RESOLUTION: A Double-blind, Randomized, Placebo-controlled, Phase II/III Study of the Efficacy and Safety of LAU-7b in the Treatment of Adult Hospitalized Patients With COVID-19 Disease
Phase: PHASE2
Conditions: COVID-19 Disease
Sponsor: Laurent Pharmaceuticals Inc.

 
 
 
 
 
 
 
COVER PAGE FOR PROTOCOL 
 
 
 
 
 
 
 
 
 
Protocol Title: RESOLUTION: A DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PILOT PHASE II STUDY OF THE EFFICACY 
AND SAFETY OF LAU-7b IN THE TREATMENT OF ADULT 
HOSPITALIZED PATIENTS WITH COVID-19 DISEASE 
 
Document date: 18 Oct 2020 
 
 
NCT number: 
 
 
04417257 
 
 
 
 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
1 of 73 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
LAURENT PHARMACEUTICALS INC. 
 
PROTOCOL NO: LAU-20-01 
 
 
 
Study title: RESOLUTION: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PILOT PHASE II STUDY OF THE EFFICACY AND SAFETY OF LAU-7b IN THE TREATMENT 
OF ADULT HOSPITALIZED PATIENTS WITH COVID-19 DISEASE 
 
 
 
Sponsor: 
Laurent Pharmaceuticals Inc. 
 
Sponsor address: 
1010 Sherbrooke St. West, Suite 2401, Montréal (Québec) H3A 2R7 Canada 
 
 
Protocol Date: 
Amendment 1, October 18th, 2020 
 
 
 
 
 
 
 
 
Confidentiality Statement 
__________________________________________________________________________________ 
This document contains proprietary and confidential information of Laurent Pharmaceuticals Inc. 
Acceptance of this document constitutes agreement by the recipient that no unpublished information 
contained herein will be published or disclosed without prior written approval from Laurent 
Pharmaceuticals, except that this document may be disclosed to study personnel under your supervision 
who need to know the contents for conducting the study and appropriate Institutional Review Boards 
under the condition that they are requested to keep it confidential. The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, Laurent Pharmaceuticals must be 
promptly informed of any such disclosure. 
__________________________________________________________________________________ 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
2 of 73 
Signature Page for Sponsor:  
 
Product:  LAU-7b 
Study No. LAU-20-01  
 
Title: RESOLUTION: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PILOT 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF LAU-7b IN THE TREATMENT OF 
ADULT HOSPITALIZED PATIENTS WITH COVID-19 DISEASE  
 
Approved by the following: 
 
 
 
 
____________________________________________ 
_______________________________ 
Larry Lands, MD, PhD 
Date 
Chief Medical Adviser 
Laurent Pharmaceuticals Inc. 
1-514-701-7231 
e-mail: larry.lands@mcgill.ca 
 
 
 
 
____________________________________________ 
_______________________________ 
Jean-Marie Houle, B.Sc.Pharm., M.Sc., PhD 
Date 
Vice President of Clinical Development, 
Laurent Pharmaceuticals Inc. 
and Study Director 
1-514-941-2313 
e-mail: jmhoule@laurentpharma.com 
 
 
 
 
____________________________________________ 
_______________________________ 
Diane Potvin, M.Sc. 
Date 
Study Statistician 
Excelsus Statistics Inc. 
4278 Hampton Ave. 
Montreal, Québec H4A 2K9 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
3 of 73 
 
Signature Page for Investigator:  
 
Product:  LAU-7b 
Study No. LAU-20-01  
 
Title: RESOLUTION: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PILOT 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF LAU-7b IN THE TREATMENT OF 
ADULT HOSPITALIZED PATIENTS WITH COVID-19 DISEASE  
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with all relevant local regulations, the current International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 
Guideline for Good Clinical Practice (GCP), and with the principles of the most recent version of the 
Declaration of Helsinki. 
 
 
Signed: 
 
 
_______________________ _____________________________ _________________________ 
Principal Investigator Name Signature 
Date 
(print in block capital letters)  
 
 
____________________________________________ 
 
Institution Name 
 
 
____________________________________________ 
_______________________________ 
City and Province/State + Postcode/Zipcode 
Country 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
4 of 73 
1 SYNOPSIS 
Note: 
This synopsis does not contain all details and therefore cannot be used as a guide for the 
operational conduct of the study. 
Title 
RESOLUTION: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PILOT PHASE II STUDY OF THE EFFICACY AND SAFETY OF LAU-7b IN THE 
TREATMENT OF ADULT HOSPITALIZED PATIENTS WITH COVID-19 DISEASE 
Investigational 
Product 
LAU-7b (fenretinide) oral capsules 
Sponsor 
Laurent Pharmaceuticals Inc. 
Study 
Objectives 
Primary objective:  
To evaluate the efficacy of LAU-7b therapy + Standard-of-Care (SOC) relative to placebo 
+ SOC in patients with COVID-19 disease with confirmed SARS-CoV-2 infection (target 
population). 
 
Secondary and exploratory objectives:  
1- To assess the safety of LAU-7b therapy in all patients who received at least one dose 
of the study medication (Safety Population), compared to placebo + SOC. 
2- To assess the efficacy of LAU-7b therapy at decreasing the rate of COVID-19 disease 
related aggravation in the target population (such as a worsening of one category on 
the ordinal scale, onset of severe categories on the ordinal scale, need for transfer to 
Intensive Care Unit (ICU), need for mechanical ventilation and death, among others), 
compared to placebo + SOC. 
3- To measure the impact of LAU-7b therapy on the time course of the COVID-19 
disease in the target population, as depicted by mean ordinal scale change from 
baseline at each assessment time, and by time-to-event analyses (time to an 
improvement of one category on the ordinal scale, time to recovery (defined), time to 
ICU transfer, time to mechanical ventilation, and time to death), compared to placebo 
+ SOC. 
4- To assess the antiviral activity of LAU-7b therapy as depicted by the time to attain an 
undetectable viral load representative of virology remission, compared to placebo + 
SOC. 
5- To assess the benefit of LAU-7b therapy on the Quality of Life, compared to placebo 
+ SOC.  
 
 
 
 
 
 
Study Rationale 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV2 is a novel coronavirus identified as the cause of the coronavirus disease 2019 
(COVID-19) that began in Wuhan, China in late 2019, and rapidly qualified as a pandemic. 
No effective therapy currently exists for treatment. While most patients with COVID-19 
disease are thought to have a favorable prognosis, older patients and those with chronic 
underlying conditions may have worse outcomes with hyper-inflammation in the lungs 
and rapid progression to acute respiratory distress syndrome (ARDS) that may result in a 
requirement for mechanical ventilation, thus creating an unsustainable burden for the 
health care system and a rapidly escalating crisis 6.  
 
One of the main mechanisms for ARDS is cytokine storm, a deadly uncontrolled systemic 
inflammatory response resulting from the release of large amounts of pro-inflammatory 
cytokines and chemokines10. Anti-inflammatory treatments that aggressively inhibit 
inflammation, such as corticosteroids, are less expected to have a significant benefit during 
the viral response phase of the disease, when the immune response is required for to 
effectively fight the infection and prevent its escalation to lung hyper-inflammatory phase 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
5 of 73 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Rationale 
(cont’d) 
that may require respiratory support11. However, mild non-steroidal anti-inflammatory 
drug (NSAID)s (such as ibuprofen and acetaminophen) are useful for decreasing fever in 
coronavirus patients12. Recent results from the RECOVERY clinical study with 
dexamethasone corticosteroid therapy in hospitalized COVID-19 patients showed a 
reduction in death incidence by one-third in patients receiving invasive mechanical 
ventilation and by one-fifth in patients receiving oxygen without invasive mechanical 
ventilation. However, it did not reduce mortality in patients not receiving respiratory 
support at randomization 13.  
 
Normally, the body is able to maintain a balance between the pro-inflammatory and the 
resolution phases of inflammation. However, in certain conditions, this balance is 
disrupted and the pro-inflammatory phase becomes over-reactive.  
All current anti-inflammatory drugs work by inhibiting parts of the pro-inflammatory 
phase of the inflammation, modulated by the Arachidonic Acid (AA) metabolic cascade. 
LAU-7b is a novel once-a-day oral form of fenretinide that is under development by 
Laurent Pharmaceuticals for its ability to trigger the body’s own resolution of 
inflammation without interfering with its immune response (a “pro-resolving” effect). 
LAU-7b is believed to act on the resolution phase of inflammation by endogenously 
modulating the metabolism of docosahexaenoic acid (DHA), an essential fatty acid 
involved in the process of healing and return to homeostasis after a pathogen attack or 
injury. Therefore, LAU-7b can be used as a balancing factor able to keep the inflammation 
process under control, complementing the action of typical anti-inflammatory drugs. 
During a drug-library screening effort conducted by scientists from the Institut Pasteur 
Korea, fenretinide was shown to also have potent antiviral activity against Middle Est 
Respiratory Syndrome coronavirus (MERS-CoV), a virus that is structurally similar to the 
virus causing COVID-1929. Very recent preliminary results using the same cellular model, 
showed that fenretinide exerts a similarly potent antiviral activity against the SARS-CoV-
2 virus (unpublished data), a very relevant finding being confirmed by additional 
experiments. 
LAU-7b is currently being evaluated in a Phase 2 clinical trial in adult patients with Cystic 
Fibrosis (CF) aiming to treat the exaggerated inflammatory response that leads to 
irreversible lung damage. An earlier Phase 1b clinical data from CF adult patients, with 
LAU-7b escalating doses of up to 300 mg administrated orally, once-a-day, showed that 
LAU-7b was safe and well tolerated, and able to maintain the balance between AA and 
DHA pathways, with a favourable effect on certain biomarkers of inflammation (IL-6, IL-
8, IL-10, neutrophils count) at the onset of a pulmonary exacerbation episode, suggestive 
of a protective effect on the lungs. 
LAU-7b’ lipid modulation activity was shown to be in conjunction with pro-resolving 
pathways of inflammation (MAPK/ERK25, NF-kB37, cPLA214), which also play a role in 
virus cellular entry, replication and avoidance of host defense system14, 15, 16. By inhibiting 
these molecular pathways, LAU-7b may not only interfere with virus spread in the body, 
but also prevent the escalation of the pro-inflammatory response resulting during the 
infection process. Due to its antiviral properties and its pro-resolving effects on 
inflammation, LAU-7b is therefore being proposed as a therapeutic with potential to 
reduce COVID-19 disease severity, maintain a balanced immune-inflammatory response 
and prevent disease progression toward an Acute Respiratory Distress Syndrome, 
especially in patients at risk because of their age, underlying conditions, or both. 
 
Study Endpoints 
 
 
Primary Endpoint: 
The main efficacy variable is the 7-point ordinal scale of the patient status and the primary 
efficacy endpoint is the proportion of patients alive and free of respiratory failure on Day 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
6 of 73 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Endpoints 
(cont’d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
29 (Ordinal scale scores 1-4 inclusively), compared between the active and control 
(placebo) arms of the study; all patients will undergo the SOC at their institution. The 
ordinal scale is presented below and further definitions of categories 1-6 are presented in 
the body of the protocol Section 7.1.1. 
Ordinal Scale  
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 (extra-corporeal 
membrane oxygenation);  
7. Death. 
The ordinal scale is an assessment of the health status on a given study day, summarizing 
the previous day of observation. Each day, the worst health status during the previous 
day gets scored with the scale and will be recorded. i.e. on Day 3, the worst Day 2 health 
status is obtained, scored and recorded as Day 2 score in the CRF. 
 
Secondary Endpoints:  
1. Safety: The safety of LAU-7b therapy will be assessed through the monitoring of 
treatment emergent adverse events and serious adverse events, vital signs including 
oxygen saturation and body temperature, symptom-directed physical examinations 
and safety laboratory tests. It is important to note that most of these assessments are 
also SOC for hospitalized patients with COVID-19 disease and changes from baseline 
can depict improvement or worsening of the condition. 
2. Efficacy: Patient status on the 7-point ordinal scale on Days 14 and 29; compared 
between the active and control (placebo) arms of the study. 
3. Efficacy: Rate of all-causes death, depicted by a change from baseline in the ordinal 
scale position to category 7 by Days 29 and 60, compared between the active and 
control (placebo) arms of the study. 
4. Efficacy: Rate of COVID-19 disease-related aggravation, depicted by a change from 
baseline in the ordinal scale position of at least one category, compared between the 
active and control (placebo) arms of the study. 
5. Efficacy: Rate of COVID-19 disease-related transfer to ICU, depicted by a change 
from baseline in the ordinal scale position to categories 5 or 6, compared between the 
active and control (placebo) arms of the study. 
6. Efficacy: Rate of COVID-19 disease-related transfer to mechanical ventilation, 
depicted by a change from baseline in the ordinal scale position to category 6, 
compared between the active and control (placebo) arms of the study. 
7. Efficacy: Mean change from baseline of the ordinal scale patient status as a function 
of assessment time, compared between the active and control (placebo) arms of the 
study. 
8. Efficacy: Time to an improvement of one category on the ordinal scale patient status, 
compared between the active and control (placebo) arms of the study. 
9. Efficacy: Time to recovery, defined here as a move from baseline to categories 2 or 1 
on the ordinal scale patient status (first occurrence if more than one), compared 
between the active and control (placebo) arms of the study. 
10. Efficacy: Time to mechanical ventilation, defined here as a move from baseline to 
category 6 on the ordinal scale patient status, compared between the active and control 
(placebo) arms of the study. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
7 of 73 
 
 
 
 
 
Study Endpoints 
(cont’d) 
11. Efficacy: Time to death, defined here as a move from baseline to category 7 on the 
ordinal scale patient status, censored to Day 60 if it happens later than Day 60, 
compared between the active and control (placebo) arms of the study. 
12. Efficacy: Duration of hospitalization (days) within the study period Days 1-60, 
compared between the active and control (placebo) arms of the study. 
13. Efficacy: Time to attain an undetectable viral load through oropharyngeal swabs done 
at specified times, compared between the active and control (placebo) arms of the 
study. This is an optional endpoint for clinical sites able to obtain serial samples until 
discharge of patients. 
14. Quality-of-Life: The change from baseline to Days 14, 29, 45 and 60 in the score 
obtained on the EQ-5D-5L survey, a well-documented scoring system that has been 
widely used and validated as a QoL assessment tool, compared between the active and 
control (placebo) arms of the study, in patients reaching Days 14, 29, 45 and 60 and 
able to fill the questionnaire. A longer term assessment is set around 2 months’ post-
randomization. 
 
 
 
 
 
Study Design 
Overview 
 
 
 
 
 
 
RESOLUTION a randomized, double-blind (patients, investigators and blinded study 
staff), placebo-controlled Pilot Study of LAU-7b against confirmed COVID-19 disease. 
All patients, hospitalized because of their health condition and aggravating factors, 
suspected or confirmed to be infected with SARS-CoV-2 virus, will undergo the SOC for 
their stage of COVID-19 disease at their institution. This design is appropriate for this 
phase of development as it caters to individuals at a greater risk of aggravation but do not 
yet require intensive care.  
Up to approximately 240 patients will be recruited and randomized for the treatment phase 
of the study with the expectation that at least 200 patients complete the study as per 
protocol. Patients will be enrolled at approximately 15 centers in the United States of 
America and in Canada. Below is a schematic of the study structure: 
 
 
 
Adult male and female patients 18 years and older, exhibiting a symptomatology typical 
of COVID-19 disease, suspected or confirmed to be positive for SARS-CoV-2 and 
admitted in the hospital for preventative reasons, will be offered to participate in this pilot 
interventional study. There is no time limit between the onset of symptoms, the start of 
hospitalization or the confirmation of SARS-CoV-2 infection, and the screening. 
If agreeable, patients will be consented and eligibility will be confirmed. Eligible patients 
will be randomized (1:1) to receive in a blinded fashion, either LAU-7b 300 mg per day 
(3 capsules of 100 mg each), once a day for 3 days, or a matching placebo administered in 
the same fashion (the “Initial Treatment”). 
Suspected or confirmed 
COVID-19 disease patients, 
n= circa 240 
Confirmed LAU-7b 
+ standard of care 
n=110 
Confirmed Placebo 
+ Standard of care 
n=110 
Final assessment  
on Day 60 or  
early termination 
Blinded efficacy 
& safety 
evaluation of 
each patient by 
Site staff  

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
8 of 73 
Patients who receive a positive SARS-CoV-2 test result during Days 1-3, will continue 
the treatment with LAU-7b 200 mg per day (2 capsules of 100 mg each), once a day for 
the remaining 11 days, or a matching placebo administered in the same fashion, on top of 
SOC (the “Follow-up Treatment”).  
For suspected cases, if the SARS-CoV-2 test result is negative or not received by pre-dose 
on Day 4, patient will be withdrawn from further treatment, will be assessed for safety at 
time of withdrawal only or until ongoing AE have resolved/stabilized and in any instances 
no later than Day 29, and will revert to SOC. 
All eligible and confirmed patients will be treated and closely monitored for a period of 
up to 2 weeks or until early termination. The last day of follow-up will be on Day 60, or 
may correspond to early termination due to withdrawal or death, whichever comes first. 
An aggravation preventing oral intake of study medication in its intact form is not an early 
termination as the patients will continue to undergo the SOC and planned study 
assessment, whenever possible. 
A Data and Safety Monitoring Board (DSMB) will be created for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Inclusion Criteria: 
 
1- Subjects must exhibit symptoms of COVID-19 disease at screening; 
2- Subjects must be 18 years and older, of either gender; 
3- Subjects must have at least one of the following factors/co-morbidities: 
a) Controlled or uncontrolled diabetes; 
b) Pre-existing cardiovascular disease, including hypertension; 
c) Pre-existing respiratory disease such as COPD, asthma, emphysema; 
d) Active smoker with a 20 pack-years of smoking; 
e) Obesity as depicted by BMI≥30; 
f) Laboratory tests indicative of a higher risk of COVID-19-related 
complications, such as troponin >1.5 ULN and/or CRP >1.5 ULN; 
g) Patient aged 70 years and older who, based on the judgment of the 
Investigator, is at a higher risk of developing complications. 
4- Subjects must have a documented positive test for the SARS-CoV-2 virus or be 
suspected to be positive and with a test result pending; 
5- Subjects must be under observation by, or admitted to a controlled facility or 
hospital to receive SOC for COVID-19 disease;  
6- Subject’s health status must be 3, 4 or 5 on the Ordinal Scale and not previously a 
“6”;  
7- If female, must be either post-menopausal (one year or greater without menses), 
surgically sterile, or, for female subjects of child-bearing potential who are capable 
of conception, must be: practicing a highly effective method of birth control 
(acceptable methods include intrauterine device, complete abstinence, spermicide + 
barrier, male partner surgical sterilization, or hormonal contraception) during the 
study and through 30 days after the last dose of the study medication. Periodical 
abstinence is not classified as an effective method of birth control. A pregnancy test 
must be negative at the Screening Visit; 
8- Subjects must have the ability to understand and give informed consent, which can 
be verbal with a witness, according to local requirements; 
9- Subjects deemed capable of adequate compliance including attending scheduled 
visits for the duration of the study; 
10- Subjects must be able to swallow the study drug capsules. 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
9 of 73 
 
 
 
 
 
 
 
 
 
Study Population 
(cont’d) 
Study Exclusion Criteria: 
1. Pregnancy or breastfeeding; 
2. Health condition deemed to possibly interfere with the study endpoints and/or 
the safety of the patients. For example, the following conditions 
should be considered contraindicated for participation in the study, but this is not an 
exhaustive list. In case of doubt, the Investigator should consult with 
the Sponsor’s medical representative: 
a) Presence of inherited retinitis pigmentosa; 
b) Presence or history of liver failure; 
c) Presence or history of stage 4 severe chronic kidney disease or dialysis 
requirement; 
d) Febrile neutropenia; 
e) Presence of active cancer treated with systemic chemotherapy or 
radiotherapy. 
 
3. Known history of a severe allergy or sensitivity to retinoids, or with known allergies 
to excipients in the oral capsule formulation proposed to be used in the study; 
4. Participation in another drug clinical trial within 30 days (or a minimum of 5 
elimination half-lives) prior to screening, except ongoing participation in non-
interventional studies; 
5. Calculated creatinine clearance (CrCL, using the Cockroft-Gault equation for 
example) <60 ml/min; 
6. Presence of total bilirubin >1.5 x ULN (in the absence of demonstrated Gilbert’s 
syndrome), ALT and/or AST > 2.5 x ULN. 
 
 
Dose and Mode of 
Administration 
Dose rationale in COVID-19 disease. An initial load dose of 300 mg will be administered 
PO once-a-day, in the first three days of treatment, for a faster achievement of fenretinide 
plasma concentrations eliciting antiviral effect. A maintenance dose of 200 mg will then 
be administered PO once-a-day on Days 4-14, to maintain a plasma concentration 
expected to have both antiviral activity and a pro-resolving effect on inflammation. On the 
exposure standpoint, this regimen should achieve average circulating level of circa 2 µM, 
which corresponds to the concentrations eliciting the cytokine storm protection in the mice 
model of sepsis (1-2 µM) and close to the IC50 for the antiviral activity against the MERS-
CoV virus (2.8 µM). 
A study treatment consisting of up to fourteen (14) consecutive days of treatment with 
LAU-7b or placebo, administered as follows: 
• Initial Treatment on Days 1-3: LAU-7b 300 mg per day (3 capsules of 100 mg each), or 
matching placebo, once a day for 3 days in the fed state, preferably the main meal of the 
day, followed by the 
• Follow-up Treatment on Days 4-14: LAU-7b 200 mg per day (2 capsules of 100 mg 
each), or matching placebo, once a day in the fed state, preferably the main meal of the 
day. Only patients confirmed with SARS-CoV-2 infection no later than pre-dose on Day 
4, will receive the Follow-up Treatment. 
• The capsules should not be broken down to administer their content through a feeding 
tube if the patient is intubated and cannot ingest anymore the capsules intact. 
 
Study treatment will be administered on top of current Standard of Care therapies. 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
10 of 73 
Statistical 
Analysis 
 
Sample size:  
A target of 220 SARS-CoV-2 positive patients total sample size is required in this study 
in order to complete about 200 patients, and to account for on-study withdrawals (10% 
rate). It is expected that up to approximately 240 suspected and confirmed SARS-CoV-2 
patients will need to be randomized for the “Initial Treatment” portion of the study, in 
order to get the 220 confirmed cases who will receive the “Follow up Treatment” portion 
of study treatment. 
Sample size rationale: This is a pilot study and therefore only informal sample size 
calculation has been done.  
Using the proportion of patients alive and free of respiratory failure at Day 29, an effect 
size of 12% change (i.e. 78% in the control group vs. 90% in the investigational group), 
comparing the active arm versus the control (placebo) arm, it is possible to estimate that 
the proposed total sample size of 200 will result in a power of approximately 75% of 
detecting a difference in proportions of 12% as statistically significant using a one-tailed 
test with an alpha of 0.05 (5%). The statistical power is considered appropriate for a pilot 
study. 
This sample size is in the upper realm of other pilot studies in this indication for 
hospitalized patients with COVID-19 disease. 
 
Primary Efficacy Endpoint Analysis: 
The primary hypothesis test will be based on a test of a null hypothesis that the proportions 
of patients alive and free of respiratory failure for the two treatment groups are the same 
against the alternative hypothesis that the investigational group is superior to the control 
group.  
 
The statistical analyses for the other study parameters are summarized in the Statistical 
Analysis, Section 12, and will be detailed in the SAP.  
 
A formal futility analysis will be performed when a minimum of half of the enrolled 
patients have completed their LAU-7b (or placebo) treatment period and selected health 
status/efficacy information is available. 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
11 of 73 
2 SCHEDULE OF EVENTS 
 
Screening 
Pre-
randomization 
on Day 1 
Randomiz
ation on 
Day 1 
In-Hospital  
Days  
2, 3, 4 , 6 , 7, 9, 
10, 11, 13 
In-
Hospital 
Days  
5, 8, 12 
End-of–
Hospital 
Stay or Day 
14 
Contacts in 
hospital after 
Day 14 or after 
discharge every 
3 days up to Day 
298 
Contacts on 
Day 29 and 
Day 45 
End-of-Study / 
Long term 
follow-up Day 
60 
Early 
termination  
due to 
(-) SARS-CoV-2 
or else 
Visit number 
0 
1 
2, 3, 4 , 6 , 7, 9, 
10, 11, 13 
 5, 8, 12 
n/a 
variable 
n/a 
n/a 
n/a 
Verification of ID and age 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demographics and Medical 
History  
X 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
 
 
X 
X 
X 
X 
 
X 
Standard of Care procedures 
Directed Physical 
Examination 
X 
 
 
X 
X3 
 
 
 
 
Height, weight and Body 
Mass Index calculated1 
X 
 
 
 
X 
 
 
 
 
Vital Signs including 
respiratory rate, oxygen 
saturation and body  
temperature2 
X 
X 
X 
X 
X 
 
 
 
X 
Oropharyngeal Swab 
(optional for certain sites)  
X 
 
 
X 
X3 
 
 
 
 
COVID-19 symptom check  
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety laboratory tests, 
including hematology with 
differentials4, serum 
chemistry5 and urinalysis6 
X 
 
 
X 
X3 
 
 
 
 
Study-specific procedures 
Pregnancy Test for women 
(serum or urine) 
X 
 
 
 
X 
 
 
 
X 
Health status using Ordinal 
Scale 
X 
 
X 
X 
X 
X 
X 
X 
 
QOL: EQ-5D-5L 
X 
 
 
 
X 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispensing of Initial 
Treatment 
 
X 
 
 
 
 
 
 
 
Dispensing of Follow-up 
Treatment 
 
 
X  
on Day 4 only 
 
 
 
 
 
 
Study drug verification7 
 
 
 
 
X 
X 
 
 
 
Open-ended safety questions 
 
 
 
X 
X3 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Height only measured/estimated during Visit 0 
2 According to SOC, may be done on several occasions each day; for the purpose of data collection for the study, collect twice per day during hospitalization 
3 Will not be repeated if assessment done within 2 days from the discharge day 
4 Hematology: CBC, hemoglobin, hematocrit, differentials, platelets 
5 Serum Chemistry: Includes at a minimum creatinine, BUN, bilirubin, alkaline phosphatase, AST, ALT, albumin 
6 Urinalysis: According to SOC, could include pH, urobilinogen, protein, blood, bilirubin and glucose 
7 Verification will be done prior on discharge day, remaining study medication will be provided to Patient for at-home administration, where applicable.  
8 Contacts in hospital after Day 14 or after discharge will have a one-day window (i.e. ± 1 day on either side of the target visit day). 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
12 of 73 
 
TABLE OF CONTENT 
1 
SYNOPSIS .............................................................................................................................................................................. 4 
2 
SCHEDULE OF EVENTS ............................................................................................................................................. 11 
3 
GLOSSARY OF TERMS AND ABBREVIATIONS ........................................................................................... 15 
4 
STUDY PERSONNEL .................................................................................................................................................... 17 
5 
INTRODUCTION ............................................................................................................................................................. 18 
5.1 
Investigational product ........................................................................................................................................... 18 
5.1.1 
Rationale for LAU-7b, a novel and improved oral formulation of fenretinide .................. 18 
5.2 
COVID-19 Disease Overview ............................................................................................................................. 19 
5.3 
Treatment of COVID-19 Disease ....................................................................................................................... 20 
5.4 
Study Rationale ......................................................................................................................................................... 20 
5.4.1 
Proposed Mechanism of Action in COVID-19 disease .................................................................. 22 
5.4.2 
Supportive Clinical Evidences ................................................................................................................. 24 
5.4.3 
Specific Rationales for the proposed Phase II study ..................................................................... 30 
6 
STUDY OBJECTIVES ................................................................................................................................................... 32 
7 
STUDY DESIGN .............................................................................................................................................................. 33 
7.1 
Endpoints .................................................................................................................................................................... 33 
7.1.1 
Efficacy Variable: .......................................................................................................................................... 33 
7.1.2 
Primary Efficacy Endpoint ....................................................................................................................... 33 
7.1.3 
Justification for the main Efficacy Variable and the Primary Efficacy Endpoint .............. 34 
7.1.4 
Secondary Endpoints .................................................................................................................................. 34 
7.2 
Study Overview ........................................................................................................................................................ 35 
7.2.1 
Description ...................................................................................................................................................... 35 
7.2.2 
DSMB .................................................................................................................................................................. 36 
7.2.3 
Study Stopping Rule Guideline ............................................................................................................... 37 
7.3 
Blinding and Randomization ................................................................................................................................ 37 
7.3.1 
Rationale for Placebo Control ................................................................................................................. 37 
7.3.2 
Blinding and Breaking the Blind ............................................................................................................ 38 
7.3.3 
Randomization Scheme and Stratification ........................................................................................ 38 
8 
SELECTION AND WITHDRAWAL OF PATIENTS ........................................................................................ 38 
8.1 
Screening Inclusion Criteria ................................................................................................................................. 38 
8.2 
Screening Exclusion Criteria ................................................................................................................................ 39 
8.3 
Study Drug Discontinuation and Withdrawal of Patients .......................................................................... 39 
8.4 
Replacement of Patients ......................................................................................................................................... 40 
9 
STUDY CONDUCT ......................................................................................................................................................... 41 
9.1 
Timing of Assessments .......................................................................................................................................... 41 
9.2 
Study Visits and Procedures ................................................................................................................................. 41 
9.2.1 
Screening and Eligibility Assessments (Visit 0, pre-randomization): ................................... 41 
9.2.2 
Randomization and First Dosing (Visit 1, Day 1) ........................................................................... 42 
9.2.3 
In-Hospital Days ............................................................................................................................................ 42 
9.2.4 
Contacts in hospital after Day 14 or after discharge once every 3 days (±1 day from 
target) and up to Day 29 ............................................................................................................................................... 44 
9.2.5 
Contacts on Days 29 and 45 ..................................................................................................................... 44 
9.2.6 
End-of-Study / Long-term Follow-up .................................................................................................. 44 
9.3 
Study Drug Treatment ............................................................................................................................................ 45 
9.3.1 
LAU-7b (fenretinide) .................................................................................................................................. 45 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
13 of 73 
9.3.2 
Placebo .............................................................................................................................................................. 45 
9.3.3 
Packaging, Labeling, and Shipping ........................................................................................................ 46 
9.3.4 
Storage, Dispensing and Compliance Verification of Study Drug ............................................ 46 
9.3.5 
Administration of Study Drug Treatment .......................................................................................... 46 
9.3.6 
Study Drug Reconciliation and Destruction ...................................................................................... 46 
9.4 
Treatment and Protocol Compliance ................................................................................................................. 47 
9.5 
Allowed and Disallowed Concomitant Medications .................................................................................... 47 
9.5.1 
Disallowed medications: ........................................................................................................................... 47 
10 
EFFICACY ASSESSMENTS .................................................................................................................................. 48 
10.1 
Health Status using the 7-point Ordinal Scale ................................................................................................ 48 
10.2 
Viral shedding by Oropharyngeal swabs ......................................................................................................... 48 
10.3 
Body height, weight, with BMI calculated ...................................................................................................... 48 
10.4 
Quality-of-Life evaluations .................................................................................................................................. 48 
11 
SAFETY ASSESSMENTS ....................................................................................................................................... 50 
11.1 
Adverse Events ......................................................................................................................................................... 50 
11.1.1 
Documentation of Adverse Events ........................................................................................................ 50 
11.1.2 
Clinically Significant Assessments ........................................................................................................ 54 
11.1.3 
Serious Adverse Events ............................................................................................................................. 54 
11.2 
Clinical Laboratory Assessments ....................................................................................................................... 56 
11.3 
Vital Signs and Physical Examinations ............................................................................................................ 57 
11.4 
Liver Safety Algorithm for the Management of Hepatic Impairment .................................................... 57 
12 
STATISTICAL ANALYSIS ..................................................................................................................................... 58 
12.1 
Sample Size Determination .................................................................................................................................. 58 
12.2 
Analysis Populations ............................................................................................................................................... 59 
12.3 
Subject Disposition and Discontinuations ....................................................................................................... 60 
12.4 
Baseline and Demographic Characteristics ..................................................................................................... 60 
12.4.1 
Prior and Concomitant Medications .................................................................................................... 60 
12.4.2 
Study Drug Exposure .................................................................................................................................. 60 
12.4.3 
Study Drug Compliance ............................................................................................................................. 61 
12.5 
Efficacy Analysis ..................................................................................................................................................... 61 
12.5.1 
Analysis of Primary Endpoint ................................................................................................................. 61 
12.5.2 
Analysis of Secondary Efficacy Endpoints ......................................................................................... 61 
12.6 
Safety Analyses ........................................................................................................................................................ 63 
12.6.1 
Adverse Events .............................................................................................................................................. 63 
12.6.2 
Clinical Laboratory Assessments ........................................................................................................... 63 
12.6.3 
Vital Signs ........................................................................................................................................................ 64 
13 
DATA HANDLING AND RECORD KEEPING ............................................................................................. 64 
13.1 
Case Report Forms .................................................................................................................................................. 64 
13.1.1 
Source Documentation ............................................................................................................................... 64 
13.1.2 
Record Retention .......................................................................................................................................... 65 
14 
MONITORING ............................................................................................................................................................. 65 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................................................. 65 
16 
COMPLIANCE, PROTOCOL AMENDMENT AND DEVIATION ........................................................ 66 
16.1 
Compliance ................................................................................................................................................................ 66 
16.2 
Protocol Amendment .............................................................................................................................................. 66 
16.3 
Protocol Deviation ................................................................................................................................................... 66 
17 
STUDY TERMINATION ......................................................................................................................................... 66 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
14 of 73 
18 
ETHICAL CONSIDERATIONS ............................................................................................................................ 67 
19 
FINANCING AND INSURANCE ......................................................................................................................... 67 
20 
PUBLICATION POLICY AND CLINICAL STUDY REPORT ................................................................ 67 
20.1 
Confidentiality and Publication Policy ............................................................................................................. 67 
20.2 
Clinical Study Report ............................................................................................................................................. 68 
21 
REFERENCES .............................................................................................................................................................. 69 
 
 
LIST OF FIGURES 
 
Figure 1: Fenretinide proposed mode of action in COVID-19 disease .......................................................... 23 
Figure 2: Overall structure of the study ......................................................................................................... 36 
 
 
LIST OF TABLES 
 
Table 1: Laboratory Tests Panels ................................................................................................................... 56 
 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
15 of 73 
3 GLOSSARY OF TERMS AND ABBREVIATIONS 
AA: Arachidonic Acid 
AE: Adverse Event 
ALT: Alanine Aminotransferase 
AMD: Age Related Macular Degeneration 
ANCOVA: analysis of covariance 
AST: Aspartate Aminotransferase 
ATRA: All-Trans Retinoic Acid 
AUC: Area Under the Curve 
BID: Bis In Die (Latin), twice daily 
BHA: Butylated Hydroxyanisole 
BMI: Body Mass Index 
BW: Body Weight 
CBC: Complete Blood Count 
CF: Cystic Fibrosis 
CFTR: Cystic Fibrosis Transmembrane Conductance Regulator 
Cmin : Minimal Concentration in Matrix (plasma, blood….etc) 
Cmax: Maximal Concentration in Matrix (plasma, blood…etc) 
CrCL: Creatinine clearance 
CRF: Case Report Form 
CRO: Contract Research Organization 
CTCAE: Common Terminology Criteria for Adverse Events  
CV: Curriculum Vitae 
Css: Concentration at Steady State 
DHA: Docosahexaenoic Acid 
DILI: Drug Induced Liver Injury 
DLT: Dose Limiting Toxicity 
DSMB: Data and Safety Monitoring Board 
EC: Ethics Committee 
ECG: Electrocardiogram 
ERK1/2: Extracellular Signal-Regulated Kinase 1/2 
FRD: Fenretinide, 4-HPR 
GCP: Good Clinical Practice 
CRP: C-Reactive Protein 
ICF: Study Informed Consent Form 
IL-1ra: Interleukin 1 receptor antagonist 
IL-6: Interleukin 6 
IL-8: Interleukin 8 
IL-10: Interleukin 10 
IP: Intra-Peritoneal 
IRB: Institutional Review Board 
ITT : Intent-to-Treat 
IV : Intravenous 
IWRS: Interactive Web Response System 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
16 of 73 
KO : Knock-Out 
MedDRA: Medical Dictionary for Regulatory Activities 
MTD: Maximally Tolerated Dose 
MUHC: McGill University Health Centre 
NF-κB: Nuclear Factor-kappaB 
NSAID: Non-steroidal anti-inflammatory drug 
PD: Pharmacodynamic 
PI: Principal Investigator 
PK: Pharmacokinetic 
PO: per os (Latin), by mouth, orally 
PP: Per Protocol 
PPAR: Peroxisome Proliferator Activating Receptor 
PsA: Pseudomonas aeruginosa 
QD: Quaque Die (Latin), every day/daily 
QTc: QT corrected for heart rate 
RAR: Retinoic Acid Receptor 
RBC: Red Blood Cells 
RBP: Retinol Binding Protein 
RXR: Retinoid-X-Receptor 
SAE: Serious Adverse Event 
SAP: Statistical Analysis Plan 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 
SC: Subcutaneous 
SD: Standard Deviation 
SUSAR: Suspected Unexpected Serious Adverse Reactions 
TEAE: Treatment Emergent Adverse Event 
TID: Ter In Die (Latin), three times daily 
TMF: Trial Master File 
TNF-α: Tissue Necrosis Factor Alpha 
VLCC: Very Long Chain Ceramides 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
17 of 73 
4 STUDY PERSONNEL 
Sponsor: 
Laurent Pharmaceuticals Inc. 
1010 Sherbrooke St. West, Suite 2401, 
Montreal, Quebec  
H3A 2R7 
 
Larry Lands, MD, Ph.D., 
Chief Medical Adviser 
Phone: 1-514-701-7231 
e-mail: larry.lands@mcgill.ca 
 
Jean-Marie Houle, B.Sc.Pharm., M.Sc., Ph.D. 
Vice President of Clinical Development 
and Study Director 
Phone: +1 514 941 2313 
e-mail: jmhoule@laurentpharma.com 
 
Monitors: 
The sponsor has contracted with a Contract Research Organization (CRO) to help manage the trial. 
Specific Contact information for the below CRO contact and each study monitor is maintained in the study 
monitoring plan and on file at each investigator’s site. 
 
CRO Senior Contact: 
Sheila Ernest, PhD 
Associate Clinical Project Manager | Clinical Operations 
T: +1 (514) 564-3466 | ext. 230 
 
 
Manufacturer: 
Genvion Corporation 
500 Camiel Sys St,  
Winnipeg, MB R2J 4K2 
Canada 
 
Serious Adverse Event (SAE) Reporting: 
Dr. Tony Verco, MD, MBA 
Contact Number: +1-805-235-9193 
Email: tony@vantagebiotrials.com 
 
 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
18 of 73 
5 INTRODUCTION 
5.1 Investigational product 
LAU-7b is a solid oral dosage form of fenretinide (100 mg capsules). Fenretinide, a small molecule synthetic 
retinoid derivative, is an investigational drug (new chemical entity) with well-documented history of safety 
in non-clinical and clinical studies (R.W. Johnson, US National Cancer Institute (NCI) since 1992). The 
active product ingredient is N-(4-hydroxyphenyl)retinamide, also referred to as 4-HPR or FRD, and is a 
synthetic amide of all-trans retinoic acid with a molecular formula C26H33NO2.  
Fenretinide is an investigational synthetic retinoid that was extensively tested in clinical studies (Phases 1 to 
3), involving more than 3,000 patients (mostly in oncologic indications), and was proven to be safe and 
relatively well tolerated for long term use 1. Fenretinide has not yet been commercialized in any country.  
 
LAU-7b is a novel and improved oral formulation of fenretinide. The investigational product formulation of 
LAU-7b contains the following non-medicinal ingredients: polyvinylpyrrolidone, butylated hydroxyanisole, 
butylated hydroxytoluene, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, dibasic 
calcium phosphate dihydrate and ascorbic acid. The capsule shell contains the following dyes: FD&C Red 
#3, FD&C Yellow #6 and titanium dioxide. 
 
An orange opaque, size 00 hard gelatin capsule without active substance will be used as a control and 
matching placebo for blinding purposes and contains the same non-medicinal ingredients. 
 
5.1.1 Rationale for LAU-7b, a novel and improved oral formulation of fenretinide 
 
Fenretinide is poorly absorbed following oral administration, and it suffers from a wide inter-patient variation 
in bioavailability when delivered orally in an oily vehicle, such as the softgel capsules used in most oncology 
trials, containing fenretinide suspended in corn oil. The poor bioavailability and the large size of the softgel 
capsules was a limiting factor in the clinical studies conducted so far, particularly in the pediatric population. 
In the past, fenretinide has also been formulated in a lipid matrix, Lym-X-Sorb (LXS) 2, containing 2% of 
fenretinide and administrated as an oral powder delivered in non-milk fat-containing foods, and especially 
as a slurry in non-milk fat-containing, or soy-based nutritional supplements. However, this formulation has 
been shown to be associated with significant gastrointestinal side-effects, especially at higher doses3, as well 
as to significant patient withdrawal due to the taste and texture of the medication.   
There was thus a need for new pharmaceutical dosage form of fenretinide, especially for oral administration, 
capable of overcoming the poor oral bioavailability of corn-oil based formulation and the fair patient 
compliance. Dosage forms such as hard gelatin capsules, tablets, caplets, suspensions, or powders for 
suspensions were to be considered.  
Laurent Pharmaceuticals has developed a novel oral dosage form of fenretinide with increased oral 
bioavailability and formulated as a powder that can be encapsulated or compressed in various sizes, thus with 
expected better compliance for both adult and pediatric patient populations, more specifically by reducing 
the size/number of unit dosage forms to ingest. The new formulation (LAU-7b) is an amorphous solid 
dispersion of fenretinide obtained by spray-drying and formulated as 100 mg, size 00, hard gelatin capsules. 
A first generation of this capsule formulation was successfully tested by Laurent Pharmaceuticals in a Phase 
1b study involving adult Cystic Fibrosis (CF) patients 4. A slightly modified, second generation capsule 
formulation was developed for a large Phase 2 study in CF (ongoing) and will also be used in this study, 
having an improved chemical stability allowing storage under refrigerated conditions (2-8°C). These changes 
consist in adding non-medicinal anti-oxidants that are not expected to modify the oral bioavailability and 
pharmacokinetic profile of fenretinide. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
19 of 73 
5.2 COVID-19 Disease Overview 
 
SARS-CoV2 is a novel coronavirus identified as the cause of the coronavirus disease 2019 (COVID-19 
disease) that began in Wuhan, China in late 2019, and rapidly qualified as a pandemic. Coronaviruses are a 
large family of RNA viruses that are found diversely in animal species. They are known to cause diseases of 
the respiratory, hepatic, nervous system, and gastrointestinal systems in humans. 
Although the outbreak is likely to have started from a zoonotic transmission event associated with a large 
seafood market that also traded in live wild animals, it soon became clear that efficient person-to-person 
transmission was also occurring 5. The clinical spectrum of SARS-CoV-2 infection appears to be wide, 
encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with 
respiratory failure and even death, with many patients who got hospitalized with pneumonia in Wuhan 6, 7, 8.  
A retrospective analysis of the risk factors of severity and mortality in a sizeable cohort of patients in China 
using multivariable regression showed increasing odds of in-hospital death associated with older age (odds 
ratio 1.10, 95% CI 1.03–1.17, per year increase; p=0.0043), higher Sequential Organ Failure Assessment 
score (5.65, 2.61–12.23; p<0.0001), and d-dimer greater than 1 μg/L (18.42, 2.64–128.55; p=0.0033) on 
admission. Median duration of viral shedding was 20.0 days (IQR 17.0–24.0) in survivors, but SARS-CoV-
2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors 
was 37 days 9. 
While most patients with COVID-19 disease are thought to have a favorable prognosis, older patients and 
those with chronic underlying conditions may have worse outcomes with rapid progression to acute 
respiratory distress syndrome (ARDS) and requirement for mechanical ventilation, thus creating an 
unsustainable burden for the health care system and a rapidly escalating crisis 5.  
One of the main mechanisms for ARDS is cytokine storm, a deadly uncontrolled systemic inflammatory 
response resulting from the release of large amounts of pro-inflammatory cytokines and chemokine 10. Anti-
inflammatory treatments that aggressively inhibit inflammation, such as corticosteroids, are less expected to 
have a significant benefit during the viral response phase of the disease, when the immune response is 
required to effectively fight the infection and prevent its escalation to lung hyper-inflammatory phase that 
may require respiratory support 11. However, mild anti-inflammatory NSAIDs (such as ibuprofen and 
acetaminophen) are useful for decreasing fever in coronavirus patients 12 . Recent results from the 
RECOVERY clinical study with dexamethasone corticosteroid therapy in hospitalized COVID-19 patients, 
showed a reduction in deaths by one-third in patients receiving invasive mechanical ventilation and by one-
fifth in patients receiving oxygen without invasive mechanical ventilation. However, it did not reduce 
mortality in patients not receiving respiratory support at randomization 13. 
The controversy around the use of typical anti-inflammatory drugs in severe inflammatory diseases is not 
new. On one hand, during the viral phase of the disease it is desired to have the right amount of inflammation 
capable to stimulate an immune response and fighting the infection, and on the other hand, there is a need to 
avoid the inflammation process to become excessive, uncontrolled and potentially harmful. Normally, the 
body is able to maintain a balance between the pro-inflammatory and the resolution phases of inflammation. 
However, in certain conditions, this balance is disrupted and the pro-inflammatory phase becomes over-
reactive, the disease enters into a lung hyper-inflammatory phase leading to ARDS, and a certain level of 
immune-suppression may be required.  
Recent publications have cited MAPK/ERK 14, 15, NF-κB 16  and cPLA2 14 as important molecular pathways 
required for coronavirus cellular entry, replication and avoidance of the host defense system, all potential 
targets against the virus spread. These are all potential targets for limiting the virus spread in the body and 
the COVID-19 disease. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
20 of 73 
Tracing a parallel with CF, the CF patients display an increased level of arachidonic acid (AA), having role 
in pro-inflammatory pathways, and a low level of docosahexaenoic acid (DHA) involved in anti-
inflammatory, protective and pro-resolving roles during the inflammatory process 17. AA and DHA are 
essential fatty acids that cannot be synthesized de-novo by humans, and are derived from nutritional intake. 
Their metabolism is the source for the synthesis of eicosanoids (AA-derived, such as prostaglandins, 
leukotrienes and lipoxins), and docosanoids (DHA-derived, such as resolvins and protectins). Eicosanoids 
and docosanoids are key inflammatory mediators involved in the modulation of the innate immune-
inflammatory response following bacterial challenge or other type of injury. Thus, the timely homeostasis of 
eicosanoids and docosanoids is crucial in maintaining an efficient and balanced immune-inflammatory 
response.  
The persisting, high AA levels displayed in CF patients may increase the pro-inflammatory factors and 
stimulate mucus secretion, while the low DHA levels, important in the anti-inflammatory defense and the 
resolution of inflammation, may explain why CF patients have an exaggerated and unresolved inflammatory 
response that, paradoxically, is unable to fight opportunistic infections 18, 19, 20. 
 
5.3 Treatment of COVID-19 Disease 
No effective therapy currently exists for treatment and isolation remains the most effective measure for 
containment of COVID-19. No specific antiviral medication or vaccine is currently available 21. Therefore, 
the treatment of COVID-19 includes symptomatic care and oxygen therapy. Patients with mild infections 
require early supportive management. This can be achieved with the use of acetaminophen, external cooling, 
oxygen therapy, nutritional supplements, and anti-bacterial therapy 22.  
Critically ill patients require high flow oxygen, mechanical ventilation, extracorporeal membrane 
oxygenation (ECMO), glucocorticoid therapy, and convalescent plasma 22. However, the administration of 
systemic corticosteroids is not recommended to treat ARDS. Moreover, unnecessary administration of 
antibiotics should also be avoided. Patients with respiratory failure may require intubation, mechanical 
ventilation, high-flow nasal oxygen, or non-invasive ventilation. ECMO should be considered in patients 
with refractory hypoxemia despite undergoing protective ventilation. Treatment of septic shock requires 
hemodynamic support with the administration of vasopressors. Organ function support is necessary for 
patients with multiple organ dysfunction 21. 
Therapeutically, aerosol administration of alpha-interferon (5 million units twice daily), chloroquine 
phosphate, and lopinavir/ritonavir have been suggested 21, however the recently reported results were 
deceptive so far. Other suggested antivirals include ribavirin and abidor 22. The use of three or more anti-
viral drugs simultaneously is not recommended. Recent clinical studies have concluded that remdesivir 
(GS5734) can be used for prophylaxis and therapy to speed up the recovery of hospitalized patients, however 
there is no evidence that this drug can reduce mortality in COVID-19 patients. Similarly, for patients 
receiving supplemental oxygen, a very recent study demonstrated that dexamethasone administered 
intravenously or orally can be of benefit in reducing mortality in severe and critically ill patients 13.  
 
 
5.4 Study Rationale 
 
LAU-7b is being proposed for its dual antiviral and inflammation-controlling properties, with potential 
benefits during the viral response phase of the COVID-19 disease by reducing the severity of the viral 
infection, as well as having potential benefits in the prevention and/or reduction of the hyper-inflammation 
of the lung.  
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
21 of 73 
LAU-7b lipid modulation and the pro-resolving effects on inflammation 
LAU-7b is being developed for its potential to trigger the body’s own ability to damping down inflammation 
without interfering with its immune response (a “pro-resolving” effect). Therefore, LAU-7b can be used as 
a balancing factor able to keep the inflammation process under control, complementing the action of typical 
anti-inflammatory drugs. 
This effect was first observed in preclinical models of CF, then reproduced in CF exacerbating patients. 
There are many similarities between the aberrant inflammatory response in the lung of exacerbating CF 
patients and the pathogenesis of pulmonary complications associated with the COVID-19 infection.  
CF is characterized by an abnormally activated inflammatory response in the lung, which overreacts in the 
presence of pathogens and leads to irreversible lung damage. Due to its abnormality and chronic 
manifestations, the regulation of inflammatory response remains one of the most important and unaddressed 
pathogenic mechanisms in CF. Previous attempts to control inflammation in the inflamed CF lungs by 
various anti-inflammatory drugs have been unsuccessful and, in some cases, resulted in frequent lung 
exacerbations and serious adverse events 23. This is likely due to the fact that inhibition of the innate 
inflammation pathways can also inhibit the ability of patient’s immune system to fight infections 24. 
All current anti-inflammatory drugs work by inhibiting parts of the pro-inflammatory phase of the 
inflammation, modulated by the AA metabolic cascade. LAU-7b is believed to act on the resolution phase 
of inflammation by endogenously modulating the metabolism of DHA cascade, involved in the process of 
healing and return to homeostasis after a pathogen attack or injury. Recently, LAU-7b was shown to also 
modulate sphingolipids micro-domains in the apical membrane of airways cells affected by Cystic Fibrosis 
(CF), resulting in protective effects on the CFTR membrane protein under cellular stress (unpublished data). 
LAU-7b is currently being evaluated in a Phase 2 clinical trial in adult patients with CF aiming to treat the 
exaggerated inflammatory response that leads to irreversible lung damage. Earlier Phase 1b clinical data 
from CF adult patients, with LAU-7b escalating doses of up to 300 mg administrated orally, once-a-day, 
showed that LAU-7b was safe and well tolerated, and able to maintain the balance between AA and DHA 
pathways, with a favourable effect on certain biomarkers of inflammation (IL-6, IL-8, IL-10, neutrophils 
count) at the onset of a pulmonary exacerbation episode, suggestive of a protective effect on the lungs. 
Fenretinide’s lipid modulating properties and resulting pro-resolving effect on inflammation at low doses 
were demonstrated in multiple preclinical models of acute and chronic inflammation, including a mice model 
of septic shock and cytokine storm induced by Streptococcus suis 25, CF mice model of inflammation and 
infection induced by Pseudomonas aeruginosa 26, mice models of allergic asthma 27  and spinal cord injury 
28. 
 
LAU-7b antiviral effects 
Fenretinide was recently shown during a drug-library screening effort conducted by scientists from the 
Institut Pasteur Korea, to have potent antiviral activity (50% inhibitory concentration (IC50) of 2.8uM) 
against the Middle Est Respiratory Syndrome coronavirus (MERS-CoV), a virus that is structurally similar 
to COVID-19 virus 29. Very recent preliminary data using the same cellular model, showed that fenretinide 
exerts a similarly potent antiviral activity against the SARS-CoV-2 virus (unpublished data), a very relevant 
finding currently being confirmed by additional experiments. This is in line with the dose rationale for 
fenretinide in inflammatory diseases. Previous studies have also shown fenretinide’s broad antiviral potential 
in preclinical testing against Dengue fever 30, Zika virus 31 and HIV 32. 
 
 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
22 of 73 
Treatment goal and expected clinical benefits 
Due to its antiviral properties and its pro-resolving effects on inflammation, LAU-7b is being proposed to 
potentially reduce COVID-19 disease severity, maintain a balanced immune-inflammatory response and 
prevent disease progression toward Acute Respiratory Distress Syndrome, especially in patients at risk 
because of their age, underlying conditions, or both. 
The timely resolution of inflammation is as important as its initiation phase and a good balance between pro- 
inflammatory and pro-resolving mediators is key to maintaining an efficient and harmless inflammatory 
response. Incomplete resolution leads to chronic inflammation and destruction of lung tissue, and ultimately 
to lung insufficiency and impairment 20, 33. 
It is unlikely that a single defect in one pathway accounts for the entirety of the exaggerated inflammatory 
response. For example, airway surface fluid from CF patients contains large concentrations of pro-
inflammatory mediators including the tissue necrosis factor alpha (TNF-α), IL-1β, IL-6, IL-8, IL-17, and 
granulocyte-macrophage colony-stimulating factor (GM-CSF) 34 . The synthesis of these mediators is 
promoted by a few transcription factors including AP-1, nuclear factor (NF)-κB, and mitogen-activated 
protein kinases (MAPK), extracellular signal-regulated kinase (ERK1/2). In addition to a heightened pro-
inflammatory arm, there appear to be inappropriately decreased counter-regulatory pathways, particularly 
those involving IL-10 and nitric oxide. 
 
5.4.1 Proposed Mechanism of Action in COVID-19 disease 
LAU-7b was shown to be a master regulator of key membrane lipids (essential fatty acids and sphingolipids) 
in conjunction with the inhibition of certain inflammation signaling pathways (MAPK/ERK1/2, NF-kB, 
cPLA2), which are believed to play an essential role in 1) the resolution of inflammation and prevention of 
an over-reactive response; and 2) the coronavirus cellular entry, replication and avoidance of the host 
defense.  
Therefore, LAU-7b is proposed as a therapy for COVID-19 disease, for its antiviral properties and the 
potential to maintain a balanced inflammatory response. 
Fenretinide is not a typical retinoid; it does not have a terminal carboxyl group believed to be an essential 
feature for active retinoids. However, it has been shown to have certain biological activities associated with 
the retinoid class. Fenretinide is a potent transactivator of retinoid acid receptor (RAR)γ and a moderate 
activator of RARβ, but is not an activator of RARα and retinoid-X-receptor (RXR)α 35. 
Although the complete mechanism of action in COVID-19 is not fully elucidated, it was shown in animal 
models and in humans that fenretinide corrects the AA/DHA imbalance and inhibits macrophage 
inflammatory mediators via the ERK 1/2 pathway 36. Fenretinide was also shown to inhibit the activation of 
the pro-inflammatory transcriptional NF-κB 37, as well as inhibit the downregulation of PPARγ, which is 
known to have a role in lipid metabolism 38. More recently, it was demonstrated that fenretinide has the 
ability to inhibit the activity of cytosolic phospholipases (cPLA2), which was previously described as a factor 
for the abnormal high levels of pro-inflammatory AA present in the cell membrane of CF patients. Recent 
evidence demonstrated fenretinide’s ability to modulate membrane sphingolipids biosynthesis 39 and to 
increase the function of CFTR surface protein through its activity on the lipid microdomains (rafts) in the 
cell membrane.  
Considering the involvement of previously cited MAPK/ERK14, 15, NF-κb16 and cPLA214 pathways in the 
various steps of viral entry, replication and immunological avoidance, and the fact that these pathways are 
also inhibited by fenretinide as part of its pro-resolving effect on inflammation, by modulating these 
pathways, LAU-7b may not only interfere with virus replication, but also prevent the escalation of the pro-
inflammatory response resulting during the infection process (Figure 1). 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
23 of 73 
 
Figure 1: Fenretinide proposed mode of action in COVID-19 disease 
5.4.1.1 Fenretinide Nonclinical Toxicity 
 
R.W. Johnson conducted toxicity studies of fenretinide via per-os (PO), intra-peritoneal (IP), or intravenous 
(IV) routes of administration in mice, rats, rabbits, and dogs, and many of the studies carried out were 
published 40, 41, 42, 43. Doses of up to 7000 mg/kg were given in acute studies, while in multiple-dose studies 
doses of up to 1800 mg/kg/day were administered. No mortality was observed in acute studies. Clinical 
observations following administration of high oral doses consisted primarily of diarrhea, loose stools, 
unkempt appearance, and reduced spontaneous activity. In multiple dose toxicity studies, up to one-year 
duration, mortality in fenretinide-treated animals was rare and occurred in less than 5% of animals tested. 
Dose-related toxicities were observed in some of these studies including mild intermittent reductions in body 
weight and food consumption, decreased erythrocyte parameters and serum protein levels, and increased 
plasma alkaline phosphatase and serum cholesterol levels. In addition, modest dose-related elevations in 
serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels were observed in the 
3-month rat and 1-year dog studies. Collectively, the reduction in serum protein levels and elevations in 
serum cholesterol and liver enzymes levels may be indicative of a mild hepatic dysfunction following high 
doses of fenretinide. Pathologic or histopathologic evidence of liver damage was generally not observed in 
toxicity studies with fenretinide, although liver pathology was observed in the 3-week IP studies in rats and 
mice at doses equivalent to the 21-day estimated LD50 values for fenretinide in these species. Finally, in a 
dog cardiovascular toxicity study, fenretinide up to 10 mg/kg was not shown to affect cardiovascular 
parameters, including ECG, heart rate and mean arterial pressure. 
 
Carcinogenic Potential. The carcinogenic potential of fenretinide administered PO in the food was 
evaluated in 2-year studies in rats and mice. After 24 months of treatment, there were no gross observations 
of tumors at necropsy in the rat study. However, histopathologic examination during a 1-year interim analysis 
of the 2-year mouse study revealed an increased incidence of hemangiosarcomas at the highest dose of 
fenretinide administered (1000 mg/kg/day). After 20 months of treatment, tumors were also found in animals 
administered with 100 mg/kg/day (males only) and 300 mg/kg/day of fenretinide. The occurrence was dose 
and time dependent 41. The clinical significance of this finding is uncertain due to over 10,000-fold higher 
susceptibility of hemangiosarcomas to develop in mice than in humans44.  
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
24 of 73 
Reproductive Toxicity Studies. Doses ranging from 20 to 800 mg/kg/day (120 - 4800 mg/m2) had no effect 
on the fertility and general reproductive performance of female or male rats; however, the complete inhibition 
of uterine implantation has been reported in mice receiving 100 mg/kg/day of fenretinide. Studies in rats and 
rabbits indicated that 800 mg/kg/day dose of fenretinide was teratogenic. The key role of retinoic acid in 
embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin 
used for treatment of cancer and acne. Oral megadoses of pre-formed vitamin A (retinyl palmitate), and 
retinoic acid itself, also have teratogenic potential by this same mechanism. A screen of retinoids for 
developmental toxicity following single-dose PO administration to hamsters on Day 8 of gestation suggested 
that fenretinide was less teratogenic than ATRA 45, 46. Late gestation, parturition and pup survival were 
unaffected in a peri-postnatal toxicity study.  
 
Genetic Toxicity Studies. In a variety of in vitro and in vivo test systems, fenretinide did not induce any 
genotoxic effects 47. Its major metabolite, 4-MPR, was also negative in the mammalian cell mutation assay. 
 
Metabolism and Excretion. Animal and human studies indicate that fenretinide undergoes significant phase 
1 and phase 2 biotransformation in-vivo. The most abundant metabolite produced in human, dogs and rodents 
in in-vivo is N-(4-methoxyphenyl)retinamide (4-MPR) 48, 49, whereas additional minor metabolites, 4-oxo-
N-(4 hydroxyphenyl)retinamide (4-oxo-fenretinide) and 4-hydroxy-N-(4 hydroxyphenyl)retinamide (4-OH-
fenretinide), have been subsequently reported 50. In contrast to rodents, 4-oxo-fenretinide is present at low 
concentrations in humans. Although 4-MPR is now generally considered to be inactive 51 , 52 , 4-oxo 
fenretinide was found to be an active metabolite that inhibits cell proliferation 50, 53. 
The enzymes responsible for production of 4-MPR (phase 2, methylation reaction) were not clearly 
determined, however they include microsomal amine-N-methyltransferases, that are known to be involved 
in the metabolism of many drugs and carcinogens 54. The oxidative metabolism (phase1) is predominantly 
carried out by cytochromes P450 (CYP)s 3A4, 3A5, 2C8 and 26A1. Glucuronidation was shown to not 
playing a major role in the metabolism and clearance of fenretinide and its metabolites at clinically relevant 
levels 55. The metabolic profile of fenretinide in human indicates a relatively low potential for drug-drug 
interactions. 
5.4.2 Supportive Clinical Evidences  
5.4.2.1 Phase Ib with LAU-7b in Adult CF Patients 
 
Laurent Pharmaceuticals in collaboration with The Research Institute of the McGill University Health Centre 
completed a Phase Ib, First-In-CF-Patients study 4. It was a single-site, double-blind, placebo-controlled 
escalating multiple oral dose study of fenretinide (LAU-7b formulation) in adult CF patients. It involved 15 
patients randomized 3:1 (active:placebo) who received each dose level in a sequential fashion,  for cycles of 
21 days spaced by drug-free periods of a minimum of 7 days. The study drug or matching placebo was to be 
taken once a day, orally, along with the morning meal in addition to current Standard of Care therapies. Three 
(3) ascending dose levels of fenretinide as LAU-7b were administered (100 mg, 200 mg and 300 mg/day). 
The rationale behind the dose selection was to achieve, on average, a mean plasma concentration at steady 
state (Css) between 1-2 µM. This target was based on pre-clinical evidences in the mouse model. 
All tests relating to safety, PK and PD were performed at screening to obtain baseline values and then 
repeated at the end of each treatment cycle. The end of each treatment cycle was scheduled 21 days (± 2 
days) from the first day of treatment. In total, these tests were performed four times throughout the study 
period. The tests included safety laboratory tests, PD laboratory tests, lung function tests and physical 
examination. For patients enrolled in the PK portion of the study (first 12 patients enrolled), the blood 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
25 of 73 
samples for safety and efficacy were obtained prior to taking the drug dose for that day, and on Day 21 this 
meant approximately 24 hours after their previous dose. The main objectives of the study were: 
Primary objective  
• To establish the safety and tolerability of fenretinide in adult CF patients, using a novel oral formulation 
designed to optimize fenretinide bioavailability. 
Secondary objectives 
• To evaluate the PK profile of fenretinide at multiple dose levels; 
• To determine the recommended doses of fenretinide to be used in future Phase II trials; 
• To evaluate the preliminary PD of fenretinide using the plasma AA/DHA ratio as a surrogate lipidomic 
marker; 
• To evaluate selected plasma and urine inflammatory markers and explore potential correlation with 
lipidomic markers. 
Study Patients 
The key inclusion/exclusion criteria were as follows: 
Inclusions: Men and women 18 years and older, having a diagnosis of CF, Chronic CF lung disease with 
baseline FEV1 equal or superior to 40% predicted, stable at time of enrollment, Chronic pulmonary 
Pseudomonas aeruginosa colonization and/or infection. 
Exclusions: Pregnant or breastfeeding women, inadequate contraception, presence of nyctalopia, other 
serious ophthalmological condition, serious dermatological conditions at enrolment, clinically abnormal liver 
or renal functions, history of gastrointestinal surgery or underlying gastrointestinal disorders of motility, and 
unstable intake of retinoids or lipid supplements. 
 
Results and conclusions of the study 
SAFETY RESULTS: 
Overall, fenretinide was shown to be safe at all three doses studied for 21 days. The vast majority of adverse 
events (AEs) reported were mild, reversible with no sequelae, and without any action needed. Interestingly, 
the number of AEs in the active group decreased with the increase in fenretinide dosing. Many of these events 
were expected within the CF population studied, such as pulmonary exacerbations, characteristic of CF 
evolution, as well as reversible nyctalopia and dry skin which have been reported for fenretinide in other 
patient populations. 
Biochemical and hematological safety parameters were not affected by fenretinide at all dose levels. The 
reduction of serum retinol levels as compared to baseline appeared to be smaller in CF patients than those 
reported in other patient populations. Two (2) SAEs occurred during this study, both classified as unrelated 
to fenretinide with one related to CF disease (exacerbation with hospitalization) and easily explained by the 
condition of the patient, and one related to a concomitant disease (varicella case). 
In conclusion, the safety and tolerability of fenretinide in adult CF patients was comparable with the reported 
safety profile associated with the use of this drug in other patient populations over similar or longer periods 
of treatment, and with comparable systemic exposure levels. The study Safety Review Committee has 
acknowledged the safety of the drug in this patient population and has recommended 300 mg QD as the dose 
to be tested in Phase II trial 4. 
 
PHARMACOKINETIC RESULTS: 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
26 of 73 
Following single and multiple doses of fenretinide as LAU-7b, plasma exposure (Cmax and AUC) increased 
with dose, and this increase was judged dose proportional (p-value > 0.05). The plasma concentration profile 
indicated first-order elimination kinetics. The concentration at 8 hours (C8h and Css8h, following the first and 
last doses, respectively) reached the fenretinide plasma concentration target range of 1–2 μM at the 200 mg 
dose level with mean values of 1.32 μM and 1.85 μM following single and multiple doses of fenretinide, 
respectively (Cavg: 1.40 µM at steady-state). Not all patients had a C8h reaching the lower value of the target 
concentration range. At the 300 mg dose level, C8h fell within the target range on Day 1 for all patients (mean 
of 1.81 μM) and Css8h was slightly above the target range on Day 21 (mean of 2.70 μM, and Cavg: 2.06 µM). 
Generally, inter-patient variability was modest for the fenretinide PK parameters, even with the small sample 
size. After a single dose, the mean t1/2 was consistent across the dose range studied with values ranging from 
6.99 h to 7.50 h. Mean t1/2 values at PK steady-state ranged from 8.25 h to 16.65 h. Taking into consideration 
the expected higher bioavailability of LAU-7b based on modeling from pre-clinical pharmacokinetic study, 
exposure and disposition kinetics in adult CF patients are comparable to what was observed in non-CF adults, 
themselves comparable to non-CF pediatric populations. 
 
EFFICACY RESULTS: 
In this study, we showed an association between a fenretinide dose-related increase in the DHA levels, a 
decrease in the AA/DHA ratio in plasma phospholipids and a decrease in the markers of oxidative stress that 
may be indicative of a reduced peroxidation and better protection of DHA, especially during episodes of 
increased inflammation such as pulmonary exacerbations. The improvement of the CF-associated AA/DHA 
imbalance, as well as a decreased oxidative stress in a majority of patients, appears to produce a shift towards 
an anti-inflammatory pattern, particularly at the highest dose. While the changes were not significant 
statistically, the expected rise in certain inflammatory markers during PEx seemed blunted in participants 
while on LAU-7b, and the rise in IL-8 during the course of the study was numerically less when on LAU-
7b.  
This improvement in inflammatory markers is presumed to be caused by treatment with fenretinide which 
resulted in a dose-dependent normalization of the plasma AA, DHA and AA/DHA ratio at the onset of PEx. 
The effect on AA and DHA was superior to what was measured at onset and during the treatment of PEx 
with antibiotics in the previous, non-interventional, cohort characterization study conducted in the same type 
of CF patient cohort of the same clinical site in Montreal 4. At the highest dose (300mg), the improvement 
of the anti-inflammatory profile at onset of PEx in the Phase 1b study was comparable (IL-6 and neutrophils) 
or better (IL-8 and IL-10) than at the end of the PEx treatment in the cohort characterization study. A better 
systemic anti-inflammatory profile at onset of PEx was shown to correlate with increased odds to better 
respond to antibiotics for PEx 56, 4. It is hypothesized that the cumulated benefits of fenretinide, both during 
and outside the PEx episodes, will translate into clinical benefits such as pulmonary function preservation, 
reduced incidence and severity of PEx episodes, and ultimately a better Quality of Life for CF patients. 
In conclusion, the Phase Ib study attained its objectives of demonstrating safety of fenretinide in CF patients, 
enhanced systemic exposure comparable to non-CF population after taking into consideration the higher 
bioavailability of fenretinide afforded by LAU-7b and observing a convergence of dose-related 
pharmacodynamic effects of fenretinide on markers of lipid imbalance, oxidative stress and inflammation. 
Moreover, the highest dosing regimen tested (300 mg/day for 21 consecutive days) was recommended as an 
optimal dose for the ongoing Phase 2 trial, summarized below, since it was deemed safe and achieved the 1-
2 µM fenretinide target plasma Css8h in all patients treated, as well as the Cavg. 
5.4.2.2 APPLAUD, an International Phase 2 with LAU-7b in Adult CF Patients 
Laurent Pharmaceuticals is currently conducting a large Phase 2 study in adult CF patients across 39 clinical 
sites located in Canada, the United States of America and Australia. APPLAUD is an international, 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
27 of 73 
multicentre, randomized, double-blind (patients, Investigators and blinded study staff), placebo-controlled 
Phase II study of LAU-7b for the treatment of CF through its effect on the CF-linked AA/DHA imbalance.  
To be eligible for the study, patients must have a diagnosis of CF, be aged 18 years and above, have 
undergone at least one IV or oral antibiotic-treated PEx in the year prior and meet all other study inclusion 
and none of the exclusion criteria at screening. Eligible patients are randomized 1:1, after stratification, to 
either LAU-7b (active) group or placebo (control) group. All patients continue their CF Standard of Care at 
their institution. Below is an illustration of the overall study structure: 
 
A minimum of 136 patients are planned to be recruited and randomized for the treatment phase of the study 
in the expectation that at least 120 patients complete the study as per protocol. At this time, a total of 127 
adults with CF have been randomized and were dosed with LAU-7b or placebo (1:1), out of the planned 136 
patients. A total of 86 patients have completed the 6-months treatment period and the study as per protocol, 
24 patients have ended prematurely their participation, mainly for the following reasons: personal 
choice/burden of study, termination due to starting a new CFTR modulator treatment or termination due to 
COVID-19 restrictions at clinical sites or personal choice due to COVID-19 concerns. About 20 patients are 
currently receiving the study drug in the study. 
The study is active and therefore only blinded (both study groups together) safety information is available at 
this point. The aggregated demographics as of March 4th, 2020 data cutoff (safety population, n=96) is as 
follows: Mean age: 32.9 years (range 18-70), 62% women and 38% men, of which 95% white, 1% American 
Indian, 3% black and 1% other. 
The study is independently monitored for safety by an independent Data Monitoring Committee from the CF 
Foundation Therapeutic Development Network. A total of three (3) meetings occurred so far, the latest on 
March 25th, 2020, and on all three occasions, the Committee recommended to continue the study unchanged 
owing to no safety concerns. The Committee reviewed both the aggregated safety data and the unblinded 
safety data by treatment group. 
Overall, the safety observations, including 22 treatment-emergent AEs of Pulmonary Exacerbation reaching 
the criteria of seriousness due to the hospitalization required to administer intravenous antibiotics, are typical 
of those found in CF studies with patients with moderate disease. The typical adverse events of fenretinide 
have been observed and their incidence remain low, such as the perception of changes in vision under dark 
and bright light conditions (around 6% of TEAEs) and in great majority of mild intensity. None resulted in 
study discontinuation. No SUSAR were reported. 
In summary, taking the severe nature of the CF disease, the study does not reveal a concerning safety signal 
and continues as planned. 
5.4.2.3 Additional Supportive clinical experience with fenretinide 
Fenretinide has been extensively studied in humans, mostly for the prevention and treatment of cancer. There 
is a large body of safety data existing for fenretinide from previous low-dose/long-term clinical studies (1-
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
N=68
LAU-7b
LAU-7b
LAU-7b
LAU-7b
LAU-7b
LAU-7b
Randomization (1:1)
N=68
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Weeks
 1               3
4
7
8
11
12
15
16
19
20
23
27
Visits
X
X              X
X
X
X
X
X
Day
-28  to  0
 1             21
49
77
105
161
189
follow-up
Screening      
follow-up

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
28 of 73 
2μM plasma concentration) and mid/high-dose clinical studies (2-14.5μM plasma concentrations) using oral 
administration of fenretinide, as well as very high doses (up to 28 μM plasma concentration) with IV 
administration. These Phase I to Phase III studies have been carried out in more than 3,000 subjects, including 
both adults and pediatric patient populations, some for as long as 5 years of treatment (with the low doses). 
Most recent clinical studies have been carried out by the US National Cancer Institute (NCI) using the 
original corn-oil based softgels formulation. In total, NCI conducted 19 clinical studies: 5 low-dose (2x Phase 
II and 3x Phase III) and 14 high-dose (4x Phase I, 1x Phase I/II and 9x Phase II). A decision in 2013 was 
taken to stop the development of the drug and request withdrawal of their IND because the development of 
the original oral (corn-oil based) softgel formulation has been discontinued. 
Fenretinide was originally explored in adult patients primarily as a chemopreventive agent, and in that setting 
it was used at low doses to avoid side effects. Numerous clinical studies employing chronic oral doses of 200 
to 800 mg fenretinide/day (≤ 3 μM plasma levels) using the corn-oil based formulation, have been well 
tolerated in previous trials, with the 200 mg/day dose tolerated for as long as five years in the case of 
chemoprevention trials 57, 58, 59, 60. Most of these studies utilized a once daily administration, some with a 3-
day drug-free rest period every 4 weeks to prevent potential symptoms of nyctalopia.  
 
Low-dose / long-term clinical trials 
Toxicity of oral chronic doses achieving 1-2 μM plasma levels of fenretinide in chemoprevention clinical 
trials has been minimal 57, 58, 61.  
Fenretinide has been safely administered in chemoprevention trials up to dose of 300 mg per day (1-1.5 μM 
plasma levels) for prolonged periods of time from 6 months to 5 years in large cancer populations with no 
significant toxicity57, 60, 61, 62, 63, 64,. Mild grade of nyctalopia and dermatologic disorders (dry skin, pruritus) 
were the most common side-effects of fenretinide treatment; rate of occurrence of both types of events tended 
to decrease with time or to recover spontaneously during the treatment period or shortly after cessation of 
dosing. Fenretinide plasma concentration (12 h post dose) at steady state was estimated to be ~1µM at 200 
mg dose and ~1.5µM at 300 mg dose. Adverse effects typical of other retinoids, such as decreased bone 
density, ligament calcification, and skeletal hyperostosis were not observed in these studies. Even after five 
years of therapy, abnormalities in night vision improved significantly after 7 days off therapy, and completely 
resolved one month after stopping fenretinide; plasma retinol concentrations returned to normal in one month 
following discontinuation of fenretinide 63, 64.  
Single and repeat daily dose PK studies with fenretinide softgel formulation in healthy subjects and patient 
population indicate that fenretinide plasma exposure (Cmax, AUC) also increased upon repeat daily dosing to 
reach a steady state level at 4-5 days 65, 58, 66. Presence of food increased significantly the plasma levels of 
the drug and has been used since as standard recommendation for fenretinide dosing58. The increase in 
exposure was dose proportional up to 800 mg. Plasma exposure on Day 21 with 300 mg/day dose of LAU-
7b formulation in adult CF patients was approximately equivalent to the exposure at the dose of 800 mg on 
Day 28 in healthy adults with the softgel formulation, indicating an increase in fenretinide bioavailability by 
a factor of >2 with LAU-7b. 
 
 
High-dose clinical trials 
Phase I trials of high-dose (up to 14.5 μM plasma levels) oral fenretinide in pediatric solid tumors have been 
conducted with the corn-oil softgel formulation 59, 62, 67.  

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
29 of 73 
In two Phase I studies in children with neuroblastoma, fenretinide was given up to the dose of 4000 
mg/m2/day over 28 days (3-6 patients/dose level), followed by a 7-day interruption, for a period of 6-25 
courses without dose-limiting (DLT) toxicity 59, 67. Fenretinide pharmacokinetics was linear in the dose range 
100–1,700 mg/m2. Steady state peak plasma concentrations between 1.3 µM at 100 mg/m2 and 14.5 µM at 
4000 mg/m2 were observed in the first course of treatment on Day 28.  Similar to what has been observed in 
adult patients, cutaneous toxicity (dry skin and lips) and nyctalopia (Grade 1-2) were the most common 
adverse effects observed at most dose levels which rapidly reversed during the 7-day drug-free intervals and 
did not appear to be dose related. Grade 2 toxicities included skin xerosis (6 cases), hepatic toxicity (1 case), 
diarrhea (1 case), nyctalopia (3 cases), and headache (1 case). Nyctalopia of grade 3 occurred in one patient 
with the 1000 mg/m2 dose. None of the patients discontinued the drug because of toxicity. The maximum 
tolerated dose was not reached in these studies; however, they were terminated due to difficulties with patient 
compliance in consuming the required number of corn-oil based softgel capsules. 
In a study in 54 children (2-20 years old) with high-risk solid tumors conducted by the Children's Cancer 
Group “CCG”, a maximum tolerated dose (MTD) of oral fenretinide, divided BID - TID, given for 7 days, 
every 3 weeks, was defined as 2475 mg/m2/day, which achieved fenretinide peak plasma levels of 9.9 ± 5 
μM with minimal systemic toxicity 62. Increased steady-state fenretinide levels were seen by Day 7 of 
therapy. Plasma retinol levels were decreased on Day 1 at all levels, and further decreased to an average of 
33% of baseline by Day 7, with recovery to 55-106% of baseline by Day 21 (start of next course).  
In all these high-dose pediatric studies, a wide range of peak plasma concentrations were observed at a given 
dose. It is possible that the differences of tolerability observed in these two studies (MTD achieved vs. no 
DLT observed) was dose-schedule dependent (i.e., TID vs. QD).  
5.4.2.4 Conclusion 
The results from both adult (Phases I-III) and pediatric Phase I trials of high-dose oral fenretinide suggest 
that peak plasma levels exceeding 10 μM can be achieved with tolerable toxicity.  
Prolonged periods of fenretinide treatment (up to 5 years) in the cancer prevention studies were associated 
with fenretinide steady-state peak plasma concentrations of 1-2 µM at daily doses of 200 to 400 mg and no 
significant toxicity/safety concerns. In the cancer treatment studies in children the peak plasma 
concentrations reached 14.5 µM with relatively mild adverse effects. In general, no significant toxicity was 
observed in children with peak plasma levels below 3µM. The incidence and severity of the most commonly 
observed toxicities related to fenretinide treatment such as nyctalopia, headache, dry eye, cutaneous, ungual, 
or mucosal toxicities observed in patients with 3–10 µM peak levels increased at peak levels >10 µM. The 
adverse events were resolved after dose reduction or after discontinuation of the treatment. Maximum 
tolerated dose was not reached in children with neuroblastoma at daily doses of 4000mg/m2 and fenretinide 
plasma peak levels of 14.5 µM.  
Fenretinide reduces plasma retinol levels and retinol binding protein potentially leading to development of 
symptoms of nyctalopia in some patients. This effect was rarely dose limiting, and quickly reversible 
following dose reduction or discontinuation of treatment. Moreover, this effect does not seem to be 
proportional to the dose. In previous fenretinide clinical studies a drug free period of 3-7 days following a 
28-day oral exposure was proven to help prevent or alleviate nyctalopia and was integrated in all clinical 
studies. 
Based on the Phase Ib study data in adult CF patients, the dose of 300mg/day (equivalent to 800 mg/day of 
corn-oil formulation of fenretinide) resulted in steady state 8-hour plasma concentration of fenretinide on 
Day 21 of 2.7 µM and average drug plasma concentration of 2.06 µM, at the upper range of “low doses”. 
There were no serious adverse events related to fenretinide recorded in the study, and the overall number of 
adverse events tended to decrease with the increase of the dose. The incidence of nyctalopia symptoms 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
30 of 73 
reported in this study is consistent with the incidence of symptoms of diminished dark adaptation reported 
in other clinical trials with fenretinide.  Ad-hoc and scheduled ophthalmological examinations did not reveal 
any abnormality or signs of retinal damage in these patients. The reduction of serum retinol levels, as 
compared to baseline, appears to be smaller in CF patients than other patient populations for which lower 
doses of fenretinide were used. This might be explained by the fact that current practices of vitamin A 
supplementation in CF patients may protect these patients from fenretinide-induced retinol decreases. 
The ongoing APPLAUD Phase 2 clinical trial also has an aggregated safety profile compatible with the 
severe nature of CF disease, and does not reveal, so far, a concerning safety signal, as evidenced by the 
favourable decisions rendered by the independent Data Monitoring Committee on three occasions so far. 
These results in adults and children are supporting the safety of the selected Initial Treatment and Follow-up 
Treatment dose of 300 mg and 200 mg/day, respectively with LAU-7b formulation in this planned Phase 2 
study in adults with COVID-19 disease and the proposed dosing regimen of up to 14 days, to exert the 
maximal antiviral activity and the pro-resolving effects on inflammation. 
5.4.3 Specific Rationales for the proposed Phase II study 
5.4.3.1 Design/Structure and Dosing Regimen 
This pilot study aims at gathering preliminary efficacy information about LAU-7b in patients with COVID-
19 disease susceptible to aggravate owing to the presence of risk factors. It will guide further development 
in larger well-controlled clinical trials.  
Since time is of the essence during the COVID-19 pandemic to identify useful treatments for affected 
patients, the study is simple in design, is short in duration and makes use of assessments commonly done in 
patients hospitalized for the disease. The primary objective of the study is to measure the impact of LAU-7b 
on the recovery rate and on the frequency, severity and timing of COVID-19 disease aggravation and 
outcomes. 
This is a randomized, double-blind (patients, Investigators and blinded study staff), placebo controlled, Phase 
II study (details are presented in Section 7.2). This study is randomized and placebo-controlled to reinforce 
its conclusiveness and the robustness of its outcomes, in order to provide key information in the design of 
subsequent well controlled clinical trials of LAU-7b in the treatment of COVID-19 disease. 
There will be no active control treatment but patients will undergo the Standard of Care at their institution. 
A randomized, double-blind study design will avoid observer bias and reduce symptoms or outcomes arising 
from the patients' knowledge of treatment. A parallel design is most appropriate for this type of acute 
indication and with a short impactful period. 
While the Phase Ib study with fenretinide was conducted in adult CF patients and there is an ongoing Phase 
2 in the CF indication in adult CF patients, the treatment paradigm for the treatment of COVID-19 disease is 
very different; it is a short, one-time 14-Day usage while the CF indication calls for longer term chronic 
administration.  
5.4.3.2 Rationale for dose selection:  
In the previous Phase Ib study in CF, three doses of LAU-7b were investigated and all showed good 
tolerability. Doses for that study were chosen based on the enhanced bioavailability that LAU-7b capsule 
formulation conferred to fenretinide, the active product ingredient, and the target concentrations derived from 
pre-clinical pharmacology experiments conducted in vitro and in vivo (1-3 µM plasma concentration).  
 
In essence, the Phase Ib was a concentration-driven study, while aiming at finding a maximum tolerated 
dose. On the exposure standpoint, the Phase Ib dose of 200 mg (middle dose) achieved the average circulating 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
31 of 73 
level (circa 2 µM Css) which corresponds to the concentrations eliciting the cytokine storm protection in the 
mice model of sepsis (1-2 µM) 25 and close to the IC50 for the antiviral activity against the MERS-CoV virus 
(2.8 µM)29 and the SARS-CoV-2 virus (unpublished results, currently subject of confirmatory studies).  
 
Because CF patients have a different pharmacokinetic profile than other patient populations, usually 
requiring higher doses, it is expected that in COVID patients, the 300mg dose should achieve a concentration 
slightly higher than seen with CF patients, and this is why this dose will be administered in the first three 
days, for a faster onset of a concentration eliciting antiviral effect. 
 
The maintenance dose of 200 mg, administered on Days 4-14, is expected to maintain a plasma concentration 
expected to have both antiviral activity and a pro-resolving effect on inflammation. Since a low LAU-7b 
dose is used in this study, no dose reductions are planned. 
The administration of the study treatment is split in two regimens:  
 
1. Initial Treatment (Days 1-3) is given to all randomized patients, even those with suspected infection who 
do not have yet a positive SARS-CoV-2 test result, in order to start the treatment as early as possible. 
The Initial Treatment daily dose is higher (300 mg) for a faster onset of a concentration eliciting antiviral 
effect. 
2. Follow-up Treatment (Days 4-14) is given only to patients that received a positive SARS-CoV-2 test 
result. The Follow-up Treatment daily dose is lower (200 mg) to maintain plasma concentrations that 
support both antiviral and inflammation-controlling effects. 
 
This pilot study is intended to be conclusive yet being a pilot study, in order to inform further development, 
including identifying any subgroup with better activity or tolerability. 
 
5.4.3.3 Rationale for Study Assessments 
The study assessments are generally part of the SOC for patients hospitalized for suspected or confirmed 
SARS-CoV-2 infection with the presence of underlying conditions or measurement associated with a greater 
risk of complications. Most are frequently assessed during hospitalization and includes vital signs, symptom 
check, safety laboratory tests, assessing the need or not for supplemental oxygenation or for a transfer to the 
intensive care unit (ICU), as well as determining if hospitalization can end (patient discharge). It is 
recognized that during the pandemic, institution/departmental policies for preventative reasons can change 
very rapidly and affect the hospitalization thresholds.  
EQ-5D-5L Quality of Life questionnaire: This questionnaire is a well-documented scoring system that have 
been widely used and validated as QoL assessment tool for this type of population. It will be filled at 
screening and by fully eligible patients (confirmed SARS-CoV-2 infection) reaching Days 14, 29 and 45 
(and at the longer-term safety/QoL assessment, around 2 months after study start), and able to fill the 
questionnaire. This is not part of Standard of Care, but this is relevant for outcomes since patients with 
varying degrees of functionality will represent a variable pharmacoeconomic weight. 
Scoring the Heath Status of the patients using the ordinal scale: Performed on specific days by the study 
coordinators or other delegated and trained staff, this assessment aims at formally determine in which 
category the patient is, each period of 24 hours (a study Day) once at a time. This is not done as part of SOC, 
but is key for this study. Several variables are derived from it. 
Serial oropharyngeal swabs to detect SARS-CoV-2 virus: This is an optional objective measurement of the 
virus presence and allows to determine how long the virus shedding lasts from the oropharyngeal cavity. 
While it is not SOC, it permits characterization of the virus inactivation properties of LAU-7b, relative to 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
32 of 73 
placebo treated patients, and to calculate with a certain accuracy if LAU-7b accelerates the virological 
recovery of the patient. It is however understood that this cannot happen at all sites, since some have limited 
swabbing and testing capabilities, resources being allocated in priority at identifying new cases of COVID 
infection. For sites able to collect a sample at the required time points, this will cause some additional 
inconvenience to the patients, but the patients may on the other hand get confirmation of virus eradication. 
 
6 STUDY OBJECTIVES 
 
Primary objective:  
To evaluate the efficacy of LAU-7b therapy + Standard-of-Care (SOC) relative to placebo + SOC in patients 
with COVID-19 disease with confirmed SARS-CoV-2 infection (target population). 
 
Secondary objectives:  
1- To assess the safety of LAU-7b therapy in all patients who received at least one dose of the study 
medication (Safety Population), compared to placebo + SOC. 
2- To assess the efficacy of LAU-7b therapy at decreasing the rate of COVID-19 disease related aggravation 
in the target population (such as a worsening of one category on the ordinal scale, onset of severe 
categories on the ordinal scale, need for transfer to Intensive Care Unit (ICU), need for mechanical 
ventilation and death, among others), compared to placebo + SOC. 
3- To measure the impact of LAU-7b therapy on the time course of the COVID-19 disease in the target 
population, as depicted by mean ordinal scale change from baseline at each assessment time, and by time-
to-event analyses (time to an improvement of one category on the ordinal scale, time to recovery 
(defined), time to ICU transfer, time to mechanical ventilation, and time to death), compared to placebo 
+ SOC. 
4- To assess the antiviral activity of LAU-7b therapy as depicted by the time to attain an undetectable viral 
load representative of virology remission, compared to placebo + SOC. 
5- To assess the benefit of LAU-7b therapy on the Quality of Life, compared to placebo + SOC.  
 
Rationale for the selection of objectives: 
 
The primary objective of this study has been selected because it is simple and clinically relevant; what impact 
LAU-7b therapy has on hospitalized patients in terms of outcomes by Day 29 post-randomization. In the 
context of limited ICU resources and equipment, any reduction in the burden of intensive care will free up 
resources and have a huge pharmacoeconomic impact. Moreover, since patient who remain mildly affected 
recover more rapidly from COVID-19 disease, it allows a better flattening of the prevalence as a function of 
time. 
 
The secondary objectives, besides safety, are aligned with the properties of LAU-7b/fenretinide 
demonstrated in humans and preclinical studies, such as the protection from an excessive pro-inflammatory 
response, the promotion of the resolution of inflammation and the demonstrated antiviral properties. 
 
This will help guiding further development of LAU-7b in the treatment of COVID-19 disease, and may also 
contribute to its development in CF, due to the possible commonality between CF Pulmonary Exacerbations 
and the exaggerated inflammatory response seen in aggravated COVID-19 patients. Furthermore, the 
knowledge derived from this study may find applications with other acute infections causing dysregulated 
inflammation in the lung. 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
33 of 73 
7 STUDY DESIGN 
7.1 Endpoints 
7.1.1 Efficacy Variable: 
The main efficacy variable is the 7-point ordinal scale of the patient status. The ordinal scale is presented 
below, and categories 1-6 are further detailed: 
 
Ordinal Scale  
1. Not hospitalized, no limitations on activities 
a. Able to carry on regular daily activities; 
b. May experience light symptoms that do not interfere with daily activities. 
2. Not hospitalized, limitation on activities 
a. Cannot carry on daily activities like prior to COVID-19; 
b. Lingering symptoms of sufficient intensity to interfere with daily activities; 
c. Periods of rest during the day to help recovery. 
3. Hospitalized, not requiring supplemental oxygen 
a. Remain bedridden most of the day; 
b. Ambulates without significant help; 
c. Under room air, able to maintain oxygen saturation at 93% and above; 
d. Does not require oxygen cannula, even at low flow of oxygen. 
4. Hospitalized, requiring supplemental oxygen 
a. Remain bedridden most of the day; 
b. Ambulates with help; 
c. Under room air, unable to maintain oxygen saturation at 93% and above; 
d. Requires oxygen cannula at flows up to 4 LPM. 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
a. Bedridden; 
b. Does not ambulate easily and requires help; 
c. Unable to maintain oxygen saturation at 93% and above with oxygen flows less than 4 l/min., or 
d. Requires non-invasive ventilation with instruments such as a Continuous Positive Airway 
Pressure (CPAP) machine to maintain adequate oxygen saturation. 
6. Hospitalized, on invasive mechanical ventilation or ECMO (extra-corporeal membrane oxygenation); 
a. Bedridden in ICU 
b. Intubated and connected to a mechanical ventilator, or 
c. Connected to an ECMO. 
7. Death. 
 
The ordinal scale is an assessment of health status on a given study day, summarizing the previous day of 
observation. Each day, the worst health status during the previous day gets scored with the scale and will be 
recorded. i.e. on Day 3, the worst Day 2 health status is obtained, scored and recorded as Day 2 score in the 
CRF. 
7.1.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients alive and free of respiratory failure on Day 29, 
compared between the active and control (placebo) arms of the study. Using the 7-point ordinal scale 
described above and the definition of “respiratory failure” in the FDA Guidance “COVID-19: Developing 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
34 of 73 
drugs and biological products for treatment or prevention”, this corresponds to patients with scores 1-4 
inclusively. 
7.1.3 Justification for the main Efficacy Variable and the Primary Efficacy Endpoint 
LAU-7b is proposed to act through a multi-prong approach against COVID-19 disease. It is hypothesized 
that these effects will reduce the odds of aggravation for the at-risk population that is admitted at the hospital 
for the COVID-19 disease. This will translate in a higher proportion of patients that recover and are 
discharged earlier from the hospital compared to those treated with the SOC alone + placebo. The use of the 
7-point Ordinal Scale proposed by the World Health Organization for COVID-19 clinical trials is ideally 
suited for establishing the proportion of patients alive and free of respiratory failure assessing the proportion 
of patients alive and free of respiratory failure (WHO Ordinal Scale scores 1-4 inclusively) as primary 
endpoint, particularly if assessed regularly during the course of the study. The time course of the COVID-19 
disease is quite short but its complications are devastating and entail a huge burden on caretakers. This 
efficacy variable and the proportion of patients alive and free of respiratory failure (ordinal scale scores 1-4 
inclusively) on Day 29, coined here as the primary efficacy endpoint, will permit both an overall picture of 
the impact of LAU-7b on patient outcomes, and a clinically meaningful assessment of the impact of LAU-
7b on the proportion of patients avoiding the ICU and death. Any positive impact elicited by LAU-7b will 
be picked up with sufficient sensitivity to inform confirmatory trials as well as any modification of the study 
design and endpoints. 
In addition, changes in the health status depicted by the Ordinal Scale category changes will permit to derive 
several secondary endpoints listed below. 
7.1.4 Secondary Endpoints 
1. Safety: the safety of LAU-7b therapy will be assessed through the monitoring of treatment emergent 
adverse events and serious adverse events, vital signs including oxygen saturation and body temperature, 
symptom-directed physical examinations and safety laboratory tests. It is important to note that most of 
these assessments are also SOC for hospitalized patients with COVID-19 disease and changes from 
baseline can depict improvement or worsening of the condition. 
2. Efficacy: Patient status on the 7-point ordinal scale on Days 14 and 29; compared between the active and 
control (placebo) arms of the study. 
3. Efficacy: Rate of all-causes death, depicted by a change from baseline in the ordinal scale position to 
category 7 by Days 29 and 60, compared between the active and control (placebo) arms of the study. 
4. Efficacy: Rate of COVID-19 disease-related aggravation, depicted by a change from baseline in the 
ordinal scale position of at least one category, compared between the active and control (placebo) arms 
of the study. 
5. Efficacy: Rate of COVID-19 disease-related transfer to ICU, depicted by a change from baseline in the 
ordinal scale position to categories 5 or 6, compared between the active and control (placebo) arms of 
the study. 
6. Efficacy: Rate of COVID-19 disease-related transfer to mechanical ventilation, depicted by a change 
from baseline in the ordinal scale position to category 6, compared between the active and control 
(placebo) arms of the study. 
7. Efficacy: Mean change from baseline of the ordinal scale patient status as a function of assessment time, 
compared between the active and control (placebo) arms of the study. 
8. Efficacy: Time to an improvement of one category on the ordinal scale patient status, compared between 
the active and control (placebo) arms of the study. 
9. Efficacy: Time to recovery, defined here as a move from baseline to categories 2 or 1 on the ordinal scale 
patient status (first occurrence if more than one), compared between the active and control (placebo) arms 
of the study. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
35 of 73 
10. Efficacy: Time to mechanical ventilation, defined here as a move from baseline to category 6 on the 
ordinal scale patient status, compared between the active and control (placebo) arms of the study. 
11. Efficacy: Time to death, defined here as a move from baseline to category 7 on the ordinal scale patient 
status, censored to Day 60 if it happens later than Day 60, compared between the active and control 
(placebo) arms of the study. 
12. Efficacy: Duration of hospitalization (days) within the study period Days 1-60, compared between the 
active and control (placebo) arms of the study. 
13. Efficacy: Time to attain an undetectable viral load through oropharyngeal swabs done at specified times, 
compared between the active and control (placebo) arms of the study. This is an optional endpoint for 
clinical sites able to obtain serial samples until discharge of patients. 
14. Quality-of-Life: The change from baseline to Days 14, 29, 45 and 60 in the score obtained on the EQ-
5D-5L survey, a well-documented scoring system that has been widely used and validated as a QoL 
assessment tool, compared between the active and control (placebo) arms of the study, in patients 
reaching Days 14, 29, 45 and 60 and able to fill the questionnaire. A longer-term assessment is set around 
2 months’ post-randomization. 
 
7.2 Study Overview 
7.2.1 Description 
RESOLUTION is a multicentre, randomized, double-blind (patients, Investigators and blinded study staff), 
placebo-controlled Phase II study of LAU-7b for the treatment of COVID-19 disease in patients at a higher 
risk than the general COVID-19 disease population to develop complications while hospitalized.  
To be eligible for the study, patients must be symptomatic of COVID-19, suspected or confirmed by PCR 
(or alternates) to have a SARS-CoV-2 infection, be aged 18 years and above, and meet all other study 
inclusion and none of the exclusion criteria at screening. There is no time limit between the onset of 
symptoms, the start of hospitalization or the confirmation of SARS-CoV-2 infection, and the screening. 
Eligible patients will be randomized 1:1, at each clinical site, to either LAU-7b (active) group or placebo 
(control) group. After randomization, patients will enter the treatment phase of the study. There will be no 
active control treatment but patients will undergo the COVID-19 disease SOC at their institution. 
Since the study will randomize both suspected and confirmed cases of SARS-CoV-2 infection and only the 
confirmed cases will participate in the two “phases” of the study (Initial treatment and Follow-up treatment), 
it is necessary to enroll more patients than the required number of completers. It is estimated that in order to 
complete 200 patients, up to approximately 240 patients will be recruited and randomized for the Initial 
treatment phase of the study in the expectation that at least 220 patients will continue into the Follow-up 
phase of the study and that approximately 200 patients complete the study as per protocol (up to Day 29 
assessment). Patients will be enrolled at approximately 15 centers in the United States of America and in 
Canada. The study treatment (LAU-7b or matching placebo) will be administered once a day in the fed state 
(with the main meal of the day if possible) for up to 14 days on treatment. 
Patients will be evaluated at pre-specified times during and after the study treatment period, for efficacy, 
safety, as well as for Quality of Life. 
This design is appropriate for this phase of development and will ensure that the highest quality of data is 
collected with minimal bias and the patient’s safety and wellbeing are preserved. A Data and Safety 
Monitoring Board (DSMB) will be created for this study. 
The overall study structure is presented below in Figure 2. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
36 of 73 
 
 
 
Figure 2: Overall structure of the study 
 
7.2.2 DSMB 
Throughout the study, the DSMB will monitor blinded safety measures and demographics at regular intervals 
as specified in the DSMB charter, or as requested by the DSMB chair. The DSMB will receive reports of 
adverse events by organ class, with emphasis on SAE’s, clinically significant adverse events with a high 
causality potential to the study treatment. Members of the DSMB will not be directly involved in the conduct 
of the study and cannot serve as Investigators in this study. 
The DSMB will be composed of: 
• Three physicians with at least one involved in the care of COVID-19 disease patients, experienced in 
clinical research, independent of Laurent Pharmaceuticals and not involved as an Investigator on the 
study. 
• One study biostatistician that can be unblinded with regards to patient randomization, meaning that he/she 
is not involved in the statistical design, analysis and reporting of the study. 
• Ad-Hoc members recruited to provide specific expertise and meet the Board’s mandate. 
 
Each DSMB member will sign a Conflict-of-Interest Statement which includes current affiliations, if any, 
with pharmaceutical and biotechnology companies (e.g., stockholder, consultant), and any other relationship 
that could be perceived as a conflict of interest related to the study and / or associated with commercial 
interests pertinent to study objectives.  
Data will be presented in a blinded manner during the open sessions of the DSMB unless noted otherwise 
below. At DSMB meetings data and discussion are confidential. Participant identities will not be known to 
the DSMB members. 
 
Mandate of the DSMB (to be defined in greater detail in the DSMB Charter): 
• Review safety information emerging from the study (and any other study of fenretinide). The DSMB will 
have access to the randomization code, if justified.  
• Meet at specific times of the study to review the safety data cumulated to date. The following specific 
times have been selected a priori: 
Suspected or confirmed 
COVID-19 disease patients, 
n=circa 240 
Confirmed LAU-7b 
+ standard of care 
n=110 
Confirmed Placebo 
+ Standard of care 
n=110 
Final assessment  
on Day 60 or  
early termination 
Blinded efficacy 
& safety 
evaluation of 
each patient by 
Site staff  

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
37 of 73 
o When a minimum of a third of the enrolled patients have completed their LAU-7b (or placebo) 
treatment period and corresponding safety information is available. This will not be a full 
unblinding; it will be an unblinded safety analysis of Active versus Placebo; 
o When a minimum of half of the enrolled patients have completed their LAU-7b (or placebo) 
treatment period and corresponding health status/efficacy information at Day 29 is available, a 
formal futility analysis (stopping rule) focusing on the proportion of patients alive and free of 
respiratory failure by treatment group, will also be performed and presented to the DSMB, 
seeking recommendation to pursue or stop the study, details can be found in the statistical 
analysis Section 12.5.2;  
o When a minimum of two thirds of the enrolled patients have completed their LAU-7b (or 
placebo) treatment period and corresponding safety data is available for review. This will not 
be a full unblinding; it will be an unblinded safety analysis of Active versus Placebo; 
o Independently of the above, every 6 months during the active randomization period; and 
o Anytime as needed for review of clinically significant safety information brought to the 
attention of the DSMB. 
 
Provide guidance to the study team with regards to safety trends. Recommendation to implement a systematic 
dose reduction, discontinue the study for futility or continue the study at the planned dose level will be made 
by the DSMB and reviewed by the Laurent Pharmaceutical’s Team, who will take the final decision to pursue 
dosing or not. 
7.2.3 Study Stopping Rule Guideline 
The following should serve as a general guide for the DSMB to recommend stopping the enrolment and/or 
further drug administration in the study for safety reasons. This is in addition to the stopping rule based on 
the futility analysis outlined in Section 12.5.2. Other considerations may be used to arrive at such decisions, 
which must involve Laurent Pharmaceuticals Executive Management. Taking in consideration the sizeable 
proportion of these at-risk patient population to develop severe complications, including death from COVID-
19 disease: 
• Occurrence of any case of death that is attributable to fenretinide (in such a case, the blind will have to 
be broken and allocated treatment identified); 
• Occurrence of an increased number, relative to placebo, of unexpected SAEs that could be attributable 
to the drug (at least probable causality relationship) that raise the DSMB/Investigators concerns about 
patients’ safety. 
 
7.3 Blinding and Randomization 
Given the potential for bias in the interpretation of the study endpoints, the RESOLUTION study must be 
placebo-controlled, double-blinded, and randomized in order to obtain sufficiently robust data and provide 
key information in the design of subsequent well controlled clinical trials of LAU-7b in the treatment of 
COVID-19 disease. 
7.3.1 Rationale for Placebo Control 
It is appropriate that this study be placebo-controlled since there is no consensual effective treatment at this 
point in time. In this pandemic circumstance where search for a treatment of COVID-19 disease is extreme, 
participation in this study will not exclude co-administration with new SOC treatments, as they become 
available (for example remdesivir and dexamethasone). This will be evaluated on a case-by-case basis. 
However, co-enrolment in other interventional studies of unproven COVID-19 treatments is not permitted. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
38 of 73 
A placebo control is suitable and will permit to have unbiased assessment of the study variables. It is essential 
to maintain the patients on their standard of care for other health conditions, assuming this meets all 
inclusion/exclusion criteria. 
7.3.2 Blinding and Breaking the Blind 
This is a double-blind study. Patients, Investigators and Site Staff, sponsor and CRO personnel, and data 
managers will be kept blinded to treatment assignments until the end of the study, except for emergency 
unblinding as described below. 
Only the Clinical Trial Material manufacturer’s and Packaging/Distribution provider’s unblinded personnel, 
duly identified members of the CRO managing the study as well as the staff coordinating the interactive web 
response system (IWRS) will be knowledgeable of individual treatment assignments. As well, in the case of 
emergency unblinding as described below, some additional people will become aware of treatment 
assignment for specific patient(s).  
The study blind may be broken for an individual patient or several patients in the event of an emergency in 
which knowledge of the treatment assignment is needed for the safety of the patient(s) and/or for medical 
decision-making or as required by local regulatory authority. Unless the event for which the blind needs 
breaking is life threatening, the investigator should first contact the CRO’s medical monitor (or designee) 
prior to breaking the blind.  
The investigator will obtain unblinding information by accessing the IWRS system. The reason and 
justification for breaking the blind must be fully documented in the source documentation and captured on 
the patient(s) electronic case report form (e-CRF). 
7.3.3 Randomization Scheme and Stratification 
Computer-generated randomization sequences will be programmed into the IWRS. At the time of 
Randomization, not before, the IWRS will assign a Subject number (Randomization Number) to each patient.  
Randomization will be stratified by clinical site and randomized in a 1:1 double-blinded fashion to either 
LAU-7b (active) group or the placebo (control) group. Stratification by clinical site is appropriate when each 
site is expected to randomize a sizeable number of patients; this will enable an even distribution of patients 
among the two treatment groups, by site. Detailed instructions for randomization will be provided separately. 
 
8 SELECTION AND WITHDRAWAL OF PATIENTS 
8.1 Screening Inclusion Criteria 
Patients may be randomized to the study only if they meet all of the following criteria at screening: 
1- Subjects must exhibit symptoms of COVID-19 disease at screening; 
2- Subjects must be 18 years and older, of either gender; 
3- Subjects must have at least one of the following factors/co-morbidities: 
a) Controlled or uncontrolled diabetes; 
b) Pre-existing cardiovascular disease, including hypertension; 
c) Pre-existing respiratory disease such as COPD, asthma, emphysema; 
d) Active smoker with a 20 pack-years of smoking; 
e) Obesity as depicted by BMI≥30; 
f) Laboratory tests indicative of a higher risk of COVID-19-related complications, such as troponin 
>1.5 ULN and/or CRP >1.5 ULN 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
39 of 73 
g) Patient aged 70 years and older who, based on the judgment of the Investigator, is at a higher risk 
of developing complications. 
4- Subjects must have a documented positive test for the SARS-CoV-2 virus or be suspected to be positive 
and with a test result pending; 
5- Subjects must be under observation by, or admitted to a controlled facility or hospital to receive SOC for 
COVID-19 disease;  
6- Subject’s health status must be 3, 4 or 5 on the Ordinal Scale and not previously a “6”; 
7- If female, must be either post-menopausal (one year or greater without menses), surgically sterile, or, for 
female subjects of child-bearing potential who are capable of conception must be: practicing a highly 
effective method of birth control (acceptable methods include intrauterine device, complete abstinence, 
spermicide + barrier, male partner surgical sterilization, or hormonal contraception) during the study and 
through 30 days after the last dose of the study medication. Periodical abstinence is not classified as an 
effective method of birth control. A pregnancy test must be negative at the Screening Visit; 
8- Subjects must have the ability to understand and give informed consent, which can be verbal with a 
witness, according to local requirements; 
9- Subjects deemed capable of adequate compliance including attending scheduled visits for the duration of 
the study; 
10- Subjects must be able to swallow the study drug capsules. 
 
8.2 Screening Exclusion Criteria 
Patients are to be excluded from the study at the time of screening for any of the following reasons: 
 
1. Pregnancy or breastfeeding; 
2. Health condition deemed to possibly interfere with the study endpoints and/or the safety of the patients. 
For example, the following conditions should be considered contraindicated for participation in the 
study, but this is not an exhaustive list. In case of doubt, the Investigator should consult with 
the Sponsor’s medical representative: 
a) Presence of inherited retinitis pigmentosa; 
b) Presence or history of liver failure; 
c) Presence or history of stage 4 severe chronic kidney disease or dialysis requirement; 
d) Febrile neutropenia; 
e) Presence of active cancer treated with systemic chemotherapy or radiotherapy; 
3. Known history of a severe allergy or sensitivity to retinoids, or with known allergies to excipients in the 
oral capsule formulation proposed to be used in the study; 
4. Participation in another drug clinical trial within 30 days (or a minimum of 5 elimination half-lives) prior 
to screening, except ongoing participation in non-interventional studies; 
5. Calculated creatinine clearance (CrCL, using the Cockroft-Gault equation for example) <60 ml/min; 
6. Presence of total bilirubin >1.5 x ULN (in the absence of demonstrated Gilbert’s syndrome), ALT and/or 
AST > 2.5 x ULN. 
 
 
8.3 Study Drug Discontinuation and Withdrawal of Patients 
Patients should discontinue permanently the study drug in the event of any of the following (Since a low 
LAU-7b dose is used in this study, no dose reductions are planned):  

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
40 of 73 
1. If the SARS-CoV-2 test result is negative or not received by pre-dose on Day 4, patient will be withdrawn 
from further treatment, will be assessed for safety at time of withdrawal only or until ongoing AE have 
resolved/stabilized and in any instances no later than Day 29, and will revert to SOC; 
2. If a patient is escalated to mechanical ventilation preventing the administration of the study medication 
intact; 
3. Occurrence of a SAE deemed related to the study drug that is a life-threatening adverse reaction or one 
resulting in prolonged non-COVID-19 disease-related hospitalization; 
4. If the patient, Investigator, or Laurent determines that it is not in the best interest of the patient to continue 
treatment;  
5. If a patient is serially and persistently noncompliant with study procedures and/or assessments, the 
investigator or the sponsor may withdraw the patient from further treatment; 
6. A patient's treatment is unblinded by the Investigator;  
7. If a female patient has a confirmed pregnancy (with the exception of a pregnancy resulting from in-vitro 
fertilization), this should be immediately reported to the Medical Monitor and Laurent Pharmaceuticals 
(within 24 hours awareness) and the patient shall discontinue the study drug. Pregnancy, whether in a 
patient or in a partner of a patient should be followed up until conclusion, with an assessment of child 
health at birth; 
8. Patients showing possible kidney impairment as assessed by an increase from screening in serum 
creatinine of 0.3 mg/dL or 1.5x the screening value; 
9. Patients showing possible liver impairment as assessed with the liver safety algorithm based on the Drug 
Induced Liver Injury (DILI) algorithm, described in Section 11.4 
10. As soon as the site is informed, patients missing two consecutive doses or more than two non-consecutive 
doses at any point during the treatment period. 
 
Patients withdrawn from further treatment but agreeable to provide outcome information should continue to 
undergo the safety and efficacy assessments as per protocol, whenever possible, up to Day 29. In all cases, 
the reason for study drug discontinuation will be noted on the CRF. 
 
Patients should be withdrawn from the study in the event of any of the following: 
 
1. If the patient withdraws consent to participate in the study as a whole; 
2. If the patient is lost to follow-up. 
 
The patient has the right to withdraw from the study at any time. Nevertheless, investigators will be trained 
to minimize full withdrawals from study wherever possible. 
 
The reason for patient withdrawal from the study will be noted on the CRF. Where applicable, the 
investigator should attempt to follow patients withdrawn from study until resolution of any adverse events. 
Upon withdrawal, no further dosing should be performed for these patients. Investigators shall make 
reasonable attempts to contact lost-to-follow-up patients for evaluation.  
 
8.4 Replacement of Patients 
Patients who withdraw their consent or are screen-failed prior to randomization, will be replaced to ensure 
that at least 220 patients will continue into the Follow-up phase of the study. Patients who withdraw (study 
or further treatment) after randomization will not be replaced. 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
41 of 73 
9 STUDY CONDUCT 
9.1 Timing of Assessments 
For the sake of simplicity, the timing of assessments is not specified. Investigator and their staff should 
however use their judgment to avoid the interference of more invasive procedures on sensitive procedures. 
9.2 Study Visits and Procedures 
9.2.1 Screening and Eligibility Assessments (Visit 0, pre-randomization): 
Prior to randomization, potentially eligible and interested patients will undergo the following: 
1. Verification of identity and age; 
2. Prior to any study specific screening activities, all potential patients will sign the Study Informed Consent 
Form (ICF), since paper copies are deemed contaminated, it is possible to take a picture of the signed 
page when possible. The consent can also be obtained verbally per COVID-19 regulatory requirements 
or local recommendations and use a witness to attest of the verbal consent. The consent forms will comply 
with all applicable regulations governing the protection of human subjects. An ICF Form, approved by 
Laurent Pharmaceuticals and the site's institutional review board (IRB or REB, as applicable), must be 
used. At this point, the patient’s initials are used for identification purposes and to identify the patient at 
the time of randomization in the IWRS. The IWRS will issue the Subject Number (Randomization 
Number); it will be used from that point forward for the entire study participation, to identify the patient. 
3. Verification of all inclusion and exclusion criteria; 
4. Obtain demographic information and medical history. Particular attention will be put on confirming the 
underlying disease or factors susceptible to affect the prognosis of COVID-19 disease progression and 
used to determine eligibility; 
5. Verification of the concomitant medications, including any supplemental oxygen currently in use; 
6. Body weight, height, with BMI calculated (measured if possible); 
7. Directed physical examination (symptom- and disease-driven); 
8. From SOC, collect the vital signs including heart rate, respiratory rate, oxygen saturation (under room 
air if possible, or value obtained prior to administering supplemental oxygen, from patient chart) and 
body temperature; 
9. If SARS-CoV-2 infection is not already confirmed and documented, or suspected with test result pending, 
an oropharyngeal swab for determining if SARS-CoV-2 infection is present, will be collected and sent 
for testing as per SOC; 
10. COVID-19 symptom check (including but not limited to, fever, myalgia, coughing, dyspnea, smell and 
taste alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
11. SOC laboratory tests including at a minimum, urinalysis (dipstick), hematology, serum chemistry and 
urine (or serum) pregnancy test if applicable. The pregnancy test result must be available before 
randomization and it must be negative; 
12. Health status determination using the 7-point ordinal scale; 
13. Quality-of-Life questionnaire: EQ-5D-5L questionnaire. 
The clinical site or Investigator may request additional procedures/tests that are part of the COVID-19 disease 
SOC at the institution or are required based on the patient’s condition; these will not be captured in the CRF 
but should be recorded in the patient’s source documentation. 
9.2.1.1 Repeat performance of screening assessment(s) 
Repeat of individual screening assessment(s) that did not meet eligibility criteria is not permitted unless there 
is clear and documented evidence of a laboratory error (e.g., hemolyzed sample) or equipment malfunction. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
42 of 73 
If the repeat values of the individual assessment(s) are within the eligibility criteria and completed before 
randomization, then the patient is eligible for the study. 
9.2.1.2 Rescreening 
Not applicable. 
9.2.2 Randomization and First Dosing (Visit 1, Day 1) 
It is expected and desirable that once all screening procedures are complete and eligibility is confirmed, that 
the patient transitions directly to randomization, without delay. Randomization will be performed on the 
IWRS platform and the assigned Initial treatment container (9 capsules) will be retrieved from the pharmacy 
(where applicable) and stored in the ward’s refrigerator, as per site procedures. 
 
Randomized patients will receive their first dose of 3 capsules of study treatment, under fed condition. As 
patient is hospitalized, there is no mandatory supervision period. 
9.2.3 In-Hospital Days 
 
For this study in hospitalized patients with suspected or confirmed COVID-19 disease, the hospital stay 
duration will vary as a function of complications/improvement observed with each given patient, if there is 
or not a confirmed SARS-CoV-2 infection, the bed and resources availability, rules and restrictions imposed 
by Health Authorities (Institution, Governmental…etc.). In order to minimize the burden of this study on the 
hospital resources, the in-hospital study requirements will piggyback on the SOC, with some exceptions. The 
overall scheme can be found in the Schedule of Event on page 11. Details are presented below. 
 
1. Pre-Dose on Day 4 only: 
Verification that the patient has a confirmed SARS-CoV-2 infection; if not, then the patient should 
discontinue the study drug and will undergo the early-termination visit. 
If the patient has a confirmed SARS-CoV-2 infection and has tolerated the Initial treatment of 3 days, 
a replenishment will be requested in the IWRS and the Follow-up treatment container (22 capsules) 
will be retrieved from the pharmacy (where applicable) and stored in the ward’s refrigerator. 
 
2. On Days 5, 8 and 12 (visits 5, 8 and 12), assuming the patient is confirmed for SARS-CoV-2 infection 
by no later that Day 4 pre-dose, the following assessments will be done:  
a. Concomitant medication verification, including any supplemental oxygen currently in use; 
b. Directed physical examination (symptom- and disease-driven); 
c. From SOC, collect the vital signs including heart rate, respiratory rate, oxygen saturation and 
body temperature (can be done multiple times during each day as part of SOC, but at a minimum 
twice); 
d. Where possible (optional) an oropharyngeal swab for determining if SARS-CoV-2 virus is still 
present, will be collected and sent for testing as per SOC; 
e. COVID-19 symptom check (including but not limited to, fever, myalgia, coughing, dyspnea, 
smell and taste alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
f. SOC laboratory tests including at a minimum, urinalysis (dipstick), hematology and serum 
chemistry; 
g. Health status determination using the 7-point ordinal scale; 
h. Handing study medication for intake during the main meal of the day; 
i. Asking safety-focused open-ended questions: 
i. How is your health today? 
ii. How is your vision today? 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
43 of 73 
iii. How is your skin today? 
j. Adverse event verification and follow-up on ongoing adverse events. 
 
3. On Day 14 or on the Day of hospital discharge (not a preset visit number), assuming the patient is 
confirmed for SARS-CoV-2 infection by no later that Day 4 pre-dose, the following assessments will 
be done; 
a. Concomitant medication verification, including any supplemental oxygen currently in use; 
b. Directed physical examination (symptom- and disease-driven, will not be repeated if assessment 
done within 2 days from the discharge day); 
c. Body weight with BMI calculated (measured if possible); 
d. From SOC, collect the vital signs including heart rate, respiratory rate, oxygen saturation and 
body temperature; 
e. Where possible (optional) an oropharyngeal swab for determining if SARS-CoV-2 virus is still 
present, will be collected and sent for testing as per SOC (will not be repeated if assessment done 
within 2 days from the discharge day); 
f. COVID-19 symptom check (including but not limited to, fever, myalgia, coughing, smell and 
taste alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
g. SOC laboratory tests including at a minimum, urinalysis (dipstick), hematology and serum 
chemistry (will not be repeated if assessment done within 2 days from the discharge day); 
h. Urine (or serum) pregnancy test if applicable; 
i. Health status determination using the 7-point ordinal scale; 
j. Quality-of-Life questionnaire: EQ-5D-5L questionnaire; 
k. If applicable, dispensing to the patient the remaining study drug treatment with instructions for 
storage in the home refrigerator, self-administration, and return of unused study drug in a pre-
labeled envelope; 
l. Asking safety-focused open-ended questions: 
i. How is your health today? 
ii. How is your vision today? 
iii. How is your skin today? 
m. Adverse event verification and follow-up on ongoing adverse events. 
 
4. On all other Days in Hospital until the day before discharge or before Day 14 (Visit numbers = Day 
of the study): The following assessments will be done, including Day 4 onward assuming the patient is 
confirmed for SARS-CoV-2 infection by no later that Day 4 pre-dose: 
a. From SOC, collect the vital signs including heart rate, respiratory rate, oxygen saturation and 
body temperature (can be done multiple times during each day as part of SOC, but at a minimum 
twice); 
b. COVID-19 symptom check (including but not limited to, fever, myalgia, coughing, smell and 
taste alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
c. Health status determination using the 7-point ordinal scale; 
d. Handing study medication for intake during the main meal of the day; 
e. Adverse event verification and follow-up on ongoing adverse events. 
 
5. Early-Termination Visit 
This visit may happen anytime a patient is meeting a study withdrawal criterion, as detailed in Section 
8.3. The following assessments can be performed, sometimes indirectly since the patient may not be 
able to contribute. 
a. Concomitant medication verification, including any supplemental oxygen currently in use; 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
44 of 73 
b. If possible, collect the vital signs including heart rate, respiratory rate, oxygen saturation and body 
temperature; 
c. Urine (or serum) pregnancy test if applicable; 
d. Adverse event verification and follow-up on ongoing adverse events. 
The patient should continue to be assessed for survival until Day 60 or earlier if death occurs. 
9.2.4 Contacts in hospital after Day 14 or after discharge once every 3 days (±1 day from target) 
and up to Day 29 
 (not a preset visit number) 
The following assessments will be done, either at the hospital, or by phone or using an electronic platform 
compatible with mobile phones or tablets.  
e. Concomitant medication verification, including any supplemental oxygen currently in use; 
f. COVID-19 symptom check (including but not limited to, fever, myalgia, coughing, smell and 
taste alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
g. Health status determination using the 7-point ordinal scale; 
h. Verification of the study drug intake and accountability, where applicable; 
i. Asking safety-focused open-ended questions: 
i. How is your health today? 
ii. How is your vision today? 
iii. How is your skin today? 
j. Adverse event verification and follow-up on ongoing adverse events.  
9.2.5 Contacts on Days 29 and 45  
(not a preset visit number) 
The following assessments will be done, either by phone or using an electronic platform compatible with 
mobile phones or tablets. Based on the patient responses, actions may be taken including inviting the 
patient to visit the hospital or meet a health professional. 
a. Concomitant medication verification, including any supplemental oxygen currently in use; 
b. COVID-19 symptom check (including but not limited to, myalgia, coughing, smell and taste 
alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
c. Health status determination using the 7-point ordinal scale; 
d. Quality-of-Life questionnaire: EQ-5D-5L questionnaire; 
e. Asking safety-focused open-ended questions: 
i. How is your health today? 
ii. How is your vision today? 
iii. How is your skin today? 
f. Adverse event verification and follow-up on ongoing adverse events. 
9.2.6 End-of-Study / Long-term Follow-up  
(around 2 months (Day 60) after randomization, not a preset visit number) 
The following assessments will be done, either by phone or using an electronic platform compatible with 
mobile phones or tablets. 
a. COVID-19 symptom check (including but not limited to, myalgia, coughing, smell and taste 
alteration, headache, gastrointestinal disorders...etc.) as per SOC; 
b. Health status determination using the 7-point ordinal scale; 
c. Quality-of-Life questionnaire: EQ-5D-5L questionnaire; 
d. Adverse event verification and follow-up on ongoing adverse events. 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
45 of 73 
9.3 Study Drug Treatment 
The total duration of study treatment is up to 14 consecutive days of either LAU-7b or placebo, as follows: 
Eligible patients will be randomized (1:1) to receive in a blinded fashion, either LAU-7b 300 mg per day (3 
capsules of 100 mg each), once a day for 3 days, or a matching placebo administered in the same fashion 
(the “Initial Treatment”). 
Patients who receive a positive SARS-CoV-2 test result during Days 1-3, will continue the treatment with 
LAU-7b 200 mg per day (2 capsules of 100 mg each), once a day for the remaining 11 days, or a matching 
placebo administered in the same fashion (the “Follow-up Treatment”).  
For suspected cases, if the SARS-CoV-2 test result is negative or not received by pre-dose on Day 4, patient 
will be withdrawn from further treatment, will be assessed for safety at time of withdrawal only or until 
ongoing AE have resolved/stabilized and in any instances no later than Day 29, and will revert to SOC. 
All eligible and confirmed patients will be treated and closely monitored for a period of up to 2 weeks or 
until early termination. The last day of study drug treatment will be on Day 14 or earlier due to aggravation 
preventing oral intake of study medication or death, whichever comes first. Specifically, patients undergoing 
intubation preventing oral intake of study medication will not receive the drug by other means such as 
through a feeding tube. Patients will continue their study participation as planned except for procedures that 
cannot be performed due to disease aggravation. 
In all cases, the study treatment will be administered on top of current SOC therapies for COVID-19 disease.  
9.3.1 LAU-7b (fenretinide) 
It consists of an orange opaque, size 00, hard gelatin capsule containing 100 mg of fenretinide. The 
formulation contains the following non-medicinal ingredients: polyvinylpyrrolidone, butylated 
hydroxyanisole, butylated hydroxytoluene, croscarmellose sodium, magnesium stearate, microcrystalline 
cellulose, dibasic calcium phosphate dihydrate, ascorbic acid. The capsule shell contains the following dyes: 
FD&C Red #3, FD&C Yellow #6 and titanium dioxide.  
The capsules are dispensed in HDPE bottles containing either 9 capsules (Initial Treatment) or 22 capsules 
(Follow-up Treatment). Study medication will be handled as follows:  
• Shipped refrigerated (2 to 8°C, 36-46°F) to the Hospital pharmacy; 
• Stored refrigerated (2 to 8°C, 36-46°F) in the Hospital pharmacy and wards, and where applicable, 
• Stored refrigerated (2 to 8°C, 36-46°F) at the patient’s home. 
9.3.2 Placebo 
A matching orange opaque, size 00 hard gelatin capsule without fenretinide will be used as a placebo for 
blinding purposes and will contain the same non-medicinal ingredients. 
The capsules are dispensed in HDPE bottles containing either 9 capsules (Initial Treatment) or 22 capsules 
(Follow-up Treatment). Study medication will be handled as follows:  
• Shipped refrigerated (2 to 8°C, 36-46°F) to the Hospital pharmacy; 
• Stored refrigerated (2 to 8°C, 36-46°F) in the Hospital pharmacy and wards, and where applicable, 
• Stored refrigerated (2 to 8°C, 36-46°F) at the patient’s home. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
46 of 73 
9.3.3 Packaging, Labeling, and Shipping 
Study medication will be provided in appropriately-sized HDPE bottles containing enough medication for 
either the Initial Treatment phase (9 capsules) or the Follow-up Treatment phase (22 capsules). Study drug 
will be specifically identified and bear instructions to ensure proper intake. The details will be described in 
the Pharmacy Manual. 
Shipments will be done using a Sponsor-defined courier, under refrigerated temperature (target 2 to 8°C, 36-
46°F), a temperature data logger may accompany the shipment to ensure an adequate chain of custody. 
9.3.4 Storage, Dispensing and Compliance Verification of Study Drug 
Upon receipt of the study drug shipper container, the investigator should record the receipt, date, time, and 
temperature of the product based on inspection or on the temperature logger reading, where applicable. Any 
study drug that arrives in improper storage conditions or is damaged in any way must be reported to the 
Laurent designee, as instructed in the Pharmacy Manual, as soon as possible and shall not be administered 
until instructed otherwise. 
At the clinical sites, the study drug bottles will initially be stored in a suitable refrigerator (2 to 8°C, 36-46°F) 
in a secure location with limited access. Most preferably, the storage refrigerator will be continually 
monitored and alarmed in order to document any excursion outside the desired temperature range. 
Alternatively, the use of a calibrated min-max thermometer in the storage refrigerator is acceptable as long 
as the thermometer readings are taken daily during weekdays, at a minimum. On the hospital ward, the drug 
should also be stored in the refrigerator, and most preferably, also monitored similarly. 
Upon instructions from the IWRS, the pharmacy/site staff will, at the time of dispensing, formally identify 
and remove the assigned treatment bottle from the secure refrigerator and will check the expiry date on the 
labels, at a minimum. Where applicable, the necessary treatment bottle will be sent to the site staff on the 
ward actually dispensing the study drug to the patients.  
To avoid incorrect patient dosing, the instructions/paperwork/bottles must bear clearly the “subject number” 
and site staff must be trained to correlate the treatment bottle with the target patient, since there will be 
multiple patients active on the study medication at any point in time. 
The study drug may only be used as directed in this RESOLUTION protocol. It is against regulations to use 
investigational products for other purposes. 
9.3.5 Administration of Study Drug Treatment 
On each inpatient Day at the Hospital, the patient will be handed the required quantity of capsules to ingest 
with the main meal of the day (if possible). The capsules should not be broken down to administer their 
content through a feeding tube if the patient is intubated and cannot ingest anymore the capsules intact. If 
the patient is discharged from the clinical site before Day 14 (the last day of study drug intake), the patient 
will be dispensed the remaining capsules of study drug and will receive instructions to continue the intake 
until Day 14. 
9.3.6 Study Drug Reconciliation and Destruction 
Investigators must maintain accurate records regarding the receipt, dispensing, and where applicable, return 
or destruction of study drug for each patient in the study. Patients discharged from hospital prior to the end 
of study drug treatment will be given a pre-labeled+paid return envelope and will be instructed to keep the 
bottle and any content remaining after completing the study drug intake until the next phone contact, which 
will enable a verbal reconciliation. Patients will then be instructed to return the study medication in the 
provided envelope. At the site, any used study drug containers, as well as any unused containers or unused 
portions of containers, must be maintained until accounted for by the monitor. After accountability by the 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
47 of 73 
monitor and approval from the sponsor, the study drug and containers should be destroyed per the site’s SOP 
for destruction of biological waste or returned to the Sponsor or Sponsor designee for disposition. 
9.4 Treatment and Protocol Compliance 
Patients are expected to receive oral daily doses based on the protocol schedule and have all procedures done 
within the allowable time windows (outlined in the Schedule of Events, page 11 and further detailed in Study 
Visits and Procedures).  
Regardless of allowable visit windows, study drug treatment should target a total of 14 days. In the event a 
patient misses an outpatient dose, he/she should not double-dose on the next dosing day; instead, he/she 
should continue as planned and take a note of this omission for disclosure at the next outpatient contact.  
In the event a patient misses a scheduled in-hospital/outpatient contact, this should be rescheduled for the 
earliest possible date. Patients who are persistently noncompliant may be withdrawn from the study at the 
investigator’s or the sponsor’s discretion. 
9.5 Allowed and Disallowed Concomitant Medications  
The standard of care for patients with COVID-19 disease is continually evolving and may include several 
medications and procedures destined to improve their outcome, treat symptoms and prevent aggravation. 
Considering the very short study treatment duration and the lack of clinically proven drug interactions for 
fenretinide, there is only a limited number of disallowed medications for this study. The COVID-19 SOC 
should be used, with the following restrictions, always weighing the risk versus benefit of co-administration. 
Co-enrolment in other interventional studies of unproven COVID-19 treatments is not permitted. 
Based on the available in-vitro and in-vivo data from animal studies and human clinical trials, the short term 
fenretinide treatment in the RESOLUTION study (only 14 days) is not expected to cause any clinically 
significant Drug-Drug Interactions in COVID-19 patients with concomitant administration of most 
commonly used drugs for diseases such as Type-2 diabetes, hypertension or asthma, some being metabolized 
by CYP enzymes. There is no real risk either for clinically significant interactions with drugs potentially 
added to SOC, such as remdesivir and dexamethasone, for the same reasons. Furthermore, since fenretinide 
is marginally eliminated in urine and eventually co-administered antibiotics are mostly eliminated by the 
kidneys, the risk of interactions with these drugs is improbable. 
9.5.1 Disallowed medications: 
After consulting the Study Reference Manual, in case of doubt about a patient’s concomitant medication, 
study personnel should consult with the Sponsor’s representative before enrolling/pursue participation of a 
patient on study. 
1. Concomitant use of Narrow Therapeutic Index drugs that are sensitive CYP substrates (e.g.:  amiodarone, 
carbamazepine, cyclosporine, digitoxin, theophylline, phenytoin, warfarin, etc. See list in study reference 
manual) is prohibited, unless absolutely mandatory. If concomitant use is required, then adverse events 
should be monitored closely; 
2. Concomitant use of known strong inducers or inhibitors of hepatic CYP450 isoenzyme (e.g.:  
ketoconazole, fluoxetine, clopidogrel, rifampin, etc. See list in study reference manual) is 
contraindicated, unless they are absolutely mandatory and after a consultation with the Sponsor’s 
representative; 
3. Concomitant use of medications that may potentially act as modulators of intracellular ceramide levels 
or ceramide cytotoxicity, sphingolipids transport, or p-glycoprotein “MDR1” or “MRP1” drug/lipid 
transporters, such as: cyclosporine A or analogue; verapamil; tamoxifen or analogue; ketoconazole, 
chlorpromazine and thioridazine; RU486 (mifepristone); indomethacin; or sulfinpyrazone is prohibited. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
48 of 73 
While the concomitant use of drugs known to prolong QT significantly is permissible in this study, the 
cardiac safety of the combination should be monitored by performing 12-lead ECG during the stay in the 
hospital; specifically, before starting the initial and follow-up study medication treatment phases, and 
approximately once every 2-3 days thereafter during the hospital stay. Appropriate actions may be taken 
subsequent to QT prolongation from baseline exceeding 50 msec or a treatment-emergent QT segment 
exceeding 500 msec. 
10 EFFICACY ASSESSMENTS 
10.1 Health Status using the 7-point Ordinal Scale 
 
This is the main efficacy variable of the study. It will be assessed post-randomization daily in hospital as 
listed in the Schedule of Events, page 11, and on Day 14 (or assessed upon discharge if discharged earlier 
than Day 14), and at each of the outpatient contacts (once every 3 days up to Day 29, and on Days 45 and 
60). The ordinal scale is an assessment of the health status on a given study day, summarizing the previous 
day of observation. Each day, the worst health status gets scored on the Ordinal scale for the previous day 
and the score will be recorded. i.e. on Day 5, the worst Day 4 health status is scored and recorded as Day 4 
score in the CRF. The scale is as follows and further details on each of the categories 1-6 are presented in 
7.1.1. 
 
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 (extra-corporeal membrane oxygenation);  
7. Death. 
10.2 Viral shedding by Oropharyngeal swabs 
This is an optional efficacy variable to be done only at clinical sites who volunteer for the assessment for all 
their patients on the RESOLUTION study. It will be assessed post-randomization only for confirmed cases 
of SARS-CoV-2 infection at time points listed in the Schedule of Events, page 11, specifically at screening 
and on Days 5, 8, 12, and 14 during the hospital stay (or assessed upon discharge if discharged earlier than 
Day 14). The samples will be sent to a laboratory for PCR (or alternate) quantitative measure of SARS-CoV-
2 virus presence, as per SOC. Details concerning the selected laboratory for each participating clinical site 
will be known at time of Site Qualification and will be provided in the qualification/selection visit report. 
This may also change during the course of the study, as techniques evolve and laboratory’s availability to 
provide the service. The clinical site should contact the Sponsor if there is a change of provider or there are 
limitations of service, including shortage of required supplies or reagents. 
10.3 Body height, weight, with BMI calculated 
 
Height (screening only) and weight will be measured with shoes off at time points listed in the Schedule of 
Events, page 11, specifically at screening and on Day 14 (or earlier discharge from hospital). The body mass 
index (BMI) will be calculated using standard methods, most likely automatically by the eCRF platform. 
10.4 Quality-of-Life evaluations 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
49 of 73 
The patient’s Quality of Life (QoL) will be assessed at time points listed in the Schedule of Events, page 11, 
specifically at screening, on Day 14 (or earlier discharge from hospital), on Days 29 and 45, and also be 
assessed at a longer-term time point approximately 2 months (Day 60) after randomization. A well 
characterized and widely used QoL instrument will be used, the EQ-5D-5L (EuroQol 5 dimensions) 
questionnaire. It is relevant to the condition being treated, the inpatient/outpatient settings, is short to answer 
and is available in both English and French. 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
50 of 73 
 
11 SAFETY ASSESSMENTS 
 
Safety evaluations will include reporting of Adverse Events (AEs), clinical laboratory assessments, and SOC 
evaluation of vital signs. 
 
11.1 Adverse Events 
 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
11.1.1 Documentation of Adverse Events 
 
Adverse events will be collected from the time of informed consent until the End-of-Study follow-up, on 
Day 60, or until early termination or death, whichever occurs first. An AE is any untoward medical 
occurrence (which does not necessarily have to have a causal relationship with this treatment). An AE can 
be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, 
or disease temporally associated with the use of an investigational product, whether or not related to the study 
drug. This includes any occurrence that was new in onset or aggravated in severity or frequency from the 
screening condition. As the study subjects are hospitalized, planned surgical procedures for an illness or 
disease that existed before the patient was screened in the study are not to be considered AEs.   
 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are considered AEs if 
they result in any one of the following:   
• Discontinuation of study treatment; 
• Require treatment or any other therapeutic intervention; 
• The necessity for further diagnostic evaluation (excluding a repetition of the same procedure to confirm 
the abnormality); 
• Association with clinical signs or symptoms that may have a significant clinical impact, as determined 
by the Investigator.  
 
Patients are encouraged to report AEs spontaneously or in response to general, non-directed questioning. All 
AEs are to be followed until resolution or until a stable clinical endpoint is reached. The investigator should 
question patients about AEs and changes in pre-existing illnesses since their last visit and must record the 
information in the patients’ medical records. The onset and end dates, severity, relationship to study agent, 
action taken, and outcome must be recorded for each AE. All AEs are to be recorded on the appropriate CRF 
and in detail on the source documents. 
 
Any AE that occurs from the first dose of study treatment (or prior to the first dose of study treatment, and 
worsening after first dose of study treatment) until the End-of-Study follow-up, on Day 60, or until early 
termination or death, whichever occurs first, will be considered treatment emergent (TEAE) and must be 
recorded in the CRF and, if an SAE, reported immediately to the Sponsor. Adverse events that are ongoing 
at the end of the follow-up period should be marked as ongoing. However, it is the responsibility of the 
Investigator to follow up on these events until resolution, where possible, according to standard medical care.   
 
Any AE or SAE that the investigator becomes aware of outside of the reporting period until the end of the 
study participation of a patient that has or is believed to have a causal relationship to the study drug should 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
51 of 73 
be reported to Laurent Pharmaceuticals via telephone.  Patients who experience AEs will be monitored with 
relevant clinical assessments and laboratory tests, as determined by the Investigator. All AEs and laboratory 
abnormalities encountered during the study should be followed until resolution or stabilization of the 
event(s). Any action taken and follow-up results must be recorded in the patient’s medical record. Follow-
up laboratory results should be filed with the patient’s source documentation and CRF. For all AEs that 
require the patient to discontinue treatment, relevant clinical assessments and laboratory tests should be 
performed until final resolution or stabilization of the event(s). These assessments should be captured in the 
source data and SAE forms but will not be entered in the CRF. 
 
All AEs for randomized patients will be recorded in the CRF and the patient's source documents. AEs for 
patients who are screened but not subsequently randomized in the study will be recorded in the patient's 
source documents and in the CRF. The following data should be documented for each AE:  
• Description of the event; 
• Classification of "serious" or "not serious"; 
• Date of first occurrence and date of resolution (if applicable); 
• Severity; 
• Causal relationship to study drug(s); 
• Action taken; 
• Outcome; 
• Concomitant medication or other treatment given   
 
An independent DSMB will assess AEs that are reported from study sites. The DSMB will meet at regular 
intervals throughout the duration of the study or will meet as determined by the DSMB chair, and may 
recommend systematic treatment arm dose reduction or early termination of the study for safety reasons (see 
Sections 7.2.2 and 7.2.3) 
11.1.1.1 Adverse Event Severity 
 
The Investigator must determine and record the severity of all serious and non-serious AEs. The Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03, (Cancer Therapy Evaluation Program 
website; 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
; 
accessed 01 December 2015) should be used for grading the severity of AEs. AEs of CTCAE Grades 4 and 
5 should be documented as "life-threatening." 
 
The severity of an AE that does not appear in the CTCAE scale should be determined according to the 
definitions below. Clinically significant laboratory tests should be recorded as AEs in the patient's source 
documents and e-CRF.  
 
Severity will be assessed according to the following criteria: 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular 
activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes 
with regular activities 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
52 of 73 
Severe (Grade 3) 
Significant level of discomfort and prevents regular 
activities 
Life-threatening (Grade 4) 
Any adverse drug experience that places the patient, in the 
view of the investigator, at immediate risk of death 
11.1.1.2 Adverse Event Causality 
 
Every effort should be made by the investigator to assess the relationship of the AE, if any, to the study drug. 
Causality should be classified using the following criteria: 
Classification 
Definition 
Related 
There is an association between the event and the 
administration of investigational study drug, a plausible 
mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study 
drug have been ruled out, and/or the event re-appeared on 
re-exposure to the investigational study drug. 
Possibly Related 
There is an association between the event and the 
administration of the investigational study drug and there is 
a plausible mechanism for the event to be related to 
investigational study drug, but there may also be alternative 
etiology, such as characteristics of the subject's clinical 
status or underlying disease.  
Unlikely Related  
The event is unlikely to be related to the investigational 
study drug and likely to be related to factors other than 
investigational study drug. 
Not Related 
Does not have a temporal relationship. Or, 
The event is related to an etiology other than the 
investigational study drug (the alternative etiology must be 
documented in the study subject's medical record). 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are facts 
[evidence] or arguments to suggest a causal relationship.” 
The causality assessment must be made by the Investigator based on information available at the time that 
the AE/SAE worksheet is completed. The initial causality assessment may be revised as new information 
becomes available. Possibly Related and Related will be considered related and Not Related and Unlikely 
Related will be considered not related, for summary purposes. 
 
11.1.1.3 Study Drug Action Taken 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
53 of 73 
The investigator will classify the study drug action taken with regard to the AE. The action taken should be 
classified according to the categories shown below: 
 
Classification 
Definition 
Dose Not Changed 
Study drug dose not changed in response to an AE; 
Dose Interrupted  
Study drug administration interrupted in response to an AE; 
Drug Withdrawn 
Study drug administration permanently discontinued in 
response to an AE; 
Not Applicable 
Action taken regarding study drug administration does not 
apply. "Not applicable" should be used in circumstances 
such as when the investigational treatment had been 
completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is 
possible. 
 
11.1.1.4 Adverse Event Outcome 
 
An AE should be followed until the investigator has determined and provided the final outcome. The outcome 
should be classified according to the categories shown below: 
 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms; 
Recovered/Resolved with 
Sequelae 
Resolution of an AE with residual signs or symptoms; 
Not Recovered/Resolved 
(Continuing) 
Either incomplete improvement or no improvement of an 
AE, such that it remains ongoing; 
Fatal 
Outcome of an AE is death. "Fatal" should be used when 
death is at least possibly related to the AE; 
Unknown 
Outcome of an AE is not known (e.g., a patient lost to 
follow-up). 
 
11.1.1.5 Treatment Administered 
 
The Investigator will ensure adequate medical care is provided to patients for any AEs, including clinically 
significant laboratory values related to study drug. In addition, the Investigator will describe whether any 
treatment was administered for the AE. "Yes" is used if any treatment was administered in response to an 
AE and may include treatments such as other medications, hospitalization, surgery, or physical therapy. "No" 
indicates the absence of any kind of treatment for an AE. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
54 of 73 
11.1.2 Clinically Significant Assessments 
 
Study assessments including laboratory tests and vital signs should be assessed and those deemed a clinically 
significant worsening from baseline documented as an AE. When possible, a clinical diagnosis for the study 
assessment should be provided rather than the abnormal test result alone (e.g. urinary tract infection, anemia). 
In the absence of a diagnosis, the abnormal study assessment itself should be listed as the AE (e.g. bacteria 
in urine or decreased hemoglobin).  
An abnormal study assessment is considered clinically significant if the patient has one or more of the 
following: 
• Concomitant signs or symptoms related to the abnormal study assessment; 
• Further diagnostic testing or medical/surgical intervention; 
• A change in the dose of study drug or discontinuation from study drug treatment.  
 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above criteria, does 
not necessarily meet clinically significant criteria. The determination of whether the study assessment results 
are clinically significant must be made by the Investigator. A laboratory abnormality judged to be Grade 4, 
in itself, may not constitute an SAE unless the clinical status of the patient indicates a life-threatening AE. 
 
11.1.3 Serious Adverse Events 
 
SAEs are generally any AEs that result in one or more of the following:   
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after participation 
in the study but within 30 days post-study (Day 90), and is suspected of being a delayed toxicity due to 
administration of the study drug); 
• Is immediately life threatening (i.e., presents an immediate risk of death at the time of the AE, not an AE 
that hypothetically might have caused death if it were more severe);  
• Requires or prolongs inpatient hospitalization*; 
• Causes persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; 
• Other important medical events that may not be immediately life threatening or result in death or 
hospitalization but, based upon appropriate medical judgment, are thought to jeopardize the patient and/or 
require medical or surgical intervention to prevent one of the outcomes defining an SAE**. 
 
*An inpatient hospitalization is defined as an admission for any length of time. In this specific case of 
COVID-19 patients already hospitalized, other hospitalization for routine or planned clinical procedures, 
prolongation of hospitalization for any COVID-19-related adverse change in the patient’s condition, or for 
“social” reasons, should not be considered an AE and should not be reported as a SAE. 
** While prolongation of hospitalization and/or transfer to Intensive Care Unit per se shall not be considered 
a AE/SAE, if invasive mechanical ventilation/ECMO is started, the cause for it is an important medical event 
and therefore reaches the criteria of seriousness to be reported as a SAE. 
 
 
Definition of Life-Threatening Adverse Experience: 
An adverse experience is life threatening if the patient was at immediate risk of death from the event as it 
occurred (i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
55 of 73 
death). For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life threatening, even though drug-induced hepatitis can be fatal. 
 
Definition of Disabling/Incapacitating Experience:  
An adverse experience is incapacitating or disabling if the experience results in a substantial and/or 
permanent disruption of the patient’s ability to carry out normal life functions.  
 
Medical Monitor: 
Dr. Tony Verco, MD, MBA 
Contact Number: +1-805-235-9193 
Email: tony@vantagebiotrials.com 
  
11.1.3.1 Serious Adverse Event Reporting  
Any SAE that occurs during this study, including death from any cause other than disease progression, 
must be reported to the designated contact for SAE reporting within 24 hours from time of awareness via 
Electronic Data Capture (EDC) tool, telephone, fax, or email, whether or not related to the study agents. If 
initially reported via telephone or short email notification, this must be followed up by an EDC entry or a 
written report submitted by email within 24 hours of the occurrence of the SAE. Under all circumstances, a 
written follow-up report must be submitted after the initial report, including the causality assessment and an 
event description, via e-mail using the paper SAE report form. It is imperative that the safety desk be 
informed within 24 hours of an SAE so that reporting to the health authority can be met, if applicable, within 
the required time frame.  
Because of the need to report to health authorities all serious adverse reactions in a timely manner, it is vitally 
important that an Investigator report immediately any adverse experiences which would be considered 
serious, even if the Investigator does not consider the adverse experience to be clinically significant or drug 
related. Should the Investigator become aware of an SAE (regardless of relationship to study drug) that 
occurs until the last scheduled study follow-up, on Day 60, or until early termination or death, whichever 
occurs first, the SAE must be reported in accordance with the procedures specified in this protocol.  
 
All SAEs that are not resolved by the end of the study, or that were not resolved upon discontinuation of the 
patient’s participation in the study, are to be followed until the AE resolves, the AE stabilizes, the AE returns 
to baseline values (if a baseline value is available), or it is shown that the AE is not attributable to the study 
drug or study conduct. If a patient becomes pregnant during the study, the patient will be removed from the 
study without receiving further study medication. Follow-up regarding the outcome of the pregnancy and 
any postnatal sequelae in the infant is required. Pregnancies are considered immediately reportable AEs 
(within 24 hours of awareness) and are to be documented in the e-CRF. 
11.1.3.2 Suspected Unexpected Serious Adverse Reactions (SUSAR)  
SUSARs are SAEs that are possibly related or related to the study drug and are unexpected (i.e., not listed in 
the investigator brochure). SUSARs will be collected and reported expeditiously to competent authorities 
and independent ethics committees (IECs)/institutional review boards (IRBs) according to regulations. 
Medical and scientific judgment is to be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as for important medical events that are not immediately life threatening or do not 
result in death or hospitalization, but jeopardize the patient or the patient population. 
For the RESOLUTION study, the following AEs will not require expedited reporting based upon the 
judgment of the Investigator: 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
56 of 73 
• AEs that occur due to Standard-of-Care COVID-19 therapies and are consistent with the package labels 
for such products; 
• AEs due to aggravation of the COVID-19 disease, including death, and unrelated to the study drug. 
The investigator should consult with the medical monitor if there is any doubt regarding classification of an 
SAE. 
 
11.2 Clinical Laboratory Assessments 
Blood and urine samples will be collected according to the Schedule of Events (page 11) and analyzed locally 
at the clinical site’s laboratory as per their SOC. Laboratory test results that are abnormal and considered 
clinically significant must be reported as AEs (as per Section 11.1.1). Screening laboratory results must be 
available and reviewed by the Investigator before randomization. The typical safety laboratory test panels 
are shown in Table 1 below (it is acceptable that SOC varies between clinical sites regarding some tests, but 
testing must include at the minimum tests evaluating the hematologic status, the kidney and the liver 
functions. The tests marked by a (+) are suggested: 
 
Table 1: Laboratory Tests Panels 
Serum Chemistry 
Hematology 
Urinalysis* 
Albumin+ 
Hematocrit+ 
Nitrite 
Creatinine+ 
Hemoglobin+ 
Urobilinogen+ 
Total protein 
Red blood cells+ 
Protein+ 
Potassium 
Mean corpuscular hemoglobin 
pH+ 
Sodium 
Mean corpuscular hemoglobin 
Blood+ 
Calcium 
Mean corpuscular volume 
Leucocyte esterase 
Bicarbonate 
Reticulocytes+ 
Specific gravity 
Phosphate 
Platelet count+ 
Ketones 
Alkaline phosphatase+ 
Leucocytes+ 
Bilirubin+ 
ALT+ 
Differential (absolute and %) 
Glucose+ 
AST+ 
Eosinophils 
Appearance 
GGT 
Basophils 
 
Total bilirubin+ 
Neutrophils+ 
 
Blood urea nitrogen+ 
Lymphocytes+ 
 
Glucose 
Monocytes 
 
* If urine is positive for leukocyte esterase, nitrite, urobilinogen, protein, or blood, if part of SOC, 
microscopic examination of urine will be performed for leukocytes, erythrocytes, crystals, bacteria, and casts, 
as per SOC. 
 
For the purpose of this study conduct, the laboratory tests performed in the local laboratory are the primary 
tests. Normal ranges and accreditations should be current and filed in the Investigator Site File and in the 
study’s Trial Master File.  
 
In addition, according to the Schedule of Events, pregnancy tests (β-human chorionic gonadotropin) for 
females of childbearing potential: Urine (or serum) samples will be obtained as specified in the Schedule of 
Events, page 11 and tested. The urine (or serum) pregnancy test pre-randomization must be negative before 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
57 of 73 
the first dose of study drug. Finally, clinical laboratory evaluations may be performed at other times if judged 
to be clinically appropriate by the Investigator. 
 
 
11.3 Vital Signs and Physical Examinations 
 
Consistent with the site’s SOC, vital signs, directed Physical Examinations will be performed according to 
the Schedule of Events, page 11, and will be symptom- or disease-driven. After screening, any clinically 
significant abnormal findings in physical examination should be reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral or tympanic, consistently 
determined being a key COVID-19 sign), pulse rate, oxygen saturation and respiratory rate. Oxygen 
saturation may be performed while the patient is stabilized on room air, in the view of determining if oxygen 
supplementation is needed. 
11.4 Liver Safety Algorithm for the Management of Hepatic Impairment 
 
The following instructions are to be followed if liver function markers and clinical presentation suggest the 
onset of hepatic impairment on study. The hepatic safety of all randomized patients will be assessed through 
the use of the following algorithm based on FDA DILI management guidelines: 
• If ALT or AST rises > 5x the Upper Limit of Normal (ULN): LAU-7b treatment is discontinued 
and patient is closely monitored until recovery; 
• If subjects with abnormal baseline liver indices develop elevations of AST or ALT >2x the baseline 
values or total bilirubin (TBL) >1.5x the baseline values during the study, repeat testing should be 
performed within 48 -72 hours. If there are persistent elevations (ALT or AST >2x the baseline 
values or TBL >1.5x the baseline values) upon repeat testing, LAU-7b should be discontinued 
unless LAU-7b is clearly not the cause of the elevation; 
• If baseline measurements were <2x ULN, discontinue LAU-7b if ALT or AST increases to > 4x the 
baseline values; 
• If baseline values are ≥2x ULN but <5x ULN, discontinue LAU-7b if ALT or AST increases to > 
2x the baseline values; 
• Discontinue LAU-7b if ALT or AST increase >2x the baseline values AND the increase is 
accompanied by a concomitant increase in TBL >1.5x the baseline value OR the International 
Normalized Ratio (INR) concomitantly increases by >0.2 
• Discontinue LAU-7b treatment if alkaline phosphatase increases to > 2x the baseline value. 
• Discontinue LAU-7b in any subject with multiple signs or symptoms suggestive of liver injury such 
as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%). 
 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
58 of 73 
 
12 STATISTICAL ANALYSIS 
 
A statistical analysis plan (SAP) will provide details of the methods of analysis to address all study objectives. 
The SAP may be amended during the course of the study, but will be finalized before the cutoff date for any 
analysis, interim or final.  
 
Data summaries by treatment group will be presented. For categorical data such as the 7-point Ordinal Scale, 
data will be tabulated in frequency tables to display the number and proportion of patients for each category 
by treatment group. For continuous variables, data will be summarized with the number of patients, mean, 
standard deviation, median, and minimum and maximum values by treatment group. Baseline assessments 
for each outcome variable will be defined as the screening measurement unless a repeat value was obtained, 
see restrictions in Section 9.2.1.1, before the first dose of study drug. Statistical significance will be set at 
the 5% level (one-sided). Consideration will be given for adjusting for pre-specified prognostic baseline 
factors such as age, the ordinal scale health status at baseline and comorbidities, where applicable. 
 
Diligent efforts will be made to prevent missing data in the study. For example, patients who discontinue the 
study treatment early should still be followed for all regularly scheduled visits for safety and relevant efficacy 
assessments, until the Day 60 follow-up. A clear distinction should be made between treatment 
discontinuation and study withdrawal. Efficacy assessments occurring after treatment discontinuation should 
not be included in the per-protocol analysis. 
 
12.1 Sample Size Determination 
The main efficacy variable is the 7-point Ordinal Scale of the patient Health Status and the primary efficacy 
endpoint is the proportion of patients alive and free of respiratory failure (ordinal scale scores 1-4 inclusively) 
on Day 29 compared between the active and control (placebo) arms of the study. The sample size has been 
estimated for this endpoint. 
A target of 220 SARS-CoV-2 positive patients are required in this study in order to complete about 200 
patients, to account for on-study withdrawals (10% rate). It is expected that up to approximately 240 
suspected and confirmed SARS-CoV-2 patients will need to be randomized for the “Initial Treatment” 
portion of the study, in order to get the 220 confirmed cases who will receive the “Follow up Treatment” 
portion of study treatment. 
Sample size rationale: This is a pilot study and therefore only informal sample size calculation has been done. 
Based on the WHO Master Protocol 68, utilization of the main efficacy variable that uses an ordinal severity 
scale with 7 categories, enables the calculation of numerous study endpoints including the primary efficacy 
endpoint, the proportion of patients alive and free of respiratory failure. The primary hypothesis test will be 
based on a test of a null hypothesis that the proportions of patients alive and free of respiratory failure for the 
two treatment groups are the same against the alternative hypothesis that the investigational group is superior 
to the control group.  
 
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
59 of 73 
Seven (7)-Points ordinal scale and hypothetical proportions of patients in each category using the more severe 
scenario proposed by WHO Master Protocol, considering the enrolled population is admitted to hospital in a 
preventative fashion: 
 
Category 
% control arm 
% active arm 
1. Not hospitalized, no limitations on activities  
25 
40 
2. Not hospitalized, limitation on activities 
33 
33.4 
3. Hospitalized, not requiring supplemental oxygen 
23 
16.1 
4. Hospitalized, requiring supplemental oxygen 
9 
5.2 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
4 
2.2 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
3 
1.6 
7. Death 
3 
1.5 
 
More recent data published by Kim et al.69 based on a sample of 2491 confirmed, hospitalized cases of 
COVID-19 in the United States, show that among all patients hospitalized, 92% had one or more underlying 
conditions, 32% were escalated to ICU, 19% were placed on invasive ventilation and 17% died. It also 
provides information on the length of ICU stay and the time between admission and transfer to ICU. Data 
shows that the stay in ICU is relatively short with a median of 6 days (Interquartile Range, 2–11) and happens 
relatively soon after hospital admission, median of 1 day (range, 0–19; Interquartile Range, 0–2).  
Considering that in this study the primary efficacy endpoint is assessed on Day 29, it is appropriate to infer 
that a sizeable proportion of patients escalated to the ICU may return to normal care before Day 29, increasing 
the proportion of patients alive and free of respiratory failure on Day 29 compared to earlier timepoints. We 
have assumed that 5% of the patients escalated to ICU would still be in ICU by Day 29, resulting in 78% 
(i.e. excluding 19% of death and 5% of patients still in ICU) of patients alive and free of respiratory failure 
on Day 29 in the control group (Standard of Care).   
Using the proportion of patients alive and free of respiratory failure at Day 29, an effect size of 12% change 
(i.e. 78% in the control group vs. 90% in the investigational group), comparing the active arm versus the 
control (placebo) arm, it is possible to estimate that the proposed total sample size of 200 will result in a 
power of approximately 75% of detecting a difference in proportions of 12% as statistically significant using 
a one-tailed test with an alpha of 0.05 (5%). The statistical power is considered appropriate for a pilot study. 
This sample size is in the upper realm of other pilot studies in this indication for hospitalized patients with 
COVID-19 disease. 
 
12.2 Analysis Populations 
 
• The intent-to-treat (ITT) population will include all patients randomized to a treatment group who 
are randomized and receive at least one dose of the study drug. The ITT population will be used for 
the primary analyses of all study endpoints, taking into consideration the specific populations 
described below. The patients will be kept in their randomized treatment arm for the analyses. 
• The per-protocol (PP) population will include all patients randomized to a treatment group to whom 
at least 12 days of study treatment are administered in accordance with the protocol (i.e. without 
major protocol deviations as pre-identified prior to the database lock) and without interruption 
triggering withdrawal from further treatment (see Section 8.3). The PP population will serve as the 
basis for secondary analyses of all study endpoints. The patients will be kept in the treatment arm that 
they actually received for the analyses. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
60 of 73 
• The safety population will include all patients randomized to a treatment group who received at 
least one dose of study drug treatment. This population will serve as the basis for analyses of all safety 
endpoints. The patients will be kept in the treatment arm that they actually received for the analyses. 
 
12.3 Subject Disposition and Discontinuations 
Patient disposition will be summarized for the total enrolled population and by treatment group. The 
following data will be presented: 
• The number of patients who were screened and randomized; 
• The number and proportion of patients in each analysis population; 
• The number and percentage of patients who completed the study; 
• The number and percentage of patients who discontinued prematurely from the study and the associated 
reasons; 
• The number and percentage of patients who attended each follow-up visit. 
 
 
12.4 Baseline and Demographic Characteristics 
 
Demographic and baseline data will be summarized by treatment group using descriptive statistics. 
Demographics will include, among others, age, gender, ethnicity, weight, height, body mass index. Protocol 
deviations/violations will be provided as a patient data listing only. Major protocol deviations/ violations 
will be identified and their impact rated for analysis purposes. 
 
The demographics and baseline characteristics summary will be presented for the ITT and the PP populations 
to allow review of the characteristics of those included in the efficacy analyses, which will be based on these 
analysis sets. 
12.4.1 Prior and Concomitant Medications 
 
Medications used in this study will be coded by using the World Health Organization Drug Dictionary 
Enhanced and categorized as the following:  
• Prior medication: Any medication that started before the first dose of study drug, independently of when 
it ended. 
• Concomitant medication: Medication continued or newly received at or after first dose of study drug to 
the follow-up on Day 45 or earlier if early-terminated. 
• Post-treatment medication: not applicable. 
 
A given medication can be classified using the above, in one or more categories. If a medication has a missing 
or partial missing start/end date or time and cannot be determined whether was taken before the first dose of 
study drug, or concomitantly, it will be considered as prior and concomitant. Prior medications and 
concomitant medications will be summarized descriptively based on the ITT population. 
12.4.2 Study Drug Exposure 
 
The duration of study drug exposure is defined as follows: Last dose date minus first dose date plus 1 day, 
regardless of any interruptions in dosing. If the last dose date of study drug is missing, the patient's 
discontinuation or completion date will be used for analysis purpose. Duration of study drug exposure will 
be summarized descriptively as a continuous variable (number, mean, SD, median, minimum, and 
maximum), by study group, using the safety population subset of the ITT population. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
61 of 73 
12.4.3 Study Drug Compliance 
 
Study drug compliance will be performed on the Safety population. Study drug compliance will be assessed 
by calculating as follows: 100 × (1 − [total number of days of study drug interruption]/(duration of study 
drug exposure)). The total number of days of study drug interruption is defined as the sum of (number of 
days of each study drug interruption), where number of days of each study drug interruption is defined as the 
interruption end date minus the corresponding interruption start date plus 1 day. Treatment compliance 
percentages will be summarized descriptively as continuous variables (number, mean, SD, median, 
minimum, and maximum). The percentage of patients whose compliance is <80% or ≥80% will be 
summarized, by study group. 
 
 
 
12.5 Efficacy Analysis  
12.5.1 Analysis of Primary Endpoint  
 
The proportion of patients alive and free of respiratory failure on Day 29 will be analyzed using a Chi-Square 
test (or a Fisher exact test if the expected values in any of the cells of the contingency table are below 5).  
Logistic regression including treatment group, age group and other prognostic factors at baseline will also 
be performed. 
Missing observations will be treated as a non-response (i.e. patient not considered as alive and free of 
respiratory failure) for the primary analyses on ITT.  
Additional post-hoc analyses may be performed in an exploratory manner depending on the frequency of 
other phenotypes or concomitant drugs. 
Full details will be specified in the SAP. 
12.5.2 Analysis of Secondary Efficacy Endpoints 
 
Pre-defined Clinical Parameters: 
 
• The ordinal scale will be used to estimate a proportional odds model. The primary hypothesis test will be 
based on a test of whether the common odds ratio for treatment is equal to one. The model fit using a 
goodness-of-fit likelihood ratio test will be evaluated. The distribution of severity results will be 
summarized by treatment arm as percentages. The validity of the proportionality assumption will be 
evaluated and tested. Participants without final outcome data will be excluded from the analysis. 
Sensitivity analyses will evaluate the impact of making different assumptions about missing observations. 
These sensitivity analyses will be fully defined in the SAP. 
• Count data variables: The number of days of hospitalization, the number of days in ICU, the number of 
days under mechanical ventilation…etc., will be tabulated by treatment and compared with an 
appropriate count data model, e.g., ANOVA model (if assumptions of normality and homogeneity of 
variance appear acceptable), Poisson regression, negative binomial regression, zero-inflated regression, 
etc., depending on their distribution. 
• Time to event data variables: The time to mechanical ventilation, time to recovery, time to aggravation 
(worsening by one category on the ordinal scale), time to attain an undetectable viral load (if performed 
in a sufficient number of sites and patients) and time to death will be tabulated by treatment and compared 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
62 of 73 
using a Cox proportional hazards model. If the proportional hazards assumption is violated, a stratified 
analysis will be conducted using stratified Cox regression. Additionally, Kaplan-Meier methods will be 
used to produce graphical presentations of the survival (aggravation-free survival, survival) by treatment 
group and to estimate cumulative aggravation-free survival and survival rates by treatment group. 
• Change in ordinal scale at specific time points will be summarized by proportions (e.g., proportion who 
have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point worsening). 
• Mean change-from-baseline for the ordinal scale will be analyzed through time, using a mixed model 
repeated measure (MMRM) model. 
• Body weight and BMI changes from screening will be summarized using descriptive statistics by 
treatment and compared between treatments using an analysis of covariance (ANCOVA) with treatment 
as fixed effect; and adjustment for screening Ordinal Scale Health Status, and weight or BMI at baseline 
as covariates. 
 
Formal Futility Analysis: 
 
When approximately 50 patients per arm will be available for health status/efficacy data from Day 29, a 
formal futility analysis based on the primary efficacy endpoint derived from the 7-point Ordinal Scale data 
will be carried out and reported to the DSMB for formulation of a recommendation to the Sponsor. The aim 
of this futility analysis/stopping rule is to ensure that there is a high probability of stopping the study when 
there is a true underlying excess risk of disease deterioration with the use of the investigational product, and 
a low probability of stopping the study when there is no such risk. 
 
In this study, an appropriate stopping rule will be based on the proportion of patients alive and free of 
respiratory failure, corresponding to Ordinal Scale scores of 1 to 4 inclusively, on Day 29. The proportion of 
patients alive and free of respiratory failure has an expected frequency in the control arm of 78% (Kim et al. 
69). The proportion of patients on the investigational product should be improved.  
 
The rule is to stop the study if the observed investigational product rate is numerically lower than the 
observed control (placebo) arm rate. Based on Kim et al. 69, assuming that the true underlying control arm 
(placebo) rate is 78% and using a normal approximation when comparing proportions, it is estimated that 
when using this rule: 
 
a. the probability of stopping the study is ~5% if the true underlying investigational product rate 
is 90%. 
b. the probability of stopping the study is ~50% if the true underlying investigational product 
rate is 78% (equal to the assumed true underlying control arm rate). 
c. the probability of stopping the study is ~91% if the true underlying investigational product 
rate is 66%. 
 
 
Quality of Life Endpoints: 
 
Quality-of-life data will be derived from the questionnaire according to the corresponding scoring manual 
and will be summarized by treatment group. Patients’ health state will be derived from the EQ-5D-5L 
questionnaire. Data will be summarized by treatment group using descriptive statistics.  Analysis of the 
absolute change from screening for the EQ-5D-5L will be performed using an ANCOVA with treatment as 
fixed effect and EQ-5D-5L score at baseline as a covariate. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
63 of 73 
12.6 Safety Analyses  
 
The safety analyses will be performed at least thrice, 1- when a minimum of one third of the enrolled patients 
have completed their LAU-7b (or placebo) treatment period and corresponding safety information is 
available, 2- when at least two thirds of the enrolled patients have completed their LAU-7b (or placebo) 
treatment period, and 3- at the time of final analysis. Safety analyses will be performed on the safety 
population (those patients who receive at least one dose of study drug). Blinded safety data will be assessed 
by the DSMB at regular meetings. The DSMB may request unblinding of patients for safety concerns in 
addition to receiving the unblinded interim analyses results. The study will remain double blinded to the 
Investigators, patients and sponsor’s staff until the end of the study, unless circumstances require unblinding. 
 
Safety and tolerability will be assessed by the following:  
• Adverse events described and categorized according to the MedDRA, version 16 or more recent.  
• Clinically relevant changes from baseline in vital signs  
• Clinically relevant changes from baseline in directed physical examinations  
• Clinically relevant changes from baseline in safety laboratory assessments (hematology with differential 
count, biochemistry, and urinalysis). 
12.6.1 Adverse Events 
Adverse events will be tabulated with reported incidences by treatment, number of patients that presented 
adverse events by treatment, serious adverse events by treatment, number of adverse events by body system 
and by treatment. Summaries will be presented by MedDRA system organ class and preferred term.  
For the purpose of analyses and tabulations, AEs will be classified as pretreatment AEs and TEAEs. More 
specifically: Pretreatment AE are those that started after consent signature and before the first dose of study 
drug and did not increase in severity. TEAE are those that increased in severity or that was appeared at or 
after the first dose of study drug and before or at the last follow-up, on Day 60, or earlier if early terminated. 
Post-treatment AEs are not collected in this study. For AEs with missing or incomplete start dates, if there is 
no clear evidence that the AEs started before or after the first dose of study drug, then the AEs will be 
classified as TEAEs.  
AE summary tables will be presented for TEAE only and will include the following: All TEAEs, TEAEs by 
relationship, TEAEs by maximal severity, TEAEs leading to treatment discontinuation, Serious TEAEs and 
fatal TEAEs. All AEs, including pre-and post-treatment AEs, will be presented in individual patient data 
listings. 
The number and percentage of patients with at least one AE, as classified by preferred term and system organ 
class, will be summarized for each treatment group. For these summaries, patients with multiple events will 
be counted only once per preferred term. AEs will also be summarized by severity and relationship to study 
drug. At each level of summarization, the event with the highest level of severity or strongest drug 
relationship will be presented. 
All AEs must be listed. In addition, detailed listings will be provided for patients who die, experience a SAE, 
or discontinue the study because of an AE. These listings will include treatment, patient’s age, duration of 
follow-up, amount of fenretinide received, and time since last intake. 
12.6.2 Clinical Laboratory Assessments 
 
Safety laboratory variables (e.g., hematology, biochemistry, and urinalysis results) will be presented in SI 
units, if available, at each time point using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum). 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
64 of 73 
12.6.3 Vital Signs 
 
Vital signs (blood pressure, temperature, heart rate, oxygen saturation and respiration rate) will be presented 
at each time point using descriptive statistics (mean, standard deviation, median, minimum, and maximum). 
Change from baseline values for each variable will also be presented by treatment group.  
 
The number and percentage of patients that meet the abnormal criteria for with shift changes from baseline 
of the vital signs during the TEAE period will be presented by treatment group. The specific changes of 
interest are:  
• Diastolic Blood Pressure ≤45 mmHg and decrease from baseline ≥10 mmHg, Diastolic Blood Pressure 
≥110 mmHg and increase from baseline ≥10 mmHg; 
• Systolic Blood Pressure ≥160 mmHg and increase from baseline ≥20 mmHg, Diastolic Blood Pressure 
≤45 mmHg and decrease from baseline ≥10 mmHg; 
• Temperature ≤35oC and ≥38oC 
• Heart rate ≤50 bpm and decrease from baseline ≥20 bpm, heart rate ≥120 bpm and increase from baseline 
≥20 bpm; 
• Oxygen saturation values and respiratory rate determined by the Investigator to be clinically abnormal 
(and reported as an AE). More specifically, the incidence of oxygen saturation being 92% or lower when 
measured in patient stabilized on room air, will be presented by treatment group. 
No statistical analyses of vital signs are planned. 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 Case Report Forms  
 
All patient data generated by the study will be recorded in each patient’s CRFs. Data reported on the CRFs 
that are derived from source documents should be consistent with the source documents or the discrepancies 
should be explained. CRFs will be considered complete when all missing and/or incorrect data have been 
resolved and all safety data have been recorded. 
 
The Investigator, or designated representative, should complete the CRF as soon as possible after information 
is collected. CRFs must be completed only by persons designated by the Investigator. The completed CRF 
will be reviewed by Laurent Pharmaceuticals or its agents on a routine basis. 
 
The Investigator must approve formally all the information in the CRFs for the patients for whom he/she is 
responsible. The United States Food and Drug Administration (FDA) or Health Canada may inspect all 
records related to the study. 
13.1.1 Source Documentation 
 
Source documents are considered to be all information in original records and certified copies of original 
records of clinical findings, observations, data, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. The Investigator and designees agree to maintain accurate e-CRFs 
and source documentation as part of the case histories. Source documents are the originals of any documents 
used by the Investigator, sub-Investigator, or hospital/institution that will allow verification of the existence 
of the patient and substantiate the integrity of the data collected during the trial. All data entered into the 
CRF also must be available in the source documents. The Investigator will allow designated representatives 
of Laurent Pharmaceuticals, IRB/IEC and regulatory bodies, including the FDA to have direct access to the 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
65 of 73 
source documents to verify the data reported in the CRFs. Personally identifiable source documentation shall 
not be copied or removed from the Investigator site, and to the extent permitted by law and/or regulations, 
will not be made publicly available. All representatives of Laurent Pharmaceuticals, IRB/IEC and regulatory 
bodies must respect confidentiality. 
13.1.2 Record Retention  
 
Study records and source documents need to be preserved for at least 25 years after the completion or 
discontinuation of/withdrawal from the study, or 2 years after the last approval of a marketing application in 
an International Conference on Harmonization (ICH) region, whichever is the longest time period.  
 
 
14 MONITORING 
 
In accordance with current applicable regulations, Good Clinical Practice (GCP), and Laurent 
Pharmaceuticals procedures, monitors will contact the site before the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and Laurent 
Pharmaceuticals requirements. When reviewing procedures for data collection, the discussion will include 
identification, agreement, and documentation of data items which will be recorded in each patient’s CRF. 
 
The study will be monitored to ensure the following: 
• Data are authentic, accurate, and complete; 
• The safety and rights of patients are being protected; 
• The study is being conducted in accordance with the currently approved protocol, any other study 
agreements, GCP, and all applicable regulatory requirements.  
 
The Investigator and the head of the medical institution (where applicable) agree to allow the monitor direct 
access to all relevant documents. 
 
15 QUALITY CONTROL AND QUALITY ASSURANCE 
 
The sponsor or its designee will perform the quality assurance and quality control activities of this study. 
However, responsibility for the accuracy, completeness, and reliability of the study data presented to Laurent 
Pharmaceuticals lies with the principal or qualified Investigator generating the data. 
 
Laurent Pharmaceuticals or its designated representative will conduct a in-person or remote study site visit 
to verify the qualifications of the principal Investigator and sub-Investigators, may inspect clinical site 
facilities as needed, and inform the Investigator of responsibilities and procedures for ensuring adequate and 
correct study documentation. During COVID-19-related site restrictions, some site qualification and 
initiation activities may be carried out remotely, with study documentation supporting in lieu the 
qualification until the time allows in-person confirmation to happen. 
 
Instances of missing, discrepant, or uninterpretable data will be queried with the Investigator for resolution. 
Any changes to study data will be enacted in the CRF and documented in an audit trail, which will be 
maintained within the clinical database. 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
66 of 73 
16 COMPLIANCE, PROTOCOL AMENDMENT AND DEVIATION 
16.1 Compliance 
 
It is very important that no modifications to the protocol should be made without the approval of Laurent 
Pharmaceuticals and Investigators. Changes that significantly affect the safety of the patients, the nature, the 
scope and the scientific integrity of the study will require IRB/IEC notification/approval before their 
implementation. Exceptions are cases where the modification is necessary to abrogate an apparent immediate 
risk to the patients. Laurent Pharmaceuticals or designee will submit all protocol modifications to IRB/IEC 
and the required regulatory authorities. When there is a need for immediate deviation from procedures 
enunciated in the protocol, the Investigator will contact Laurent Pharmaceuticals to discuss the course of 
action and possible alternatives, if at all possible, before any implementation of changes. Any deviation from 
protocol must be fully documented in the source documentation and in the study documentation on protocol 
deviations. 
 
16.2 Protocol Amendment  
 
Administrative amendments to the protocol will be classified as amendments of typographical errors, 
clarifications of confusing wording, name changes, and minor modifications that have no impact on the safety 
of the patients or the science of the study. Administrative amendments will be submitted to the IRB/IEC for 
information only. Laurent Pharmaceuticals will ensure that acknowledgement is received and filed. Any 
other amendment will be classified as a substantial amendment and will be submitted to the appropriate 
regulatory authorities and the IRBs/IECs for approval. 
 
16.3 Protocol Deviation 
 
Should a protocol deviation occur, Laurent Pharmaceuticals must be informed as soon as possible. Important 
protocol deviations and their reasons will be summarized in the clinical study report. In accordance with 
applicable regulatory authority mandates, the investigator is responsible for reporting protocol deviations to 
the IRB/IEC.  
 
 
17 STUDY TERMINATION 
 
At any time, Laurent Pharmaceuticals may terminate this study in its entirety or at specific clinical site. In 
addition, for reasonable cause, the IRB/IEC and/or the Investigator at a clinical site may terminate the study 
at their center.  In such cases, Laurent Pharmaceuticals should be informed immediately and if at all possible, 
before implementation. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited to:  
• Investigator noncompliance and/or lack of adherence to protocol procedures; 
• Unsatisfactory patient enrollment; 
• Lack of evaluable and/or complete data; 
• Potentially unacceptable risk to patients (see Section 7.2.3 for additional guidance); 
• Changes in Laurent Pharmaceuticals drug development plans; 
• Decision by the FDA or Health Canada. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
67 of 73 
 
The reason(s) for clinical study termination must be properly documented.  
 
18 ETHICAL CONSIDERATIONS 
 
The study will be conducted according to current GCP, including any future revisions, all relevant local laws 
and regulations, as well as the principles of the Declaration of Helsinki and its amendments. IRB/IEC 
committees will review and approve this protocol and informed consent. All patients must provide written 
informed consent where applicable, before participation in the study. 
 
This study will be performed by qualified clinical investigators and in accordance with GCP. The study 
specifically incorporates all of the following features:  
• Multicenter, randomized study design; 
• Prospectively stated objectives and analytical plan; 
• Accepted, pre-specified outcome measures for safety and efficacy; 
• Investigator meeting (or equivalent) prior to study start and a detailed protocol to promote consistency 
across sites; 
• Compliance with current GCP, with assessment via regular monitoring; 
• Quality assurance procedures performed at study sites and during data management to ensure that safety 
and efficacy data are adequate and well documented. 
 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, 
Investigator's Brochure, sample ICF, advertisements (if applicable), written information given to the patients, 
safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC 
by the investigator or Laurent Pharmaceuticals, as allowable by local applicable laws and regulations. 
 
19 FINANCING AND INSURANCE 
 
Financial aspects of the study are addressed in a separate clinical study agreement.  
 
The Investigator/institution is required to have adequate current insurance to cover claims for negligence 
and/or malpractice according to national regulations. Laurent Pharmaceuticals will provide insurance 
coverage for the clinical study as required by national regulations. 
 
20 PUBLICATION POLICY AND CLINICAL STUDY REPORT 
20.1 Confidentiality and Publication Policy 
 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Any and all scientific, commercial, and technical information disclosed by Laurent Pharmaceuticals in this 
protocol or any other documents and communications should be considered the confidential and proprietary 
property of Laurent Pharmaceuticals. The Investigator shall hold such information in confidence and shall 
not disclose the information to any third party except to the Investigator's staff on a “need to know” basis, as 
long as the said staff has been made aware that the information is confidential and who are bound to treat it 
as such.  

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
68 of 73 
The Investigator shall not use any and all information for any purpose other than determining interest in 
performing the study and, if the parties decide to proceed with the study, for the purpose of conducting the 
study. The Investigator understands that the information developed from this clinical study will be used by 
Laurent Pharmaceuticals for the development of the study drug and therefore may be disclosed as required 
to other clinical Investigators, potential and current business partners and associates, Health Canada, the 
FDA, and possibly other agencies, without bearing any personally identifiable information. The Investigator 
also understands that, to allow for the use of the information derived from the clinical study, he/she has the 
obligation to provide Laurent Pharmaceuticals with complete results and accompanying data developed in 
the study. 
No publication or disclosure of study results will be permitted except under the terms and conditions of a 
separate written agreement between Laurent Pharmaceuticals and the Investigator and/or the Investigator's 
institution. In all instances, personally and individually identifiable information shall not be published. 
 
20.2 Clinical Study Report 
 
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in accordance 
with local regulations. 
  
 
 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
69 of 73 
 
21 REFERENCES 
 
 
1 Camerini T, Mariani L, De Palo G, Marubini E, Di Mauro MG, Decensi A, Costa A, Veronesi U. Safety 
of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of 
contralateral breast cancer. J Clin Oncol. 2001 Mar 15;19(6):1664-70. 
2 Maurer BJ, Kalous O, Yesair DW, Wu X, Janeba J, Maldonado V, Khankaldyyan V, Frgala T, Sun BC, 
McKee RT, Burgess SW, Shaw WA, Reynolds CP. Improved oral delivery of N-(4-hydroxyphenyl) 
retinamide with a novel LYM-X-SORB organized lipid complex. Clin Cancer Res. 2007 May 
15;13(10):3079-86. 
3 Kummar S, Gutierrez ME, Maurer BJ, Reynolds CP, Kang M, Singh H, Crandon S, Murgo AJ, Doroshow 
JH. Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas. 
Anticancer Res. 2011 Mar;31(3):961-6. 
4 Clinical Study Report of Study MGU- 4HPR-13-01, dated 02 September 2015.  Principal Investigator: Dr 
Elias Matouk. 
5 Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, 
Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou 
S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, 
Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early Transmission Dynamics in 
Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020 Mar 26;382(13):1199-
1207. 
6 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei 
Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, 
Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 
Lancet. 2020 Feb 15;395(10223):497-506. 
7 Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, 
Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-
Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb 7. 
8 Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, 
Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in 
Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. 
9 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, 
Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. 
10 Xiaowei Li et al, Molecular immune pathogenesis and diagnosis of COVID-19. Journal of 
Pharmaceutical Analysis (2020). 
11 Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-
nCoV lung injury. Lancet. 2020 Feb 15;395(10223):473-475. 
12 FitzGerald GA. Misguided drug advice for COVID-19. Science. 2020 Mar 27;367(6485):1434. 
13 Horby P et al, Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report 
BMJ 2020; 370:m2648. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
70 of 73 
 
14 Müller C, Hardt M, Schwudke D, Neuman BW, Pleschka S, Ziebuhr J. Inhibition of Cytosolic 
Phospholipase A(2)α Impairs an Early Step of Coronavirus Replication in Cell Culture. J Virol. 2018 Jan 
30;92(4). 
15 Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against 
coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 Mar 12:105938. 
16 Lim YX, Ng YL, Tam JP, Liu DX. Human Coronaviruses: A Review of Virus-Host Interactions. 
Diseases. 2016 Jul 25;4(3). 
17 Ollero M, Astarita G, Guerrera IC, Sermet-Gaudelus I, Trudel S, Piomelli D, Edelman A. Plasma 
lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients. J Lipid Res. 
2011 May;52(5):1011-22. 
18 Zhou JJ, Linsdell P, Molecular mechanism of arachidonic acid inhibition of the CFTR chloride channel, 
Eur J Pharmacol. 2007 Jun 1;563(1-3):88-91. 
19 Higgins G, Ringholz F, Buchanan P, McNally P, Urbach V. Physiological impact of abnormal lipoxin A₄ 
production on cystic fibrosis airway epithelium and therapeutic potential. Biomed Res Int. 
2015;2015:781087. 
20 Kohli P, Levy BD. Resolvins and protectins: mediating solutions to inflammation. Br J Pharmacol. 2009 
Oct;158(4):960-71. 
21 Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment 
Coronavirus (COVID-19). 2020 Mar 20. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 
2020 Jan-. 
22 Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 
novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol. 2020 Mar 5. 
23 Chmiel JF, Konstan MW, Elborn JS. Antibiotic and anti-inflammatory therapies for cystic fibrosis. Cold 
Spring Harb Perspect Med. 2013 Oct 1;3(10):a009779. 
24 Cohen TS, Prince A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med. 2012 Apr 
5;18(4):509-19. 
25 Lachance C, Segura M, Dominguez-Punaro MC, Wojewodka G, De Sanctis JB, Radzioch D, Gottschalk 
M. Deregulated balance of omega-6 and omega-3 polyunsaturated fatty acids following infection by the 
zoonotic pathogen Streptococcus suis. Infect Immun. 2014 May;82(5):1778-85. 
26 Guilbault C, Wojewodka G, Saeed Z, Hajduch M, Matouk E, De Sanctis JB, Radzioch D. Cystic Fibrosis 
Fatty Acid Imbalance is Linked to Ceramide Deficiency and Corrected by Fenretinide. Am J Respir Cell 
Mol Biol. Am J Respir Cell Mol Biol. 2009 Jul;41(1):100-6. 
27 Kanagaratham C, Kalivodová A, Najdekr L, Friedecký D, Adam T, Hajduch M, De Sanctis JB, Radzioch 
D. Fenretinide prevents inflammation and airway hyperresponsiveness in a mouse model of allergic 
asthma. Am J Respir Cell Mol Biol. 2014 Dec;51(6):783-92. 
28 Lopez-Vales R, Redensek A, Skinner TA, Rathore KI, Ghasemlou N, Wojewodka G, DeSanctis J, 
Radzioch D, David S. Fenretinide promotes functional recovery and tissue protection after spinal cord 
contusion injury in mice. J. Neuroscience. 2010 Mar 3; 30(9): 3220–6. 
29 Meehyun Ko et al, Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South 
Korea identifies potential therapeutic options for COVID-19. BioRxiv (2020). 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
71 of 73 
 
30 Carocci M, Hinshaw SM, Rodgers MA, Villareal VA, Burri DJ, Pilankatta R, Maharaj NP, Gack MU, 
Stavale EJ, Warfield KL, Yang PL. The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus 
replication. Antimicrob Agents Chemother. 2015 Jan;59(1):85-95. 
31 Wang C, Yang SNY, Smith K, Forwood JK, Jans DA. Nuclear import inhibitor N-(4-hydroxyphenyl) 
retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection. Biochem Biophys 
Res Commun. 2017 Dec 2;493(4):1555-1559. 
32 Finnegan CM, Blumenthal R. Fenretinide inhibits HIV infection by promoting viral endocytosis. 
Antiviral Res. 2006 Feb;69(2):116-23. 
33 Moldoveanu B, Otmishi P, Jani P, Walker J, Sarmiento X, Guardiola J, Saad M, Yu J. Inflammatory 
mechanisms in the lung. J Inflamm Res. 2009;2:1-11. 
34 Bonfield TL, Konstan MW, Berger M. Altered respiratory epithelial cell cytokine production in CF. J 
Allergy Clin Immunol 1999 Jul;104(1): 72–8. 
35 Fanjul AN, Delia D, Pierotti MA, Rideout D, Yu JQ, Pfahl M. 4-Hydroxyphenyl retinamide is a highly 
selective activator of retinoid receptors. J Biol Chem. 1996 Sep 13;271(37):22441-6. 
36 Lachance C, Wojewodka G, Skinner TA, Guilbault C, De Sanctis JB, Radzioch D. Fenretinide Corrects 
the Imbalance between Omega-6 to Omega-3 Polyunsaturated Fatty Acids and Inhibits Macrophage 
Inflammatory Mediators via the ERK Pathway. PLoS One. 2013 Sep 12;8(9):e74875. 
37 Vilela RM, Lands LC, Meehan B, Kubow S. Inhibition of IL-8 release from CFTR-deficient lung 
epithelial cells following pre-treatment with fenretinide. Int Immunopharmacol. 2006 Nov;6(11):1651-64. 
Epub 2006. 
38 Mcilroy GD, Delibegovic M, Owen C, Stoney PN, Shearer KD, McCaffery PJ, Mody N. Fenretinide 
treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene 
expression in adipose, liver, and hypothalamus. Diabetes. 2013 Mar;62(3):825-36. 
39 Bikman BT, Guan Y, Shui G, Siddique MM, Holland WL, Kim JY, Fabriàs G, Wenk MR, Summers SA. 
Fenretinide prevents lipid-induced insulin resistance by blocking ceramide biosynthesis. J Biol Chem. 2012 
May 18;287(21):17426-37. 
40 Wu WN, Ng KT, Masucci J. Metabolism of fenretinide in the rat, dog, and man [abstract]. Pharm Res. 
1986;3 :A206. 
41 Investigator's Brochure for Fenretinide (4-HPR) NSC 374551. IND 40,294. National Cancer Institute; 
2002. 
42 Hixson EJ, Denine EP. Comparative subacute toxicity of retinyl acetate and three synthetic retinamides 
in Swiss mice. J Natl Cancer Inst. 1979 Dec;63(6):1359-64. 
43 Sani BP, Meeks RG. Subacute toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide, N-2-
hydroxyethyl retinamide, and N-4-hydroxyphenyl retinamide. Toxicol Appl Pharmacol. 1983 Sep 
15;70(2):228-35. 
44 Pegg D, Bleavins M, Herman J, Wojcinski Z, Graziano M, Henck J, Criswell KA, Anderson T, Duddy S. 
Hemangiosarcoma in mice administered pregabalin: analysis of genotoxicity, tumor incidence, and tumor 
genetics. Toxicol Sci. 2012 Jul;128(1):9-21 
45 Kenel MF, Krayer JH, Merz EA, Pritchard JF. Teratogenicity of N-(4-hydroxyphenyl)- all-trans-
retinamide in rats and rabbits. Teratog Carcinog Mutagen. 1988;8(1):1-11. 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
72 of 73 
 
46 Willhite CC, Dawson MI, Williams KJ. Structure-activity relationships of retinoids in developmental 
toxicology. I. Studies on the nature of the polar terminus of the vitamin A molecule. Toxicol Appl 
Pharmacol. 1984 Jul;74(3):397-410. 
47 Paulson JD, Oldham JW, Preston RF, Newman D. Lack of genotoxicity of the cancer chemopreventive 
agent N-(4-hydroxyphenyl)retinamide. Fundam Appl Toxicol. 1985 Feb;5(1):144-50. 
48 Swanson BN, Newton DL, Roller PP, Sporn MB. Biotransformation and biological activity of N-(4-
hydroxyphenyl)retinamide derivatives in rodents. J Pharmacol Exp Ther. 1981 Dec;219(3):632-7. 
49 Hultin TA, May CM, Moon RC. N-(4-hydroxyphenyl)-all-trans-retinamide pharmacokinetics in female 
rats and mice. Drug Metab Dispos. 1986 Nov-Dec;14(6):714-7. 
50 Villani MG, Appierto V, Cavadini E, Valsecchi M, Sonnino S, Curley RW, Formelli F. Identification of 
the fenretinide metabolite 4-oxo-fenretinide present in human plasma and formed in human ovarian 
carcinoma cells through induction of cytochrome P450 26A1. Clin Cancer Res. 2004 Sep 15;10(18 Pt 
1):6265-75. 
51 Sabichi AL, Xu H, Fischer S, Zou C, Yang X, Steele VE, Kelloff GJ, Lotan R, Clifford JL. Retinoid 
receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites. 
Clin Cancer Res. 2003 Oct 1;9(12):4606-13. 
52 Mehta RR, Hawthorne ME, Graves JM, Mehta RG. Metabolism of N-[4-hydroxyphenyl]retinamide (4-
HPR) to N-[4-methoxyphenyl]retinamide (4-MPR) may serve as a biomarker for its efficacy against human 
breast cancer and melanoma cells. Eur J Cancer. 1998 May;34(6):902-7. 
53 Villani MG, Appierto V, Cavadini E, Bettiga A, Prinetti A, Clagett-Dame M, Curley RW, Formelli F. 4-
oxo-fenretinide, a recently identified fenretinide metabolite, induces marked G2-M cell cycle arrest and 
apoptosis in fenretinide-sensitive and fenretinide-resistant cell lines. Cancer Res. 2006 Mar 15;66(6):3238-
47. 
54 Ansher SS, Jakoby WB. Amine N-methyltransferases from rabbit liver. J Biol Chem. 1986 Mar 
25;261(9):3996-4001. 
55 Cooper JP, Hwang K, Singh H, Wang D, Reynolds CP, Curley RW Jr, Williams SC, Maurer BJ, Kang 
MH. Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic 
pathway to increase systemic exposure. Br J Pharmacol. 2011 Jul;163(6):1263-75. 
56 Sagel SD, Thompson V, Chmiel JF, Montgomery GS, Nasr SZ, Perkett E, Saavedra MT, Slovis B, 
Anthony MM, Emmett P, Heltshe SL. Effect of treatment of cystic fibrosis pulmonary exacerbations on 
systemic inflammation. Ann Am Thorac Soc. 2015 May;12(5):708-17. 
57 Formelli F, Clerici M, Campa T, Di Mauro MG, Magni A, Mascotti G, Moglia D, De Palo G, Costa A, 
Veronesi U. Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol 
concentrations. J Clin Oncol. 1993 Oct;11(10):2036-42 
58 Peng YM, Dalton WS, Alberts DS, Xu MJ, Lim H, Meyskens FL, Jr. Pharmacokinetics of N-4-
hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentrations in 
cancer patients 1989 Jan 15;43(1):22-26. 
59 Garaventa A, Luksch R, Lo Piccolo MS, Cavadini E, Montaldo PG, Pizzitola MR, Boni L, Ponzoni M, 
Decensi A, De Bernardi B, Bellani FF, Formelli F. Phase I trial and pharmacokinetics of fenretinide in 
children with neuroblastoma. Clin Cancer Res. 2003 Jun;9(6):2032-9. 
60 Veronesi U, De Palo G, Marubini E, Costa A, Formelli F, Mariani L, Decensi A, Camerini T, Del Turco 
MR, Di Mauro MG, Muraca MG, Del Vecchio M, Pinto C, D'Aiuto G, Boni C, Campa T, Magni A, Miceli 

Confidential and Proprietary 
Study Protocol LAU-20-01 
LAU-7b for the treatment of COVID-19 disease in Adults 
Amendment 1, V1.4.2, Oct 18th, 2020 
73 of 73 
 
R, Perloff M, Malone WF, Sporn MB. Randomized trial of fenretinide to prevent second breast malignancy 
in women with early breast cancer. J Natl Cancer Inst. 1999 Nov 3;91(21):1847-56. 
61 Costa A, Malone W, Perloff M, Buranelli F, Campa T, Dossena G, Magni A, Pizzichetta M, Andreoli C, 
Del Vecchio M, et al. Tolerability of the synthetic retinoid Fenretinide (HPR). Eur J Cancer Clin Oncol. 
1989 May;25(5):805-8. 
62 Villablanca JG, Krailo MD, Ames MM, Reid JM, Reaman GH, Reynolds CP. Phase I trial of oral 
fenretinide in children with high-risk solid tumors: a report from the Children's Oncology Group 
(CCG09709). J Clin Oncol. 2006 Jul 20;24(21):3423-30. 
63 Decensi A, Torrisi R, Polizzi A, Gesi R, Brezzo V, Rolando M, Rondanina G, Orengo MA, Formelli F, 
Costa A. Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. J Natl 
Cancer Inst. 1994 Jan 19;86(2):105-10. 
64 Torrisi R, Parodi S, Fontana V, Rondanina G, Formelli F, Costa A, Boccardo F, Decensi A. Factors 
affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in 
breast cancer patients. Cancer Epidemiol Biomarkers Prev. 1994 Sep;3(6):507-10. 
65 Doose DR, Minn FL, Stellar S, Nayak RK. Effects of meals and meal composition on the bioavailability 
of fenretinide. J Clin Pharmacol. 1992 Dec;32(12):1089-95. 
66 Phase 1 Study. 4-HPR Administration in Healthy Volunteers for 28 Consecutive Days, Protocol KA and 
KB. Fenretinide Investigator’s Brochure 1992. The R.W. Johnson Research Institute, Spring House PA, 
1947-0776 
67 Formelli F, Cavadini E, Luksch R, Garaventa A, Villani MG, Appierto V, Persiani S. Pharmacokinetics 
of oral fenretinide in neuroblastoma patients: indications for optimal dose and dosing schedule also with 
respect to the active metabolite 4-oxo-fenretinide. Cancer Chemother Pharmacol. 2008 Sep;62(4):655-65. 
68 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, 
World Health Organization, Version 2.0, 24 February 2020. 
69 Kim L et al. Risk Factors for Intensive Care Unit Admission and In-hospital Mortality among 
Hospitalized Adults Identified through the U.S. Coronavirus Disease 2019 (COVID-19)-Associated 
Hospitalization Surveillance Network (COVID-NET). Clin Infect Dis. 2020 Jul 16.