, accurate, filed, and retained. Examples of 
source documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
patient’s diaries or evaluation checklists; dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate copies; microfiche; x-ray film and 
reports; and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical trial. 
9.2 
Electronic Case Record Form 
An e-CRF system provided by an independent third-party CRO will be used for data capture. The system 
is validated and access at all levels to the system is granted/revoked following the CRO’s procedures, in 
accordance with regulatory and system requirements. 
Data should be entered into the system timely after the patient has attended a visit or after the data 
become available, as applicable. 
The Investigator will approve/authorise the e-CRF entries for each patient with an electronic signature 
which is equivalent to a handwritten signature. 
The e-CRF system and the database will be hosted at the independent third party CRO. After the trial 
database is declared clean and released to the statistician, a final copy of the database will be stored at the 
Sponsor.  The Investigator will also receive a copy of the trial site’s final and locked data (including audit 
trail, electronic signature and queries) as write-protected PDF-files produced by the independent third 
party CRO. The PDF-files will be stored on an appropriate electronic storage device and will be provided 
to the Investigator before access to the e-CRF is revoked. 
Errors occurring in the e-CRF will be corrected electronically. Such corrections/modifications will be 
automatically tracked by an audit trail detailing the date and time of the correction and the name of the 
person making the correction. 
9.3 
Data Management 
Data will be collected via e-CRF and entered into the clinical database per the CRO’s standard operating 
procedures (SOPs). This data will be electronically verified through use of programmed edit checks 
specified by the clinical team. Discrepancies in the data will be brought to the attention of the clinical 
team, and investigational site personnel, if necessary. Resolutions to these issues will be reflected in the 
database. An audit trail within the system will track all changes made to the data. 
9.4 
Records Retention 
Essential documents must be retained by Canadian Investigators for a minimum of 25 years after 
conclusion of the clinical study.  For other jurisdictions, essential documents must be retained by the 
Investigator for a minimum of 2 years after the last approval of a marketing application in an ICH region 
and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 
years have elapsed since the formal discontinuation of clinical development of the IP. The Investigator 
must retain these documents for the time period described above or according to local laws or 
requirements, whichever is longer. Essential documents are listed in Section 8 of the ICH consolidated 
guideline on GCP (Essential Documents for the Conduct of a Clinical Trial). 


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The Investigator must notify the Sponsor if he/she wishes to assign the essential documents to someone 
else, remove them to another location, or is unable to retain them for a specified period. The Investigator 
must obtain approval in writing from the Sponsor prior to destruction of any records. If the Investigator is 
unable to meet this obligation, the Investigator must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
All study documents should be made available if required by relevant health authorities. The 
Investigator/institution should take measures to prevent accidental or premature destruction of these 
documents. 
 
 


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10. STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
10.1 
Overview 
Key elements of the Statistical Analysis Plan (SAP) are outlined in this section. The comprehensive plan 
will be documented in a separate SAP. 
10.2 
Study Population Definitions 
The analysis populations are: 
• 
Intent-to-Treat (ITT): The ITT population consists of all enrolled patients assigned to receive 
treatment regardless of whether they took study drug or stopped active treatment to receive only 
SOC. Patients will be classified according to the treatment group to which they were randomized. 
• 
Per-Protocol (PP): The PP population consists of all ITT patients who are not major protocol 
violators with regards to inclusion/exclusion criteria, investigational product compliance and 
concomitant medication instructions. Protocol violations that would exclude patients from the PP 
population will be defined and documented in the SAP prior to unblinding. 
• 
Safety: The Safety population consists of all patients who received at least one dose of study 
drug. This population will be used for all assessments of safety and tolerability. Patients will be 
summarized according to actual dose of study drug taken. 
10.3 
Sample Size and Power Considerations 
 
For the pilot Phase 2b phase, a sample of 150 patients (50 in Arm A, Arm B and SOC) will be recruited. 
To account for drop out of 10%, a total of 168 patients will be enrolled. 
 
For the pivotal Phase 3 phase, A sample of 462 patients (231 in the SOC group and 231 in the active 
treatment group) achieves 90% power to detect a change in the log odds ratio of 0.5596 when the 
significance level (alpha) is 0.05 using a two-sided test. A log odds ratio of 0.5596 corresponds to an odds 
ratio of 1.75 comparing treatment to SOC. The sample size was estimated using the Tests for Two 
Ordered Categorical Variables module in PASS 14. To account for drop out of 10%, a total of 514 
patients will be enrolled. 
 
The sample size assumes that the distribution of patients on day 15 will be as shown in Table 2, which is 
scenario 4 in the WHO master protocol (2020) for enrolled patients with moderate to severe disease under 
an odds ratio of 1.75. 
 
 


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Interim analysis and increasing the sample size 
An interim analysis during Phase 2b will be conducted on the ITT population when 75 patients complete 
the clinical status assessment at day 15 (the primary endpoint). Details of outputs for interim analyses in 
Phase 3 will be specified in a separate mock shell document. A preliminary full analysis report of 150 
patients with up to Day 29 entered will also be presented. 
The following design features will also be assessed for possible changes for Phase 3 during the second 
interim analysis and/or final analysis for Phase2b. 
• 
Target population; eligibility criteria 
• 
The choice of primary endpoint 
• 
The need for seven categories in the outcome scale (versus fewer) 
• 
The distribution of patients across the outcome scale at day 15 
• 
The timing (day 15) of the primary endpoint 
10.4 
Statistical Methods 
 
Complete details of the statistical analysis methods, including data conventions, will be provided in the 
SAP. 
10.4.1 General Conventions 
Results will be presented by treatment group. 
A baseline value is defined as the most recent available value collected or derived prior to the first study 
drug administration. A change from baseline value is defined as the difference between a result at a post-
baseline time point and the baseline value. A percent change from baseline is defined as the ratio of the 
change from baseline value relative to the baseline value expressed as a percentage. 
In general, continuous variables will be summarized using descriptive statistics (e.g. arithmetic mean, 
standard deviation [SD], median, minimum and maximum), as well as change from baseline for each 
applicable scheduled time point, when appropriate. Categorical variables will be summarized by 
frequency and percent observed in each category and at each time point as applicable. 95% CI may also 
be performed for some selected key outcomes of interest. 
10.5 
Patient Disposition 
Patient disposition (analysis population allocation, entered, discontinued along with primary reason for 
discontinuation, completed) will be summarized using frequency and percentage.  
A summary of patients enrolled by site will be provided. 
Analysis sets and Protocol violations/deviations will be summarized using frequency tabulations. 
Patient disposition information will also be listed. 
10.6 
Background and Demographic Characteristics 
Patients’ age, height, weight, and other continuous demographic and baseline characteristics will be 
summarized using descriptive statistics, while gender, race, and other categorical variables will be 
provided using frequency tabulations. Medical history data will be summarized using frequency 
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10.7 
Prior and Concomitant Medication 
Concomitant medications will be coded using World Health Organization Drug Dictionary (WHO-DD) 
and are defined as all medications taken during study treatment (including day 1) up to and including the 
follow up period. The number and percentage of patients using at least one concomitant medication will 
be displayed together with the number and percentage of patients using at least one medication within 
each therapeutic class (ATC-Level 4) and preferred name (ATC-level 2). These will be summarized under 
safety analysis set and listed. 
10.8 
Treatment Exposure and Compliance 
Treatment exposure and study drug compliance will be summarized using descriptive statistics under ITT, 
PP and Safety populations and listed.  
10.9 
Efficacy 
10.9.1 Primary Efficacy Analysis 
 
The SOC and treatment arms under WHO7 ordinal scale will be compared with respect to the primary 
endpoint using proportional odds models (ordinal logistic regression) adjusted for site and age. Treatment 
will be compared to SOC by testing whether the common odds ratio differs from 1.0 at day 15 using two-
sided tests at 2.5% level of significance under the ITT population set, followed by PP population set. All 
modeling assumptions will be verified. 
Separate 95% CI and p-values will be computed across each of the ordinal scale between SOC and 
treatment arms for both ITT and PP population sets. Multiple comparison techniques (to be detailed in the 
SAP) will be employed to ensure type I error is controlled to 5% for these comparisons. 
If, following the Phase 2b interim analysis or final analysis, the primary endpoint changes for Phase 3, 
details will be written in the SAP, and a protocol amendment will be created. 
10.9.2 Secondary Efficacy Analyses 
Time to events, like initiation of mechanical ventilation, death, or hospital/ICU discharge, will be 
summarized using the Kaplan-Meier method and analyzed using proportional hazards regression where 
appropriate. VAS cough score will be summarized descriptively. All secondary efficacy analyses will be  
analyzed using an appropriate 2-sided hypothesis test at 5% level of significance using ITT and PP 
population sets. Assumptions of all models and tests will be verified. 
 
10.10 Safety Analysis 
Safety and tolerability will be assessed by AEs, laboratory testing (haematology, biochemistry, and 
urinalysis), and vital signs. 
The safety analyses will be performed using the safety population (Section 10.2). Treatment-emergent 
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) classification 
system. All TEAEs will be summarized by system organ class, preferred term, severity, and relationship 
to IP. Treatment Emergent Adverse events leading to death or to discontinuation from treatment and 
TESAEs will also be tabulated. All adverse events, regardless of whether it is treatment emergent or not, 
will be listed. 


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Laboratory data will be summarized descriptively by visit. In addition, shift tables showing the number of 
patients with values low, normal, and high compared to the normal ranges pre-treatment versus post-
treatment will be provided for the applicable lab parameters. Change from baseline analysis will also be 
reported if applicable. All laboratory data will be listed. 
Vital sign measurements, including weight, will be summarized descriptively by visit and presented as 
shift tables and listed. 
10.11 Missing Data 
Imputation will not be done unless stated otherwise 
 
 
 


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11. CHANGES IN THE CONDUCT OF THE TRIAL 
11.1 
Protocol Amendments 
Any change to this Protocol will be documented in a Protocol Amendment, issued by either Algernon 
Pharmaceuticals or designated CRO, and agreed upon by both the Algernon Pharmaceuticals and the 
Investigator prior to its implementation. 
Protocol amendments will be submitted for notification of Regulatory authorities and IECs in accordance 
with local regulations. IEC approval is required for any substantial amendment i.e. one which could affect 
the safety of the patients, or which entails a change to the design and/or scope of the trial. 
Changes to the protocol intended to eliminate immediate hazards to trial patients may be implemented 
prior to IEC approval. 
11.2 
Deviations from the Protocol 
Deviations from protocol should not occur. In the event of a deviation from protocol, the Investigator 
must inform the Monitor, and the implications of the deviation must be reviewed and discussed. Any 
deviation must be documented in writing (and included in e-CRF data). A set of deviations must also be 
accompanied by a description of the deviation, the relevant dates, and the action taken. A Log of Protocol 
Deviation Reports will be maintained by the Investigator or CRO. Deviation reports and supporting 
documentation must be kept in the Investigator’s File and the Trial Master File. 
11.3 
Premature Trial Termination 
Both the Sponsor and the Investigator (with regard to his/her participation) reserve the right to terminate 
the trial at any time. Should this become necessary, the procedure shall be agreed upon following 
consultation between Sponsor and the Investigator. Both the Investigator and the Sponsor will ensure that 
appropriate consideration is given to the protection of the best interests of the patients. Regulatory 
authorities and IECs will be informed. 
In addition, the Sponsor reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include but are not limited to: insufficient adherence to protocol 
requirements; failure to enter patients at an acceptable rate; falsification of records; and GCP non-
compliance. 
 
 


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12. MONITORING PROCEDURES 
12.1 
Study Monitoring and Source Data Verification 
In accordance with applicable regulations including GCP, Monitors from the CRO will contact the site 
prior to the start of the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory and ethical requirements. 
When reviewing data collection procedures, the discussion will also include identification, agreement and 
documentation of data items for which the e-CRF will serve as the source document. 
The monitor will verify that the: 
• 
Data are authentic, accurate, and complete 
• 
Safety and rights of patients are being protected 
• 
Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP, and all applicable regulatory requirements 
The investigator and the head of the medical institution (where applicable) agrees to allow the monitor 
direct access to all relevant documents. 
Accuracy will be checked by performing source data verification that is a direct comparison of the entries 
made onto the e-CRFs against the appropriate source documentation. Any resulting discrepancies will be 
reviewed with the Investigator and/or his/her staff. Any necessary corrections will be made directly to the 
e-CRFs or via queries by the Investigator and/or his/her staff. Monitoring procedures require that 
informed consents, adherence to inclusion/exclusion criteria, and documentation of SAEs and their proper 
recording be verified. Additional monitoring activities may be outlined in a study-specific monitoring 
plan. 
Remote monitoring considerations:   
Remote monitoring activities may be used as a method to assess a site’s compliance with the protocol, 
ICH GCP and applicable regulatory requirements. Examples of when remote monitoring may be utilized 
are in preparation for or in between on-site monitoring visits, interim data analyses and data locks. During 
remote monitoring, eCRF data can be reviewed for timeliness of entry, completeness, internal 
consistency, protocol and ICH GCP compliance and logic. Remote monitoring activities may also include 
selected source data review and verification where source documents are available remotely. There are 
certain limitations when conducting remote monitoring as there is no physical or direct access to review 
source documentation, facilities and Investigational Product (IP). In exceptional circumstances, remote 
monitoring may be conducted in lieu of on-site monitoring, e.g. implementation of restrictive site policies 
due to a major COVID-19 disease outbreak or other health crises. Remote monitoring can be conducted 
when it is included in the study-specific monitoring plan. 
12.2 
Audits and Inspections 
To ensure compliance with GCP and all applicable regulatory requirements, the Monitor may conduct a 
quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the 
advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time 
and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to 


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implement any corrective and/or preventative actions to address any findings/issues identified. If the 
Investigator is contacted by any regulatory authority regarding an inspection, he/she should contact the 
Sponsor immediately. 
 
 


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13. REPORTING AND PUBLICATION 
13.1 
Clinical Trial Report 
The data generated and information collected during this trial will be used by the Sponsor or CRO to 
create a clinical trial report, which will be submitted to the Investigator for comments. 
13.2 
Confidentiality and Ownership of Trial Data 
Any and all confidential information relating to the IP or the trial including any data and results from the 
trial will be the exclusive property of the Sponsor. The investigator and any other persons involved in the 
trial will protect the confidentiality of this proprietary information belonging to the Sponsor. 
13.3 
Publications and Public Disclosure 
13.3.1 Publication Policy 
Upon conclusion of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the Investigator(s) offered authorship and the Sponsor. Further details on 
publication are included in the Investigators’ agreements. 
13.3.2 Public Disclosure 
In accordance with the policy of the International Committee of Medical Journal Editors (ICMJE), all 
clinical trials must be registered in a public clinical trials registry as a condition for publication. It is the 
responsibility of the Sponsor to register the trial in appropriate registries. 
 
 


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14. REGULATORY AND ETHICAL ASPECTS 
14.1 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and documentation of 
this study are designed to ensure that the Sponsor, its authorized representative, and Investigator abide by 
GCP, as described in ICH Guideline E6, and in accordance with the general ethical principles outlined in 
the Declaration of Helsinki. The study will receive approval from an IRB/IEC prior to commencement. 
The Investigator will conduct all aspects of this study in accordance with applicable national, state, and 
local laws of the pertinent regulatory authorities. 
14.2 
Investigator Responsibilities 
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local regulations. The 
Sponsor or an authorized representative will evaluate and approve all Investigators who in turn will select 
their staff.  
The Investigator should ensure that all persons assisting with the study are adequately informed about the 
protocol, amendments, study treatments, and their study-related duties and functions. The Investigator 
should maintain a list of sub-Investigators and other appropriately qualified persons to whom he or she 
has delegated significant study-related duties. 
The Investigator is responsible for keeping a record of all patients who sign an ICF and are screened for 
entry into the study. Patients who fail screening must have the reason(s) recorded in the patient’s source 
documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available during monitoring 
visits to review data, resolve queries, and allow direct access to patient records (e.g. medical records, 
office charts, hospital charts, and study-related charts) for source data verification. The Investigator must 
ensure timely and accurate completion of e-CRFs and queries. 
14.3 
Patient Information and Informed Consent 
An English master version of the Patient Information and Informed Consent documents will be provided 
for translation and adaptation into local languages. If changes are made to the Patient Information and 
Informed Consent documents by the IEC and/or the trial sites, the amended documents must be submitted 
back to the Sponsor for approval. 
The patient will receive a copy of the patient information and his/her signed consent. 
The Investigator will obtain a freely given written consent from each patient after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects of the trial 
which are relevant to the patient’s decision to participate. The trial patient must be given ample time to 
consider participation in the trial, before the consent is obtained. The informed consent form must be 
signed and dated by the patient before he is exposed to any trial-related procedure, including screening 
tests for eligibility. The Investigator will also sign and date the form. 
The Investigator will explain that the patients are completely free to refuse to enter the trial or to 
withdraw from it at any time, without any consequences for their further care and without the need to 
justify their decision. 
If new information becomes available that may be relevant to the trial patient’s willingness to continue 
participation in the trial, a new patient information and informed consent form will be forwarded to the 


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IECs (and regulatory authority, if required). The trial patients will be informed about this new information 
and re-consent will be obtained. 
Each patient will be informed that the monitor(s), quality assurance auditor(s) assigned by sponsor or 
mandated by regulatory authority inspector(s), in accordance with applicable regulatory requirements, 
may review his/her source records and data. Data protection will be handled in compliance with ICH 
guideline, local laws, and local regulations. 
14.4 
Confidentiality 
The Sponsor affirms the patient's right to protection against invasion of privacy and to be in compliance 
with ICH and other local regulations (whichever is most stringent). The Sponsor requires the Investigator 
will permit the Sponsor’s representatives and, when necessary, representatives from regulatory authorities 
to review and/or copy any medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the patient’s 
signed ICF, it is the responsibility of the Investigator to obtain such permission in writing from the patient 
or his/her legal representative. 
14.5 
Institutional Review Board/Independent Ethics Committee 
Before the start of the study, the study protocol, ICF, and any other appropriate documents will be 
submitted to the IRB/IEC with a cover letter or a form listing the documents submitted, their dates of 
issue, and the site (or region or area of jurisdiction, as applicable) for which approval is sought. If 
applicable, the documents will also be submitted to the authorities in accordance with local legal 
requirements. 
Investigational product can only be supplied to an Investigator by the Sponsor or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has been 
received by the Sponsor or its authorized representative. This documentation must also include a list of 
the members of the IRB/IEC and their occupation and qualifications. If the IRB/IEC will not disclose the 
names, occupations, and qualifications of the committee members, it should be asked to issue a statement 
confirming that the composition of the committee is in accordance with GCP. For example, the IRB 
General Assurance Number may be accepted as a substitute for this list. Formal approval by the IRB/IEC 
should mention the protocol title, number, amendment number (if applicable), study site (or region or area 
of jurisdiction, as applicable), and any other documents reviewed. It must mention the date on which the 
decision was made and must be officially signed by a committee member. Before the first patient is 
enrolled in the study, all ethical and legal requirements must be met. 
The IRB/IEC and, if applicable, the authorities must be informed of all subsequent protocol amendments 
in accordance with local legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the ICF should also be revised. 
14.6 
End-of-Trial and End-of-Trial Notification 
End-of-Trial is defined as the date the last patient performs the last visit in the trial. At the end of the trial, 
the regulatory authorities and IECs will be notified of trial completion according to national requirements.  
 
 


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15. REFERENCES 
 
Algernon Pharmaceuticals document: Investigators Brochure for COVID - Ifenprodil, Version 1.1. 
Altman, D. G., Schulz, K. F., Moher, D., Egger, M., Davidoff, F., Elbourne, D., et al. (2001) The revised 
CONSORT statement for reporting randomized trials: explanation and elaboration. Ann. Int. Med. 
134:663-694.  
Birring, S., Spinou, A. (2015) How best to measure cough clinically.  Current Opinion in Pharmacology 
22: 37-40. 
CONSORT statement: http://www.consort-statement.org.  
Del Arroyo, A.G. et al. (2019) NMDA receptor modulation of glutamate release in activated neutrophils. 
EBioMedicine 47: 457-469.  
ICH E6 Consolidated Guidelines on GCP: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guidelin
e.pdf. 
Kawai, S., Hirakawa, T., Sugisawa, A., Motomura, I. (1975a) Acute and Subacute Toxicity Studies of 
Ifenprodil (in Japanese). Applied Pharmacology 10 (6), 785-799. 
Kawai, S., Miura, K., Doi, Y., Motomura, I. (1975b) Chronic Toxicity Studies of Ifenprodil (in Japanese). 
Applied Pharmacology 10 (6), 801-817.  
Kawai, S. Hirakawa, K., Miura, K., Motomura , I. (1976) Subacute toxicity test of Ifenprodil in rabbits (in 
Japanese) Yakubutsu Ryoho. Medicinal Treatment. 9 (3), 375-384. 
Kahlfuss,S., N. Simma, J. Mankiewicz, T. Bose, T. Lowinus, S. Klein-Hessling, R. Sprengel, B. 
Schraven, M. Heine, and Bommhardt, U. (2014) Immunosuppression by N-methyl-D-Aspartate receptor 
antagonists is mediated through inhibition of Kv1.3 and Kca3.1 channels in T cells. Molecular and 
Cellular Biology 34:820-831. 
Kotajima-Murakami, H. et al. (2019) Study of effects of ifenprodil in patients with methamphetamine 
dependence: Protocol for an exploratory, randomized, double-blind, placebo-controlled trial. 
Neuropsychopharmacology Reports 39, 90-99.   
Li, Y. et al. (2015) NMDA receptor antagonist attenuates bleomycin-induced acute lung injury. PLOS 
One 10(5): e0125873. 
Martin, C., Papazian, L., Payan, M. J., Saux, P., Gouin, F. (1995) Pulmonary fibrosis correlates with 
outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. Chest 107: 
196-200. 
Nagata, T., Katai, N., Aramaki, Y., Isaka, H., Enomoto, M. (1977) Acute Toxicity Study, and Oral 
Chronic Toxicity Study for 6-months and Recovery Test with Ifenprodil in Beagle-dogs (in Japanese). 
Applied Pharmacology 14 (3), 415-496. 
Nair, A.B and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. 
J Basic Clin Pharm: 7(2): 27-41 


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National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
Novel Coronavirus Pneumonia Diagnosis and Treatment Plan, 7th edition. English version accessed at: 
https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/. Last accessed March 9, 2020. 
Pang, P.S., Collins, S.P., Sauser, K., Andrei, A-C, Storrow, A.B., Hollander, J.E., Tavares, M., Spinar, J., 
Macarie, C., Raev, D., Nowak, R., Gheorghiade, M., Mebazza, A. (2014) Assessment of Dyspnea early in 
acute heart failure:  Patient Characteristics and Response Differences Between Likert and Visual Analog 
Scales.  Acad Emerg Med 21: 659-666. 
PASS 14 Power Analysis and Sample Size Software (2015). NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass. 
Qiao J, Zhang M, Bi J, et al. (2009) Pulmonary fibrosis induced by H5N1 viral infection in mice. Respir 
Res. 10 (1), 107. doi:10.1186/1465-9921-10-107. 
Royal College of Physicians (2012) National Early Warning Score (NEWS): Standardising the 
assessment of acute-illness severity in the NHS. Report of a working party. London. 
Royal College of Physicians (2017) National Early Warning Score (NEWS) 2. Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. London.  
Ruan, Q., Yang, K., Wang, W., Jiang, L., Song, J. (2020) Clinical predictors of mortality due to COVID-
19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine 
https://doi.org/10.1007/s00134-020-05991-x 
WHO R&D Blueprint (2020) Master Protocol.  A Multi-centre, Adaptive, Randomized, Double-Blind, 
Placebo-Controlled Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the 
Treatment of COVID-19 in Hospitalized Patients. Version 2.0, February 24, 2020. 
WHO R&D Blueprint. (2020) Novel Coronavirus. COVID-19 Therapeutic Trial Synopsis.  February 18, 
2020, Geneva, Switzerland. 
Williams, K. (2001) Ifenprodil, a novel NMDA receptor antagonist: Site and mechanism of action. Curr. 
Drug. Targets. 2(3):285-298. 
Zhang, C., Zhang, Y., Qin, Y., Zhang, Q., Liu, Q., Shang, D., Lu, H., Li, X., Zhou, C., Huang, F., Jin, N., 
Jiang, C. (2019) Ifenprodil and Flavopiridol Identified by Genomewide RNA Interference Screening as 
Effective Drugs To Ameliorate Murine Acute Lung Injury after Influenza A H5N1 Virus Infection. 
mSystems 4 (6). doi:10.1128/msystems.00431-19 
Zhe, Z., Hongyuan, B., Wenjuan, Q., Peng, W., Xiaowei, L., Yan, G. (2018) Blockade of glutamate 
receptor ameliorates lipopolysaccharide-induced sepsis through regulation of neuropeptides. Biosci Rep. 
38(3). doi:10.1042/BSR20171629 
 
 
 


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16. APPENDICES 
 
16.1 National Early Warning (NEW) Score 
(WHO Blueprint Master Protocol; Royal College of Physicians 2012) 
 
PHYSIOLOGICAL 
PARAMETERS 
3 
2 
1 
0 
1 
2 
3 
Respiration Rate 
(per minute) 
≤8 
 
9 - 11 
12 - 20 
 
21 - 24 
≥25 
Oxygen Saturations 
(%) 
≤91 
92 - 93 
94 - 95 
≥96 
 
 
 
Any Supplemental 
Oxygen 
 
Yes 
 
No 
 
 
 
Temperature (°C) 
≤35.0 
 
35.1 – 
36.0 
36.1 – 
38.0 
38.1 – 
39.0 
≥39.1 
 
Systolic BP 
(mmHg) 
≤90 
91 - 100 
101 - 
110 
111 - 
219 
 
 
≥220 
Heart Rate (per 
minute) 
≤40 
 
41 - 50 
51 - 90 
91 - 110 
111 - 
130 
≥131 
Level of 
Consciousness 
 
 
 
A 
 
 
V, P, or 
U 
Level of consciousness = alert (A), and arousable only to voice (V) or pain (P), and unresponsive 
(U). 
 
The aggregate results from all 7 physiological parameters are used to obtain the NEW Score.  


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16.2 Extent of Dyspnea (Likert Scale) 
(Pang et al, 2014) 
 
☐ Not completed 
 
How is your shortness of breath now compared to when you first started this study?   
Note: for your first questionnaire (at baseline), please compare your current shortness of breath 
to your shortness of breath when you are well.   
 
 
DO NOT PHOTOCOPY – ONLY USE ORIGINAL FOR SUBJECT COMPLETION 
Likert Dyspnea Scale Version 3.0_3Apr2020 
 
 
 
Subject ID: _________________                                                               Date: _ _/_ _ _/_ _ _ _ 
 
       Clinician’s Initials: _ _ _  
 
           
                                                                                                                      Time (24-hour clock): _ _h_ _ 
 
 
Time Period: 
☐ baseline          ☐ Day 2          ☐ Day 4         ☐ Day 8         ☐ Day 14/15        ☐ Day 29          
 
Grade 
 
              Shortness of Breath  
Please Choose One 
(mark with an ‘X’) 
+3 
              Markedly Better 
 
 
+2 
              Moderately Better 
 
 
+1 
              Minimally Better 
 
 
0 
              No Change 
 
 
-1 
              Minimally Worse 
 
 
-2 
              Moderately Worse 
 
 
-3 
              Markedly Worse 
 
 


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16.3 Cough Severity Visual Analogue Scale 
(Birring and Spinou, 2015) 
Protocol:  AGN120-3 
 
Subject #: _______________ 
Clinicians initials: _________Time (24-hour clock): _ _h_ _ 
 
Visit #: ____________ 
 
 
 
Date:  ______/________/__________ 
 
 
 
 
 
 
 
 
 dd 
  mmm  
yyyy 
☐ Not completed 
 
Cough Severity Visual Analogue Scale (VAS) 
 
How severe has your cough been over the last 24 hours? 
Rate the severity of your cough by placing a single vertical line on the scale. 
 
 
 
 
 
 
 
 
 
Date of Completion: _________________(dd/mmm/yyyy) 
 
Measurement: ________ mm (to be completed by study staff) 
 
DO NOT PHOTOCOPY – ONLY USE ORIGINAL FOR SUBJECT COMPLETION 
Cough Severity Visual Analogue Scale (VAS) Version 2.0_3Apr2020 
No Cough 
Worst Cough 

SAP_001.pdf: 
Protocol Number: AGN120-3 
 
2021-01-15 
Document status: Final Version 1.2 
 
 
Novotech - Strictly Confidential 
Page 1 of 38 
 
 
 
STATISTICAL ANALYSIS PLAN 
A RANDOMIZED OPEN LABEL PHASE 2B/3 STUDY OF THE SAFETY AND 
EFFICACY OF NP-120 (IFENPRODIL) FOR THE TREATMENT OF 
HOSPITALIZED PATIENTS WITH CONFIRMED COVID-19 DISEASE (Pilot Phase) 
 
PROTOCOL NO.: 
AGN120-3 
 
PRODUCT CODE: NP-120 
 
PREPARED FOR: 
Algernon Pharmaceuticals 
 
915 – 700 West Pender Street, 
 
Vancouver, BC, Canada, 
 
V6C 1G8 
 
PREPARED BY: 
Novotech (Australia) Pty Ltd 
 
Level 3, 235 Pyrmont Street 
 
Pyrmont, NSW, 2009  
 
Australia  
 
DATE OF ISSUE: 
2021-01-15 
 
 
VERSION/STATUS: 
Final Version 1.2 
 
 
VERSION HISTORY: 2020-11-06, Final Version 1.1 
2020-09-21, Final Version 1.0 
 
AUTHOR: 
Steve Su 
 
The information in this document is confidential and proprietary to Novotech Pty Ltd and its 
clients. The information may only be used by the entities to which it was disclosed for the purpose 
it was disclosed. To the maximum extent permissible by law, the information must not be 
disclosed to any third parties without the prior written consent of Novotech. 


Protocol Number: AGN120-3 
 
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Document status: Final Version 1.2 
 
 
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Page 2 of 38 
SAP APPROVAL 
 
By my signature, I confirm that this SAP has been reviewed by Algernon Pharmaceuticals and has 
been approved for use on the AGN120-3 study: 
 
Name 
Title / Company 
Signature 
Date 
Nancy Stewart 
Senior Scientific 
Manager/GVICDS 
 
 
Mark Williams 
CEO/Algernon 
 
 
Steve Su 
Principal 
Biostatistician/Novotech 
 
 
Jan Steyn 
Manager/Novotech 
 
 
 
 
 
 
 


Protocol Number: AGN120-3 
 
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Page 3 of 38 
Table of contents 
 
1. 
INTRODUCTION 
7 
2. 
PROJECT OVERVIEW 
8 
2.1 
Study Design 
8 
2.2 
Objectives 
10 
2.3 
Endpoints 
11 
2.4 
Safety Endpoints: 
12 
2.5 
Sample Size 
12 
2.6 
Randomization 
12 
3. 
STATISTICAL CONSIDERATIONS 
13 
3.1 
General Considerations 
13 
3.2 
General Key Definitions 
14 
3.3 
Handling of Missing Data 
14 
3.4 
Treatment Groups 
14 
4. 
ANALYSIS POPULATIONS (ANALYSIS SETS) 
15 
4.1 
Population Descriptions 
15 
5. 
PARTICIPANT DISPOSITION 
16 
6. 
PROTOCOL DEVIATIONS 
17 
7. 
Analysis Populations 
18 
8. 
DEMOGRAPHICs AND MEDICAL HISTORY 
19 
8.1 
Demography and Baseline Characteristics 
19 
8.2 
Site and Age 
19 
8.3 
Medical /Surgical history 
19 
9. 
PRIOR AND CONCOMITANT MEDICATIONS & THERAPIES 
20 
10. 
TREATMENT EXPOSURE and compliance 
21 
11. 
EFFICACY and exploratory analyses 
22 
11.1 
Primary Efficacy Analysis 
22 
11.2 
Secondary Efficacy Analysis: General Population Considerations 
22 
11.3 
Secondary Efficacy Analysis: Time to Event General Considerations 
22 
11.4 
Secondary Efficacy Analysis: WHO-7 Ordinal Scale 
23 
11.5 
Secondary Efficacy Analysis: NEWS 
23 
11.6 
Secondary Efficacy Analysis: Respiratory Support 
24 
11.7 
Secondary Efficacy Analysis: Oxygenation 
26 
11.8 
Secondary Efficacy Analysis: Hospitalization and ICU 
27 
11.9 
Secondary Efficacy Analysis: Mortality 
28 
11.10 Exploratory Analysis: Dyspnea 
28 
11.11 Exploratory Analysis: Cough VAS and D-dimer 
28 


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11.12 Exploratory Analysis: Qualitative and Quantitative PCR SARS-Cov-2 
28 
11.13 Cytokine Marker Results 
28 
12. 
SAFETY 
30 
12.1 
Adverse Events 
30 
12.2 
Safety Laboratory Assessments 
31 
12.3 
Vital Signs 
32 
12.4 
12-Lead Electrocardiogram (ECG) 
32 
12.5 
Physical Examinations 
33 
12.6 
Pregnancy Test Results 
33 
12.7 
Child Pugh Score 
33 
13. 
CHANGES TO THE PLANNED ANALYSIS 
34 
14. 
INTERIM AND FINAL ANALYSIS 
35 
14.1 
Interim Analyses 
35 
14.2 
Final Analysis (End of Study) 
35 
15. 
SOFTWARE 
36 
16. 
TABLES, listings and figures 
37 
17. 
REFERENCES 
38 


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List of Abbreviations 
Abbreviation 
Term 
aPTT 
Activated Partial Thromboplastin Time  
AE 
Adverse Event  
ALT 
Alanine Aminotransferase  
ALP 
Alkaline Phosphatase  
ATC 
Anatomical Therapeutic Chemical  
AST 
Aspartate Aminotransferase  
BUN 
Blood Urea Nitrogen  
CSRs 
Clinical Study Reports  
CIs 
Confidence Intervals  
COVID-19 
Coronavirus Disease Of 2019  
CIF 
Cumulative Incidence Function  
DBP 
Diastolic Blood Pressure  
eCRF 
Electronic Clinical Reporting Form  
ECMO 
Extracorporeal Membrane Oxygenation  
FiO2 
Fraction Of Inspired Oxygen  
γ-GT/GGT 
Gamma Glutamyl Transpeptidase  
GCP 
Good Clinical Practice  
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor  
ID 
Identifier  
ICU 
Intensive Care Unit  
ITT 
Intent-To-Treat  
IL-12 
Interleukin 12  
IL-6 
Interleukin 6  
INR 
International Normalised Ratio  
IP 
Investigational Product  
KM 
Kaplan-Meier  
MP 
Master Protocol  
NEWS 
National Early Warning Score  
O2 
Oxygen  
SpO2 
Oxygen Saturation  
PaO2 
Partial Pressure Of Oxygen  
PP 
Per Protocol  
PCR 
Polymerase Chain Reaction  
PT 
Prothrombin Time  
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2  
SD 
Standard Deviation  
SOC 
Standard Of Care  
SOPs 
Standard Operating Procedures  
SAP 
Statistical Analysis Plan  
SBP 
Systolic Blood Pressure  
TID 
Ter In Die  
TEAEs 
Treatment Emergent Adverse Events  
TNF-alpha 
Tumor Necrosis Factor Alpha  
IFNγ 
Type II Interferon  
VAS 
Visual Analog Scale  
WHO 
World Health Organisation  


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Abbreviation 
Term 
WHO-DD 
World Health Organization Drug Dictionary  
 
 
 


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1. 
INTRODUCTION 
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of the data 
collected from the AGN120-3 study (protocol version 2.0 dated 16 November 2020). This SAP only 
covers the Phase2b part of the trial.  
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), regulatory 
submissions, or future manuscripts. Also, post hoc exploratory analyses not necessarily identified in this 
SAP may be performed to further examine study data. Any post hoc, or unplanned, exploratory analyses 
performed will be clearly identified as such in the final CSR. 


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2. 
PROJECT OVERVIEW 
2.1 
Study Design 
 
This is a Phase 2b/3, multicenter, open label, randomized, parallel group study to evaluate the efficacy 
of Ifenprodil in patients with coronavirus disease of 2019 (COVID-19) disease. 
In the Phase 2b phase, patients will be randomized in a ratio of 1:1:1 to either a) 20 mg TID IP plus 
Standard of Care group, b) 40 mg TID IP plus Standard of Care or c) Standard of Care only group. 
Investigators will collectively enroll approximately 50 evaluable patients in each treatment group, for a 
total of 150 patients. Patients receive either oral Ifenprodil (20 or 40 mg ter in die (TID)) for up to 14 
days in addition to Standard of Care, or Standard of Care only.  The Standard of Care (SOC) for each 
patient will be captured in the electronic clinical reporting form (eCRF). 
 
Randomization will be stratified by site, and age (<65 versus ≥65).  
 
For Phase 2b, one interim statistical analysis will be performed on selected efficacy endpoints and for 
safety for each arm after the first 75 patients have completed up to 2 weeks of treatment (Day 15).  
This analysis is being done to allow safety assessment and some snapshots of efficacy assessments as 
the trial progresses. 
 
The Phase 2b study will also evaluate the different constructs of the ordinal scale (different days and 
different number of categories) by severity (severe vs. mild-moderate). Data from the Phase 2b study 
will be used to down select and prioritize the secondary endpoints.  The protocol would then be 
amended for Phase 3 study to include the additional required number of patients to be recruited for the 
study to meet statistical significance in its primary endpoint. 
 
An additional placebo arm will be added in the Phase 3 portion of the study. The number of 
participants to be enrolled in Phase 3 pivotal stage will be determined based upon the outcome of pilot 
Phase2b stage of the study. Participants will be randomized to receive investigational product (IP) plus 
SOC, or Placebo plus SOC. Details will be outlined in a protocol amendment 
 
Figure 1: Trial Design 
 
 
 
 


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Table 1 
Schedule of Events 
Trial Activity 
Screening/Baseline/ 
Enrolment visit 
Daily until 
hospital 
discharge 
End of 
treatment  
Follow-up period 
Day 
1 
2-14 
15 
29 
60 
Allowed window for visit 
(±) 
-1a 
 
2 
2 
3 
Visit 
1 
 
2b 
3 
4 
Informed consent 
● 
 
 
 
 
Inclusion/exclusion criteria 
including confirmation of 
COVID-19 diagnosis 
● 
 
 
 
 
Confirmation SARS-CoV-
2h 
● 
● 
● 
● 
 
Pregnancy test 
● 
 
 
 
 
Demographics/Medical 
History 
● 
 
 
 
 
Physical Exam 
● 
 
 
 
 
Vital signsc 
● 
● 
● 
● 
 
Clinical support data 
collectionf 
● 
● 
● 
● 
 
Safety Laboratory Testingd 
● 
● 
● 
● 
 
Cytokine Markersk 
● 
● 
● 
 
 
Child-Pugh Scorei 
● 
● 
 
 
 
PaO2 and PaO2/FiO2 ratioj 
● 
● 
● 
● 
 
ECG 
● 
 
 
 
 
Cough Severity (VAS)e 
● 
● 
● 
● 
 
Extent of Dyspnea (Likert 
Scale)e 
● 
● 
● 
● 
 
Adverse Events 
documented 
● 
● 
● 
● 
● 
Concomitant Medications 
● 
● 
● 
● 
 
Randomization 
● 
 
 
 
 
Administer IP 
● 
● 
 
 
 
Vital Status 
 
 
 
 
●g 
a Screening/baseline may occur up to 24 hours prior to randomization 
bTreatment can be given up to 14 days post randomization, or until hospital discharge, whichever comes first. If patient is 
discharged prior to Day 14, the next visit should be Visit 2. 
c Includes blood pressure (measured after the patient has been in a seated position (if possible) for ≥3 minutes of rest), pulse, 
respiratory rate, body temperature, and SpO2.  Body weight and height will be measured at the screening visit only. 
d Baseline, Days 3, 5, 8, 11 if hospitalized, Day 15, Day 29 
e Baseline, Days 2, 4, 8, and 14 if hospitalized, Day 15 (if not done Day 14), Day 29 
f Includes NEW Score, on Baseline, Days 3, 5, 8, 11 if hospitalized, Day 15, Day 29 
g Vital status (is patient alive) 
h Baseline, Days 5 (or discharge, whichever comes first) and 15.  Day 29 for patients with viral RNA detected at Day 15. 
Qualitative (mandatory) and Quantitative (if available) testing done all days. 
i Baseline, Days 3, 5, 8, 11 if hospitalized  
j Minimum complete baseline, Days 3, 5, 8, 11, 15 and 29.  If PaO2 not able to be taken, SpO2 should be obtained using a 
forehead sensor.  Fingertip probes may be used if forehead sensors are not available. Remain consistent with the method of 
testing for the patient over the course of the study.   
k Cytokine markers at Baseline, Day 5, Day 15 (if available per local lab):  IFN-γ, GM-CSF, IL-6, IL-12, TNF-α 
 
 


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2.2 
Objectives 
2.2.1 
Primary objectives 
To investigate the clinical efficacy and safety of NP-120 (20 and 40 mg TID) compared to standard of 
care in patients hospitalized with COVID-19 disease. 
 
• 
The choice of the primary outcome measure will be determined by a pilot study of the first 
150 patients. 
• 
Patient clinical status (on the WHO 7-point ordinal scale) at day 15 is the default primary 
endpoint 
2.2.2 
Secondary objectives 
To investigate the clinical efficacy of NP-120 (20 and 40 mg TID) as compared to the control arm as 
assessed by: 
 
• 
Ordinal scale: 
o Time to an improvement of one category from baseline on an ordinal scale. 
o Patient clinical status on an ordinal scale at days 3, 5, 8, 11, and 29. 
o Mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 15 
and 29 from baseline 
• 
National Early Warning Score (NEWS) 
o The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever 
occurs first. 
o Change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS 
• 
Oxygenation: 
o Oxygenation free days in the first 28 days (to day 29) 
o Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio 
taken at baseline and measured once daily up to 2 weeks of treatment in IP versus 
control group patients 
• 
Mechanical Ventilation: 
o Ventilator free days in the first 28 days (to day 29) 
o Incidence and duration of new mechanical ventilation use during the trial 
• 
Hospitalization: 
o Duration of hospitalization (days) 
o Time to discharge (days) 
• 
Mortality: 
o 15-day mortality 
o 28-day mortality 
2.2.3 
Exploratory objective 
To investigate the effects of NP-120 (20 and 40 mg TID) on lung function, health status, and SARS-
CoV-2 RNA status in hospitalized patients with COVID-19 disease.  
2.2.4 
Safety objective 
To study the safety of NP-120 (20 and 40 mg TID) in hospitalized patients with COVID-19 disease. 
 
 


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2.3 
Endpoints 
2.3.1 
Primary endpoint 
 
Patient clinical status (on the WHO 7-point ordinal scale) at day 15 in IP versus SOC control group 
patients:  
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
2.3.2 
Secondary endpoints 
 
• 
Status on an ordinal scale assessed daily while hospitalized and on days 15 and 28 in IP versus 
control group patients 
• 
NEWS assessed days 3, 5, 8 ,11 while hospitalized and on days 15 and 29 in IP versus control 
group patients 
• 
Rate of mechanical ventilation in IP versus control group patients 
• 
Duration of mechanical ventilation (if applicable) in IP versus control group patients 
• 
Duration of supplemental oxygen in IP versus control group patients 
• 
Time to return to SpO2 > 94% on room air 
• 
Duration in ICU (if applicable) in IP versus control group patients 
• 
Rate of Mortality in IP versus control group patients 
• 
Duration of hospitalization in IP versus control group patients 
• 
Time to discharge in IP versus control group patients 
• 
Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio taken at 
baseline and measured once daily up to 2 weeks of treatment in IP versus control group patients 
2.3.3 
Exploratory efficacy endpoints 
• 
Changes in the extent of dyspnea from baseline, using a Likert scale, at Days 2, 4, 8, and 14 in 
IP versus control group   
[Likert scale: The patient grades his/her current breathing compared to when he/she first 
started the study (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately 
better, "3" =markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly 
worse].  For the first questionnaire (at baseline), the patient compares their current shortness of 
breath to their shortness of breath when they are well. 
• 
Rate of change to patient’s experience of cough (Visual analog scale [VAS]) at Days 2, 4, 8,  
and 14 in IP versus control group 
VAS: The patient draws a vertical line on an axial graph (from 0 to 100) to show the degree of 
how he/she feels about coughing. The number "100" equals the worst coughing the patient has 
ever felt and the number "0" equals the best he/she has felt since baseline. 
• 
Changes in D-dimer in IP versus control group 
• 
Qualitative PCR for SARS-CoV-2 at baseline, days 5 (while hospitalized, and days 15 and 29 
(if able to return to clinic or still hospitalized) 
• 
Quantitative PCR (if available) for SARS-CoV-2 at baseline, days 5 (while hospitalized, and 
days 15 and 29 (if able to return to clinic or still hospitalized) 


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2.4 
Safety Endpoints: 
• 
Type, frequency, severity, and relationship of AEs to investigational product (IP)  
• 
Number of patients who discontinue IP due to any AE 
• 
Frequency of clinically significant changes in vital signs and/or laboratory findings 
 
2.5 
Sample Size 
 
For the pilot phase, a sample of 150 patients (50 in Arm A, Arm B and SOC) will be recruited. To 
account for drop out of 10%, a total of 168 patients will be enrolled. 
 
For the pivotal phase, A sample of 462 patients (231 in the SOC group and 231 in the active treatment 
group) achieves 90% power to detect a change in the log odds ratio of 0.5596 when the significance 
level (alpha) is 0.05 using a two-sided test. A log odds ratio of 0.5596 corresponds to an odds ratio of 
1.75 comparing treatment to SOC. The sample size was estimated using the Tests for Two Ordered 
Categorical Variables module in PASS 14. To account for drop out of 10%, a total of 514 patients will 
be enrolled. 
 
The sample size assumes that the distribution of patients on day 15 will be as shown in Table 2, which 
is scenario 4 in the WHO master protocol (2020) for enrolled patients with moderate to severe disease 
under an odds ratio of 1.75.  
 
Table 2 Distribution of Patients Across Outcome Categories at Day 15: SOC (WHO MP 
Scenario 4) and Treatment (Assuming OR of 1.75)  
 
 
Percent of Patients 
Outcome 
SOC 
Treatment 
7. Death 
2 
1.0 
6. Hospitalized & on mechanical ventilation or 
ECMO 
1 
0.6 
5. Hospitalized & on non-invasive ventilation or 
high flow O2 
2 
1.2 
4. Hospitalized & requires supplemental O2 
5 
3.03 
3. Hospitalized not requiring supplemental O2 
17 
11.45 
2. Not hospitalized but limitations on activities 
36 
31.90 
1. Not hospitalized & no limitations on activities 
37 
50.70 
 
2.6 
Randomization 
Static randomization using block size of 3 will be employed with stratification by site and age (<65 
versus ≥65). Patients who withdraw from the study or are lost to follow-up after signing the informed 
consent form and randomization will not be replaced. 


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3. 
STATISTICAL CONSIDERATIONS 
Data will be handled and processed per the sponsor’s representative (Novotech) Standard Operating 
Procedures (SOPs), which are written based on the principles of good clinical practice (GCP).  
3.1 
General Considerations 
All data collected on the electronic case report form (eCRF) will be presented in the data listings and 
will be listed and sorted by treatment arm, participant number and visit, where applicable. All descriptive 
summaries will be presented by treatment group and scheduled visit/time point (where applicable).  
Unless otherwise stated, the following methods will be applied: 
• 
Continuous variables: Descriptive statistics will include the number of non-missing values (n), 
arithmetic mean, standard deviation (SD), median, minimum and maximum values.  
The minimum and maximum values will be displayed to the same decimal precision as the source 
data, the arithmetic mean, SD and median values and other derived values will be displayed to one 
more decimal than the source data for the specific variable. 
95% Confidence Intervals (CIs), mean differences (among treatments and from baseline) and 
adjusted means values will be displayed to one more decimal than the source data for a specific 
variable. P-values will be displayed to 3 decimal places. 
The appropriate precision for derived variables will be determined based on the precision of the 
data on which the derivations are based, and statistics will be presented in accordance with the 
aforementioned rules. 
• 
Categorical variables: Descriptive statistics will include counts and percentages per category. The 
denominator in all percentage calculations will be the number of participants in the relevant 
analysis population with non-missing data, unless specifically stated otherwise. Percentages will 
be displayed to one decimal place. Proportions will be displayed to 3 decimal places. 
95% Confidence Intervals (CIs), difference in proportions, odds ratio’s and other categorical 
parameters will be displayed to one decimal place for percentages. Proportions will be displayed 
to 3 decimal places. P-values will be displayed to 3 decimal places. 
• 
Repeat/unscheduled assessments: Only values collected at scheduled study visits/time points will 
be presented in summary tables. If a repeat assessment was performed, the result from the original 
assessment will be presented as the result at the specific visit/time point. All collected data will be 
included in the data listings. 
• 
Assessment windows: All assessments will be included in the data listings and no visit windows 
will be applied to exclude assessments that were performed outside of the protocol specified 
procedure windows. 
• 
Result display convention: Results will be center aligned in all summary tables and listings. 
Participant identifiers visit and parameter labels may be left-aligned if required. 
• 
Date and time display conventions: The following display conventions will be applied in all 
outputs where dates and/or times are displayed: 
Date only: YYYY-MM-DD 
Date and time: YYYY-MM-DD HH:MM 
If only partial information is available, unknown components of the date or time will be presented as 
‘NK’ (not known), i.e., ‘2016-NK-NK’. Times will be reported in military time. 
• 
Specific items in relation to multiple comparisons, missing values, coding of medical, AE and 
medications and inferential statistics are covered in each of the specialized sections. 
 


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3.2 
General Key Definitions 
The following definitions will be used: 
• 
Date of the First Study Treatment Administration:  The date of the first study treatment 
administration is defined as the earliest date on which a study treatment was administered. 
• 
Date of the Last Study Treatment Administration:  The date of the last study treatment 
administration is defined as the latest known date on which a study treatment was administered. 
• 
Baseline:  The Baseline value is value taken on Day 1. If Day 1 value is missing, Baseline is 
defined as the last available valid, non-missing observation for each patient prior to first study 
treatment administration on Day 1.  Repeat and unscheduled assessments will be included in the 
derivation of the Baseline values only if Baseline visit value is missing. 
• 
Change from Baseline:  The absolute change from Baseline value is defined as the difference 
between the result collected/derived at a post-baseline visit and the Baseline value. 
The change from Baseline value at each post-baseline visit will be calculated for all continuous 
parameters using the following formula: 
 
Change from Baseline Value = Result at post-baseline visit – Baseline Value 
 
The change from Baseline value will only be calculated if the specific post-baseline visit result 
and the Baseline value for the parameter are both available and will be treated as missing 
otherwise. In the data listings, the change values will be set to ‘-’ (not applicable) for pre-baseline 
assessments. 
 
The rate of change from baseline is defined as: Change from Baseline value/Baseline Value 
 
• 
Study Day:  The study day of an event is defined as the relative day of the event starting with 
the date of the first study treatment administration (reference date) as Day 1 (there will be no 
Day 0). 
The study day of events occurring before the first study treatment administration will be 
calculated as: 
 
Study Day = (Date of Event - Date of First Study Treatment Administration) 
For events occurring on or after Day 1, study day will be calculated as: 
 
Study Day = (Date of Event - Date of First Study Treatment Administration) + 1 
Study days will only be calculated for events with complete dates and will be undefined for 
events that are ‘Ongoing’ at the end of the study. 
3.3 
Handling of Missing Data 
 
All data will be analysed as collected and missing values will not be imputed or replaced unless stated 
otherwise. 
3.4 
Treatment Groups 
• 
Arm A: Ifenprodil (20 mg TID)  
• 
Arm B: Ifenprodil (40 mg TID)  
• 
SOC: Standard of Care  
 


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4. 
ANALYSIS POPULATIONS (ANALYSIS SETS) 
In this study three analysis populations are defined: The Intent-to-Treat (ITT), Per Protocol (PP) and the 
Safety population. 
4.1 
Population Descriptions 
4.1.1 
ITT  
The ITT population consists of all enrolled patients assigned to receive treatment regardless of whether 
they took study drug or stopped active treatment to receive only SOC. Patients will be classified 
according to the treatment group to which they were randomized. 
4.1.2 
PP 
The PP population consists of all ITT patients who are not major protocol violators with regards to 
inclusion/exclusion criteria, investigational product compliance and concomitant medication 
instructions. Protocol violations that would exclude patients from the PP population will be defined 
and documented in the SAP prior to unblinding. 
4.1.3 
Safety 
The Safety population consists of all patients who received at least one dose of study drug. This 
population will be used for all assessments of safety and tolerability. Patients will be summarized 
according to actual dose of study drug taken. 
 
 
 


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5. 
PARTICIPANT DISPOSITION  
Participant disposition and analysis population analysis will be based on the all patient population. 
Participant disposition and analysis populations will be summarized descriptively as described in 3.1. 
 
The following participant enrolment and disposition information will be reported: 
 
Summary of Enrolment: 
 
• 
Number of Patients Enrolled 
• 
Number of Patients Re-screened 
• 
Number of Screen Failures 
• 
Reasons for Screen Failure (percentage denominator based on number of screen failures): 
o Failed I/E criteria 
 
Summary of Disposition: 
 
• 
Number of Patients Completed 
• 
Number of Patients Withdrawn/Not Completed 
• 
Reason for Withdrawal/Non-Completion (percentage denominator based on number of 
withdrawn patients) 
 
Counts and percentages will be reported for summary of enrolment, for all enrolled patients who gave 
consent. For the summary of disposition counts and percentages will be provided for the ITT population 
for treatment groups defined in section 3.4.  
 
Listings will be provided for summary of enrolment along with the date the participant provided 
informed consent, date received study drug/treatment received and sorted by patient ID . For summary 
of disposition, listing will be provided by treatment arm (section 3.4) sorted by patient ID for the Safety 
population, along with the date of randomization, date and time of first study drug administration, date 
of treatment termination/last visit. 
 
 


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6. 
PROTOCOL DEVIATIONS 
All protocol deviations and important protocol deviations leading to exclusion from PPS will be 
categorized as per protocol deviation management plan version 1.0, 14 July 2020. 
 
Listing of protocol deviation including information on whether the protocol deviation lead to exclusion 
from PPS will be provided by treatment arm (section 3.4) sorted by patient ID for the Safety 
population. Age and sex of the patient, date and time of first study drug administration, date of 
treatment termination/last visit, and whether the patient completed the study will also be included in 
the listing. 
 
 


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7. 
ANALYSIS POPULATIONS 
 
The following analysis set information will be reported: 
 
• 
Patients included in ITT 
• 
Patients included in PPS 
• 
Patients included in Safety 
 
Counts and percentages for these patients under this population set will be provided using the Safety 
population for treatment groups defined in section 3.4 
 
Listing of patients in analysis sets will be provided by treatment arm (section 3.4) sorted by patient ID 
for the ITT population, along with date and time of study drug administration, date of treatment 
termination/last visit, and whether the patient completed the study. 
 
 


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8. 
DEMOGRAPHICS AND MEDICAL HISTORY 
8.1 
Demography and Baseline Characteristics 
The demographics variables to be reported are listed below: 
 
• 
Age (years)  
• 
Age classification (< 65 and ≥ 65) 
• 
Gender 
• 
Women of child-bearing potential 
• 
Contraception used – Female 
• 
Contraception used – Male 
• 
Ethnicity 
• 
Race 
• 
Height (cm) at Baseline 
• 
Weight (kg) at Baseline 
• 
BMI (kg/m2) at Baseline 
• 
BMI<18.5 (Underweight), 18.5 ≤ BMI < 25 (Normal), 25≤ BMI < 30 (Overweight) and BMI>30 
(Obese). 
 
These variables will be summarized using descriptive statistics in accordance to section 3.1 under ITT 
and PPS population for treatment groups defined in section 3.4. Demographics variables and site will 
also be listed by treatment arm (section 3.4) under ITT population sorted by patient ID. 
 
8.2 
Site and Age 
Counts and percentages of patients classified by age (< 65 and ≥ 65) at each site will be summarized 
using ITT population by treatment groups defined in section 3.4. Denominator for site will be based on 
number of patients in ITT population for each treatment group and denominator for age classification 
will be based on number of patients within each site for each treatment group. 
 
8.3 
Medical /Surgical history 
Medical history conditions, medical procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 23. Patients with any medical history, any ongoing medical 
history, any medical history resulting in concomitant medication, any medical history resulting in 
concomitant procedure will be summarized by counts and percentages by treatment arm. Patients with 
any medical history (SOC and PT) will be summarized using counts and percentages for the Safety 
population by treatment groups defined in section 3.4. Medical history will be ordered by the highest 
frequency in the overall column by SOC and PT. 
 
Medical history listings will be provided by treatment arm (grouping provided in section 3.4) sorted by 
patient ID for the Safety population, along with ongoing status of medical history and age/sex/baseline 
weight of the patient. 
 
 


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9. 
PRIOR AND CONCOMITANT MEDICATIONS & THERAPIES 
Prior and concomitant medications and therapies will be coded using Anatomical Therapeutic Chemical 
(ATC) classification system version March 2020 which is controlled by the World Health Organization 
Drug Dictionary (WHO-DD). Medications will be mapped to the full WHO-DD Anatomical Therapeutic 
Chemical (ATC) class hierarchy, with ATC Level 2, ATC Level 4 presented as the primary interest for 
the analysis. 
Concomitant medications and therapies are additional medications or therapies taken on or after the first 
dose of study treatment up and including the follow up period. Medications or therapies taken before 
first dose of study drug and stopped before the first dose of study drug will be classified as prior 
medication/therapy. If missing dates prevent a clear determination as to whether the medication or 
therapy is concomitant, the medication will be regarded as concomitant.  
The number and percentage of patients using at least one prior or concomitant medication/therapy will 
be displayed together with the number and percentage of patients using at least one medication/therapy 
within each therapeutic class and preferred term. These will be summarized under Safety population for 
treatment groups defined in section 3.4 and repeated for concomitant medication/therapy used for 
different purposes: adverse events, medical history or other. 
Listing of full details of prior and concomitant medications/therapy (classification, medication taken, 
indication (adverse events, medical history or other), corresponding AE or medical history number, 
dosage, unit and route, start and stop dates/ongoing status will be provided by treatment arm (grouping 
provided in section 3.4) sorted by patient ID and visit for the Safety population, along with the age and 
sex and baseline weight of the patient. 


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10. 
TREATMENT EXPOSURE AND COMPLIANCE 
SOC medications and therapies will be coded in the same manner as prior and concomitant 
medication/therapy with ATC Level 2, ATC Level 4 presented as the primary interest for the analysis. 
Summary of counts and percentages will be provided for all sites and for each site for the ITT, PPS and 
Safety population, with denominator being the available patients at each site. 
• 
The Treatment Exposure (duration in days) is defined as: 
Date of Last Study Drug Administration - Date of First Study Drug Administration + 1. 
 
• 
The COVID-19 Treatment Exposure (duration) from randomization during the study is defined as: 
Date and Last treatment - Date of Randomization + 1 
• 
The overall COVID-19 Treatment Exposure (duration) during the study is defined as: 
Date and Last treatment - Date of First COVID19 medication/treatment + 1Both of these COVID-19 
treatment exposure durations will be categorized into ≤ 15 days, > 15 days but ≤ 29 days, and > 29 days  
 
• 
The Treatment Compliance is defined as: 
For arm A: Total dosage taken / (3×{Number of days in hospital up to 14 days}×20 
mg=840mg) 
For arm B: Total dosage taken / (3×{Number of days in hospital up to 14 days}×40 
mg=1680mg) 
No treatment compliance is calculated for SOC as this differs between sites and regimen. 
 
Treatment compliance with respect to counts and percentage of patients with  <80% and 
≥ 80% compliance will be reported. 
 
• 
The Number of Days in Hospital (duration in days) is defined as: 
Maximum of {Date and Time of First Hospital Discharge - Date and Time of First 
Hospital Admission + 1 or 14 days}. 
 
Treatment exposure in duration and compliance will be summarized using descriptive statistics in 
accordance to section 3.1 under ITT, PPS and Safety for treatment groups defined in section 3.4. These 
information will be listed by Arm A and B sorted by patient ID and visit for the ITT and Safety 
population, along with the age, sex, baseline weight of the patient as well as the dates and times of 
study drug administration at each visit, whether the patient is in PPS, route and method of 
administration (after food, crushed) and whether drug administration was interrupted or missed and 
reasons for dose/study drug not administered. 
 
For SOC, the listing will cover treatment exposure and will be sorted by patient ID and visit for the 
ITT and Safety population, along with the age, sex, baseline weight of the patient as well as site, ATC 
Level 2, ATC Level 4 classification of SOC medication/therapy, dosage, unit and route, start and stop 
dates/ongoing status. 
 
 


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11. 
EFFICACY AND EXPLORATORY ANALYSES 
 
All efficacy and exploratory analyses will be conducted for ITT and PPS. Listings for all efficacy and 
exploratory endpoints will be provided at each scheduled timepoints for the ITT population, with an 
additional flag indicating the inclusion in PPS. All of these will be provided for each treatment arm, 
sorted by patient ID, along with the age, sex and baseline weight of the patient.  
 
11.1 
Primary Efficacy Analysis 
 
For patients who died, their WHO7 responses of 7 (death) will be carried forward to all applicable 
visits. For example, a patient who died on Day 9, will be recorded as having WHO7 response of 7 on 
Day 11, 15 and 29.  
 
The SOC and treatment arms under WHO7 ordinal scale will be compared with respect to the primary 
endpoint using proportional odds models (ordinal logistic regression) adjusted for site and age. 
Treatment will be compared to SOC by testing whether the common odds ratio differs from 1.0 at day 
15 using two-sided tests at 2.5% level of significance under the ITT population set, followed by PP 
population set. All modeling assumptions will be verified. 
 
The relevant SAS code for proportional odds model takes the following form, where Treatment 
represents SOC, Arm A, Arm B and Response represents the WHO7 ordinal scale categories.  
 
proc logistic data=dataset; 
class Treatment Response Site/ param=ref ref=first; 
model Response = Treatment Age Site; 
run; 
 
The odds ratio under the fitted proportional odds model will be reported for Arm A and B vs SOC, 
along with the Wald 95% CI and corresponding Chi-squared p-value. Score test p-value testing the 
assumption of proportional odds will also be reported. To adjust for multiple comparison, p-values 
must be < 0.025 to be considered statistically significant. P-values < 0.05 may still be considered as 
potentially promising for the next study phase. 
 
In addition, counts and percentages of patients in each of the WHO-7 category will also be reported for 
each treatment arm. 
 
Separate 95% CIs (Newcombe) and p-values (Chi-Squared test without continuity correction) will be 
computed across each of the ordinal scale between SOC and treatment arms A and B. To adjust for 
multiple comparison, p-values must be < 
1
280 or (0.05/14) to be considered statistically significant. The 
reason for adopting the most stringent rule for multiple adjustment is because this pilot phase of the 
study is essentially exploratory in nature, and care must be taken to minimize the event of a premature 
conclusion being made purely due to chance.  
 
The above analyses will be done for ITT and PPS. 
 
11.2 
Secondary Efficacy Analysis: General Population Considerations 
All secondary efficacy analyses will be performed for ITT and PPS. 
11.3 
Secondary Efficacy Analysis: Time to Event General Considerations 
 
 


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Time to event endpoints will not be evaluated if any subjects experienced an event prior to 
randomization in any of the treatment arms. 
 
Time-to-event endpoints without competing risk will be analysed for each dosing group using the 
Kaplan-Meier (KM) method.  Medians (with corresponding 95% confidence intervals) and quartiles 
(25th and 75th percentiles), minimum, and maximum survival times will be presented. In addition, the 
number of patients with an event and the number of censored patients will also be reported.  The 
corresponding Kaplan-Meier survival plot will also be presented along with number at risk statistics at 
the appropriate time points. Adjusted hazard ratio, 95% CIs and p-values between active treatment 
groups to SOC under Cox proportional hazard model with age, site and treatment groups as covariates 
will be reported. 
 
Time-to-event endpoints with competing risk will be analysed for each dosing group using the 
Cumulative Incidence Function-CIF (KM) graphical display. Adjusted hazard ratio, 95% CIs and p-
values between active treatment groups to SOC under Fine‐Gray sub-distribution hazard model with 
age, site and treatment groups as covariates will be reported. Competing risk is identified by the 
presence of death outcome, which prevent the observation of the current outcome of interest. 
11.4 
Secondary Efficacy Analysis: WHO-7 Ordinal Scale 
11.4.1 Time to first improvement of one category from baseline on WHO-7 
The time to first improvement of one category on WHO-7 scale from baseline (Days) is defined as: 
 
Date of First Improvement on Ordinal Scale – Date of Baseline Assessment + 1.  
 
If the patient did not experience an improvement, the patient will be censored at the last known date 
the patient is known to not have experienced an improvement: 
 
Final Date of Confirmation of No Improvement - Date of Baseline Assessment + 1. 
11.4.2 WHO-7 Ordinal scale by timepoint 
Descriptive statistics treating WHO-7 scale as continuous data in accordance to section 3.1 will be 
reported for each treatment arm and overall at Baseline, Day 3, 5, 8, 11, 15 and 29. Change from 
baseline descriptive statistics will also be given for these timepoints for each treatment arm and overall. 
P-values and 95% CI comparing the differences between SOC and treatment arms A and B will also be 
provided for change from baseline analysis using a mixed model with baseline, treatment arm, age, 
day, site, interaction between day and treatment arm as fixed effects and patients as random effects 
with random intercepts using unstructured covariance structure. In the event of non-convergence, a 
simplified covariance structure may be chosen. 
 
Proc Mixed data = adeff; 
class site trt subjid day; 
model chg_bl = baseline site trt age day trt*day/ddfm=kr; 
random int/sub= subjid type= un; 
LSMEANS Trt*day / AT MEANS CL DIFF SLICE = day; 
run; 
 
11.5 
Secondary Efficacy Analysis: NEWS 
11.5.1 Time to the earlier of discharge or NEWS of ≤ 2 maintained for 24 hours  
 
The time to earlier of discharge or NEWS of ≤ 2 maintained for 24 hours (Days) is defined as: 
 


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Date of First earlier of discharge or NEWS of ≤ 2 maintained for 24 hours – Date of Baseline 
Assessment + 1.  
 
If the patient did not experience discharge or NEWS of ≤ 2 maintained for 24 hours, the patient will be 
censored at the last known date the patient is known to not have experienced either of these events: 
 
Final Date of Confirmation of no discharge nor NEWS of ≤ 2 maintained for 24 hours - Date of 
Baseline Assessment + 1. 
 
If a patient died before discharge or NEWS of ≤ 2 maintained for 24 hours, the patient will be censored 
as a competing risk based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
11.5.2 NEWS by timepoint 
Descriptive statistics treating NEWS scale as continuous data in accordance to section 3.1 will be 
reported for each treatment arm and overall at Baseline, Day 3, 5, 8, 11, 15 and 29. Change from 
baseline descriptive statistics will also be given for these timepoints for each treatment arm and overall. 
P-values and 95% CI comparing the differences between SOC and treatment arms A and B will also be 
provided for change from baseline analysis using a mixed model with treatment arm, age, day, site, 
interaction between day and treatment arm as fixed effects and patients as random effects with random 
intercepts. 
11.6 
Secondary Efficacy Analysis: Respiratory Support 
For the part of the analysis, respiratory support is defined as: 
 
• 
Any respiratory support (any of Oxygenation only, Mechanical Ventilation (Invasive and non 
invasive), ECMO 
• 
Oxygenation only 
• 
Invasive Mechanical Ventilation 
• 
Non Invasive Mechanical Ventilation 
• 
ECMO 
11.6.1 Rate of Respiratory Support: Oxygenation only, Mechanical Ventilation (Invasive and 
non invasive), ECMO  
Counts and percentages of patients for respiratory support at least once will be reported for each 
treatment arm. If patients were eligible for respiratory support but did not receive one due to lack of 
resources, an additional analysis on counts and percentages of patients required to receive respiratory 
support will be reported for each treatment arm. Separate 95% CIs (Newcombe) and p-values (Chi-
Squared test without continuity correction) will be computed between SOC and treatment arms A and 
B for patients with at least one respiratory support. 
11.6.2 Duration of Respiratory Support: Oxygenation only, Mechanical Ventilation (Invasive 
and non invasive), ECMO  
Counts and percentages of patients with the following categories (based on total number of hours of 
respiratory support) will be reported for each type of respiratory support and for each treatment arm. 
The duration calculation is only applicable to patient with respiratory support. For patients with 
ongoing respiratory support with no end date and time at data cut off, the date of data cut off will be 
used to calculate the end date for the ongoing at time of data cut off category. 
 
The duration is defined as: 
 
Date and time at end of respiratory support-Date and time at end of respiratory support. 


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• 
< 6 hours 
• 
≥ 6 hours but < 12 hours 
• 
≥ 12 hours but < 24 hours 
• 
≥ 24 hours but < 72 hours 
• 
≥ 72 hours but < 120 hours 
• 
> 120 hours 
• 
Ongoing at time of data cut off (≥ 6 hours) [The hour can be amended based on real data] 
• 
Ongoing at time of data cut off (≥ 12 hours) [The hour can be amended based on real data] 
• 
Ongoing at time of data cut off ((≥ XX hours) etc… 
• 
Prolonged respiratory support (consecutive respiratory support for 21 days with at least ≥ 6 
hours per day) 
 
Separate 95% CIs (Newcombe) and p-values (Chi-Squared test without continuity correction) will be 
computed between SOC and treatment arms A and B for prolonged respiratory support. 
 
 
11.6.3 Time to Respiratory Support: Oxygenation only, Mechanical Ventilation (Invasive and 
non invasive), ECMO  
 
The time to respiratory support (Day) is defined as: 
 
Date of first respiratory support – Date of Baseline Assessment + 1.  
 
If the patient did not require respiratory support, the patient will be censored at the last known date the 
patient is known to not require respiratory support: 
 
Final Date of Confirmation of no respiratory support needed - Date of Baseline Assessment + 1. 
 
If a patient died before obtaining respirator support, the patient will be censored as a competing risk 
based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
 
11.6.4 Time from first Oxygenation Support to first termination of Oxygenation Support:  
This calculation is only applicable for those with oxygenation support. 
 
The time to from first oxygenation support to first termination of oxygenation support is defined as: 
 
Date of first termination of oxygenation support – Date of first oxygenation support + 1.  
 
If the patient was still on oxygenation support, the patient will be censored at the last known date the 
patient is known to still on oxygenation support: 
 
Final date of confirmation of still on oxygenation support - Date of first oxygenation support + 1.  
 
If a patient died before terminating oxygenation support, the patient will be censored as a competing 
risk based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
 


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11.7 
Secondary Efficacy Analysis: Oxygenation 
11.7.1 PaO2 and PaO2/FiO2 
Continuous data descriptive statistics (3.1) for PaO2 and PaO2/FiO2, change from baseline, percentage 
of change from baseline in accordance to 3.2 will be reported for each treatment arm at all scheduled 
visits. T-test assuming unequal variance p-values and 95% CI comparing the differences between SOC 
and treatment arms A and B will also be provided for percentage change from baseline analysis. 
11.7.2 Time to first return to SpO2 > 94% on room air 
 
The time first return to SpO2 on room air (Day) is defined as: 
 
Date of first return to SpO2>94% on room air – Date of Baseline Assessment + 1.  
 
If the patient did not experience a return of SpO2>94% on room air the patient will be censored at the 
last known date the patient is known to not have achieved this criterion: 
 
Final Date of Confirmation of no return to SpO2>94% on room air - Date of Baseline Assessment + 1. 
 
If a patient died before achieving a return of SpO2>94% on room air, the patient will be censored as a 
competing risk based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
11.7.3 Time to first return to PaO2 of 80-100 mmHg. 
 
The time first return to PaO2 of 80-100 mmHg is defined as: 
 
Date of first return to PaO2 of 80-100 mmHg – Date of Baseline Assessment + 1.  
 
If the patient did not experience a return to PaO2 of 80-100 mmHg the patient will be censored at the 
last known date the patient is known to not have achieved this criterion: 
 
Final Date of Confirmation of no return to PaO2 of 80-100 mmHg - Date of Baseline Assessment + 1. 
 
If a patient died before achieving a return to PaO2 of 80-100 mmHg, the patient will be censored as a 
competing risk based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
 
11.7.4 Time to first return to PaO2/FiO2 of > 400 mmHg. 
 
The time first return to PaO2/FiO2 of > 400 mmHg is defined as: 
 
Date of first return to PaO2/FiO2 of > 400 mmHg – Date of Baseline Assessment + 1.  
 
If the patient did not experience a return to PaO2/FiO2 of > 400 mmHg the patient will be censored at 
the last known date the patient is known to not have achieved this criterion: 
 
Final Date of Confirmation of no return to PaO2/FiO2 of > 400 mmHg - Date of Baseline Assessment 
+ 1. 
 


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If a patient died before achieving a return to PaO2/FiO2 of > 400 mmHg, the patient will be censored 
as a competing risk based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
11.8 
Secondary Efficacy Analysis: Hospitalization and ICU 
11.8.1 Duration of Hospitalization and ICU 
Counts and percentages of patients with the following durations for hospitalization and ICU will be 
reported separately for each treatment arm. The duration calculation is only applicable to patient with 
the respective hospital or ICU stay. For patients with ongoing hospital or ICU stay with no end date at 
data cut off, the date of data cut off will be used to calculate the end date for the ongoing at time of 
data cut off category. 
 
The duration for hospital/ICU stay (Day) is defined as: 
 
Date at hospital discharge-Date of hospital admission+1. 
Date at ICU discharge-Date of ICU admission+1. 
 
• 
< 1 Day 
• 
≥ 1 Day but < 3 Days 
• 
≥ 3 Days but < 7 Days 
• 
≥ 7 Days but < 10 Days 
• 
≥ 7 Days but < 14 Days 
• 
≥ 10 Days but < 14 Days 
• 
≥ 14 Days but < 21 Days 
• 
> 21 Days 
• 
Ongoing at time of data cut off (≥ 1 Day) [The day can be amended based on real data] 
• 
Ongoing at time of data cut off (≥ 3 Days) [The day can be amended based on real data] 
• 
Ongoing at time of data cut off ((≥ XX Days) etc… 
 
11.8.2 Time to Hospitalization and ICU discharge 
 
The time to discharge is defined as: 
 
Date of discharge from hospital – Date of Baseline Assessment + 1. (For hospitalization) 
Date of discharge from ICU – Date of Baseline Assessment + 1. (For ICU) 
 
If the patient did not discharge from hospital or ICU patient will be censored at the last known date the 
patient is known to be still in hospital/ICU according to the following: 
 
Final Date of Confirmation the patient is still in hospital - Date of Baseline Assessment + 1. (For 
hospitalization) 
 
Final Date of Confirmation the patient is still in ICU - Date of Baseline Assessment + 1. (For ICU) 
 
If a patient died discharge, the patient will be censored as a competing risk based on the following: 
 
Date of Death - Date of Baseline Assessment + 1. 
 


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11.9 
Secondary Efficacy Analysis: Mortality 
Counts and percentages of patients who died by Day 15 and Day 28 and overall will be reported 
separately for each treatment arm. Separate 95% CIs (Newcombe) and p-values (Chi-Squared test 
without continuity correction) will be computed between SOC and treatment arms A and B. 
 
Time to death (Day) will be reported using KM method as described on 11.3. Time to death will be 
calculated as follows: 
 
Date of Death - Date of Baseline Assessment + 1. 
 
If the patient did not die the patient will be censored at the last known date the patient is known to be 
still alive: 
 
Final Date of Confirmation the patient is still alive - Date of Baseline Assessment + 1. 
 
11.10 Exploratory Analysis: Dyspnea 
The Likert scale categories (0" = no change, "1" =minimally better, "2" =moderately better, "3" 
=markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse) will be 
reported using counts and percentages at all scheduled timepoints for all treatment arms and overall.  
 
11.11 Exploratory Analysis: Cough VAS and D-dimer 
Percentage of change from baseline (defined in 3.2), change from baseline and actual values of Cough 
VAS and D-dimer at all scheduled timepoints will be summarized using continuous descriptive 
statistics (defined in 3.1) for all treatment arms and overall. T-test assuming unequal variance p-values 
and 95% CI comparing the differences between SOC and treatment arms A and B will also be provided 
for the percentage of change analysis. 
 
11.12 Exploratory Analysis: Qualitative and Quantitative PCR SARS-Cov-2 
Counts and percentages for type of sample (nasal, nasopharyngeal, oropharyngeal, blood and other) for 
qualitative and quantitative PCR SARS-Cov-2 will be provided for all treatment arms and overall at all 
scheduled time points. 
 
Continuous data involving log 10 transformed quantitative viral RNA load results and change from 
baseline will be reported in accordance to 3.1 for all treatment arms and overall at all scheduled time 
points. 
 
11.13 Cytokine Marker Results 
 
The following Cytoking marker will be taken at the time points specified in the study procedure schedule 
(section Table 1): 
• 
IFNγ   
• 
GM-CSF  
• 
IL-6  
• 
IL-12  
• 
TNF-alpha  
 


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Summary statistics for cytokine markers in accordance to section 3.1 will be presented for baseline and 
for each scheduled pre and post-baseline visit (which also includes change from baseline, clinical 
significance) where applicable. These summary tables will be done for ITT and PPS populations for 
treatment groups defined in section 3.4. 
All information related to cytokine marker (cytokine marker type, result, reasons not done, date and time 
of sample collection) will be presented in the by-participant data listings by treatment arm (grouping 
provided in section 3.4) sorted by patient ID and visit for the Safety population, along with the age and 
sex and baseline weight of the patient. 
 
 
 


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12. 
SAFETY  
All Safety endpoints will be analysed using the Safety analysis set. 
 
12.1 
Dose Limiting Toxicity 
The occurrence of any of the following toxicities from the initial dose of Ifenprodil administration (in 
combination with Standard of Care (SOC)) which results in: 
a. The necessity to delay ifenprodil administration in the participant, OR 
b. To reduce the dose of ifenprodil administered, either for the participant, or for subsequent 
participants, 
will be considered a DLT, if judged by the investigator to have a reasonable possibility of being related 
to the ifenprodil administration.   
 
Severity is graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0 equivalents of mild, moderate or severe: 
1. Grade 3 or higher toxicity, except elevations in gamma-glutamyltransferase (GGT) 
2. Grade ≥ 3 AST/ALT elevation 
3. Grade ≥ 2 AST/ALT elevation with Grade ≥ 2 bilirubin elevation 
Dose Limiting Toxicity will be identified in AE listings. 
12.2 
Adverse Events 
All AE verbatim terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 21. Chest X-ray resulting in AEs will also be reported. Treatment Emergent Adverse Events 
(TEAEs) are all events which start or worsen after the first dose of study drug up to and including the 
follow up period. If missing dates or time prevent a clear determination as to whether the AE is treatment 
emergent, the adverse event will be regarded TEAE. If a patient experienced the same adverse event 
multiple times, this will only be counted once for the purpose of counting the number of patients 
experiencing that adverse event. For the SOC arm, all AEs are considered TEAEs. 
An overall summary of TEAEs for counts and percentages by treatment groups defined in section 3.4 
will be provided for the following items: 
• 
Any TEAE 
• 
Any Serious TEAE 
• 
Any type of serious TEAE (Result in Death, Immediately Life-Threatening, Inpatient 
hospitalization or prolongation of existing hospitalization, Persistent or Significant Disability or 
Incapacity, Congenital abnormality or birth effect, Important Medical event may require medical 
intervention to prevent events above) 
• 
Any TEAE grade (intensity) experienced (Mild [Grade 1] Moderate [Grade 2] Severe [Grade 3] 
Life-Threatening [Grade 4] Fatal [Grade 5]) 
• 
Worst TEAE grade (intensity) experienced (Mild [Grade 1] Moderate [Grade 2] Severe [Grade 
3] Life-Threatening [Grade 4] Fatal [Grade 5]) 
• 
Action taken (None, Medication Given, Procedure/Intervention Needed, Other) 
• 
Action taken for Ifenprodil (Dose discontinuation, Drug interrupted, Unknown, None, Not 
Applicable) 
• 
Action taken for SOC (Dose discontinuation, Drug interrupted, Unknown, None, Not 
Applicable)  
• 
Outcome of TEAE (Recovered/Resolved, Recovering/Resolving, Recovered/Resolved with 
Sequelae, Not recovered, Death, Unknown, Patient discontinued from study) 


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• 
Relationship to Ifenprodil/SOC (Reasonable Possibility, No Reasonable Possibility, Not 
Applicable) 
The following table summaries (counts, percentages and number of events) will be presented by System 
Organ Class and Preferred Term by treatment arm (defined in section 3.4): 
• 
Summary of TEAEs  
• 
Summary of Serious TEAEs. 
• 
Summary of TEAEs (grade 1 or 2). 
• 
Summary of TEAE (grade of 3 or more) 
• 
Summary of Ifenprodil related TEAEs (applicable to Arm A and B only) 
• 
Summary of SOC related TEAEs (applicable to all treatment arms) 
• 
Summary of Ifenprodil related Serious TEAEs (applicable to Arm A and B only) 
• 
Summary of SOC related Serious TEAEs (applicable to all treatment arms) 
• 
Summary of TEAEs Leading to Study Discontinuation.  
• 
Summary of TEAEs Leading to Death. 
All AEs will be listed and will include the start and stop date of AEs, AE number, verbatim term, 
Preferred Term, System Organ Class, treatment, SAE/Type, TEAE, actions taken for AE, actions taken 
with SOC/Ifenprodil, causality to SOC/Ifenprodil and outcome. Separate listings will be created for 
SAEs. These listings will be presented by treatment arm (grouping provided in section 3.4) sorted by 
patient ID and AE start date for the Safety population, along with age, sex and baseline weight of the 
patient.  
12.3 
Safety Laboratory Assessments 
The following laboratory measurements will be taken at the time points specified in the study procedure 
schedule (Table 1): 
1) Hematology: Hemoglobin, hematocrit, white blood cell counts, including differential, platelet 
count, red blood cell count, myoglobin 
 
2) Biochemical tests: Glucose, blood urea nitrogen (BUN), serum creatinine, sodium, potassium, 
chloride, bicarbonate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), gamma glutamyl transpeptidase (γ-GT/GGT), total bilirubin, 
calcium, phosphorus, albumin, total protein, uric acid 
 
3)  Coagulation: activated partial thromboplastin time (aPTT) prothrombin time (PT), international 
normalised ratio (INR), D-dimer. 
 
4) Urinalysis: Specific gravity, hydrogen ion concentration (pH), protein, glucose, bilirubin, 
ketone, urobilinogen, blood, leukocytes, casts, bacteria. 
 
In some instances, continuous variables are expressed as a range (i.e. < 10). In such cases, as long as the 
limit of quantification is at least 1, values may be converted to the range boundary (upper or lower limit 
as applicable) by subtracting or adding the smallest whole number of the limit of quantification. As an 
example, a value of <10 may be converted to 9. A value of > 100 may be converted to 101. Such 
substitutions will be clearly documented in the footnotes of relevant outputs.  
For the hematology, blood coagulation, chemistry, continuous and discrete (low, normal, high) data 
summary statistics (as described in section 3.1) will be presented for values and change from baseline 
value/shift from baseline at each visit. For urinalysis, discrete data summary statistics on categorical 
results (as described in section 3.1) will be presented for values at each visit. For pH the result will be 


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classified into <5, 5 to 8 and >8. For Specific Gravity, the result will be classified into ≤ 1.015, 1.061 to 
1.021, 1.021 to 1.025, 1.026 to 1.030 and > 1.030. For Urobilinogen, the result will be classified into ≤ 
1 mg/dL, 1 mg/dL to < 2 mg/dL and > 2 mg/dL. These summary tables will be done for Safety population 
for treatment groups defined in section 3.4 
The listings of laboratory parameters (hematology, chemistry and urinalysis) will include all the 
information collected. In addition, the observations that are used as the baseline record (value) for each 
parameter will be flagged, and the change from baseline values (where applicable) at each pre and post 
baseline (scheduled and unscheduled) visit will be presented, along with reasons for laboratory 
assessments not done. These listings will be presented by treatment arm (grouping provided in section 
3.4) sorted by patient ID and visit for the Safety population, along with age, sex and baseline weight of 
the patient.  
12.4 
Vital Signs 
The following vital signs measurements will be taken at the time points specified in the study procedure 
schedule (section Table 1): 
• 
Systolic blood pressure (SBP) (mmHg) 
• 
Diastolic blood pressure (DBP) (mmHg) 
• 
Pulse Rate (beats/min) 
• 
Respiratory rate (breaths/min) 
• 
Body Temperature (ºC) 
• 
Oxygen Saturation SpO2 (%) 
• 
Level of Consciousness (Alert, Arousable only to voice, Arousable only to pain, Unresponsive) 
• 
Presence of clinically significant result 
Summary statistics for vital sign parameters in accordance to section 3.1 will be presented for baseline 
and for each scheduled pre and post-baseline visit (which also includes change from baseline, clinical 
significance) where applicable. These summary tables will be done for Safety population for treatment 
groups defined in section 3.4. 
The listing of vital sign parameters will include all the information collected. In addition, the 
observations that are used as the baseline record (value) for each parameter will be flagged, and the 
change from baseline values at each pre and post baseline (scheduled and unscheduled) visit will be 
presented along with whether the result was clinically significant (AE/MH numbers if applicable) and 
reasons not done. This listing will be presented by treatment arm (grouping provided in section 3.4) 
sorted by patient ID and visit for the Safety population, along with the age and sex and baseline weight 
of the patient.  
12.5 
12-Lead Electrocardiogram (ECG) 
The following ECG measurements will be taken at the time points specified in the study procedure 
schedule (section Table 1): 
• 
Ventricular HR (beats/min) 
• 
PR interval (msec) 
• 
QRS interval (msec) 
• 
ST segment (msec) 
• 
QTcF interval (msec) 
• 
Presence of clinically significant result (normal, abnormal not clinically significant, abnormal and 
clinically significant) 


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Summary statistics for 12-Lead ECG parameters in accordance to section 3.1 will be presented for 
baseline and for each scheduled pre and post-baseline visit (which also includes change from baseline). 
These summary tables will be done for Safety population for treatment groups defined in section 3.4 
The listing of 12-Lead ECG parameters will include all the information collected (including an overall 
assessment of presence of clinically significant result). In addition, the observations that are used as the 
baseline record (value) for each parameter will be flagged, and the change from baseline values at each 
pre and post baseline (scheduled and unscheduled) visit will be presented along with whether the result 
was clinically significant (AE/MH numbers if applicable) and reasons not done. This listing will be 
presented by treatment arm (grouping provided in section 3.4) sorted by patient ID and visit for the 
Safety population, along with the age and sex and baseline weight of the patient.  
12.6 
Physical Examinations 
By-participant data listings will be created for all physical examination parameters and all time points 
by treatment arm (grouping provided in section 3.4) along descriptions of abnormality, associated 
AE/MH numbers where applicable, and reasons not done, sorted by patient ID and visit for the Safety 
population, along with the age and sex and baseline weight of the patient. 
12.7 
Pregnancy Test Results 
All information related to pregnancy testing (whether urine and serum based, result, reasons not done, 
date and time of sample collection) will be presented in the by-participant data listings by treatment arm 
(grouping provided in section 3.4) sorted by patient ID and visit for the Safety population, along with 
the age and sex and baseline weight of the patient. 
12.8 
Child Pugh Score 
Summary statistics for total Child Pugh score in accordance to section 3.1 will be presented for baseline 
and for each scheduled pre and post-baseline visit (which also includes change from baseline, clinical 
significance) where applicable. These summary tables will be done for Safety population for treatment 
groups defined in section 3.4 
All information related to child Pugh score (component of child Pugh score, total child Pugh score, result, 
reasons not done, date and time of sample collection) will be presented in the by-participant data listings 
by treatment arm (grouping provided in section 3.4) sorted by patient ID and visit for the Safety 
population, along with the age and sex and baseline weight of the patient. 
 
 


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13. 
CHANGES TO THE PLANNED ANALYSIS 
14. 
AN AD-HOC ANALYSIS BASED ON ALL PATIENTS WHO RECEIVED 
REMDESIVIR AS PART OF THEIR SOC IN ALL TREATMENT ARMS MAY BE 
PERFORMED AS DESCRIBED IN 14.3.


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INTERIM AND FINAL ANALYSIS 
14.1 
Interim Analyses 
The DSMB will review safety data after every 25 patients are entered into the trial up to 100 patients, 
and then at every 50 patients. Ad hoc reviews will be undertaken if there are other specific safety 
concerns. The study will not stop enrolment awaiting these DSMB reviews, though the DSMB may 
recommend temporary or permanent cessation of enrolment based on their safety reviews. Based on 
the recommendations of the WHO R&D Blueprint Clinical Trials Expert Group and given the severity 
of illness in COVID-19, there are no pre-specified study stopping rules for safety.  
 
 
For Phase 2b, an interim analysis will also be performed when 75 patients completed Day 15 
assessments for primary endpoint. For this interim analysis with first 75 patients with Day 15 efficacy 
data, in addition to standard DSMB outputs, the following descriptive statistics efficacy analysis will 
also be presented: 
 
1. WHO-7 efficacy with Day 15 assessment 
2. Status on an ordinal scale assessed daily while hospitalized and on days 15 
3. NEWS assessed days 3, 5, 8 ,11 while hospitalized and on days 15 in IP versus control group 
patients 
4. Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio taken at 
baseline and measured once daily up to 2 weeks of treatment in IP versus control group 
patients 
5. Rate of mechanical ventilation in IP versus control group patients (Patients who received 
Invasive/non-invasive Mechanical Ventilation by Day 15)  
 
For item 5, if a patient did not experience mechanical ventilation by Day 15, he/she will be marked as a 
negative response even if the patient did experience mechanical ventilation past Day 15. This is 
different to the final analysis described above. 
 
A preliminary full analysis report of 150 patients with up to Day 29 data entered may also be 
presented. 
 
14.2 
Final Analysis (End of Study) 
The final analysis will be conducted after all participants have completed the study, the clinical database 
has been locked, the analysis populations have been approved. 
The final analysis will be based on the final version of the SAP. Any deviations from the planned analysis 
will be documented in the CSR. 
 
14.3 
Ad-hoc Analysis (End of Study) 
An ad-hoc analysis may be reran for all outputs for all patients who received Remdesivir as part of their 
SOC in all treatment arms. 
 
 
 


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15. 
SOFTWARE 
• 
SAS® Version 9.4 or higher (SAS Institute, Cary, North Carolina, USA). 
.


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16. 
TABLES, LISTINGS AND FIGURES 
Please refer to mock shell template. A separate DSMB tables listings and figures mock shell is also available. 
 


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17. 
REFERENCES 
1) 
Clinical Study Protocol Version 2.0 dated 16 November 2020. 
2) 
Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med 1998; 17: 873–890