A Multi-center, Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Safety and Efficacy of Hydroxychloroquine Monotherapy and in Combination With Azithromycin in Patients With Moderate and Severe COVID-19 Disease
Phase: PHASE3
Conditions: Covid-19
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
JWT629 (Hydroxychloroquine)
Clinical Trial Protocol CJWT629A12301 / NCT04358081
A multi-center, randomized, double-blinded, placebo-controlled 
study to evaluate the safety and efficacy of hydroxychloroquine 
monotherapy and in combination with azithromycin in patients with 
moderate and severe COVID-19 disease
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
00 (Original Protocol)
Clinical Trial Phase:
III
Release date:
08-Apr-2020 (content final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020)

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Clinical Trial Protocol (Version No. 00)
Protocol No. CJWT629A12301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................15
2
Objectives and endpoints...................................................................................................16
2.1
Primary estimand...................................................................................................18
2.2
Secondary estimands .............................................................................................18
3
Study design ......................................................................................................................19
4
Rationale............................................................................................................................20
4.1
Rationale for study design .....................................................................................20
4.1.1
Rationale for choice of background therapy.........................................21
4.2
Rationale for dose/regimen and duration of treatment ..........................................21
4.2.1
Rationale for hydroxychloroquine ........................................................21
4.2.1
Rationale for combination.....................................................................21
4.2.2
Rationale for treatment duration ...........................................................22
4.2.3
Rationale for dose regimen ...................................................................22
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................25
4.4
Purpose and timing of interim analyses/design adaptations..................................25
4.5
Risks and benefits..................................................................................................25
5
Study Population ...............................................................................................................26
5.1
Inclusion criteria ....................................................................................................26
5.2
Exclusion criteria...................................................................................................26
6
Treatment...........................................................................................................................28
6.1
Study treatment......................................................................................................28
6.1.1
Investigational and control drugs..........................................................28
6.1.2
Treatment arms/group ...........................................................................28
6.1.3
Treatment duration................................................................................29
6.2
Other treatment(s)..................................................................................................29
6.2.1
Concomitant therapy.............................................................................29
6.2.2
Rescue medication ................................................................................29

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6.2.3
Prohibited medication ...........................................................................30
6.3
Participant numbering, treatment assignment, randomization ..............................30
6.3.1
Participant numbering...........................................................................30
6.3.2
Treatment assignment, randomization ..................................................30
6.4
Treatment blinding.................................................................................................31
6.5
Additional treatment guidance...............................................................................31
6.5.1
Treatment compliance...........................................................................31
6.5.2
Emergency breaking of assigned treatment code..................................32
6.6
Preparation and dispensation.................................................................................32
6.6.1
Handling of study treatment and additional treatment..........................32
7
Informed consent procedures ............................................................................................33
8
Visit schedule and assessments .........................................................................................34
8.1
Screening ...............................................................................................................36
8.1.1
Information to be collected on screening failures.................................36
8.2
Participant demographics/other baseline characteristics .......................................36
8.2.1
SARS-COV-2 testing............................................................................36
8.2.2
Demographic information.....................................................................36
8.2.3
Prior and concomitant medications.......................................................37
8.2.4
COVID-19 Participant status ................................................................37
8.2.5
Other baseline characteristics................................................................37
8.3
Efficacy..................................................................................................................37
8.3.1
COVID-19 Participant status ................................................................37
8.3.2
SARS-COV-2 testing............................................................................38
8.3.3
Appropriateness of efficacy assessments..............................................38
8.4
Safety and tolerability............................................................................................39
8.4.1
Physical examination ............................................................................39
8.4.2
Vital signs and body measurements......................................................39
8.4.3
Laboratory evaluations..........................................................................39
8.4.4
Electrocardiogram (ECG) .....................................................................39
8.4.5
Pregnancy test .......................................................................................40
8.4.6
Appropriateness of safety measurements..............................................40
8.5
Additional assessments..........................................................................................41
8.5.1
Unscheduled assessments......................................................................41
8.5.2
Assessments pre and post hospital discharge........................................41
8.5.3
Biomarkers............................................................................................41
9
Study discontinuation and completion ..............................................................................41

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9.1
Discontinuation and completion............................................................................41
9.1.1
Study treatment discontinuation and study discontinuation..................41
9.1.2
Withdrawal of informed consent...........................................................42
9.1.3
Lost to follow-up...................................................................................43
9.1.4
Early study termination by the sponsor.................................................43
9.2
Study completion and post-study treatment ..........................................................43
10 Safety monitoring and reporting........................................................................................44
10.1
Definition of adverse events and reporting requirements......................................44
10.1.1
Adverse events ......................................................................................44
10.1.2
Serious adverse events ..........................................................................45
10.1.3
SAE reporting........................................................................................46
10.1.4
Pregnancy reporting ..............................................................................47
10.1.5
Reporting of study treatment errors including misuse/abuse................47
10.2
Additional Safety Monitoring................................................................................48
10.2.1
Cardiac safety monitoring.....................................................................48
10.2.2
Liver safety monitoring.........................................................................48
10.2.3
Renal safety monitoring........................................................................49
10.2.4
Data Monitoring Committee .................................................................49
11 Data Collection and Database management......................................................................49
11.1
Data collection.......................................................................................................49
11.2
Database management and quality control............................................................50
11.3
Site monitoring ......................................................................................................51
12 Data analysis and statistical methods ................................................................................51
12.1
Analysis sets ..........................................................................................................52
12.2
Participant demographics and other baseline characteristics.................................52
12.3
Treatments .............................................................................................................52
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................53
12.4.1
Definition of primary estimand(s).........................................................53
12.4.2
Statistical model, hypothesis, and method of analysis..........................53
12.4.3
Handling of remaining intercurrent events of primary estimand..........54
12.4.4
Handling of missing values not related to intercurrent event ...............54
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................54
12.4.6
Supplementary analysis.........................................................................54
12.4.7
Supportive analyses...............................................................................54
12.5
Analysis of secondary estimands...........................................................................55
12.5.1
Safety endpoints....................................................................................55

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12.5.2
Biomarkers............................................................................................56
57
12.7
Interim analyses.....................................................................................................57
12.8
Sample size calculation..........................................................................................57
12.8.1
Primary endpoint(s)...............................................................................57
12.8.2
Secondary endpoint(s)...........................................................................58
13 Ethical considerations and administrative procedures ......................................................58
13.1
Regulatory and ethical compliance........................................................................58
13.2
Responsibilities of the investigator and IRB/IEC..................................................58
13.3
Publication of study protocol and results...............................................................59
13.4
Quality Control and Quality Assurance.................................................................59
14 Protocol adherence ............................................................................................................59
14.1
Protocol amendments.............................................................................................60
15 References .........................................................................................................................61
16 Appendices ........................................................................................................................63
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................63
16.2
Appendix 2: Suggested Liver event and laboratory trigger definitions & 
follow-up requirements..........................................................................................64
16.3
Appendix 3: Suggested Specific Renal Alert Criteria and Actions and Event 
Follow-up...............................................................................................................67
List of tables
Table 2-1
Objectives and related endpoints ..........................................................16
Table 4-1
Human PK parameters from 3-compartment model describing 
human total blood hydroxychloroquine ................................................24
Table 4-2
Predicted  human exposure for 600 mg loading dose and 200 mg 
t.i.d. maintenance dose of hydroxychloroquine sulfate.........................25
Table 6-1
Investigational and control drug............................................................28
Table 6-2
Prohibited medication ...........................................................................30
Table 8-1
Assessment schedule.............................................................................35
Table 8-2
Laboratory parameters (local lab) .........................................................39
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................47
Table 12-1
Sensitivity of sample size to different response rates for 148 
participants per group (N=444) and treatment differences for level 
of significance alpha = 0.05 ..................................................................57
Table 16-1
Liver event and laboratory trigger definitions ......................................64

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Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms ..............................................................................................64
Table 16-3
Follow up requirements for liver laboratory triggers............................65
Table 16-4
Specific Renal Alert Criteria and Actions.............................................67
List of figures
Figure 3-1
Study design..........................................................................................20
Figure 4-1
Predicted concentrations of hydroxychloroquine in the lung and 
blood compartments..............................................................................24

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List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the curve
AZI
Azithromycin
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CL
Clearance
Cmax
Minimum (peak) plasma drug concentration
Cmin
Maximum plasma drug concentration
CMO&PS 
Chief Medical Office and Patient Safety
CoV(s)
Coronavirus(es)
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
F
Bioavailability (systemic availability of the administered dose)
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
h
Hour
HCQ
Hydroxychloroquine
HCT
Hematocrit
Hgb
Hemoglobin
HSS
Department of Health and Human Services
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
IND
Investigational new drug application
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology

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K
Potassium
ka
Absorption rate constant (first order)
KG
Kilogram
LFT
Liver function test 
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities 
Med hx
Medical history
MERS-CoV
Middle Eastern respiratory syndrome coronavirus
mg
milligram(s)
Mg
Magnesium
mL
milliliter(s)
msec
Millisecond(s)
Na
Sodium
ng
nanogram
o.d.
Once a day
PCR
Polymerase chain reaction
PLT
Platelets
p.o.
oral(ly)
PK
Pharmacokinetic(s)
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV
severe acute respiratory syndrome coronavirus
sCR
serum creatinine
SD
standard deviation
SMQ
Standardized MedDRA Query
SoC
Standard of care
SpO2
Peripheral capillary oxygen saturation
SUSAR
Suspected Unexpected Serious Adverse Reaction
t.i.d.
Three times a day (ter in die)
µg
Microgram
ULOQ
Upper limit of quantification
ULN
upper limit of normal
µM
Micro Molar Unit
USPI
United States package insert
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent

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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol 
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained 
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis

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Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Randomization 
number
A unique identifier assigned to each randomized participant
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data

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Protocol summary
Protocol number
JWT629A12301
Full Title
A multi-center, randomized, double-blinded, placebo-controlled study to 
evaluate the safety and efficacy of hydroxychloroquine monotherapy and in 
combination with azithromycin in patients with moderate and severe COVID-
19 disease
Brief title
Hydroxychloroquine monotherapy and in combination with azithromycin in 
patients with moderate and severe COVID-19 disease
Sponsor and 
Clinical Phase
Novartis
III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
Recently, there has been  excitement to repurpose chloroquine and 
hydroxychloroquine (HCQ) for the treatment of the patients with COVID-19, 
therefore there is an urgent need to conduct prospective, randomized, 
double-blind, controlled clinical trials to definitively establish the benefit of 
hydroxychloroquine and the combination of hydroxychloroquine with 
azithromycin in patients with COVID-19 disease.
This clinical trial is designed to evaluate the efficacy and safety of HCQ and 
HCQ in combination with azithromycin compared to a placebo in adult 
participants hospitalized with moderate to severe COVID-19 disease, 
excluding critically ill participants (i.e. those needing ICU admission or 
mechanical ventilation at study start).
Primary 
Objective(s)
The primary objective of this study is to demonstrate superiority of 
hydroxychloroquine or hydroxychloroquine plus azithromycin compared to 
placebo in achieving clinical response by Day 15.
The primary clinical question of interest is: What is the effect of the 
hydroxychloroquine and hydroxychoroquine plus azithromycin versus 
placebo on the percentage of participants achieving clinical response by Day 
15 in participants with moderate to severe COVID-19 disease excluding 
critically ill participants (i.e. those needing ICU admission or mechanical 
ventilation at study start) who are receiving standard of care?
Secondary 
Objectives
The secondary objectives are:
To demonstrate superiority of hydroxychloroquine or hydroxychloroquine plus 
azithromycin  compared to placebo in achieving viral clearance by Day 15 by 
assessing SARS-COV-2 PCR qualitative testing by day 15
To evaluate the time to discharge from the hospital in participants receiving 
hydroxychloroquine or hydroxychloroquine plus azithromycin relative to 
placebo by assessing time to discharge (or ready for discharge) 
To evaluate the time to return to pre-morbid supplemental oxygen 
requirement in participants receiving hydroxychloroquine or 
hydroxychloroquine plus azithromycin relative to placebo by assessing the 
time to return to pre-morbid supplemental oxygen requirements 
To evaluate the time to SARS-COV-2 negativity in participants receiving 
hydroxychloroquine or hydroxychloroquine plus azithromycin relative to 
placebo by assessing the time to SARS-COV-2 negativity

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To assess safety of participants receiving hydroxychloroquine or 
hydroxychloroquine plus azithromycin as compared to placebo by assessing 
the number of participants with adverse events, serious adverse events, 
clinically significant changes in laboratory measures, ECG and vital signs 
The clinical question of interest is: What is the effect of the 
hydroxychloroquine and hydroxychloroquine plus azithromycin versus 
placebo on the presence or absence of virus which will be represented by the 
percentage of participants achieving viral clearance by Day 15 in participants 
with moderate to severe COVID-19 disease excluding critically ill participants 
(i.e. those needing ICU admission or mechanical ventilation at study start) 
who are receiving standard of care?
Study design
This study is a multi-center, randomized, blinded, three-arm parallel-group, 
placebo-controlled trial to evaluate the safety and efficacy of 
hydroxychloroquine monotherapy or in combination with azithromycin in 
participants with moderate and severe COVID-19 disease excluding critically 
ill participants (i.e. those needing ICU admission or mechanical ventilation at 
study start).
The study will include: Screening period of up to four days to obtain the 
informed consent and assess participant’s eligibility; Treatment period of 10 
days; and an observation period of an additional 30 days (until Day 40) with 
Day 40 being the end of study visit.
Study population
The study population will consist of approximately 444 male and female adult 
participants with moderate to severe COVID-19 disease excluding critically ill 
participants (i.e. those needing ICU admission or mechanical ventilation at 
study start) receiving standard of care to be randomized into 
hydroxychloroquine, hydroxychloroquine plus azithromycin, or placebo in 
1:1:1 ratio (148 participants / arm).
Key Inclusion 
criteria

Informed consent must be obtained prior to participation in the study

Adult patient ≥ 18 years old

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 
infection confirmed by polymerase chain reaction (PCR) test or rapid test 
from respiratory tract specimen (e.g. nasopharyngeal swab) within 4 days 
prior to randomization

Currently hospitalized or requiring hospitalization due to COVID-19 
disease
Key Exclusion 
criteria

Use of other investigational drugs within 5 half-lives or 30 days of 
enrollment

Participation in any other clinical trial of an experimental treatment for 
COVID-19 within 5 half-lives or 30 days of enrollment 

Expectation of concurrent treatment with other agents with actual or 
potential direct acting antiviral activity against SARS-CoV-2

History of hypersensitivity to any of the study treatments or its excipients 
or to drugs of similar chemical classes.

Requires, in the judgement of the investigator, admission to the intensive 
care unit (ICU) or mechanical ventilatory support (invasive or non-
invasive) prior to the initiation of study drug

Evidence of cytokine storm syndrome or multi-organ system failure or 
confirmed co-infection with influenza

History or current diagnosis of ECG abnormalities

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
Pregnant or lactating women
Study treatment
Hydroxychloroquine and matching placebo, azithromycin and matching 
placebo
Treatment of 
interest
The study treatment consists of:

Investigational drug

Hydroxychloroquine (HCQ): doses of 200 mg or placebo

Azithromycin (AZI): dose of 250 mg or placebo
All participants will receive best standard of care as background therapy. 
Further details about the investigational treatment and control treatment are 
provided in Section 6.
Efficacy 
assessments
COVID-19 participant status 
 
 
), SARS-COV-2 testing
Key safety 
assessments
Adverse event monitoring, Physical examinations, vital signs, monitoring of 
laboratory markers in blood and urine etc. ECGs
Other 
assessments 
Data analysis
The primary efficacy endpoint (percentage of participants with clinical 
response by Day 15) is defined:

for participants with a pre-morbid oxygen requirement: as discharge (or 
ready to discharge as evidenced by normal body temperature and 
respiratory rate, and stable oxygen saturation on ambient air or ≤ 2L 
supplemental oxygen) OR survival without need for mechanical 
ventilation

for participants without a pre-morbid oxygen requirement: as discharge 
(or ready for discharge) OR survival without need for mechanical 
ventilation or oxygen supplementation for the last 24 hours.
The primary analysis will use a logistic regression model. 
The secondary endpoint controlled for multiplicity, will be the percentage of 
participants with viral clearance (SARS-CoV-2 negativity) by day 15. This 
endpoint will be analyzed using a logistic regression model. 
Key words
COVID-19, corona virus, SARS-CoV

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1
Introduction
1.1
Background
Coronavirus (CoVs) are positive-sense single stranded enveloped RNA viruses, many of which 
are commonly found in humans and cause mild symptoms. Over the past two decades, emerging 
pathogenic CoVs capable of causing life-threatening disease in humans and animals have been 
identified, namely severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle 
Eastern respiratory syndrome coronavirus (MERS-CoV).
In December 2019, the Wuhan Municipal Health Committee (Wuhan, China) identified an 
outbreak of viral pneumonia cases of unknown cause. Coronavirus RNA was quickly identified 
in some of these patients. This novel coronavirus has been abbreviated as SARS-CoV-2 and 
has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human 
SARS-CoV-1. Initially, most of the infections outside China were travel-associated cases in 
those who had recently visited the city of Wuhan, and thought to have acquired the virus through 
contact with infected animals or contact with infected people. However, in recent weeks, the 
world has seen an increasing number of cases (> 800,000 confirmed cases worldwide and > 
180,000 confirmed cases in the US by 31st March 2020), primarily the result of community 
transmission according to World Health Organization (WHO 2020). 
The novel coronavirus has been designated SARS-CoV-2, and the disease caused by it has been 
designated COVID-19, which leads to substantial morbidity and mortality. Outbreak 
forecasting and mathematical modeling suggests that these numbers will continue to rise
(Ferguson et al 2020). Global efforts to evaluate novel antivirals and therapeutic strategies to 
treat COVID-19 have intensified. There are currently no vaccine or therapies to prevent or treat 
SARS-CoV-2 infection. Therefore, there is an urgent public health need for rapid research and 
development of novel therapeutics.
Recently, there has been excitement to repurpose chloroquine and hydroxychloroquine (HCQ) 
for the treatment of the patients with COVID-19; these are products that were originally 
approved for malaria in 1949 and 1955, respectively.  Both products have well-established 
safety profiles, with marketed use over 60 years for treatment of malaria, rheumatoid arthritis, 
and systemic lupus erythematosus. Both have anti-viral as well as immunomodulatory effects, 
including effects on innate immune pathways and downstream cytokines like IL-6 (van den 
Borne et al 1997). Further, there are several publications out of China on the use of chloroquine,
and there are 16 clinical studies ongoing with chloroquine according to the clinical trial registry 
in China (accessed on March 22nd, 2020).
HCQ is reported to have a more favorable safety profile, with less toxicity and drug interactions 
compared to chloroquine. In addition, a recent publication has reported that compared to 
chloroquine, HCQ also has greater potency in vitro against SARS-CoV-2 (Liu et al 2020).
However, hydroxychloroquine has potential short and long-term toxicities, and definitive 
benefit needs to be established to outweigh the known potential risks.
Data from a small open label study in France using HCQ, with or without addition of 
azithromycin, was recently reported (Gautret et al 2020). In this study 26 patients with COVID-
19 were treated with 600 mg daily of HCQ (200 mg t.i.d.) for 10 days (with 6 of these patients 
also receiving azithromycin). The endpoint was virologic clearance from nasopharyngeal swabs 

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at Day 6. External controls included patients at another center, or patients at the same center 
who declined participation, or had an exclusion criteria. Six of the 26 patients were lost to 
follow-up (3 to ICU; 1 death; 1 left the hospital; 1 stopped treatment due to nausea).  Of the 
remaining 20 who completed, 70% of patients with HCQ were virologically cured compared 
with only 12.5% of the sixteen control subjects. Further, a recent re-analysis of the data suggests
a potential benefit of the combination (Lover 2020).
In addition, a small blinded, randomized, controlled study from Wuhan in patients with 
COVID-19 pneumonia (31 patients in the treatment group and 31 in the control group), reported 
after five days of treatment with hydroxychloroquine, significant improvements in the treatment 
group in fever, cough, and in pneumonia (Chen et al 2020). There is an urgent need to conduct 
prospective, randomized, double-blind, controlled clinical trials to definitively establish the 
benefit of hydroxychloroquine and the combination of hydroxychloroquine with azithromycin 
in patients with COVID-19 disease.
1.2
Purpose
This clinical trial is designed to evaluate the efficacy and safety of HCQ and HCQ in 
combination with azithromycin compared to a placebo in adult participants hospitalized with
moderate to severe COVID-19 disease.
Patients with moderate COVID-19 disease are considered to be those with peripheral capillary 
oxygen saturation (SpO2) > 94% on room air and requiring hospitalization; patients with severe 
COVID-19 disease are those requiring hospitalization with peripheral capillary oxygen 
saturation (SpO2) ≤ 94% on room air, or the need for oxygen supplementation; respiratory 
rate >24 breaths per min; heart rate >100 beats per min; systolic blood pressure <90 mm Hg). 
However, in this study, participants critically ill who require mechanical ventilation or 
admission to an intensive care unit prior to the initiation of study treatment are excluded.
This study is being conducted to determine whether oral hydroxychloroquine can safely and 
effectively be used to mitigate, treat, or cure COVID-19 or limit the harm of the COVID-19 
pandemic in accordance with the Secretary of the Department of Health and Human Services’ 
(HHS’s) Declaration under the Public Readiness and Emergency Preparedness Act for medical 
countermeasures against COVID-19 (COVID-19 Declaration) effective February 4, 2020. In 
addition, the purpose of this study is to test whether oral hydroxycholorquine drug product, 
either as a monotherapy or in combination with azithromycin, results in clinical benefit in 
patients hospitalized with COVID-19. This study is authorized to proceed under an approved 
investigational new drug application (IND) in accordance with the public health and medical 
response of FDA, an Authority Having Jurisdiction as described under the PREP Act, to 
prescribe, administer, deliver, distribute or dispense this Covered Countermeasure as defined 
by and following the HHS’s COVID-19 Declaration.

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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary Objective

To demonstrate superiority of 
hydroxychloroquine or 
hydroxychloroquine plus azithromycin  
compared to placebo in achieving clinical 
response by Day 15
Endpoints for primary objective
The percentage of participants who achieve clinical 
response by Day 15 defined as: 

For participants with a pre-morbid oxygen 
requirement:

Discharge (or ready for discharge as 
evidenced by normal body temperature and 
respiratory rate, and stable oxygen 
saturation on ambient air or ≤2L 
supplemental oxygen) OR

Survival without need for mechanical 
ventilation

For participants without a pre-morbid oxygen 
requirement:

Discharge (or ready for discharge); OR

Survival without need for mechanical 
ventilation or oxygen supplementation for 
the last 24 hours
Secondary Objectives
Endpoints for secondary objectives

To demonstrate superiority of 
hydroxychloroquine or 
hydroxychloroquine plus azithromycin  
compared to placebo in achieving viral 
clearance by Day 15

The percentage of participants with negative or 
below LLOQ SARS-COV-2 based on 
polymerase chain reaction (PCR) test by Day
15

To evaluate the time to discharge from 
the hospital in participants receiving 
hydroxychloroquine or 
hydroxychloroquine plus azithromycin
relative to placebo

Time to discharge (or ready for discharge)  

To evaluate the time to return to pre-
morbid supplemental oxygen 
requirement in participants receiving 
hydroxychloroquine or 
hydroxychloroquine plus azithromycin 
relative to placebo
For the subset of patients who require supplemental 
oxygen at the time of randomization:

Time to return to pre-morbid supplemental 
oxygen requirement

To evaluate the time to SARS-CoV-2 
negativity in participants receiving 
hydroxychloroquine or 
hydroxychloroquine plus azithromycin 
relative to placebo

Time to SARS-CoV-2 negativity

To assess safety of participants 
receiving hydroxychloroquine or 
hydroxychloroquine plus azithromycin as 
compared to placebo

Number of participants with adverse events
(AE), serious adverse events (SAE), clinically 
significant changes in laboratory measures, 
ECG and vital signs 

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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Objectives
Endpoints
 
 
 
 
 
2.1
Primary estimand
The primary clinical question of interest is: What is the effect of the hydroxychloroquine and 
hydroxychoroquine plus azithromycin versus placebo on the percentage of participants
achieving clinical response by Day 15 in participants with moderate to severe COVID-19 
disease who are receiving standard of care?
The justification for the primary estimand is that it will capture both the effect of the study 
treatments and the effect of any standard of care treatments, dosed as required that they are 
receiving at the time of randomization, mirroring the conditions in clinical practice. Further 
details can be found in Section 12.
The primary estimand is described by the following attributes:
Population: Adults at least 18 years of age, with SARS-COV-2 confirmed by PCR or rapid test 
≤4 days prior to randomization who are currently hospitalized or who require hospitalization
for COVID-19 disease. Further details about the population are provided in Section 5.
Endpoint: Clinical response by Day 15 defined for participants with a pre-morbid oxygen 
requirement as: Discharge (or ready for discharge as evidenced by normal body temperature 
and respiratory rate, and stable oxygen saturation on ambient air or ≤2L supplemental oxygen) 
OR survival without need for mechanical ventilation.
Clinical response by Day 15 defined for participants without a pre-morbid oxygen requirement 
as: Discharge (or ready for discharge) OR survival without need for mechanical ventilation or 
oxygen supplementation for the last 24 hours.
Treatment of interest: The randomized treatment (hydroxychloroquine or hydroxychloroquine
plus azithromycin or placebo) added to concomitant standard of care treatments used to treat 
moderate-severe COVID-19 disease. Further details about the investigational treatment and 
control treatment are provided in Section 6.
Based on the definition of the endpoint there are no intercurrent events which need to be 
accounted for outside of the treatment of interest attribute of the estimand. 
The summary measure: Odds-ratio comparing experimental treatments of interest to placebo
2.2
Secondary estimands
The clinical question of interest is: What is the effect of the hydroxychloroquine and 
hydroxychloroquine plus azithromycin versus placebo on the presence or absence of virus 
which will be represented by the percentage of participants achieving viral clearance by Day 15
in participants with moderate to severe COVID-19 disease who are receiving standard of care?

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The justification for the secondary estimand is that it will capture both the effect of the study 
treatments and the effect of any standard of care treatments, dosed as required at the time of 
randomization, mirroring the conditions in clinical practice. Further details can be found in 
Section 12.
The secondary estimand is described by the following attributes:
Population: Adults at least 18 years of age, with SARS-COV-2 confirmed by PCR or rapid test 
≤4 days prior to randomization who are currently hospitalized or who require hospitalization 
for COVID-19 disease. Further details about the population are provided in Section 5.
Endpoint: The percentage of participants with negative or below LLOQ - SARS-COV-2 based 
on PCR by Day 15
Treatment of interest: the randomized treatment (hydroxychloroquine or hydroxychloroquine
plus azithromycin or placebo) added to concomitant standard of care, used to treat moderate-
severe COVID-19 disease. Further details about the investigational treatment and control 
treatment are provided in Section 6.
Handling of remaining intercurrent events will be considered as treatment failures (Composite 
strategy):

Death
The summary measure: Odds-ratio comparing experimental treatments of interest to placebo
3
Study design
This study is a multi-center, randomized, blinded, three-arm parallel-group, placebo-controlled 
trial to evaluate the safety and efficacy of hydroxychloroquine monotherapy or in combination 
with azithromycin in participants with moderate and severe COVID-19 disease.
The study will include: Screening period of up to four days to obtain the informed consent and 
assess participant’s eligibility; Treatment period of 10 days; and an observation period of an 
additional 30 days (until Day 40) with Day 40 being the end of study visit. All participants are 
expected to be treated with available standard of care (SoC) therapy for COVID-19 disease 
throughout the study. Approximately 444 participants will be randomized into either of three 
arms with 1:1:1 ratio. The clinical visit schedule and the details of procedures to be performed 
at each visit are listed in Table 8-1.

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Figure 3-1
Study design
All participants will be treated with the best available standard of care for COVID-19 disease throughout the study
1 The total treatment duration of hydroxychloroquine will be 10 days. The total treatment duration of azithromycin will be 
5 days. In case a participant is discharged before the end of treatment period (Day 10) he/she may continue study 
medication at home until Day 10 if QTcF ≤ 480 ms at the time of discharge based on the local ECG data. Otherwise, 
treatment will be discontinued at the time of discharge (before Day 10).
2 The loading dose of AZI/matching placebo (Day 1) should be taken 4 hours after loading dose of HCQ/matching 
placebo
3 After HCQ/matching placebo loading dose on Day 1, the following HCQ/matching placebo doses as a maintenance 
therapy should be initiated within approximately 8 hours (not to exceed 12 hours).
HCQ: hydroxychloroquine, AZI: azithromycin, o.d.: once a day, t.i.d: three times a day
4
Rationale
4.1
Rationale for study design
The study is designed as a prospective randomized, double blind, placebo-controlled trial in 
order to reduce the likelihood of imbalances in the study population, and bias in the evaluation
of clinical response. The three-arm parallel design allows contemporaneous evaluations of three 
treatment regimens, and mitigates confounders related to the rapidly changing landscape of 
therapies and outcomes across various healthcare systems.
Inclusion of hospitalized patients allows for careful assessment of clinical response and 
monitoring of safety. The study includes a population who is moderately to severely ill, and at 
risk for developing complications of COVID-19 disease, in order to demonstrate the potential 
benefit in the clinical response and impact on the progression of disease. The study excludes 
patients who are critically ill at screening to reduce efficacy and safety confounders and as there 
is no evidence at this stage to assume the study treatment would be beneficial at this stage of 
the disease.

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4.1.1
Rationale for choice of background therapy
All participants will receive best standard of care as background therapy. Although there are no 
specific therapies approved for the treatment of COVID-19, participants with moderate and 
severe disease are expected to receive supportive care as dictated by local treatment guidelines. 
Depending on the disease severity, supportive care may include the use of oxygen 
supplementation, antibiotic prophylaxis, and other concomitant medications for comorbidities, 
ventilator support, and intensive care management in the event of disease progression.
4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Rationale for hydroxychloroquine
Hydroxychloroquine is a medication approved by the US Food and Drug Administration for a 
variety of indications, including treatment of malaria, rheumatoid arthritis, and systemic lupus
erythematosus (Schrezenmeier and Dorner 2020). Hydroxychloroquine and chloroquine are 
alkalinizing lysosomatropic drugs that accumulate in lysosomes (Vincent et al 2005 and 
Ponticelli and Moroni 2017) and block viral infection by increasing endosomal pH, which is 
required for viral participles to fuse with a cell. The effect of hydroxychloroquine on the 
replication of SARS-CoV-2 and similar coronaviruses has been recently described in the 
laboratory (Yao et al 2020). In addition to its antiviral properties, hydroxychloroquine treatment 
may inhibit several pathways relevant to COVID-19 pathology, including inhibition of viral 
nucleic acid-mediated activation of various innate immune pathways (Toll-like receptors 7, 8 
and 9) (Schrezenmeier and Dorner 2020). Modulation of these pathways would result in 
inhibition of viral nucleic acid-induced cytokine production, reducing levels of interleukin (IL)-
6, IL-1b, type 1 interferons (IFNs) and tumor necrosis factor (TNF), and potentially reducing 
the clinical sequelae of excessive immune activation, including cytokine release syndrome 
(CRS) (Mehta et al 2020). Furthermore, hydroxychloroquine would be expected to block other 
immune effector functions dependent on lysosomal-endosomal function, including antigen 
presentation, which in the context of excessive tissue inflammation, may also reduce tissue 
damage mediated by T cells. Recent small clinical studies and clinical case series in COVID-
19-infected patients have suggested that hydroxychloroquine and chloroquine are superior to 
control treatments in inhibiting the exacerbation of pneumonia, shortening the disease, 
improving lung imaging findings and viral clearance. (Gao et al 2020 and Gautret et al 2020). 
Taken together these data suggest that hydroxychloroquine may be beneficial in the treatment 
of patients with moderate to severe COVID-19 disease (Colson et al 2020).
4.2.1
Rationale for combination
A recent publication (Gautret et al 2020) suggested that hydroxychloroquine treatment at doses 
of 600 mg daily (200 mg t.i.d) (with or without azithromycin) resulted in virologic clearance in 
70% of treated COVID-19 patients compared with 12.5% of controls by Day 6. The results 
were most pronounced in the subjects that receive azithromycin in combination with HCQ. The 
mechanisms by which azithromycin may have contributed to enhanced viral clearance in this 
small study are unknown (Lover 2020).
Macrolide antibiotics accumulate in polymorphonuclear leukocytes and macrophages reaching 
high intracellular concentrations (Bosner et al 2005). A number of in vivo and in vitro studies, 

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as well as clinical findings, confirm macrophages as one of the target cells of macrolide 
antibiotics. Inhibitory effects of azithromycin on LPS-induced lung neutrophilia can be 
explained, at least partially, by inhibition of GM-CSF and IL-1β production by macrophages. 
Further, their ability to inhibit IL-6 and PGE2 production correlates with macrolide 
accumulation in cells, as well as with their binding to phospholipids (Banjanac et al 2012). In 
clinical studies, in addition to its antibacterial properties, azithromycin immunomodulatory 
effects have been proven beneficial in a variety of inflammatory acute and chronic lung diseases 
such as, community acquired pneumonia, cystic fibrosis, bronchiectasis, COPD, and others; and 
may be beneficial in patients with COVID-19 disease (Amsden 2005). Azithromycin will be 
dosed in accordance to the label for a total duration of 5 days. 
4.2.2
Rationale for treatment duration 
A short-term duration of 10 days is proposed. Modeling and simulation described in Section
4.2.3 suggest adequate concentrations in the lung for > 28 days. Clinical data suggest that the 
maximum anti-viral effect may be achieved the first 5-6 days of therapy (Gautret et al 2020), 
while anti-inflammatory effects may be beneficial over longer periods. When used for short 
periods, hydroxychloroquine is generally well tolerated, with the most common side effects 
including nausea, vomiting, diarrhea, rash, and headache (Ponticelli and Moroni 2017). Further, 
in double-blind trials in patients with rheumatoid arthritis, 6 weeks of treatment with HCQ at 
400 mg/day (n =71), 800 mg/day (n= 71), and 1,200 mg/day (n= 66), followed by 18 weeks of 
open label HCQ treatment at 400 mg/day, toxicity was not dose related and was relatively mild. 
In particular, 800 mg/day and 1,200 mg/day HCQ dosages were not associated with more ocular 
toxicity compared with the 400 mg/day (Furst et al 1999). The protocol exclusion criteria will 
be in place based on the known safety profile of HCQ, and the sponsor will closely monitor 
safety. 
4.2.3
Rationale for dose regimen
The proposed hydroxychloroquine (HCQ) regimen is 600 mg loading dose followed by 200 mg 
three times daily for the first 10 days of the study. The total treatment duration of 
hydroxychloroquine will be a maximum of 10 days. The approach includes a loading dose on 
Day 1 to reach the target concentration in the lung tissue within the first 5 hours. The proposed 
regimen is expected to enable optimal inhibition of both viral and inflammatory pathways by 
HCQ. Three times a daily regimen is selected to mitigate Cmax related to cardiac safety risk.
Recently published literature describes the effect of HCQ on the replication of SARS-CoV-2 
and similar coronaviruses, in vitro. Full dose response curves of the antiviral activity of HCQ 
in an in vitro assay using Vero E6 kidney epithelial cells infected with SARS-CoV-2 have been 
published (Yao et al 2020). Depending on the time point (24 or 48 hours post infection) the 
EC50 values range from 0.72 – 6.25 µM and the EC90 values from 1.5 – 15 µM.  Furthermore, 
HCQ EC50 values of 8 µM have been reported in similar in vitro assays for other human-tropic 
coronaviruses (Dyall et al 2014). Based on the totality of in vitro data, we anticipate a 
significant effect of HCQ on SARS-CoV-2 viral load in patients at an HCQ target 
concentrations of greater than 15 µM (5040 ng/mL) of free base in lung tissue.
The HCQ PK model was constructed based on published clinical data (Tett et al 1988 and Tett 
et al 1989). The combined clinical data was best described by a 3-compartment model with 

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absorption into and linear elimination from the central compartment, and distribution into 
peripheral compartments. The human PK parameters from the 3-compartment model are 
summarized in Table 4-1. The simulations took into consideration that an oral dosage form of 
200 mg hydroxychloroquine sulfate contains 155 mg hydroxychloroquine. The large volume of 
distribution indicates that HCQ is highly bound to tissues. To simulate the concentration of 
HCQ in the lung we assume direct and rapid partitioning from the central compartment with a 
partition coefficient of Kp = 50.6 (Wei et al 1995). 
The simulated concentration time curves for HCQ in the lung and blood for either 600 mg o.d.
HCQ sulfate (light gray, regimen),or a loading dose of 600 mg followed by 200mg t.i.d. (dark 
red) are presented in Figure 4-1. Additionally, co-administration of azithromycin is not 
expected to have an effect on HCQ concentrations (Yeates et al 1996 and Mattila et al 1994).
The dosing regimen of 600 mg loading dose followed by 200 mg t.i.d. hydroxychloroquine 
sulfate enables rapid attainment and maintenance of the target lung concentration of 15 µM. 
Table 4-2 summarizes the Cmax, Cmin and AUC values for HCQ in blood.  

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Figure 4-1
Predicted concentrations of hydroxychloroquine in the lung and blood 
compartments
Figure 4-1: A regimen consisting of a 600 mg HCQ sulfate loading dose on Day 1 followed by 200 mg t.i.d. (red) 
is compared against a 600mg o.d. regimen (grey). While the y-axis represents concentrations of HCQ (free base), 
doses are expressed as HCQ sulfate tablets. The horizontal line denotes a target threshold of 15 μM (5040 
ng/mL). a) Predicted PK profile for day 1 b) Predicted PK profile from day 1 to day 10  C) Predicted PK profile 
followed by a washout period to reach the threshold of EC90.
Table 4-1
Human PK parameters from 3-compartment model describing human 
total blood hydroxychloroquine
Parameter
Units
Estimate
95% Confidence Interval
V1
L
193.6
[161.1,228.7]
V2
L
3519.1
[3024.6,4150.2]
CL
L/h
5.67
[5.37,5.99]
Q12
L/h
2.42
[1.95,3.05]
ka
1/h
0.156
[0.125, 0.199]
F
dimensionless
0.79 (fixed)
V3
L
2274.5
[2021.1,2546.1]
Q13
L/h
47.5
[40.9,54.9]

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Table 4-2
Predicted  human exposure for 600 mg loading dose and 200 mg t.i.d. 
maintenance dose of hydroxychloroquine sulfate
Mean
95% Confidence Interval
Cmax (ng/mL)
Day 1, 0-8hr
511.8
[433.2, 600.3]
Day 1
525.2
[460.9, 600.3]
Day 10
1128.6
[1059.4, 1197.8]
Cmin (ng/mL)
Day 1
382.15
[342.4, 417.8]
Day 10
1012.5
[944.4, 1087.3]
AUC (ng/mL*hr)
Day 1
10603
[9484, 11696]
Day 10
25690
[24080, 27413]
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
All participants will receive best standard of care for the treatment of COVID-19 disease and 
therefore placebo is only used to control the blind for the arms.
4.4
Purpose and timing of interim analyses/design adaptations
No formal interim analysis is planned for this trial.  The primary endpoint analysis will be 
performed after all participants have completed Day 15 or discontinued prior to Day 15.  A final 
analysis will be performed after all participants have completed their last follow-up visit at Day 
40 (or discontinued prior to Day 40).
4.5
Risks and benefits
Appropriate eligibility criteria and clinical safety monitoring criteria are included in this 
protocol. The risk to participants in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, as well as close clinical monitoring. Refer to the
Hydroxychloroquine USPI (2018)/applicable labelling information.
There are currently no drugs approved for the treatment of patients with COVID-19, and there 
is a high medical need to control the global pandemic. Given the results of studies outlined 
above, HCQ as monotherapy or in combination with azithromycin, along with standard of care 
(SoC) treatment, offers a prospect of benefit in patients with moderate to severe COVID-19 
disease more effectively than current SoC alone. Safety data have previously been generated on 
the use of HCQ and azithromycin in other indications. Therefore, a placebo-controlled study in 
combination with SoC is justified to address the high unmet need in the target patient population.
The safety profile of HCQ is described in the USPI/ applicable labelling information and also 
re-iterated in the FDA HCQ fact sheet for health care providers Emergency Use Authorization 
(EUA) dated 3/28/2020. Long term use has been associated with ocular toxicity and caution in 
administration to patients with hepatic/renal disease are well known. Investigators should also 
be aware that other precautions should be taken as per label (e.g. participants with glucose -6-
phophate dehydrogenase (G-6-PD) deficiency) and anticipate any potential drug interactions.
For azithromycin, equal diligence should be in place for participants with impaired liver 
function (primary elimination via liver) and impaired renal function. There are clinical safety 
hepatic and renal monitoring guidance in place and should be easily monitored in the hospital

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setting. Participants should also be closely monitored for signs and symptoms of hypoglycemia, 
particularly those who are diabetic and taking anti-diabetic medications. More relevant to the 
short term administration of HCQ and azithromycin is drug-induced QT interval prolongation 
and potential pro-arrhythmic effects. To that end, in addition to relevant cardiac exclusion 
criteria, participants will also need to follow cardiac safety monitoring, with clear guidance on 
when to discontinue study medications with regard to QTcF changes. In the setting of active 
COVID-19 disease in the study population, the benefits of short-term treatment in a hospital 
setting should, in principle outweigh the known potential risks.
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the participant will 
not reliably comply, they should not be entered or continue in the study.
5
Study Population
The study population will consist of approximately 444 male and female adult participants with 
moderate to severe COVID-19 disease receiving standard of care to be randomized into 
hydroxychloroquine, hydroxychloroquine plus azithromycin, or placebo in 1:1:1 ratio (148
participants / arm).
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria prior to 
randomization:
1. Informed consent must be obtained prior to participation in the study
2. Adult patient ≥18 years old
3. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by 
polymerase chain reaction (PCR) test or rapid test from respiratory tract specimen (e.g.
nasopharyngeal swab) within 4 days prior to randomization
4. Currently hospitalized or requiring hospitalization due to COVID-19 disease
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Use of other investigational drugs within 5 half-lives or 30 days of enrollment whichever 
is longer
2. Participation in any other clinical trial of an experimental treatment for COVID-19 within 
5 half-lives or 30 days of enrollment whichever is longer
3. Expectation of concurrent treatment with other agents with actual or potential direct acting 
antiviral activity against SARS-CoV-2 during study drug dosing period, including but not 
limited to oseltamivir and protease inhibitors
4. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes.

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5. Requires, in the judgement of the investigator, admission to the intensive care unit (ICU)
or mechanical ventilatory support (invasive or non-invasive) prior to the initiation of study 
drug
(There might be a participant who cannot be admitted to the ICU, even if the participant’s 
condition is severe enough, due to administrative reasons under the current circumstances. 
This case is also considered under admission to the ICU judged by the investigator)
6. Evidence of cytokine storm syndrome or multi-organ system failure
7. Confirmed co-infection with influenza
8. Creatinine clearance < 45 mL/min or requiring acute renal replacement therapy
9. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
participants participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV

History of familial long QT syndrome or known family history of Torsades de Pointe

QTcF > 480 msec (at screening and/or Day 1 at pre-dose) based on the local ECG 
data

Uncorrected electrolyte abnormalities, such as hypokalemia, hypomagnesemia and 
hypocalcemia

Use of agents known to prolong the QT interval within 5 half-lives before screening
10. Any other condition (e.g. known liver disease) which, in the opinion of the investigator, 
would put the safety of the participant at risk, impede compliance or hinder completion of 
the study
11. Pregnant or nursing (lactating) women
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
study treatment. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant

Barrier methods of contraception: Condom or Occlusive cap (e.g. diaphragm or 
cervical/vault caps).

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 

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contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS).
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF.
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
The study treatment consists of:

Investigational drug

Hydroxychloroquine (HCQ): doses of 200 mg or placebo

Azithromycin (AZI): dose of 250 mg or placebo
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
HCQ 200 mg
Tablet
Oral use
Open label
Sponsor global
HCQ Placebo
Tablet
Oral use
Open label
Sponsor global
AZI 250 mg
Tablet
Oral use
Open label
Sponsor global
AZI Placebo
Tablet
Oral use
Open label
Sponsor global
6.1.2
Treatment arms/group
Participants will be assigned at Day 1 to one of the following 3 treatment arms in a ratio of
1:1:1. The treatment arms include:
Arm 1: hydroxychloroquine (HCQ) plus azithromycin (AZI) placebo

HCQ: 600mg o.d. as loading dose (Day 1) followed by 200 mg t.i.d. The time 
between the 600mg loading dose and first 200mg dose should be 8-hours (not to 
exceed 12 hours)

AZI placebo o.d. The loading dose of AZI placebo (Day 1) should be taken 4 hours 
after loading dose of HCQ 

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Arm 2: hydroxychloroquine (HCQ) plus azithromycin (AZI)

HCQ: 600 mg o.d. as a loading dose (Day 1) followed by 200 mg t.i.d.. The time 
between the 600mg loading dose and first 200mg dose should be 8-hours (not to 
exceed 12 hours)

AZI: 500 mg as a loading dose (Day 1) followed by 250 mg o.d. Day 2 – Day 5. The 
500mg loading dose of AZI (Day 1) should be taken 4 hours after loading dose of 
HCQ 
Arm 3: hydroxychloroquine (HCQ) placebo plus azithromycin (AZI) placebo

HCQ placebo o.d. (Day 1) followed by HCQ placebo t.i.d. The time between the first 
and the second dose should be 8 hours (not to exceed 12 hours) to match other 
treatment arms. 

AZI placebo o.d. The loading dose of AZI placebo (Day 1) should be taken 4 hours 
after loading dose of HCQ placebo
6.1.3
Treatment duration
The total treatment duration of hydroxychloroquine is 10 days. The approach to include a 
loading dose on Day 1 is preferred in order to rapidly reach higher target tissue drug 
concentrations. The total treatment duration of azithromycin will be 5 days.
In case a participant is discharged prior to Day 10, they may complete study treatment as 
planned, at home, until Day 10 if QTcF ≤ 480 ms at the time of discharge based on the local 
ECG data. Otherwise, treatment will be discontinued at the time of discharge.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All relevant medications, procedures, and significant non-drug therapies (e.g. blood 
transfusions) administered after the participant was enrolled into the study must be recorded on 
the appropriate Case Report Forms (CRFs).
6.2.1.1
Standard of care for COVID-19 disease
All participants will receive best standard of care as background therapy. Although there are no 
specific therapies approved for the treatment of COVID-19, participants with moderate and 
severe disease are expected to receive supportive care as dictated by local treatment guidelines. 
Depending on the disease severity, supportive care may include the use of oxygen 
supplementation, antibiotic prophylaxis and other concomitant medications for comorbidities, 
ventilator support, and intensive care management for disease progression.
The study permits any of standard of care for COVID-19 disease except the medications listed 
in the prohibited medication in Table 6-2.
6.2.2
Rescue medication
Rescue therapy may be used at the discretion of the Investigator if there is evidence of clinical 
deterioration of COVID-19 disease and intervention with a rescue therapy is required beyond 
the standard of care measures.

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6.2.3
Prohibited medication
Table 6-2
Prohibited medication
Medication
Prohibition period
Any drug known to prolong QTc interval
(See https://crediblemeds.org/ for details as 
well as protocol supplementary guidance)
Within 5 half-lives before screening and throughout the 
study
Antiviral agents
e.g. remdesivir, oseltamivir, interferon, 
lopinavir/ ritonavir or other protease 
inhibitors, chloroquine, nitazoxanide, 
convalescent COVID19 serum or anti-
SARS-COV-2 immunoglobulins
Up to Day 15 or until discharge whichever earlier
Except in the case these are needed to be used as 
rescue therapy (see Section 6.2.2)
Newly approved COVID-19 therapies (if 
any available since issuing the protocol)
Within 5 half-lives or 30 days of screening whichever 
is longer, and up to Day 15 or until discharge 
whichever earlier.
Except in the case these are needed to be used as 
rescue therapy (see Section 6.2.2)
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
Participant numbers are assigned when the site creates the first entry for the participant in the 
CRF, therefore CRF entry must be created prior to contacting the Interactive Response 
Technology system.
6.3.2
Treatment assignment, randomization
At Day 1, all eligible participants will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The unblinded pharmacist will contact the IRT after confirmation 
from the investigator or his/her delegate that the participant fulfills all the inclusion/exclusion 
criteria. The IRT will assign a randomization number to the participant, which will be used to 
link the participant to a treatment arm and the unblinded pharmacist will be provided with the 
treatment arm assigned to the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 

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that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
The unblinded pharmacist MUST NOT communicate the information of treatment arm to 
anyone who is involved to the study (site personnel including the investigator, participant, 
sponsor). If accidentally communicated to anyone, Novartis local monitor should be notified 
and the study treatment should be discontinued.
6.4
Treatment blinding
The study will be double-blind as both Investigator and participants will be blinded to the study 
medication from the time of randomization until the final database is locked after the last 
follow-up visit at Day 40.
Open label supply of investigational treatments (HCQ and AZI) and similar appearance placebo 
will be provided at site to the unblinded site pharmacist.
Unblinding will occur in the case of participant emergencies and will only be undertaken by the 
investigator (See Section 6.5.2). The unblinded pharmacist is not involved in emergency 
unblinding.
Designated Novartis clinical trial team members will be unblinded following data extraction for 
the primary endpoint analysis (Day 15) to perform the analysis. 
Other Novartis team members, Investigators and participants will remain blinded to individual 
treatment allocation until final database lock. In addition, for the purposes of the Data 
Monitoring Committee (DMC) analysis, there will be unblinded Independent Statisticians and 
Programmers in charge of DMC reporting activities.
6.5
Additional treatment guidance
6.5.1
Treatment compliance
The unblinded pharmacist must record all study treatment dispensed in the Drug Accountability 
Log, which must not be shared with blinded members of the site staff.
The site staff must record the date and time of dosing for each medication in the source 
documents for the participant.
In the case that a participant is discharged prior to Day 10, they should be instructed on the 
dosing requirements and contacted at Day 10 to confirm compliance. The participant must also 
be instructed to contact he investigator if he/she is unable for any reason to take the study 
treatment as prescribed.
Compliance will be assessed by the investigator and/or study personnel at each visit using the 
information provided by the participant. This information should be captured in the source 
documents.

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6.5.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Blinding codes may also be broken after a participant discontinues treatment 
due to disease progression if deemed essential to allow the investigator to select the participant’s 
next treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study participant who presents with an emergency condition. Emergency treatment 
code breaks are performed using the IRT. When the investigator contacts the system to break a 
treatment code for a participant, he/she must provide the requested participant identifying 
information and confirm the necessity to break the treatment code for the participant. The 
investigator will then receive details of the investigational drug treatment for the specified 
participant and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

name 

participant number
In addition, oral and written information must be provided to the participant on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
6.6
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
As per the treatment assigned to the participant, the unblinded pharmacist will select the study 
treatment to be dispensed to the participant. 
6.6.1
Handling of study treatment and additional treatment
6.6.1.1
Handling of study treatment
In order to ensure treatment blinding study treatment must be received, stored in a secure 
location and dispensed only by an unblinded pharmacist. All study treatment must be stored
according to the instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.

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An accurate record of the shipment and dispensing of study treatment should be maintained in 
a drug accountability log. Monitoring of drug accountability will be performed by monitors 
during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drugs can be 
found in the USPI/applicable labelling information. This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drugs that is 
identified between labelling updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant.
The following informed consents are included in this study:

Main study consent, which also includes:

A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study

As applicable, Pregnancy Outcomes Reporting Consent for female subjects or the female 
partners of any male subjects who took study treatment
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.

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Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation.

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Table 8-1
Assessment schedule
Period Screening
Treatment
Post treatment 
Visit Name Screening
Day 1
Day 2
Day 4
Day 6
Day 8
Day 10/ 
early 
discharge
Day 15 / early 
withdrawal 
Primary Endpoint
End of 
study
follow up
Unscheduled1
(report 
assessments as 
applicable) 
Days
-3 to 0
1
2
4
6
8
10
15
40
-
Informed consent
X
Inclusion / Exclusion criteria
X
X
Demography
X
Medical history/current medical conditions
X
Chest imaging 
X3
X3
Randomization
X
Drug dispensation and administration
X
Pregnancy test (serum and urine dipstick)
X
Physical Examination, vital signs and body 
measurements2
X
X
X
X
X
X
X
X
SARS-COV-2 test
X4
X
X
X
X
Electrocardiogram (ECG)
X
X5
X
X
X6
X6
X
Laboratory assessments (hematology, 
chemistry, urinalysis, 
)7
X
X
X
X3
Biomarker plasma and serum
X
X
X
Prior and concomitant medications
X 
Adverse Events
X
Study completion information
X
X Assessment to be recorded in the clinical database or received electronically from a vendor, 1 All assessments for unscheduled visits are optional, 2Height and weight 
collected at screening only, 3 If available record findings, 4 If results of a previously performed test within 4 days prior to planned randomization are available this does not 
need to be repeated for screening 5 pre-dose and 4 hours post dose, 6 If required in the opinion of the Investigator. 7Hematology: Hct, Hgb, PLT, RBC, WBC, differential 
WBC count; Chemistry: ALP, ALT, AST, Ca, Mg, K, creatinine, direct and total bilirubin, BUN, glucose, troponin (I or C), CPK, 
 

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8.1
Screening
Screening
The screening period will be a maximum of 4 days, and is used to check the participant’s
eligibility after obtaining informed consent and prior to the randomization on Day 1. The 
assessments required at screening are summarized in Table 8-1. If all eligibility criteria are 
confirmed screening and randomization may occur on the same day.
8.1.1
Information to be collected on screening failures
Participants who consented and are subsequently found to be ineligible prior to randomization 
will be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate Case Report Form. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a serious adverse event during the screening phase (see SAE section for 
reporting details). If the participant fails to be randomized, the IRT must be notified within 2 
days of the screen fail that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
All baseline assessments must be performed prior to first study treatment administration. These 
may be in the screening period (e.g. demographics) or at the randomization visit, depending on 
the assessment.
8.2.1
SARS-COV-2 testing
Respiratory tract specimen (e.g. nasopharyngeal swab, mid-nasal swab) will be taken for SARS-
COV-2 PCR or rapid test and analyzed locally whether negative (or below LLOQ) or not to 
determine eligibility. If results of a previously performed test within 4 days prior to planned 
randomization date are available this does not need to be repeated for screening.
8.2.2
Demographic information
Demographic data to be collected at screening on all participants include: year of birth or age, 
gender, race, ethnicity and child-bearing potential (for females only).
Any relevant medical history including date of onset of COVID-19 disease symptoms, date of 
diagnosis of COVID-19 disease protocol solicited medical history, and/or current medical 
conditions before obtaining informed consent will be recorded in the Medical History CRF. 
Significant findings that are observed after the participant has provided informed consent and 
that meet the definition of an AE must also be recorded in the AE CRF. Whenever possible, 
diagnoses and not symptoms will be recorded.

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Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.2.3
Prior and concomitant medications
Relevant prior and concomitant medications will be captured at the screening visit, and updated 
at the baseline visit. Any changes to the ongoing medications or any new concomitant 
medications will be recorded in CRF on an ongoing basis throughout study participation.
 
 
8.2.5
Other baseline characteristics
Baseline characteristic data to be collected for all participants listed below:

ECG, vital signs, height and body weight


date and matrix (nasopharyngeal, oropharyngeal, other) of SARS-COV-2 test

physical examination (to be recorded in source documents only)

chest imaging (date and method of assessment – x-ray or CT scan, normal or abnormal –
any clinically relevant findings to be reported in medical history)

Any other testing required for inclusion/exclusion criteria
8.3
Efficacy
8.3.1
COVID-19 Participant status
The following details on the participants’ status will be collected in the at Baseline and hospital 
discharge at a minimum, in addition any change in status must be reported in the CRF:

Hospitalization (including dates of admission and discharge* or ready for discharge)

ICU stay (including dates of admission** and discharge***)

Pre-morbid supplemental oxygen requirements and its volume if yes (start and stop dates, 
volume: L)

Mechanical ventilation requirements (start and stop dates)

Participant survival status (i.e. death)
* If a participant is unable to be discharged due to administrative reasons, then the date that the 
participant, in the opinion of the investigator, is ready to be discharged (i.e. ready for discharge 
as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on 
ambient air or ≤2L supplemental oxygen) should be reported in the hospitalization status for 
date of discharge.

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** In the case that a participant cannot be admitted to the ICU, even if the participant’s condition 
is severe enough in the opinion of the investigator (e.g. due to administrative reasons under the 
current circumstances), this is also considered under admission and date of ICU admission 
should be reported
***If a participant is unable to be discharged from ICU due to administrative reasons, then the 
date that the participant, in the opinion of the investigator, is ready to be discharged should be 
reported in the ICU status for date of discharge.
 
 
 
 
8.3.2
SARS-COV-2 testing
At each SARS-COV-2 testing time point post screening detailed in Table 8-1 a respiratory tract 
specimen (nasopharyngeal swab) will be taken for SARS-COV-2 PCR testing. This sample will 
be analyzed at a specialist virology lab to determine whether negative (or below LLOQ) or not.
An additional sample may be collected and sent to the central lab for future quantitative analysis.
Additional details on sample collection and shipping are provided in the laboratory manual.
In order to maintain consistency, every effort should be made to use the same sample site (i.e. 
nostril) for all post baseline assessments in individual participants.
8.3.3
Appropriateness of efficacy assessments
Efficacy assessments are assessments of standard supportive care required to treat COVID-19 
disease. Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events (with the exception of death due 
to COVID-19 disease progression). These data will be captured as efficacy assessment data 
only.

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8.4
Safety and tolerability
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
8.4.1
Physical examination 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being obtained must 
be included in the Relevant Medical History/Current Medical Conditions CRF. Significant 
findings made after informed consent is given which meet the definition of an Adverse Event 
must be recorded on the Adverse Event screen of the participants CRF.
8.4.2
Vital signs and body measurements
Systolic and diastolic blood pressure (mmHg), pulse rate (bpm), will be recorded. Peripheral 
oxygen saturation (SpO2, %) should be also measured at the same time as vital signs, height in 
centimeters (cm) will be reported at screening visit only.  
Weight in pounds (lbs) or kilograms (kg), and body temperature (including method of collection) 
in Centigrade (°C) or Fahrenheit (°F) will be recorded.
8.4.3
Laboratory evaluations
Laboratory test will be conducted as per Table 8-1 by local lab. Details on the parameters are
listed below in Table 8-2.
Clinically significant abnormal results for hematology, chemistry and urinalysis will be 
reported in the laboratory results CRF and as an AE, otherwise all these results will be kept in 
the source documents and will not need to be recorded in CRF. 
 
Table 8-2
Laboratory parameters (local lab)
Test Category
Test Name
Hematology
Hematocrit, hemoglobin, platelets, red blood cells, white blood cells
(WBC), absolute differential WBC count (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils, bands, other)
Chemistry
Alkaline phosphatase, alanine transaminase (ALT), aspartate 
aminotransferase (AST), calcium, magnesium, potassium, creatinine, 
direct bilirubin, total bilirubin, blood urea nitrogen (BUN),  glucose, 
troponin (I or C as available), CPK
Urinalysis (dipstick)
Specific gravity, pH, protein, glucose and blood
Pregnancy Test
Serum / Urine pregnancy test
8.4.4
Electrocardiogram (ECG)
ECGs (preferably 12-lead) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The preferred sequence of cardiovascular data collection during study 

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visits is ECG collection first, followed by vital signs. The Fridericia QT correction formula 
(QTcF) should be used for clinical decisions.
On Day 1 an ECG must be performed pre-dose and at 4 hours post dose.
Single ECGs (preferably 12-lead) will be collected using the sites own ECG machines and key 
parameters and the original trace available within the source data. A copy of the local tracing 
will be sent to a central ECG reader for additional safety evaluations. Any identifier details must 
be redacted e.g. subject initials, date of birth prior to sending to the central reader.
If participants are monitored by continuous telemetry, an assessment should be reported in the 
CRF for one time point on days when ECG monitoring is required and a copy of ECG tracing
for this time point sent to the central ECG reader. In case of clinically significant findings the 
unscheduled visit can be used to report findings and an adverse event form completed if 
applicable.
For any ECGs with potential participant safety concerns, two additional ECGs (preferably 12-
lead) must be performed to confirm the safety finding. A local monitoring or review process 
should be in place for clinically significant ECG findings throughout the study. Clinically 
significant abnormalities must be recorded on the CRF as either medical history/current medical 
conditions or adverse events as appropriate.
Given the known QT prolonging effect and treatment regimen of both HCQ and AZI, measure 
ECG until Day 4, then if required by the investigator from Day 6.
Please also refer to the cardiac safety monitoring Section 10.2.1 for additional details.
8.4.5
Pregnancy test
All pre-menopausal women who are not surgically sterile will have urine pregnancy testing and 
serum pregnancy test at screening as per Table 8-1.
If the result of urine pregnancy test is positive, the patient must not be randomized and the result 
confirmed by the serum pregnancy test result. If the result of the serum pregnancy test is positive,
the participant must be considered as a screen failure.
A positive pregnancy test during the study requires immediate discontinuation from study drug. 
The participant must be followed to understand the outcome of the pregnancy. Refer to Section
10.1.4 for details on pregnancy reporting.
8.4.6
Appropriateness of safety measurements
The safety assessments selected are appropriate for this protocol, which utilizes a marketed 
compound where the safety profile has been established. The assessments are relevant to the 
critical care setting and will enable determination of therapeutic response in this setting.

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8.5
Additional assessments
8.5.1
Unscheduled assessments
In the case of clinically significant abnormalities, safety concerns required repeat testing or if 
additional assessments need to be performed, information should be reported in the relevant 
CRF page using the Unscheduled visit pages.
8.5.2
Assessments pre and post hospital discharge
In the case that a participant is discharged from hospital during the study, the following 
guidelines must be followed:

If the participant is discharge prior to Day 10, assessments for Day 10/early discharge visit 
should be completed prior to discharge

If the participant continues treatment up to Day 10 at home, guidelines in Section 6.1.3
should be followed. The site must contact the participant to assess compliance, and report 
any dose interruptions and stop dates of treatment, adverse events and relevant 
concomitant medications in the CRF

Day 15 and Day 40 visits may be performed via phone call, an onsite visit is not 
mandated, at a minimum COVID-19 participant status, adverse events and relevant 
concomitant medications, and study completion status (as applicable) must be assessed. 

In the case that the participant is still hospitalized for either or both Day 15 and Day 40 
visits additional assessments requested in Table 8-1 if assessed, as per local practices, may 
be reported in the relevant CRF pages.
8.5.3
Biomarkers
Serum and plasma will be stored for future biomarker analysis and will be covered by the 
secondary data use informed consent provided at time of screening.
Sample(s) will be collected at the time point(s) defined in the Assessment Schedule (Table 8-1)
when possible.
Follow instructions for sample collection, numbering, processing, and shipment provided in the 
laboratory manual.
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. The investigator must discontinue study treatment for a given participant if, he/she 
believes that continuation would negatively impact the participant's well-being.
If, for any reason, one of the study drugs should be stopped prior to day 5, then the both study 
drugs should be discontinued and the reason for discontinuation reported in the CRF.  

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Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section

Any situation in which study participation might result in a safety risk to the participant
including cardiac events (please refer to Section 10.2 and Section 16 for additional safety 
monitoring criteria) 

Following emergency unblinding

Unsatisfactory therapeutic effect

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study
If discontinuation of study treatment occurs, the investigator should record the primary reason 
for the participant’s premature discontinuation.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should be
assessed as per visit schedule in Table 8-1.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort to understand the primary 
reason for the participant’s decision to withdraw his/her consent and record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.

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Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis/Sponsor will continue to retain and use all research results (data) that have already 
been collected for the study evaluation.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the participant should be seen as soon as possible and treated as a prematurely withdrawn 
participant. Adverse events and laboratory findings will be continually reviewed during the 
study. New enrollment and/or dosing for a treatment arm or study overall may be paused in case 
of safety concerns that are suspected to be related to study drug, including:

> 2 participants with Torsade de Pointes or Ventricular Tachycardia associated with
QTcF > 500 msec and QTcF prolongation > 60 msec
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the participant’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g. Each participant will be required to complete the study in its entirety and
thereafter no further study treatment will be made available to them).
All randomized and/or treated participants should have a safety follow-up call conducted 30 
days after last administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3. Documentation of attempts to contact the participant should be recorded in the 
source documentation.
There is no planned post-study-treatment in this study.

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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The severity grade: 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

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
Drug interrupted/withdrawn
6. Its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drugs can be found in the 
USPI/applicable labelling information.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

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
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Package Insert and is thought to be related to 
the study treatment, a CMO & PS Department associate may urgently require further 
information from the investigator for health authority reporting. Novartis /Sponsor may need to 
issue an Investigator Notification (IN) to inform all investigators involved in any study with the 
same study treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day safety follow up period should only be reported to 
Novartis Safety if the investigator suspects a causal relationship to study treatment.

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10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis/Sponsor within 24 hours of learning 
of its occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis/Sponsor Chief 
Medical Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the study treatment
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.

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10.2
Additional Safety Monitoring
10.2.1
Cardiac safety monitoring
In case of QTcF > 500 msec and QTcF prolongation > 60 msec from baseline, please take 
the following steps:

Temporarily interrupt study treatment

Assess the quality of the ECG recording and the QT value and record two additional 
ECG tracings to confirm the values

Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia
and/or hypocalcemia). If abnormal, correct abnormalities before resuming study 
treatment.

Review concomitant medication use for other causes for QT prolongation (refer to 
qtdrugs.org for known QT prolonging drugs) and for drugs with the potential to 
increase the risk of drug exposure of study drugs

Check the dosing schedule and treatment compliance

Increase cardiac monitoring as indicated, (consider continuous telemetry monitoring)
until the QTcF returns to ≤ 480 msec

If QTcF is  ≤ 480 msec prior to the next dose, continue dosing with another ECG 
collected 4 hrs post dose 

If QTcF remains > 480 msec prior to the next dose discontinue study treatment for the 
participant permanently
In case of persistent QTcF > 500 msec and QTcF prolongation > 60 msec from baseline 
and/or documented new onset arrhythmia (e.g. Torsade de Pointes, Ventricular 
Tachycardia) or syncope - discontinue treatment for the participant and request evaluation by 
a cardiologist.
Please refer to Appendix 1 for notable vital signs.
Local practices should be followed to ensure participant safety for Liver and Renal 
monitoring, in addition below are suggested guidelines for safety monitoring.
10.2.2
Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 16-1 in Appendix 2 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, it is suggested that every liver event defined 
in Table 16-1 should be followed up by the investigator or designated personnel at the trial site, 
as summarized below. Additional details on actions required in case of liver events are outlined 
in Table 16-2. Repeat liver chemistry tests (i.e. ALT, AST, TBL, ALP and G-GT) to confirm 
elevation.
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeated laboratory test results must be reported as appropriate.

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
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include based on investigator’s discretion:

serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history 
of concomitant drug use, exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.3
Renal safety monitoring
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period:

Serum creatinine increase ≥ 50% compared to baseline during normal hydration status

Any one of the following:

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR

New onset dipstick proteinuria ≥ 3+, OR

New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma)
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff according to 
the local practice, guidance is summarized in Table 16-4 in Appendix 2.
10.2.4
Data Monitoring Committee
This study will include an internal data monitoring committee (DMC), which will function 
independently of all individuals associated with the conduct of this clinical trial, including the 
site investigators participating in the study. Specific details regarding composition, 
responsibilities, data monitoring and meeting frequency, documentation of DMC reports, 
minutes and recommendations will be described in a separate DMC charter.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 

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Designated investigator staff will enter the data required by the protocol and defined in the 
assessment schedule (Table 8-1) into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs, 
allow modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
This study may also incorporate electronic technology (eSource DDE) to capture source 
documents and source data electronically, consistent with final (CDER 2013) FDA guidance 
regarding electronic source and Regulations related to the maintenance of adequate participant 
case histories (21 CFR 312.62(b)). 
A Novartis representative will review the protocol and data capture requirements (i.e. eSource 
DDE and/or eCRFs) with the investigators and their staff.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures, as well as randomization codes and data 
about all study treatment (s) dispensed to the participant will be tracked using an Interactive 
Response Technology (IRT). The system will be supplied by a vendor, who will also manage 
the database. The data will be sent electronically to Novartis/Sponsor (or a designated CRO) at 
specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis/Sponsor.

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11.3
Site monitoring
Before study initiation, at an initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE and/or 
CRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will check the completeness of participant records, the accuracy of data 
capture / data entry, the adherence to the protocol and to Good Clinical Practice, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor in 
conducting these activities. Continuous monitoring of each site’s data will be performed 
throughout the conduct of the study. Additionally, a central analytics organization may analyze 
data and identify risks and trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. The investigator must maintain source 
documents for each participant in the study, consisting of case and visit notes (hospital or clinic 
medical records) containing demographic and medical information, laboratory data, 
electrocardiograms, and the results of any other tests or assessments. All information on CRFs 
must be traceable to the respective source documents. The investigator must also keep the 
original informed consent form agreed by the participant and/or legal representative (a copy is 
given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require 
verification for the presence of all informed consents, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the participants will be disclosed.
12
Data analysis and statistical methods
The primary analysis time point is Day 15.  The analyses of efficacy and safety described in 
this protocol will occur when all participants in the study have completed their final study visit 
at Day 40.
Unless otherwise specified, descriptive summaries for categorical data will include frequencies 
and percentages, and continuous data will be presented with mean, standard deviation, median, 
minimum, and maximum. For selected parameters, 25th and 75th percentiles may also be 
presented.
Differences, relative ratios (RR) or odds ratios (OR) for the comparisons between the two 
treatment arms will be presented with 2-sided 95% confidence interval (CI). P-values will be 
presented only if a formal hypothesis test is performed.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.

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12.1
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized participants regardless of 
receiving study treatment.
The Full Analysis Set (FAS) comprises all participant to whom study treatment has been 
assigned by randomization
excluding mis-randomized participants. Mis-randomized 
participants are defined as cases where IRT contact is made by the Investigator/qualified site 
staff either prematurely or inappropriately prior to confirmation of the participant’s final 
randomization eligibility and treatment is not administered to the participant. According to the 
intent to treat principle, participants will be analyzed according to the treatment they have been 
assigned to during the randomization procedure.
The Safety Set (SAF) includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned treatment if the participant took at least one dose 
of that treatment or the first treatment received if the randomized/assigned treatment was never 
received.
The analysis of the primary objective and all other efficacy variables will be performed on the 
FAS.  The Safety Set will be used in the analysis of all safety variables.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for all study participants in the FAS and safety 
set. Participant demographic and baseline characteristics will include: age, sex, race, ethnicity, 
height, weight, BMI, oxygen saturation (SpO2), duration of symptom onset to randomization, 
duration from hospital admission to randomization, SARS-COV-2-RNA/viral load PCR test 
result (negative/positive), COVID-19 abnormal chest x-ray at baseline consistent with COVID-
19 (No/Yes), requiring oxygen at randomization (No/Yes), 
 
.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Protocol-solicited medical history will be summarized by treatment group.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in days to hydroxychloroquine, azithromycin, and placebo will be 
summarized by means of descriptive statistics using the safety set.
Concomitant medications and significant non-drug therapies prior to and after the start of the
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system and preferred term, by treatment group.

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12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary analysis for this study will be conducted on the FAS using a treatment policy 
strategy.
12.4.1
Definition of primary estimand(s)
The primary objective of the study is to demonstrate in participants receiving best standard of 
care that the percentage who achieve clinical response with hydroxychloroquine or 
hydroxychloroquine plus azithromycin is superior to placebo by Day 15.
The primary efficacy estimand defined in Section 2.1 incorporates as its endpoint clinical 
response by Day 15 defined for participants with a pre-morbid oxygen requirement as: 
Discharge (or ready to discharge as evidenced by normal body temperature and respiratory rate, 
and stable oxygen saturation on ambient air or ≤2L supplemental oxygen) OR survival without 
need for mechanical ventilation. The clinical response endpoint for participants without a pre-
morbid oxygen requirement is defined as: discharge (or ready for discharge) OR survival 
without need for mechanical ventilation or oxygen supplementation for the last 24 hours.
The components of clinical response will be derived from the disease status CRF that will be 
collected whenever there is a change in disease status (Section 8.3.1). Day 15 is the last study 
day where these criteria can be met. Study participants can meet the clinical response criteria 
prior to Day 15 if the criteria for discharge are met. Handling of missing data are provided in 
Section 12.4.4.
12.4.2
Statistical model, hypothesis, and method of analysis
The numbers and percentages of responders will be summarized by treatment group. The 
difference in observed response rates between active treatment groups and placebo arms will 
be presented along with 95% confidence intervals. The statistical hypothesis tested for clinical 
response is that there is no difference in the proportion of participants achieving clinical 
response at Day 15 with hydroxychoroquine or hydroxychloroquine plus azithromycin plus 
versus placebo. 
Let pj denote the proportion of clinical responders at Day 15 for treatment groups j, j = 0,1,2 
where

0 corresponds to placebo 

1 corresponds to hydroxychloroquine plus azithromycin 

2 corresponds to hydroxychloroquine 
The following statistical hypotheses will be tested to address the primary efficacy objective:
H1: 
(	)
	() = 1, HA1: 
(	)
	() ≠1
H2: 
(	)
	() = 1, HA2: 
(	)
	() ≠1
In other words, 
H1:
hydroxychloroquine plus azithromycin is not different to placebo with respect to the 
likelihood of clinical response by Day 15

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H2:
hydroxychloroquine is not different to placebo with respect to the likelihood of clinical 
response by Day 15
The primary efficacy endpoint of clinical response at Day 15 in the FAS will be evaluated using 
a logistic regression model with treatment group and whether or not supplemental oxygen is 
required at randomization as explanatory variables. Odds ratios will be computed for each of 
active treatment comparisons to placebo.  Based on what data is available from the evolving 
COVID-19 literature, it is anticipated that hydroxychloroquine plus azithromycin will have a 
greater clinical response than hydroxychloroquine and thus each of the primary and secondary 
hypotheses will be tested first in a closed testing procedure in order to preserve familywise Type 
I error rate at 0.05 two-sided.  Details of the closed testing procedure are provided in Section
12.5.
12.4.3
Handling of remaining intercurrent events of primary estimand
The primary analysis has incorporated all potential intercurrent events related to treatment or 
concomitant therapy as part of the treatment of interest attribute of the estimand and no other 
intercurrent events are necessary.
12.4.4
Handling of missing values not related to intercurrent event
Given that the participants in this clinical trial will be hospitalized for their participation, it is 
not expected that there will be any additional missing data in the primary analysis.
12.4.5
Sensitivity analyses for primary endpoint/estimand
The following sensitivity analyses will be performed for the primary estimand, to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis.

In order to determine the robustness of the logistic regression model used for the 
primary analysis of clinical response at Day 15, a non-parametric regression model 
(Koch et al 1998) will also be evaluated using the same explanatory variables as the 
logistic regression model.
12.4.6
Supplementary analysis
No supplementary analysis are planned at this time.
12.4.7
Supportive analyses
The primary efficacy endpoint will be evaluated with respect to the following subgroups

Age (18-65, > 65 years)

SpO2 (≤94% > 94%)

Requiring supplemental oxygen at the time of randomization (No/Yes)
The primary estimand will be applied here to each of these subgroups variables adding the 
subgroup variable and treatment group by subgroup interaction to the model to evaluate whether 
there is any association between the level of subgroup variable and treatment.

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12.5
Analysis of secondary estimands
Viral clearance at Day 15
The secondary efficacy endpoint of the percentage of participants with negative or below LLOQ 
- SARS-COV-2 based on PCR by Day 15 will determined based on the PCR test that is 
performed at Day 6, Day 10, and Day 15/Day of discharge. Data available in the literature would 
indicate that when viral clearance is achieved, that participants will not reverse their viral 
clearance during the 15-day period.  The endpoint will be evaluated in the FAS using a logistic 
regression model with treatment group and whether or not supplemental oxygen is required at 
randomization as explanatory variables. Odds ratios will be computed for each of active 
treatment comparisons to placebo.  Based on what data is available from the evolving COVID-
19 literature, it is anticipated that hydroxychloroquine plus azithromycin will have a greater 
viral response than hydroxychloroquine and thus will be tested first for the secondary endpoints 
in the closed testing procedure to preserve familywise Type I error rate at 0.05 two-sided.
The hypotheses in the closed testing procedure will be evaluated in the following order:
H1:
hydroxychloroquine plus azithromycin is not different to placebo with respect to the 
percentage of participants achieving clinical response by Day 15
H2:
hydroxychloroquine is not different to placebo with respect to percentage of participants 
achieving clinical response by Day 15
H3: 
hydroxychloroquine plus azithromycin is not different to placebo with respect to the 
percentage of participants achieving viral clearance by Day 15
H4: 
hydroxychloroquine is not different to placebo with respect to the percentage of 
participants achieving viral clearance by Day 15
Time to SARS-CoV-2 negativity/ Time to return to pre-morbid oxygen 
requirement /Time to discharge (or ready for discharge)
The event rates for these different endpoints will be estimated with Kaplan-Meier product-limit 
formula.  Greenwood’s formula will be used to estimate the variance of failure rates and to 
derive 95% Z-test based confidence intervals for the difference in event rates between active 
treatment groups and placebo.
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).

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The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment.
Adverse events
A treatment-emergent AE is defined as any AE that develops after initiation of the study 
treatments or any event already present that worsens following exposure to the study treatment. 
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment-emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged. Summary statistics will be provided by treatment 
group and visit/time.
ECG
The overall interpretation of the ECGs will be summarized by treatment group and visit/time.
Any clinically significant changes in ECG parameters will be summarized by treatment group.
Summary statistics will be presented by treatment and visit/time, as appropriate.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. Shift tables using the low/normal/high/ (low and high) classification 
will be used to compare baseline to the worst on-treatment value.
12.5.2
Biomarkers
All biomarker data will be listed by treatment group, participant and visit. Summary statistics 
and graphical summaries (including spaghetti plots, boxplots and mean plots with SD) will be 
provided by treatment and visit. The number of values outside of the limits of quantification 
will be reported in each table. Values above the ULOQ will be imputed as ULOQ in graphical 

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summaries (with a special symbol) and for the calculation of the summary statistics. Values 
below the LLOQ will be imputed as LLOQ/2 for these analyses.
 
 
 
12.7
Interim analyses
No formal interim analysis is planned for this trial. The primary endpoint analysis will be 
performed after all participants have completed Day 15 or discontinued prior to Day 15. A final 
analysis will be performed after all participants have completed their last follow-up visit at Day 
40 (or discontinued prior to Day 40).
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Assuming a true treatment difference in clinical response of 20% for hydroxychloroquine plus
azithromycin plus SoC vs. placebo plus SoC, and an odds-ratio of at least 2.25, a sample size 
of 148 participants per treatment group (444 overall) provides at least 93% power that the 
primary analysis will be statistically significant at the two-sided 5% significance level.  This 
holds for a variety of different assumptions with respect to treatment and clinical response rates.
These sample size assumptions were evaluated using East Version 6.4.
The sensitivity of different assumptions for clinical response rate for treatment and control 
groups and effect size on power are summarized in Table 12-1.
Table 12-1
Sensitivity of sample size to different response rates for 148 
participants per group (N=444) and treatment differences for level of 
significance alpha = 0.05
HCQ/HCQ plus AZ 
Response Rate (%)
Standard of care 
response rate
Odds Ratio
Treatment
difference (%)
Power (%)
50
35
1.86
15
74

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HCQ/HCQ plus AZ 
Response Rate (%)
Standard of care 
response rate
Odds Ratio
Treatment
difference (%)
Power (%)
50
30
2.33
20
94
50
25
3.00
25
99
60
45
1.83
15
73
60
40
2.25
20
93
60
35
2.79
25
99
70
55
1.91
15
76
70
50
2.33
20
94
70
45
2.85
25
99
12.8.2
Secondary endpoint(s)
Data available from recent studies published by Gautret (2020) would indicate that viral 
clearance for hydroxychloroquine plus azithromycin is high. In one study all participants 
receiving this combination therapy achieved viral clearance by Day 6. Participants receiving 
standard of care generally do not achieve a response rate higher than 50%. However, many of 
these studies are small and often not randomized. If one were to assume that 
hydroxychloroquine plus azithromycin has an 80% response rate by Day 15 and standard of 
care has a 50% response rate by Day 15, under this scenario, using the sample size justified for 
the primary efficacy endpoint, the 30% treatment difference corresponds to an odds-ratio of 4.0 
and given 148 participants per treatment group.   There will be more than 99% power to detect 
such a treatment difference.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records 
to Novartis/Sponsor monitors, auditors, Novartis/Sponsor Quality Assurance representatives, 
designated agents of Novartis/Sponsor, IRBs/IECs, and regulatory authorities as required. If an 

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inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis/Sponsor immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials provided to you at the trial investigator meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.

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14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis/Sponsor, health authorities where required, and the IRB/IEC 
prior to implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request
Amsden G (2005). Anti-inflammatory effects of macrolides-an underappreciated benefit in 
the treatment of community-acquired respiratory tract infections and chronic inflammatory 
pulmonary conditions. Journal of antimicrobial chemotherapy 55:10-21.
Banjanac M, Kos VM, Nujic K, et al (2012). Anti-inflammatory mechanism of action of 
azithromycin in LPS-stimulated J774A.1 cells. Pharmacological Research. 66:357-362.
Bosner M, Kelneric Z, Munic V, et al (2005). Cellular uptake and efflux of azithromycin, 
erythromycin, clarithromycin, telithromycin and cethromycin. Antimicrobial agents and 
chemotherapy. 49(6):2372-2377.
CDER (2013) US Department of Health and Human Services, Food and Drug Administration, 
Guidance for Industry: Electronic source data in clinical investigations. Rockville, MD.
Chen, Z et al (2020). Efficacy of hydroxychloroquine in patients with COVID-19: results of a 
randomized clinical trial. doi: https://doi.org/10.1101/2020.03.22.20040758nce 
Code of federal regulations, Title 21 part 312: Investigational new drug application
Colson P, Rolain J, Lagier C, et al (2020). Chloroquine and hydroxychloroquine as available 
weapons to fight COVID-19. Int J Antimicrob Agents. Article number:105932.
Dyall J, Coleman C, Hart B, et al (2014). Repurposing of Clinically developed drugs for 
treatment of middle east respiratory syndrome coronavirus infection. Antimicrobial agents 
and chemotherapy. 58(8):4885-93.
Ferguson NM, Laydon D, Nedjati-Gilani G, et al (2020). Impact of non-pharmaceutical 
interventions (NPIs) to reduce COVID19 mortality and healthcare demand. 16 March 2020 
Imperial College COVID-19 Response Team.
Furst D, Lindsley H, Baethge B, et al (1999). Dose-loading with hydroxychloroquine 
improves the rate of response in early, active rheumatoid arthritis. Arthritis and Rheumatism. 
42(2):357-65
Gao J, Tian Z, Yang X (2020). Breakthrough: Chloroquine phosphate has shown apparent 
efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience 
trends. 14(1):72-73.
Gautret P, Lagier JC, Parola Philippe, et al (2020). Hydroxychloroquine and azithromycin as a 
treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J 
Antimicrob Agents. 105949.
Koch G, Tangen C, Jung J, et al (1998). Issues for covariance analysis of dichotomous and 
ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statistics in medicine. 17:1863-92.
Liu, Jia, Ruiyuan Cao, Mingyue Xu, et al (2020). Hydroxychloroquine, a less toxic derivative 
of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 
volume 6, Article number: 16.

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Lover AA (2020). Quantifying treatment effects of hydroxychloroquine and azithromycin for 
COVID-19: A secondary analysis of an open label, non-randomized clinical trial. 
https://doi.org/10.1101/2020.03.22.20040949doi: medRxiv preprint.
Mattila MJ1, Vanakoski J, Idänpään-Heikkilä JJ. (1994) Azithromycin does not alter the 
effects of oral midazolam on human performance. Eur J Clin Pharmacol. 47(1):49-52.
Mehta P, McAuley D, Brown M, et al (2020). COVD19: consider cytokine storm syndromes 
and immunosuppression. The Lancet. 395(10229):1033-1034.
Ponticelli C and Moroni G (2017). Hydroxychloroquine in systemic lupus erythematosus 
(SLE). Expert opinion on drug safety. 16(3):411-9.
Schrezenmeier E, Dorner T (2020). Mechanisms of action of hydroxychloroquine and 
chloroquine: implications for rheumatology. Nature rev Rheumatol. 16:155-166.
Tett S, Cutler D, Day R et al (1988). A dose-ranging study of the pharmacokinetics of 
hydroxychloroquine following intravenous administration to healthy volunteers. Br J Clin 
Pharmac. 26:303-13.
Tett S, Cutler D, Day R et al (1989). Bioavailability of hydroxychloroquine tablets in healthy 
volunteers. Br J Clin Pharmac. 27:771-79.
van den Borne BE, Dijkmans BA, de Rooij HH, et al (1997). Chloroquine and 
hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-
gamma production by peripheral blood mononuclear cells. J Rheumatol. Jan;24(1):55-60.
Vincent MJ, Bergeron E, Benjannet S, et al (2005). Chloroquine is a potent inhibitor of SARS 
coronavirus infection and spread. Virol J. 2:69.
Wei Y, Nygard GA, Ellertson SL, Khalil SK. (1995) Stereoselective disposition of 
hydroxychloroquine and its metabolite in rats. Chirality 7:598–604.
WHO (2020). https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20200401-sitrep-72-covid-19.pdf?sfvrsn=3dd8971b_2
Yao X, Ye F, Zhang M et al (2020). In vitro antiviral activity and projection of optimized 
dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious diseases. Ciaa 237.
Yeates RA1, Laufen H, Zimmermann T (1996). Interaction between midazolam and 
clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther. 34(9):400-5.

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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Investigators are responsible for reviewing abnormal laboratory values for clinical significance, 
signing the laboratory reports to indicate their review, and reporting values considered clinically 
significant in the appropriate eCRF.
Any clinically significant abnormal laboratory value should be evaluated and followed-up by
the investigator until normal or a cause for the abnormality is determined.
See Appendix 2 for specific liver event and laboratory test trigger definitions and follow-up
requirements.
See Appendix 3 for specific renal alert criteria and actions.
Post-baseline vital signs will be flagged as notable abnormalities as follows:
1. Systolic/Diastolic blood pressure: ≥25% decrease or ≥25% increase from baseline
2. Pulse: ≥110 bpm with ≥15% change from baseline, or <50 bpm with ≥15% change from 
baseline

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16.2
Appendix 2: Suggested Liver event and laboratory trigger 
definitions & follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at 
baseline: 

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known 
bone pathology)

Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent 
term)

ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a 
liver toxicity*
If ALT or AST abnormal at baseline:

ALT or AST > 2x baseline or > 300 U/L 
(whichever occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 
ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, 
ULN: upper limit of normal
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at 
baseline:
ALT > 3 x ULN
Normal
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline TBL
None

No change to 
study treatment

Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 
hours.

Follow-up for 
symptoms.
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
If normal at 
baseline:
ALT > 5 x ULN for 
more than two 
weeks
Normal
For participants 
with Gilbert’s 
syndrome: No 
None

Interrupt study 
drug

Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 

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ALT
TBL
Liver Symptoms
Action
If elevated at 
baseline:
ALT > 3 x baseline
and >10 x ULN
change in 
baseline TBL
albumin, CK, and 
GLDH in 48-72 
hours.

Follow-up for 
symptoms.

Initiate close 
monitoring and 
workup for 
competing 
etiologies.

Study drug can 
be restarted only 
if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline.
If normal at 
baseline:
ALT > 8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at 
baseline:
ALT > 3 x ULN
TBL > 2 x ULN 
For participants 
with Gilbert’s 
syndrome: 
Doubling of 
direct bilirubin
None
If elevated at 
baseline:
ALT > 2 x baseline
If normal at 
baseline:
ALT > 3 x ULN
Normal or 
elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
If elevated at 
baseline:
ALT > 2 x baseline
Table 16-3
Follow up requirements for liver laboratory triggers
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
>1.5 – 3.0 ULN

Maintain treatment

Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)

Interrupt treatment

Repeat LFT within 48-72 
hours

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin,
unconjugated [indirect] 
bilirubin)
> 10 x ULN

Discontinue the study 
treatment immediately

Establish causality

Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutiona (frequency at 
investigator discretion)

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Criteria
Actions required
Follow-up monitoring
General symptoms
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Establish causality

Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF
Investigator discretion
aResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
*(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.

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16.3
Appendix 3: Suggested Specific Renal Alert Criteria and Actions 
and Event Follow-up
Table 16-4
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase 25 - 49% compared 
to baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute kidney injury: serum creatinine increase 
≥50% compared to baseline
Follow up within 24 -48h if possible
Evaluate the need for study treatment 
interruption or discontinuation
Consider specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-
fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or
≥3 mg/mmol;
Protein-creatinine ratio (PCR) ≥150 mg/g or
≥15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Evaluate the need for study treatment interruption 
/ or
discontinuation
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional
diagnostic procedures performed
Monitor subject regularly (frequency at investigator’s discretion) until either:
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ± 10% variability over last 6 months or protein-creatinine ratio
stabilization at a new level with ± 50% variability over last 6 months.