Conditions: Covid19 Anosmia Fever Cough Shortness of Breath Sore Throat Nausea Vomiting Headache Muscle Weakness Pain, Muscle Pain, Chest Pain, Joint Pain, Abdominal Pain Irritable Mood Confusion
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 216
Healthy volunteers: no

Brief summary:
The main aim of this study is to determine the effects of short-term treatment with hesperidin on COVID-19 symptoms in comparison with a placebo. Treatment effects will be observed through a symptoms diary that will be completed by participants throughout the study and by taking the oral temperature daily.

Detailed description:
This will be a randomized, double-blind, placebo-controlled study. The study will include subjects from Quebec diagnosed with COVID-19 infections. Following informed consent, 216 subjects meeting all inclusion and no exclusion criteria will be randomized to receive either hesperidin 1000 mg once daily (q.d.)) or placebo (1:1 allocation ratio) for 14 days. Investigational drug will be delivered to the patients' homes with an electronic oral thermometer and a symptoms diary. Follow-up phone assessments will occur after 3, 7, 10, and 14 days following randomization for evaluation of COVID-19 symptoms. Electronic Case Report Form (eCRF) will be completed by the research personnel over the phone with the patients. The symptoms diary will be mailed back to the coordinating center at the end of the study in a pre-addressed envelope.

Arms:
arm 1: Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water. arm 2: Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.

Interventions: intervention 1: Hesperidin intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water. intervention 2: Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.

Protocol document:
ICF_002.pdf: 
 
 
Protocol #: MHICC‐2020‐003 
 
A phase 2, randomized, double‐blind, placebo‐controlled study of hesperidin 
therapy on COVID‐19 symptoms: 
The Hesperidin Coronavirus study (Hesperidin) 
 
NCT #: NCT04715932 
 
 
Informed Consent Form v3 
21‐Jan‐2021 























Prot_000.pdf: 
 
 
Protocol #: MHICC‐2020‐003 
 
A phase 2, randomized, double‐blind, placebo‐controlled study of hesperidin 
therapy on COVID‐19 symptoms: 
The Hesperidin Coronavirus study (Hesperidin) 
 
NCT #: NCT04715932 
 
 
Protocol V2.0 
17‐Feb‐2021 


MHICC 
PROTOCOL MHICC-2020-003 
February 17th, 2021  
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
 
Protocol # MHICC-2020-003 
A phase 2, randomized, double-blind, placebo-controlled study of hesperidin therapy on 
COVID-19 symptoms: 
The Hesperidin Coronavirus study (Hesperidin)  
  
 
 
 
Final Protocol V2.0 
 
February 17th, 2021 
 
 
 
 
SPONSOR 
 
MONTREAL HEART INSTITUTE 
 
 
 
 
 
 
CONFIDENTIALITY 
 
The Montreal Health Innovations Coordinating Center (MHICC), a division of the Montreal 
Heart Institute (MHI), considers the information contained in this document to be proprietary 
and/or confidential. It is for the use of the investigational team, and the corresponding 
applications to institutional review boards (IRBs) and independent ethics committees (IECs) in 
support of a clinical trial. Accordingly, please do not copy, use, distribute, or disclose to others 
without the written prior approval of MHICC or their designated representatives. 
 
 






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February 17th, 2021  
 
 
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Table of Contents 
INVESTIGATOR’S SIGNATURE ............................................................................................. 5 
SYNOPSIS ..................................................................................................................................... 6 
GLOSSARY................................................................................................................................. 10 
TIME PERIOD AND NUMBER OF PATIENTS: .................................................................. 11 
1 
INTRODUCTION............................................................................................................... 12 
1.1 
Background ................................................................................................................................ 12 
1.2 
Background on Hesperidin ........................................................................................................ 12 
1.3 
COVID-19 symptoms ................................................................................................................ 13 
2 
STUDY OBJECTIVES ....................................................................................................... 14 
3 
STUDY DESIGN ................................................................................................................. 15 
3.1 
Study Schedule .......................................................................................................................... 15 
3.2 
Enrollment ................................................................................................................................. 15 
3.3 
Screening Evaluations and Randomization ............................................................................... 16 
3.4 
Active Treatment Period ............................................................................................................ 16 
Table 1 
Timetable of Visits and Procedures ....................................................................... 17 
4 
STUDY POPULATION ..................................................................................................... 18 
4.1 
Source and Number of Patients ................................................................................................. 18 
4.2 
Patient Selection Criteria ........................................................................................................... 18 
4.2.1 
Inclusion Criteria: .................................................................................................................. 18 
4.2.2 
Exclusion Criteria: ................................................................................................................ 18 
4.3 
Prohibited, Allowable and Concurrent Medications ................................................................. 19 
5 
STUDY METHODOLOGY ............................................................................................... 19 
5.1 
Efficacy Outcomes .................................................................................................................... 19 
5.2 
Safety Monitoring ...................................................................................................................... 20 
5.2.1 
Adverse Event Reporting ...................................................................................................... 20 
5.3 
Withdrawal of Patients from the Study ..................................................................................... 21 
5.4 
Study Completion ...................................................................................................................... 22 
6 
STUDY MEDICATION ..................................................................................................... 22 
6.1 
Medication Dispensing .............................................................................................................. 22 
6.2 
Dosage Regimen ........................................................................................................................ 22 
7 
DATA COLLECTION ....................................................................................................... 23 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 23 
8.1 
Statistical Power and Sample Size Considerations .................................................................... 23 
8.2 
Analysis population ................................................................................................................... 23 
8.2.1 
Intent to Treat (ITT) population ............................................................................................ 23 
8.2.2 
Safety population .................................................................................................................. 23 
8.3 
Data analysis .............................................................................................................................. 23 
8.3.1 
Analysis of efficacy outcomes .............................................................................................. 23 
8.3.2 
Analysis of safety outcomes .................................................................................................. 24 


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8.3.3 
Interim analysis ..................................................................................................................... 24 
9 
STUDY COORDINATION................................................................................................ 24 
REFERENCES ............................................................................................................................ 25 
LIST OF APPENDICES ............................................................................................................ 27 
Appendix A 
Detailed Study Safety Parameters ................................................................. 28 
Appendix B 
Administrative Procedures for the Reporting of Adverse Events .............. 29 
1 
ADVERSE EVENTS DURING THE TRIAL .................................................................. 29 
1.1 
Pre-existing condition ................................................................................................................ 29 
1.2 
Adverse Event (AE) .................................................................................................................. 29 
1.3 
Related Adverse Event .............................................................................................................. 29 
1.4 
Serious Adverse Event (SAE) ................................................................................................... 29 
1.5 
Life-Threatening Adverse Event ............................................................................................... 30 
1.6 
Clinical Laboratory Adverse Event ........................................................................................... 30 
1.7 
Treatment-Emergent Signs and Symptoms (TESS) .................................................................. 30 
1.8 
Post-treatment Adverse Event ................................................................................................... 30 
2 
HANDLING OF ADVERSE EVENTS ............................................................................. 31 
2.1 
Treatment-Emergent Signs and Symptoms ............................................................................... 31 
2.2 
Serious Adverse Events ............................................................................................................. 31 
2.3 
Intensity ..................................................................................................................................... 31 
2.4 
Relationship to Study Drug – Physician’s Assessment ............................................................. 31 
2.5 
Clinical Outcome ....................................................................................................................... 31 
3 
CAPTURING AVDERSE EVENTS ................................................................................. 32 
3.1 
Pre-Existing Condition .............................................................................................................. 32 
3.2 
Clinical Laboratory Adverse Event ........................................................................................... 32 
3.3 
Hospitalization or Surgery/Procedure ....................................................................................... 32 
3.4 
Death.......................................................................................................................................... 32 
4 
REPORTING TO THE SPONSOR .................................................................................. 32 
4.1 
Immediately Reportable Adverse Events .................................................................................. 32 
4.2 
Other Adverse Events ................................................................................................................ 32 
4.3 
Follow-Up Period ...................................................................................................................... 33 
Appendix C 
Other Administrative and Regulatory Procedures ...................................... 34 
Appendix D Declaration of Helsinki ......................................................................................... 38 
Appendix E .................................................................................................................................. 45 
 


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February 17th, 2021  
 
 
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INVESTIGATOR’S SIGNATURE 
I have read the protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol, with applicable laws and regulations and in accordance with the ethical principles 
outlined in the Declaration of Helsinki. 
 
By signing below, I hereby declare that I am not debarred, disqualified, or otherwise restricted by 
any agency from conducting any research studies. 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
Signature 
 
Date 
 
 
Country: 
 
 
 
 
 
 


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February 17th, 2021  
 
 
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SYNOPSIS 
 
TITLE:  A phase 2, randomized, double-blind, placebo-controlled study of hesperidin 
therapy on COVID-19 symptoms: 
The Hesperidin Coronavirus study (Hesperidin)  
 
INDICATION: Reduction of symptoms in patients with COVID-19 infection. 
OBJECTIVES:   
 The primary objective of the study is to determine the effect of hesperidin therapy on 
the presence of selected COVID-19 symptoms (fever, cough, shortness of breath or 
anosmia) at 3, 7, 10 and 14 days following randomization. 
 
 The secondary objectives are:  
1- To determine the effect of hesperidin therapy on the mean number of COVID-19 
symptoms at 3, 7, 10 and 14 days following randomization. 
2- To determine the effect of hesperidin therapy on the duration of COVID-19 
symptoms. 
3- To determine the effect of hesperidin therapy on the presence of each individual 
COVID-19 symptoms at 3, 7, 10 and 14 days following randomization. 
 
 The exploratory objectives are: 
1- To evaluate the effect of hesperidin therapy on the presence of each individual 
COVID-19 symptoms on a daily basis based on a patient symptoms’ diary.  
2- To evaluate the effect of hesperidin therapy on COVID-19-related hospitalization, 
mechanical ventilation and death in the 14 days following randomization. 
 
 
PATIENT POPULATION:  Males and females, at least 18 years of age, who have been 
diagnosed with a COVID-19 infection and have one or more symptoms. 
Inclusion Criteria: 
 Covid-19 positive by polymerase chain reaction (PCR) testing; 
 
 Participant must be able to evaluate their symptoms and report them in the symptoms’ 
diary; 
 
 Patients must be able to take their oral temperature daily with an electronic thermometer 
provided to them with study materials. 
 
 Males and females, at least 18 years of age, capable and willing to provide informed 
consent; 


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 Female patient is either not of childbearing potential, defined as postmenopausal for at 
least 1 year or surgically sterile, or is of childbearing potential and practicing at least one 
method of contraception and preferably two complementary forms of contraception 
including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, 
jellies, diaphragm, intrauterine device (IUD)) throughout the study; 
 
 Patient must have received a diagnosis of COVID-19 infection within the last 48 hours 
and have one or more symptoms; 
 
 Outpatient setting (not currently hospitalized or under immediate consideration for 
hospitalization); 
 
 Patient must be able and willing to comply with the requirements of this study protocol. 
 
Exclusion Criteria: 
 
 Patient currently hospitalized or under immediate consideration for hospitalization; 
 
 Patient currently in shock or with hemodynamic instability; 
 
 Patient undergoing chemotherapy for cancer; 
 
 Patient is unable to take oral temperature using an electronic thermometer; 
 
 Patient who received at least one dose of the COVID-19 vaccine;  
 
 Female patient who is pregnant or breast-feeding or is considering becoming pregnant 
during the study; 
 
 
People taking anticoagulant/antiplatelet medications, those with bleeding disorders, and people 
two weeks before or after surgery;  
 
 Patient is considered by the investigator, for any reason, to be an unsuitable candidate for 
the study; 
 
 Regular consumption of natural products containing more than 150 mg of hesperidin or 
regular consumption of more than 1 glass of orange juice per day; 
 


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 
Known allergy to any of the medicinal and non-medicinal ingredient: hesperidin, 
microcrystalline cellulose, magnesium stearate. 
 
 
STUDY DESIGN:  This will be a randomized, double-blind, placebo-controlled study. The 
study will include subjects from Quebec diagnosed with COVID-19 infections. Following 
informed consent, 216 subjects meeting all inclusion and no exclusion criteria will be 
randomized to receive either hesperidin 1000 mg once daily (q.d.)) or placebo (1:1 allocation 
ratio) for 14 days. Investigational drug will be delivered to the patients’ homes with an electronic 
oral thermometer and a symptoms diary. Follow-up phone assessments will occur after 3, 7, 10, 
and 14 days following randomization for evaluation of COVID-19 symptoms.  Electronic Case 
Report Form (eCRF) will be completed by the research personnel over the phone with the 
patients. The symptoms diary will be mailed back to the coordinating center at the end of the 
study in a pre-addressed envelope.  
 
 
OUTCOMES:   
 The primary endpoint: 
Proportion of subjects with any of the following COVID-19 symptoms: fever, cough, 
shortness of breath or anosmia, at day 3, 7, 10 and 14. 
 
 The secondary endpoints: 
1- Mean number of COVID-19 symptoms (range 0-13) at day 3, 7, 10 and 14. 
2- Duration of COVID-19 symptoms, defined as the number of days between first 
symptoms and complete disappearance of any symptom. 
3- For each COVID-19 symptom listed in the appendix, proportion of subjects with the 
symptom at day 3, 7, 10 and 14. 
 
 
The exploratory endpoints:  
1- For each COVID-19 symptom listed in the appendix, proportion of subjects with the 
symptom on a daily basis based on patient-diary. 
2- Composite of COVID-19-related hospitalization, mechanic ventilation or death in the 
14 days following randomization. 
 
 
STATISTICAL RATIONALE AND ANALYSIS:  
Efficacy analysis will be based on the intent-to-treat principle. The primary analysis will 
compare the proportions of subjects with fever, cough, shortness of breath or anosmia between 
the two treatment groups using a generalized linear mixed model with terms for treatment group 
(placebo, hesperidin), time (3, 7, 10 and 14 days) and treatment group x time interaction. The 
primary analysis will be the comparison between treatment groups at day 7, although treatment 
groups will also be compared at the other time points. Mean number of COVID-19 symptoms 


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February 17th, 2021  
 
 
Page 9 of 48 
will be compared between treatment groups using a Student t-test or a Wilcoxon rank-sum test 
according to distribution. If more appropriate, a Poisson regression model will be used. Duration 
of COVID-19 symptoms will be compared between treatment groups using a log rank test and 
Kaplan-Meier curves will be presented. Subjects who will still have COVID-19 symptoms at the 
end of the study will be censored at the day of their last phone contact or videovisit. The analysis 
of individual COVID-19 symptoms over time will be similar to the analysis of the primary 
endpoint and will use generalized linear mixed models. Composite of COVID-19-related 
hospitalization, mechanic ventilation or death will be compared between treatment groups using 
a chi-square test. All statistical tests will be two-sided and conducted at the 0.05 significance 
level. Statistical analysis will be done using SAS version 9.4 or higher. 
Using a two-sided 0.05 significance level, sample sizes of 91 in both groups (182 total) will 
achieve 80% power to detect an absolute between groups difference of 20% in the proportion of 
patients with COVID-19 symptoms (fever, cough, shortness of breath or anosmia) at day 7, 
which will be the time point of primary focus. This is assuming that the proportions of patients 
with the above COVID-19 symptoms at day 7 will be 50% in the placebo group and 30% in the 
active treatment group. Factoring in a 15% drop out rate, a total of 216 patients will be 
randomized in the study (108 per group). 
A fully independent 3-member Data and Safety Monitoring Board (DSMB) will be established 
and will review unblinded safety data as detailed in the DSMB charter after randomization of 50 
subjects and after randomization of 100 subjects. If necessary, an additional meeting will take 
place after randomization of 150 subjects. The DSMB charter will pre-specify the rules for early 
study termination, approved by all board members.  
ANTICIPATED TOTAL NUMBER OF RANDOMIZED PATIENTS:  216 patients in total 
will be randomized in this study.  
 
PHASE:  2 
 
STUDY LOCATION:  Canada 


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GLOSSARY  
 
ACE2  
- 
Angiotensin Converting Enzyme 2 
AE 
 
- 
Adverse event  
eCRF  
-  
electronic Case Report Form 
DSMB  
- 
Data and Safety Monitoring Board 
EC 
 
-  
Ethics Committee 
e-Consent       -            electronic Consent 
ICF 
 
 
Informed Consent Form 
ICH 
 
- 
International Council for Harmonisation 
ITT 
 
-  
Intent-to-treat 
IUD 
 
- 
Intrauterine device 
IRB 
 
-  
Institutional Review Board 
LPS                 -           Lipopolysaccharides      
MHI 
 
- 
Montreal Heart Institute 
MHICC  
- 
Montreal Health Innovations Coordinating Center 
PCR                -           Polymerase Chain Reaction  
qPCR              -           quantitative  Polymerase Chain Reaction 
PO (po) 
- 
Per os 
PRN 
 
- 
pro re nata (as necessary) 
SAE 
 
- 
Serious adverse event 
SOPs  
- 
Standard operating procedures 
SUSAR 
- 
Suspected Unexpected Serious Adverse Reaction 
TESS  
- 
Treatment-Emergent Signs and Symptoms 
WMA  
- 
World Medical Association 


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TIME PERIOD AND NUMBER OF PATIENTS:  
  
A. Anticipated Starting Date of Study: 3Q20 
  
B. Anticipated Completion Date: 4Q20 
  
C. Anticipated Number of Patients per Site: Centralized recruitment and follow-up 
D. Anticipated Number of Sites:  Centralized recruitment and follow-up 
 
 
  
Generic  
Name 
 Strength and 
Dosage Form 
 
Therapeutic 
Classification 
 
  
 
 
Hesperidin  
 500 mg capsule 
 
Antiviral and immune-
modulatory natural 
product 
 
  
 
 
 
 
 
 Placebo to match 500 
mg capsule 
 
 
 
NA 
 
 
  


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1 
INTRODUCTION 
 
Emerging viruses are a major threat to human health and the rate at which new pathogenic 
viruses are emerging has accelerated in the past fifty years. Generally, antiviral drug 
development has focused on targeting viral components to block virus entry, replication, 
morphogenesis and propagation, or on the modulation of the host immune response. The 
frequent outbreaks have highlighted the urgent need for new antiviral treatments. 
 
1.1 
Background   
 
COVID-19 disease 
 
COVID-19 is due to an infection by the beta-coronavirus SARS-CoV-2 (1). The outbreak of 
COVID-19 disease started in December 2019 in Wuhan, Hubei Province, China (1,2), has spread 
to other parts of China and Asia, and is now a pandemic that has reached Europe and North 
America. The number of confirmed cases has reached over 12 507 849, including 560 460 
deaths, as of July 12, 2020. Patients initially present with fever with or without respiratory 
symptoms, but a large number of patients later develop various degrees of pulmonary 
abnormalities on chest imaging (3). Although the vast majority of patients only have a common, 
mild form of illness, approximately 15% of the patients fall into the severe group, with 
requirement of assisted ventilation and oxygenation (3). These patients suffer from acute 
respiratory distress syndrome. Pathologic findings reveal edema and prominent proteinaceous 
exudates, vascular congestion, and inflammatory clusters with fibrinoid material and 
multinucleated giant cells (4).  
 
This single-strand RNA virus depends on angiotensin converting enzyme 2 (ACE2) for its entry 
into cells (5). ACE2 is primarily produced in Clara cells and type II alveolar epithelial cells (6). 
 
Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have 
also a cytokine storm syndrome (7). By blocking virus entry as well as reducing this 
dysregulated (exaggerated) inflammatory response has been advocated to address the immediate 
need to reduce the rising mortality (7,8). Therefore, we hypothesize that Hesperidin, by targeting 
virus entry (binding to ACE2) and by reducing inflammation, may reduce COVID-19 infection 
and complications in adults at risk or with evidence of acute respiratory distress syndrome.  
 
 
 
1.2 
Background on Hesperidin 
 
Hesperidin, a flavonoid naturally present in citrus fruits, is a heteroside of a sugar (rutinose) and 
hesperetin. Hesperidin was discovered in 1828 and is the oldest commercially available 


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flavonoid produced from citrus fruits. Hesperetin inhibits the enzyme 3CL protease that 
contributes to SARS-CoV-2 replication (14). Pharmacological modeling further suggests that 
Hesperetin could interfere with the regional binding domain (RBD) between the spike protein of 
COVID-19 and its receptor on human endothelial and epithelial cells (ACE2) (15). Furthermore, 
Hesperidin/Hesperetin has also been shown to have anti-inflammatory effects and to reduce 
acute lung injury in models of acute respiratory distress syndromes induced by 
Lipopolysaccharides (LPS) and mechanical injury (16-19). Hesperidin could therefore interfere 
with three operative pathways of COVID-19 infection: SARS-CoV-2 binding to its lung 
epithelial cell receptor ACE2, reduction of viral replication by inhibition of 3CL protease and 
modulation of excessive lung inflammation and injury leading to respiratory failure.  
 
Hesperidin is already readily available in consumer products such as orange juice (150-200 mg 
per serving) and natural products from citrus extracts (up to 500 mg per dose). These natural 
products are advertised as “improving capillary fragility”. Hesperidin is also approved by the 
FDA and EMA as pharmaceutical, food and beverage additive used to provide texture, improve 
taste and conservation due to its anti-oxidant properties. The FDA issued a Generally 
Recognized As Safe (GRAS) notice for orange extracts with 85% Hesperidin content to be used 
in food (GRA No 796). In human, plasma concentration of hesperetin, the active component of 
hesperidin, reach ups to 2 µM after consumption of 150 mg hesperidin with peaks after 3 hours 
and with a half-life of 7 hours.  Based on safety, preclinical studies, human PK studies, and PK 
modeling of hesperidin, a dose of 1g BID of hesperidin is recommended for anticipated efficacy 
(inhibition of SARS-CoV-1 3CLPro: 8 µM). SARS-CoV-1 has 95% homology with SARS-CoV-
2 (21). A number of human studies have been performed with hesperidin and are summarized in 
the FDA GRAS notice of 2018 (GRA No 796). There have been no adverse events observed 
with high dose hesperidin consumption for long periods of time in human subjects. In particular, 
Demonty et al. studied 204 subjects and found no adverse events after administration of 800 mg 
daily hesperidin or placebo in capsules for a duration of 4 weeks (22). Hesperidin is accepted for 
human use alone or as a component of natural products and has been used for centuries in 
traditional Chinese medicine as it is major product contained in Chenpi (sun-dried tangerine 
peels).  
 
 
1.3 
COVID-19 symptoms 
 
The epidemiological and clinical characteristics of COVID-19 infection were reviewed by the 
“Institut National de Santé Publique du Québec” and are available in an online document. Based 
on a metanalysis of 43 studies including 3600 subjects the most frequently reported symptoms 
were fever in 83.3% (95% CI: 78.4 – 87.7), cough in 60.3% (54.2 -2 – 66.3), fatigue in 38% 
(29.8 – 46.5%). More recently, studies have reported that a loss of smell (anosmia) was present 
in 59% of subjects for one study in 1702 non-hospitalized COVID-19 positive subjects and in 
85.6% of 417 hospitalized subjects in another study. Other less frequent symptoms include chills, 


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sore throat, runny nose, shortness of breath, nausea/vomiting, headache, pain (muscular, chest, 
abdominal, joint etc.), irritability/confusion and diarrhea. There is therefore great variability in 
the reported prevalence of COVID-19 symptoms and unknown sensitivity and specificity of any 
single symptom. For the Hesperidin study, a composite primary endpoint of symptoms was 
therefore determined based on the current guidelines of the government of Canada for clinicians 
on COVID-19 symptoms and on guidelines for diagnosis of COVID-19 from the Institut 
National de la Santé Publique du Québec (INSPQ). The Canadian guidelines for clinicians, 
reviewed on June 18 2020, list the symptoms in three categories as more frequent (> 50%), less 
frequent (< 50%) and rare (< 10%) (table 1, available online). 
 
Table 1. Frequency of COVID‐19 symptom according to the Canadian guidelines for clinicians 
 
 
The guidelines for the diagnosis of COVID-19 from the INSPQ separated symptoms into group 
A and group B symptoms. The four group A symptoms are fever (of more than 38º C), cough 
(recent or exacerbation of chronic cough), shortness of breath and anosmia. These symptoms 
have less inherent subjectivity in their perception and are classified as more frequent in the 
Canadian guidelines (table 1). The Hesperidin study will use these group A symptoms as a 
composite primary endpoint.  A list of the COVID-19 symptoms as they will be recorded in 
patients’ diary of the Hesperidin trial is presented in appendix E. Although a proportion of 
SARS-CoV-2 infections may be asymptomatic, the exact proportion remains currently unknown. 
In symptomatic subjects, the symptoms can become quite severe causing disability and requiring 
hospitalization.  
 
 
2 
STUDY OBJECTIVES 


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 The primary objective of the study is to determine the effect of hesperidin therapy on 
the presence of selected COVID-19 symptoms (fever, cough, shortness of breath or 
anosmia) at 3, 7, 10, and 14 days following randomization. 
 
 The secondary objectives are: 
1- To determine the effect of hesperidin therapy on the mean number of COVID-19 
symptoms at 3, 7, 10, and 14 days following randomization. 
2- To determine the effect of hesperidin therapy on the duration of COVID-19 
symptoms. 
3- To determine the effect of hesperidin therapy on the presence of each individual 
COVID-19 symptoms at 3, 7, 10, and 14 days following randomization. 
 
 The exploratory objectives are: 
1- To evaluate the effect of hesperidin therapy on the presence of each individual 
COVID-19 symptoms on a daily basis based on a patient symptoms’ diary.  
2- To evaluate the effect of hesperidin therapy on COVID-19-related hospitalization, 
mechanical ventilation and death in the 14 days following randomization. 
 
 
3 
STUDY DESIGN 
 
This will be a randomized, double-blind, placebo-controlled study. The study will include 
subjects from Quebec diagnosed with COVID-19 infections. Following informed consent, 216 
subjects meeting all inclusion and no exclusion criteria will be randomized to receive either 
hesperidin (1000 mg q.d.) or placebo (1:1 allocation ratio) for 14 days. Investigational drug will 
be delivered to the patients’ homes. In addition, patients will be provided with an oral electronic 
thermometer as well as a daily symptoms diary (see appendix). Follow-up phone will occur after 
3 7, 10, and 14 days following randomization for evaluation of the occurrence of any trial 
endpoints or other adverse events.  Electronic CRF (eCRF) will be completed by the research 
personnel over the phone with the patients.  
 
 
3.1 Study Schedule 
 
The schedule of visits for this study is outlined in Table 1. However, a patient may be evaluated 
at any time for safety concerns.  
 
3.2 Enrollment 
 
Informed consent will be obtained from patients who volunteer to participate in the study prior to 
the conduct of any study-specific procedures. The patient will be considered “enrolled” into the 
study at the time an informed consent is provided. 
 


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3.3 Screening Evaluations and Randomization 
 
Screening evaluations will include a review of the patient’s medical history and assessment of 
concomitant medications to determine if the patient qualifies for the study. Patients who meet all 
inclusion criteria and no exclusion criteria will be randomized to receive the study product or 
placebo. All patients must be randomized within 2 days of the diagnosis of COVID-19 infection.  
 
Women of childbearing potential must have a negative urine pregnancy test result at the time of 
randomization in order to qualify. Qualifying patients will be randomized to receive placebo or 
hesperidin 1000 mg/day administered in a blinded manner. Blinded randomization will be 
performed through a system of envelops. 108 patients will be randomized to active treatment and 
108 patients will be randomized to placebo for a total of 216 randomized patients. 
 
3.4 Active Treatment Period 
 
All patients will receive study medication per os (PO) once daily for 14 days. If a dose is missed, 
it should not be replaced. Throughout the study, patients will undergo phone contacts (at 3, 7, 10 
and days to assess for potential study endpoints and other adverse events (AEs). Patients will be 
dispensed study medication for the 14 days, an electronic thermometer and a daily symptoms 
diary. At each phone contact, patients will be 1) questioned about COVID-19 symptoms; 2) 
questioned in a non-specific manner for the occurrence of AEs and any change in concomitant 
medications; and 3) encouraged to comply with the study protocol including adherence to study 
medication and completion of the daily symptoms diary. 
 
Please refer to Table 1 and Appendix A for Timetable of Visits and Procedures. 
 


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Table 1 Timetable of Visits and Procedures 
 
Visits 
1.  Screening / 
randomization  
(Phone call) 
2.  Contact Point 
(Phone) –no 
window** 
3. Contact Point 
(Phone ) (± 1 day) 
4. Contact Point 
(Phone) 
(± 3 days) 
5. Contact Point 
(Phone call)  
(± 3 days)  
 
Days 
0 
3 
7 
10 
14 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
Review concomitant medication 
X 
X 
X 
X 
X 
Covid-19 symptoms (including date of onset) 
X 
X 
X 
X 
X 
Review Inclusion/Exclusion criteria 
X 
 
 
 
 
Urinary pregnancy test* 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Record potential study endpoints and other AEs  
 
X 
X 
X 
X 
Study medication dispensing  
X 
 
  
 
 
Study medication compliance 
 
X 
X 
X 
X 
 
 
*For women of childbearing potential 
 
** If day 3 occurs on the weekend, contact point will be done on previous Friday or following Monday, whichever is closer to day 3.   
 


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4 
STUDY POPULATION 
 
4.1 Source and Number of Patients 
 
A total of 216 patients will be randomized.  
 
4.2 Patient Selection Criteria 
 
4.2.1 Inclusion Criteria: 
 
All of these criteria must be met: 
 
 Covid-19 positive by polymerase chain reaction (PCR) testing; 
 
 Participant must be able to evaluate their symptoms and report them in the symptoms’ 
diary; 
 
 Patients must be able to take their oral temperature daily with an electronic thermometer 
provided to them with study materials; 
 
 Males and females, at least 18 years of age, capable and willing to provide informed 
consent; 
 
 Female patient is either not of childbearing potential, defined as postmenopausal for at 
least 1 year or surgically sterile, or is of childbearing potential and practicing at least one 
method of contraception and preferably two complementary forms of contraception 
including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, 
jellies, diaphragm, intrauterine device (IUD)) throughout the study; 
 
 Patient must have received a diagnosis of COVID-19 infection within the last 48 hours 
and have one or more symptoms; 
 
 Outpatient setting (not currently hospitalized or under immediate consideration for 
hospitalization); 
 
 Patient must be able and willing to comply with the requirements of this study protocol. 
 
4.2.2 Exclusion Criteria: 
 
None of these exclusion criteria should be met: 
 Patient currently hospitalized or under immediate consideration for hospitalization; 
 
 Patient currently in shock or with hemodynamic instability; 


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 Patient undergoing chemotherapy for cancer; 
 
 Patient is unable to take oral temperature using an electronic thermometer; 
 
 Patient who received at least one dose of the COVID-19 vaccine; 
 
 Female patient who is pregnant or breast-feeding or is considering becoming pregnant 
during the study; 
 
 People taking anticoagulant/antiplatelet medications, those with bleeding disorders, and 
people two weeks before or after surgery; 
 
 Patient is considered by the investigator, for any reason, to be an unsuitable candidate for 
the study; 
 
 Regular consumption of natural products containing more than 150 mg of hesperidin or 
regular consumption of more than 1 glass of orange juice per day; 
 
 Known allergy to any of the medicinal and non-medicinal ingredient: hesperidin, 
microcrystalline cellulose, magnesium stearate. 
 
 
4.3 Prohibited, Allowable and Concurrent Medications  
 
Clinical research suggests that hesperidin may affect blood clotting and increase the risk of 
bleeding. Consequently, anticoagulant and antiplatelet medications are not allowed during the 
study.  Other medications are allowed as long as they are stabilized prior to study entry and 
maintained as stable throughout the course of the trial.   
 
The use of concomitant medications at the time of randomization will be recorded in the eCRF 
(with the exceptions of concomitant medication taken “when necessary” (PRN)). 
 
The use of natural products containing hesperidin and its content (in mg) as well as the quantity 
of orange juice consumption (in ml) will be obtained. Daily consumption of more than 150 mg of 
hesperidin daily or of more than one glass of orange juice daily will represent an exclusion 
criterion. Subjects will be encouraged to avoid hesperidin-containing supplements and orange 
juice for the duration of the study. 
 
5 
STUDY METHODOLOGY 
 
5.1 Efficacy Outcomes 
 


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 The primary endpoint: 
Proportion of subjects with any of the following COVID-19 symptoms: fever, cough, 
shortness of breath or anosmia, at day 3, 7, 10 and 14. 
 
 The secondary endpoints: 
1- Mean number of COVID-19 symptoms (range 0 – 13) at day 3, 7, 10 and 14. 
2- Duration of COVID-19 symptoms, defined as the number of days between first 
symptoms and complete disappearance of any symptom. 
3- For each COVID-19 symptom listed in the appendix, proportion of subjects with the 
symptom at day 3, 7, 10 and 14. 
 
Duration of symptoms will be determined as follows: 
- 
If randomization and study product reception by participant occur the same day, first day 
of symptoms will be defined as the day of randomization; 
- 
If randomization and study product reception by participant occur on different days, first 
day of symptoms will be defined as the day of study product reception.  
 
 
 
The exploratory endpoints:  
1- For each COVID-19 symptom listed in the appendix, proportion of subjects with the 
symptom on a daily basis based on patients’ diary. 
2- Composite of COVID-19-related hospitalization, mechanic ventilation or death in the 
14 days following randomization. 
 
 
5.2 Safety Monitoring 
 
Drug safety will be assessed by an evaluation of types, frequencies, severities and duration of 
any reported AEs.  
 
5.2.1 Adverse Event Reporting 
 
Information regarding AEs will be collected at day 3, 7, 10 and 14 after randomization. Any AEs 
prior to randomization will be recorded in the medical history and kept in the patients’ chart.  
 
All SAEs will be recorded on the appropriate eCRF section. Information collected will include 
the onset, duration, severity, relationship to study drug, and the management as outlined in 
Appendix C.  
 
5.2.1.1 Serious Adverse Events 
 
Serious Adverse Events (SAE) are those that meet any of the following International Council for 
Harmonisation (ICH) criteria: 
  
 Is fatal or immediately life-threatening; 


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 Results in persistent or significant disability/incapacity; 
 Requires or prolongs inpatient hospitalization; 
 Is a congenital anomaly/birth defect in the offspring of the patient; 
 Is a cancer; 
 Is an overdose (intentional or accidental); 
 Is judged to be medically important. 
 
Medically important events may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above. Serious Adverse Events are to be reported if they are 
known to occur within 14 days after randomization.  
Medical and scientific judgment should be exercised in deciding whether other AEs meet these 
criteria and are immediately reportable to the sponsor or designee. 
 
In the event of a serious or life-threatening adverse event, or in the event of death, immediately 
report the event on the appropriate SAE form in the eCRF.  
 
FOR ANY SAFETY QUESTIONS OR CONCERNS, PLEASE CONTACT: 
MHICC Medical Monitor 
  
Email: Hesperco_safety@mhicc.org 
 
If any SAE occurs, the study treatment may be interrupted or discontinued at the Investigator’s 
discretion. If an acute medical emergency occurs, the investigator may break the randomization 
code at any time if this is required for proper treatment of the patient and inform the person listed 
above by email.   
 
The MHICC Medical Monitor or his designated representative is responsible to report any 
Suspected Unexpected Serious Adverse Reaction (SUSAR) to the regulatory authorities and to 
notify Ingenew Pharma at time of submission. Reports to the Health Authorities must be made 
within 7 calendar days, (for death and life-threatening events) and within 15 calendar days (for 
other serious events) after being informed of an SAE by the investigator.  
 
 
5.2.1.2 Adverse Event Follow-Up 
 
Record all reportable serious and non-serious AEs on the appropriate eCRF including the onset, 
duration, severity, relationship to the study drug, and ultimate management. All AEs reported 
during the treatment phase should be recorded and followed until the AE has subsided, or 
stabilized or until the end of the study, whichever occurs first. The study will be stopped at any 
time if new knowledge is gained and the risk-benefit ratio is no longer favorable for the 
participating patients and Ingenew Pharma will then be informed immediately but no later than 3 
business days if such decision is made 
 
5.3 Withdrawal of Patients from the Study 


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Patients have the right to withdraw from the study at any time during the course of the study. 
However, every effort should be made, within the bounds of safety, patient choice and the 
provisions of informed consent, to have each patient complete the study up to and including the 
last protocol-specified phone call at Day 14. If the study medication jeopardizes the patient’s 
health or if the patient wishes to discontinue for any reason, study medication can be 
discontinued but the patient should be encouraged to remain in the study for the follow-up phone 
calls up to Day 14. Patients who are not compliant during the active treatment period should be 
counseled on the importance of complying with study requirements and be allowed to remain in 
the study.  No patient who has withdrawn his/her consent from the study during the active 
treatment period should be replaced. 
 
In the case of an adverse event or safety concern, the study medication may be withheld 
temporarily, or the dose reduced, as per investigator judgment. Investigators should discuss the 
patient condition with the MHICC medical monitor in order to determine the appropriate dose 
reduction algorithm or study medication discontinuation plan.  
 
Patients withdrawn at any time from the study during the active treatment period should 
complete all last protocol-specified phone call assessments at Day 14 (the reason for withdrawal 
from the study, the date of the last videovisit/phone call and the date of the last dose of double-
blind medication will be clearly documented in the eCRF). 
 
 
5.4 Study Completion 
 
The study will end when the last randomized patient will have completed his (or her) 14-day 
follow-up phone contact or videovisit. Completion of the study by a patient should be clearly 
indicated in the eCRF, along with the date of the last phone call and the date of the last dose of 
double-blind medication.  
 
6 
STUDY MEDICATION 
 
Ingenew Pharma will provide both hesperidin and placebo in bulk to MHI pharmacists who will 
prepare the bottles of 32 capsules of 500 mg each. At the time of randomization, the 
randomization number will be recorded on the appropriate eCRF section. Blinded medication 
will be provided as 500 mg hesperidin capsules or matching placebo capsules. A detailed set of 
dispensing instructions will be provided by the MHICC.  
 
6.1 Medication Dispensing 
 
Study medication may be dispensed by the designated pharmacist according to a detailed set of 
dispensing instructions. Study medication will be shipped directly to the patient’s home. 
 
6.2 Dosage Regimen 
 


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At randomization, patients will be dispensed hesperidin capsule or matching placebo. Patients 
will be instructed to take two capsules once daily at bedtime according to the detailed set of 
dispensing instructions outlined on the label.  
Orally, hesperidin is generally well tolerated. Headache, asthenia, muscle cramps, and 
gastrointestinal side effects such as abdominal pain, dyspepsia, nausea, and diarrhea may occur 
in some patients. There may be unknown risks with taking the investigational product.  
 
 
 
7 
DATA COLLECTION 
 
Electronic Case Report Forms (eCRF) for all patients will be supplied by MHICC. These are to 
be completed as instructed.  
 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
8.1 Statistical Power and Sample Size Considerations  
 
Sample size is based on the proportion of subjects with any of the following COVID-19 
symptoms: fever, cough, shortness of breath or anosmia at day 7 since this time point will be the 
primary focus. Using a two-sided 0.05 significance level, sample sizes of 91 in both groups (182 
total) will achieve 80% power to detect an absolute between groups difference of 20% in the 
proportion of subjects with the above COVID-19 symptoms at day 7. This is assuming that the 
proportions of patients with the above COVID-19 symptoms at day 7 will be 50% in the placebo 
group and 30% in the active treatment group. Factoring in a 15% drop out rate, a total of 216 
patients will be randomized in the study (108 per group). 
8.2 Analysis population 
 
8.2.1 Intent to Treat (ITT) population 
 
All patients randomized will be included in the ITT population. Patients will be assigned to 
treatment groups as randomized for analysis purposes. 
 
8.2.2 Safety population 
 
All patients who received at least one dose of study medication will be included in the safety 
analysis population. Patients will be assigned according to the true treatment received for 
analysis purposes. 
 
8.3 Data analysis 
 
8.3.1 Analysis of efficacy outcomes 
 


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Efficacy analysis will be based on the intent-to-treat principle. The primary analysis will 
compare the proportions of subjects with fever, cough, shortness of breath or anosmia between 
the two treatment groups using a  generalized linear mixed model with terms for treatment group 
(placebo, hesperidin), time (3, 7, 10 and 14 days) and treatment group x time interaction. The 
primary analysis will be the comparison between treatment groups at day 7, although treatment 
groups will also be compared at the other time points. Mean number of COVID-19 symptoms 
will be compared between treatment groups using a Student t-test or a Wilcoxon rank-sum test 
according to distribution. If more appropriate, a Poisson regression model will be used. Duration 
of COVID-19 symptoms will be compared between treatment groups using a log rank test and 
Kaplan-Meier curves will be presented. Subjects who will still have COVID-19 symptoms at the 
end of the study will be censored at the day of their last phone contact or videovisit. The analysis 
of individual COVID-19 symptoms over time will be similar to the analysis of the primary 
endpoint and will use generalized linear mixed models. Composite of COVID-19-related 
hospitalization, mechanic ventilation or death will be compared between treatment groups using 
a chi-square test. All statistical tests will be two-sided and conducted at the 0.05 significance 
level. Statistical analysis will be done using SAS version 9.4 or higher. 
Full details of the statistical analysis will be described in a statistical analysis plan that will be 
finalized and approved prior to database lock. 
8.3.2 Analysis of safety outcomes 
 
Safety of hesperidin will be evaluated by presenting descriptive statistics on adverse events and 
serious adverse events broken down by group. This will be done for the population of patients 
who received at least one dose of study medication (safety population). 
 
8.3.3 Interim analysis 
 
A fully independent 3-member Data and Safety Monitoring Board (DSMB) will be established 
and will review unblinded safety data as detailed in the DSMB charter after randomization of 50 
subjects and after randomization of 100 subjects. If necessary, an additional meeting will take 
place after randomization of 150 subjects. The DSMB charter will pre-specify the rules for early 
study termination, approved by all board members.  
 
9 
STUDY COORDINATION 
 
The MHICC will be responsible for processing and quality control of the data. Project 
management will be carried out as described in the MHICC standard operating procedures 
(SOPs) for clinical studies. The handling of data, including data quality control, will comply with 
all applicable regulatory guidelines, MHICC SOPs and the study Data Management Plan. 


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REFERENCES 
 
1.  Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients 
with pneumonia in China, 2019. N Engl J Med 2020.doi.org/10.1056/ NEJMoa2001017 
 
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet 2020 doi.org/10.1016/S0140-
6736(20)30183-5. 
 
3. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized 
patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 
doi.org/ 10.1001/jama.2020.1585. 
 
4. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao S-Y. Pulmonary pathology of early phase 2019 novel 
coronavirus (COVID-19) pneumonia in two patients with lung cancer, J Thor Oncology 
2020 doi: https://doi.org/10.1016/j.jtho.2020.02.010. 
 
5. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 
and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:1-10.  
 
6. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. 
Critical Care 2017;21:305-307. 
 
7. Mehta P, McAuley DF, Brown M, Emilie Sanchez E, Tattersall RS, Jessica J Manson JJ. 
COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020 
March 13  
 https://doi.org/10.1016/ S0140-6736(20)30628-0. 
 
8. Fedson DS. Treating the host response: an alternative way to manage Ebola in Africa and the 
next influenza pandemic. JOGH 2019;9: doi: 10.7189/jogh.09.010322. 
 
9. Fedson DS. Influenza, evolution, and the next pandemic. Evolution, Medicine, and Public 
Health 2018;260-269. 
 
10. Barsness KA, Bensard DD, Partrick DA, Calkins CM, Hendrickson RJ, McIntyre RC Jr. 
Endotoxin induces an exaggerated interleukin-10 response in peritoneal macrophages of 
children compared with adults. J Pediatr Surg 2004;39:912-5. 
 
11. Barsness KA, Bensard DD, Partrick DA, et al. IL-1beta induces an exaggerated pro- and anti- 
inflammatory response in peritoneal macrophages of children compared with adults. Pediatr 
Surg Int 2004;20:238-42. 
 
12. Hwang W, Lee CG, Lee C, et al. Locus-specific reversible DNA methylation regulates 
transient IL-10 expression in Th1 cells. J Immunol 2018;200:1865-75.  
 


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13.  Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 
mediated by metabolic reprogramming of macrophages. Science 2017;356:513-19. 
 
14.  Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, Hsieh CC and Chao PD. Anti-SARS 
coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic 
compounds. Antiviral Res. 2005;68:36-42. 
 
15.  Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, Wang Q, Xu Y, Li M, Li X, Zheng M, 
Chen L and Li H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of 
potential drugs by computational methods. Acta Pharmaceutica Sinica B. 2020. 
 
16.  Ye J, Guan M, Lu Y, Zhang D, Li C, Li Y and Zhou C. Protective effects of hesperetin on 
lipopolysaccharide-induced acute lung injury by targeting MD2. Eur J Pharmacol. 
2019;852:151-158. 
 
17. Wang N, Geng C, Sun H, Wang X, Li F and Liu X. Hesperetin ameliorates 
lipopolysaccharide-induced acute lung injury in mice through regulating the TLR4-MyD88-
NF-kappaB signaling pathway. Arch Pharm Res. 2019;42:1063-1070. 
 
18.  Park JH, Ku HJ and Park JW. Hesperetin mitigates acrolein-induced apoptosis in lung cells 
in vitro and in vivo. Redox Rep. 2018;23:188-193. 
 
19. Ma H, Feng X and Ding S. Hesperetin attenuates ventilator-induced acute lung injury 
through inhibition of NF-kappaB-mediated inflammation. Eur J Pharmacol. 2015;769:333-
41. 
 
20. Nielsen ILF, Chee WSS, Poulsen L, Offord-Cavin E, Rasmussen SE, Frederiksen H, Enslen 
M, Barron D, Horcajada M-N and Williamson G. Bioavailability Is Improved by Enzymatic 
Modification of the Citrus Flavonoid hesperidin in Humans: A Randomized, Double-Blind, 
Crossover Trial. The Journal of Nutrition. 2006;136:404-408. 
 
21. Chen YW, Yiu CB and Wong KY. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like 
protease (3CL (pro)) structure: virtual screening reveals velpatasvir, ledipasvir, and other 
drug repurposing candidates. F1000Res. 2020;9:129. 
 
22. Demonty I, Lin Y, Zebregs YE, Vermeer MA, van der Knaap HC, Jakel M and Trautwein 
EA. The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in 
moderately hypercholesterolemic men and women. J Nutr. 2010;140:1615-20. 
 
 
 
 
 
 
 


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LIST OF APPENDICES 
 
Appendix 
Title 
A 
Detailed Study Safety Parameters 
B 
Administrative Procedures for the Reporting of Adverse Events 
C 
Other Administrative and Regulatory Procedure 
D 
Declaration of Helsinki  
E 
Symptoms diary 
 
 


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Appendix A 
Detailed Study Safety Parameters 
 
1. Medical/Surgical History 
 
The following elements of medical/surgical history will be recorded at the Screening Visit: 
 
 age 
 ethnic origin 
 sex 
 smoking history 
 history of diabetes 
 history of hypertension 
 history of dyslipidemia 
 prior MI 
 prior PCI 
 prior CABG 
 prior stroke 
 prior heart failure 
 prior obstructive pulmonary disease 
 prior other respiratory disease 
 
2. Physical Appearance 
 
1. weight 
2. height  
3. waist circumference 


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Appendix B 
Administrative Procedures for the Reporting of Adverse Events  
 
 
The following administrative procedures for reporting AEs are to be followed during the conduct 
of this clinical trial. 
 
1 
ADVERSE EVENTS DURING THE TRIAL 
 
Each patient will be observed and queried in a non-specific manner by the investigator or study 
coordinator at each visit for any new or continuing AE since the previous visit. Any AEs prior to 
the first dose of study medication will be recorded in the medical history and kept in the patients’ 
chart. All SAEs will be recorded in the appropriate eCRF section. Information collected will 
include the onset, duration, severity, relationship to study drug, and the management. SAEs are 
to be reported if they are known to occur within 21 days after randomization.  
 
 
The investigator will review concomitant medications being taken by the patient.   
 
Definitions 
 
1.1 Pre-existing condition 
 
A pre-existing condition is one that is present prior to randomization. A worsening of a pre-
existing condition after taking the first dose of investigational product should be reported as an 
AE. 
 
1.2 Adverse Event (AE) 
 
An AE is defined as any unfavorable and unintended sign (including a clinically meaningful 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. 
 
A medical procedure is not considered and should not be reported as an AE. However, the 
medical condition which led to the procedure should be considered as an AE and be reported as 
such. 
 
1.3 Related Adverse Event 
 
A related AE is one where, according to the Investigator, there is a reasonable possibility that the 
event may have been caused by the study product. 
 
1.4 Serious Adverse Event (SAE) 
 
Serious Adverse Events (SAE) are those that meet any of the following International Council for 
Harmonisation (ICH) criteria: 
 


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 Is fatal or immediately life-threatening (NOTE: the term "Life-Threatening" refers 
to an event in which the patient was at immediate risk of death at the time of the 
event; it does not refer to an event which could hypothetically have caused death 
had it been more severe); 
 Results in persistent or significant disability/incapacity; 
 Requires or prolongs patient hospitalization; 
 Is a congenital anomaly/birth defect in the offspring of the patient; 
 Is a cancer; 
 Is an overdose (intentional or accidental); 
 Is judged to be medically important. 
 
Medically important events may not be immediately life-threatening, result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above.  Serious adverse events are to be reported if they are 
known to occur within 21 days after randomization.   
 
Medical and scientific judgment should be exercised in deciding whether other AEs meet these 
criteria and are immediately reportable to the sponsor or its designee. 
 
Hospitalization is defined as a patient admission to a hospital for medical treatment or 
observation; a visit to the emergency room for an outpatient consultation is not considered a 
hospitalization. Moreover, hospitalization for therapy of the target disease(s) of the study if the 
protocol explicitly anticipated and defined the symptoms or episodes is not considered SAEs. 
 
1.5 Life-Threatening Adverse Event 
 
A life-threatening AE is an AE that, in the opinion of the investigator, places the patient at 
immediate risk of death from the reaction as it occurred. 
 
 
1.6 Clinical Laboratory Adverse Event 
 
A clinical laboratory abnormality is regarded as an AE if it has been confirmed by at least 1 
repeat test and suggests a disease and/or organ toxicity severe enough to require active 
management.  
 
1.7 Treatment-Emergent Signs and Symptoms (TESS) 
 
A TESS event is any AE that was not present prior to randomization or that worsens in character, 
intensity or frequency while the patient is in an active treatment period. 
 
 
1.8 Post-treatment Adverse Event 
 
A post-treatment AE is any AE that occurs after treatment is discontinued.   


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2 
HANDLING OF ADVERSE EVENTS 
 
2.1 Treatment-Emergent Signs and Symptoms 
 
Any condition/diagnosis that meets the definition of a TESS event is captured adverse event 
from and kept in the patient’s chart. 
 
2.2 Serious Adverse Events 
 
All SAEs are to be immediately reported as outlined in Section 5.2.1.1., Serious Adverse Events, 
within 24 hours of the Investigator’s first knowledge of the event. 
 
2.3 Intensity 
 
The following criteria are used to assess the intensity of each AE: 
 
 Mild: The patient is aware of the sign or symptom, but finds it easily tolerated. 
 Moderate: The patient has enough discomfort to cause interference with or change 
in usual activities. 
 Severe: The patient is incapacitated and unable to work or participate in many or 
all usual activities. 
 
2.4 Relationship to Study Drug – Physician’s Assessment 
 
Causal relationship between study drug and an AE will be reported by physician’s assessment as 
follows: not related, possibly and probably.  
 
2.5 Clinical Outcome 
 
The following categories are used to assess the clinical outcome of each AE: 
 
 Recovered – The patient has fully recovered from the AE with or without 
observable residual effects. 
 Not Yet Recovered – the patient is still being treated for the residual effects of the 
original AE.  This does not include treatment for pre-existing conditions including 
the indication for the study drug. 
 With sequela.  
 Died Due to this Adverse Event 
 Died, Other Causes 
 Unknown 
 Surgery/Procedure 
 
 


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3 
CAPTURING AVDERSE EVENTS 
 
3.1 Pre-Existing Condition 
 
A pre-existing condition should be captured in the medical history and kept in the patient’s chart.  
 
3.2 Clinical Laboratory Adverse Event 
 
A clinical laboratory abnormality should be reported as an AE only if it is considered to be 
clinically significant by the investigator and confirmed by repeat testing.  
 
3.3 Hospitalization or Surgery/Procedure 
 
Any AE that results in hospitalization (admitted and not just an emergency room visit) should be 
reported as an SAE. Any condition/diagnosis responsible for surgery/procedure should be 
reported as an AE if it meets the criteria for an AE. A medical procedure is not considered and 
should not be reported as an AE. The surgery/procedure itself will be reported as a Clinical 
Outcome of the underlying event. Events that prolong any hospitalization are reported as SAEs. 
 
3.4 Death 
 
The cause of death should be reported as an AE.   
 
4 
REPORTING TO THE SPONSOR 
 
4.1 Immediately Reportable Adverse Events 
 
If an AE meets the definition of Serious, it must be reported IMMEDIATELY in the eCRF. If 
the eCRF is not available, the investigator should send the paper SAE form by fax  
(+1-514-461-1301) as soon as possible and within 24 hours of knowledge of the event. Upon 
return of the availability of the eCRF, the information written on the paper SAE form must be 
recorded in the eCRF. For any questions or concerns, the investigator may send an email to the 
MHICC Medical Monitor at Hesperco_safety@mhicc.org. If any SAE occurs the investigator, 
at his discretion, can withdraw the patient from the study while taking the appropriate follow-up 
action. 
 
MHICC Medical Monitor or his designated representative is responsible to report SUSARs to 
Regulatory Authorities and to notify Ingenew Pharma. 
 
4.2 Other Adverse Events 
 
Study endpoints are to be reported in the eCRF within 5 days of awareness of the event.  
 
In addition to SAEs and study endpoints, the only AEs to be recorded on the eCRF are those that 
are judged related to the study medication by the investigator or that are laboratory abnormalities 


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judged clinically significant by the investigator. Information collected will include the onset, 
duration, severity, relationship to study drug, and the management. 
 
4.3 Follow-Up Period 
 
For SAEs, the patient must remain under observation until the SAE has subsided or stabilized 
and all serious findings have returned to normal or stabilized. Any follow-up information to an 
initial SAE report must be updated in the eCRF. Serious Adverse Events are to be reported if 
they are known to occur within 21 days of randomization.  


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Appendix C 
Other Administrative and Regulatory Procedures 
 
This appendix provides information necessary to administer the study in compliance with global 
Good Clinical Practice (GCP) and government regulations.   
 
Your signature on this cover page of the protocol, subsequent amendments, addenda, and the 
Clinical Trial Agreement confirms that: 
 
 You have been given appropriate information on the study drug 
 You have read and understand the protocol and appendices 
 You agree to conduct the study in accordance with the provisions of the protocol and 
applicable regulations 
 You acknowledge the sponsor’s ownership of the data and results obtained from the 
conduct of the protocol 
 You agree to maintain the confidentiality of information as outlined in this protocol 
 
1. ADMINISTRATIVE PROCEDURES 
 
1.1 Ethics and Informed Consent 
 
1.1.1 Declaration of Helsinki 
 
This study will be conducted in accordance with the Declaration of Helsinki. 
 
1.1.2 Ethics Committee (EC) Review and Approval of the Study 
 
An EC that is organized and operates according to GCP and applicable laws and regulations, 
should safeguard the rights, safety, and well-being of all trial patients.  No patient should be 
admitted to a trial before the EC issues its written approval/favorable opinion of the trial. 
 
The investigator is responsible for: 
 
 Promptly reporting to the EC all changes in the research activity, all unlabeled AEs, 
and all unanticipated problems involving risks to human patients or others; 
 Not making any changes in the research without EC approval, except when absolutely 
necessary to eliminate apparent immediate hazards to human patients; 
 Submitting a progress report describing the status of the clinical investigation to the 
EC at appropriate intervals not exceeding 1 year; and 
 Submitting a final report when required by the EC within 3 months following 
completion, termination or discontinuation of the study.  Copies of these reports will 
also be provided to the sponsor or the sponsor’s designated representative. 
 
In general, all communications with the EC regarding the study will be handled by the principal 
investigator or coordinating investigator, (if applicable) of the study.  The sponsor or the 
sponsor’s designated representative may directly contact the EC if necessary, but must not 


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attempt to influence the EC in any way.  A copy of all communications from the EC to the 
investigator regarding its review of an initial approval of the study and its re-approvals at 
intervals must be provided to the sponsor by the investigator. 
 
1.1.3 Informed Consent Form (ICF) 
 
The investigator or research personnel will fully explain the purpose of the study to the patient or 
his/her guardian prior to entering the patient into the study. Informed consent will be obtained 
from patients who volunteer to participate in the study prior to the conduct of any study-specific 
procedures. The patient will be considered “enrolled” into the study at the time an informed 
consent is provided. 
 
 
1.1.4 Emergency Code Breaks 
 
The investigator will be provided with a mechanism for emergency determination of a patient’s 
treatment regimen (if required for proper treatment of the patient).  
 
1.1.5 Confidentiality of Patient Information 
 
All patients will be assigned a patient number. Subsequently, patients will be identified in the 
eCRF only by that number. Any information published as a result of the study will be such that it 
will not permit identification of any patient. The information from this study will be available 
within the sponsor organization and may be shared with the regulatory authorities.  It may also 
be the subject of an audit by a regulatory agency within the local government. The patient’s 
identity will remain protected except as required for legal or regulatory inquiries. 
 
1.1.6 Publication of Study Results 
 
All information and data regarding the study drug obtained in connection with the conduct of this 
study are considered confidential. Accordingly, the sponsor (Montreal Heart Institute) retains the 
right to review manuscripts, abstracts, and presentation material related to this protocol and its 
amendments/addenda prior to presentation or submission to a journal. This review will not 
restrict publication of facts or opinions formulated by the investigator.  
 
1.1.7 Roles and Responsibilities 
 
Montreal Heart Institute (MHI) 
The Montreal Heart Institute is responsible for the conduction of the study. 
 
Montreal Heart Institute Foundation:  
The Montreal Heart Institute Foundation is the sponsor for this study. 
 
Montreal Health Innovations Coordinating Center (MHICC) 


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The MHICC is a division of the Montreal Heart Institute, and has been designated to manage and 
coordinate this trial. These activities include overall project management, site selection, 
distribution of study materials, site management including clinical monitoring, SUSARs 
reporting to regulatory authorities, data management, biostatistical analysis and writing of the 
final clinical study report.  
 
Ingenew Pharma Inc. 
Ingenew Pharma Inc. will provide the Montreal Heart Institute with study medication and 
matched placebo for all patients for the duration of this trial according to a Clinical Supply 
Agreement between them and MHI. 
 
Investigator 
The Investigator is responsible for ensuring this trial is conducted according to the signed 
investigator statement, following ICH/GCP guidelines and all other local regulatory 
requirements; for protecting the rights, safety, and welfare of subjects under the investigator's 
care; and ensure accountability of the investigational product.   
 
It is the responsibility of the investigator(s) that: 
 
 The study is conducted in accordance with the Declaration of Helsinki and according to 
the guidelines in the attached appendices. 
 This study is conducted in compliance with all applicable laws and regulations of the 
local and country where the study is conducted. 
 This study is not initiated until the protocol and a copy of the informed and consent form 
(ICF) have been reviewed and approved by a duly constituted Ethics Committee (EC), 
and that any local institutional requirements are satisfied.  
 Each patient and/or their legal guardian (or caregiver) reads, understands, and signs an 
instrument of informed consent.    
 The patient be informed that personal information may be examined during audit by 
properly authorized individuals but that personal information will be treated as strictly 
confidential and not be publicly available. 
 The patient log and patient records are retained as detailed in this protocol. 
 
The final responsibility for the content of the informed consent statement remains with the 
investigator and the EC. Indemnification of the investigator, coworkers, and the institution is 
provided as specified in the Clinical Trial Agreement.  
 
2. PROTOCOL AMENDMENTS AND ADDENDA 
 
2.1 Definitions 
 
A protocol amendment is any systematic change (e.g., revision, addition, deletion) that is made 
to the Final Protocol in a clinical study and is identified by consecutive Arabic numerals (e.g., 


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Amendment 1, Amendment 2, etc.).  Amendments can be made regardless of whether the 
protocol has been signed by the investigator or whether or not the protocol has been 
implemented at a site. 
 
A Protocol Addendum is any systematic change (e.g., revision, addition, deletion) that is made to 
the Final Protocol and is identified by single sequentially ordered letters (e.g., Addendum A, 
Addendum B). 
 
An Urgent Protocol Amendment is one that must be instituted quickly, usually to eliminate an 
apparent immediate hazard to subjects and may be implemented prior to eventual EC review 
(within 5 working days) and submission to regulatory authorities. 
 
All amendments/addenda to the protocol must be approved by the principal investigator, the 
sponsor and the EC of the investigator's institution.  The investigator is responsible for 
submitting any proposed change in the approved protocol in writing to the EC for review and 
approval and for sending a copy of the approval to the sponsor or designee. All 
amendments/addenda will be filed with appropriate local regulatory authorities by the sponsor or 
designee. 
 
With the exception of urgent protocol amendments, as outlined below, the 
amendment/addendum will apply to all subjects/patients entered into the study (or all 
subjects/patients in affected sites for addenda) after it has gone through the applicable procedure 
described above and been approved by the EC.  Any amendments/addenda proposed in a 
multicenter protocol must be approved by the EC at the individual study site before it can be 
placed in effect at that site. 
 
2.2 Urgent Protocol Amendment 
 
If the amendment eliminates an apparent immediate safety hazard to the patient (urgent protocol 
amendment), it may be implemented immediately.  The sponsor will promptly notify the 
appropriate regulatory authorities of the amendment while the investigator will notify his/her EC 
of the change in writing within 5 working days of its implementation. 
 
3. STUDY TERMINATION 
 
The study will normally be carried to completion as described in the protocol. However, if in the 
course of the study a severe adverse reaction or intercurrent illness is noted in any patient, 
consideration may be given to abrupt termination of the study for this patient. Such a decision 
may be made by either the principal investigator or by the sponsor, or both. Likewise, the study 
may be terminated due to ethical/safety issues or at the sponsor’s discretion or for regulatory 
issues. 
 
 
 
 


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Appendix D Declaration of Helsinki 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
Preamble 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
  
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
 
General Principles 
 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient's best interest when providing 
medical care.” 
 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 


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6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 


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Risks, Burdens and Benefits  
 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. 
 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study.            
 
Vulnerable Groups and Individuals 
 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 


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Page 41 of 48 
 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions. 
  
Privacy and Confidentiality  
 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in 
a research study unless he or she freely agrees. 
 


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26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed.       
 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorized representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorized representative. The 
potential subject’s dissent should be respected. 
 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research  group. 
In such circumstances the physician must seek informed consent from the legally 
authorized representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 


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February 17th, 2021 
 
Page 43 of 48 
 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorized representative. 
 
 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention  
 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention.  
 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 


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36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 


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Appendix E 
 
                                                      
 
                                                                              
 
Protocol: MHICC-2020-003 
Home self-monitoring on COVID-19 symptoms: The Hesperidin 
Coronavirus study (Hesperidin)   
                                                                                                                
                                                 Patient #: ____ ____  ____ ____ ____ 
                                                
                                                    Diary# 
(Circle) 
                                                                                              
 
                                                                          
                                                                                       Important 
 
Please use the diaries in the order in   which they are numbered (1, 2, 3 
and 4) and have your complete diary on hand for each phone call. 
 
                                                     
                                                             
Symptoms 
 Diary 
1
2
3 
4 


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Page 46 of 48 
 
 
  
 
 
 
Instructions 
 
This diary is to be used to collect information on the daily symptoms you experience.  
 
This daily diary has been designed with check boxes to make it easier for you to fill out every day.  
 
Please check your symptoms every day for 14 days. There is one page for each week that you will be taking the 
medication starting with Day 1.   
We will ask you for the symptoms when we call at the beginning of the study and on day 3, day 7, day 10 and 14. Please 
have the diary with you.  
 
  
 
 
 
 
 
 
 


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Page 47 of 48 
 
Covid-19_ Symptoms Log 
Protocol: MHICC-2020-003 
Symptoms 
Day 1 
 
Yes  No 
Day 2 
 
Yes  No 
Day 3 
 
Yes  No 
Day 4 
 
Yes  No 
Day 5 
 
Yes  No 
Day 6 
 
Yes  No 
Day 7 
 
Yes  No 
Recent cough or aggravation of 
chronic cough 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
  
 
    
  
 
    
  
Fever (enter temperature) 
  
   
  
Feverish/chills (temperature not taken) 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Sore throat 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Runny nose 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Shortness of breath/difficulty breathing 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Nausea/vomiting  
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Headache 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
General weakness 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Pain (muscular, chest, abdominal, 
joint, etc.) 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
  
 
    
  
 
    
  
Irritability/confusion 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Diarrhea  
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
Sudden Loss of smell (anosmia) 
 
    
  
 
    
  
 
    
  
 
    
   
 
    
  
 
    
  
 
    
  
 Comment or other, specify: 
 
 
 
 
Reminder: Please have the completed diary on hand at each phone call or video contact follow up. 
 
 
 
 


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Page 48 of 48 
 
 
 
Symptoms 
Day 8 
 
Yes  No 
Day 9 
 
Yes  No 
Day 10 
 
Yes  No 
Day 11 
 
Yes  No 
Day 12 
 
Yes  No 
Day 13 
 
Yes  No 
Day 14 
 
Yes  No 
Recent cough or aggravation of 
chronic cough 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Fever (enter temperature) 
 
 
 
 
Feverish/chills (temperature not taken) 
    
    
    
    
 
    
 
    
 
    
 
Sore throat 
    
    
    
    
 
    
 
    
 
    
 
Runny nose 
    
    
    
    
 
    
 
    
 
    
 
Shortness of breath/difficulty breathing 
    
    
    
    
 
    
 
    
 
    
 
Nausea/vomiting  
    
    
    
    
 
    
 
    
 
    
 
Headache 
    
    
    
    
 
    
 
    
 
    
 
General weakness 
    
    
    
    
 
    
 
    
 
    
 
Pain (muscular, chest, abdominal, 
joint, etc.) 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Irritability/confusion 
    
    
    
    
 
    
 
    
 
    
 
Diarrhea  
    
    
    
    
 
    
 
    
 
    
 
Sudden Loss of smell (anosmia) 
    
    
    
    
 
    
 
    
 
    
 
 Comment or other, specify: 
 
 
 
 
 
Reminder: Please have the completed diary on hand at each phone call or video contact follow up. 
 
 
 

SAP_001.pdf: 
 
 
Protocol #: MHICC‐2020‐003 
 
A phase 2, randomized, double‐blind, placebo‐controlled study of hesperidin 
therapy on COVID‐19 symptoms: 
The Hesperidin Coronavirus study (Hesperidin) 
 
NCT #: NCT04715932 
 
 
Statistical Analysis Plan (SAP) 
Version 29‐Apr‐2021 


 
BS-T1-001-05 
Confidential 
Page 1 of 18 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Protocol number: MHICC-2020-003 
 
A phase 2, randomized, double-blind, placebo-controlled study of hesperidin therapy on COVID-
19 symptoms: The Hesperidin Coronavirus study 
 
Hesperidin 
 
 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
29-APR-2021 
 
 
 
 
Prepared by: 
Camille Rosa, M.Sc. 
Biostatistician 
Montreal Health Innovations Coordinating Center (MHICC) 
5000 Bélanger Street 
Montréal, QC  H1T 1C8 
Phone: 514-461-1300 ext. 2032 / Fax: 514-461-1301 
 
 
 




 
SAP: 29-APR-2021  
Protocol number: MHICC-2020-003 
 
BS-T1-001-05 
Confidential 
Page 3 of 18 
  
Revision History 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
Final 
29-APR-2021 
Camille Rosa 
Initial version 
 
 
 
 
 
 


 
SAP: 29-APR-2021  
Protocol number: MHICC-2020-003 
 
BS-T1-001-05 
Confidential 
Page 4 of 18 
 
TABLE OF CONTENTS  
 
1 
Introduction ......................................................................................................................................... 6 
2 
Study Description ................................................................................................................................. 6 
2.1 
Study Design ................................................................................................................................ 6 
2.2 
Study Objectives .......................................................................................................................... 6 
3 
Datasets Analyzed ................................................................................................................................ 7 
3.1 
Intent-To-Treat (ITT) Population ................................................................................................. 7 
3.2 
Safety Population ........................................................................................................................ 7 
4 
Efficacy Endpoints ................................................................................................................................ 7 
4.1 
Primary Efficacy Endpoint............................................................................................................ 7 
4.2 
Secondary Efficacy Endpoints ...................................................................................................... 7 
4.3 
Tertiary (or Exploratory) Efficacy Endpoints................................................................................ 8 
5 
Safety Parameters ................................................................................................................................ 9 
5.1 
Adverse Events ............................................................................................................................ 9 
5.2 
Serious Adverse Events................................................................................................................ 9 
6 
Statistical Methodology ..................................................................................................................... 10 
6.1 
Determination of Sample Size ................................................................................................... 10 
6.2 
Statistical Considerations .......................................................................................................... 10 
6.2.1 
Handling of Missing Data ...................................................................................................... 10 
6.3 
Study Subjects ........................................................................................................................... 11 
6.3.1 
Subject Disposition ................................................................................................................ 11 
6.3.2 
Protocol Deviations ............................................................................................................... 11 
6.3.3 
Datasets Analyzed ................................................................................................................. 11 
6.3.4 
Demographic and Baseline Characteristics ........................................................................... 11 
6.3.5 
Prior and Concomitant Medications ..................................................................................... 11 
6.3.6 
Study Medication Administration ......................................................................................... 12 
6.4 
Efficacy Analysis ......................................................................................................................... 12 
6.4.1 
Primary Analysis .................................................................................................................... 12 
6.4.2 
Secondary Analysis ................................................................................................................ 13 
6.4.3 
Exploratory Analysis .............................................................................................................. 13 
6.5 
Safety Analysis ........................................................................................................................... 14 
6.5.1 
Treatment Exposure .............................................................................................................. 14 
6.5.2 
Adverse Events and Serious Adverse Events ......................................................................... 14 
6.5.2.1 
Adverse Events ............................................................................................................. 14 
6.5.2.2 
Serious Adverse Events ................................................................................................ 14 
7 
Summary Tables, Figures and Listings ................................................................................................ 15 
8 
Appendices ......................................................................................................................................... 17 
APPENDIX A COVID-19_ SYMPTOMS LOG .................................................................................................... 17 
APPENDIX B TIMETABLE OF VISITS AND PROCEDURES ..................................................................................... 18 


 
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LIST OF ABBREVIATIONS 
 
ACE2 
Angiotensin Converting Enzyme 2 
AE 
Adverse Event 
eCRF 
Electronic Case Report Form 
CRF 
Case Report Form 
DSMB  
 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
e-Consent        
electronic Consent 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ITT 
Intent To Treat 
IUD 
Intrauterine device 
IRB 
Institutional Review Board 
LPS 
Lipopolysaccharides     
MHICC 
Montreal Health Innovations Coordinating Center 
PCR   
Polymerase Chain Reaction 
qPCR   
quantitative  Polymerase Chain Reaction 
PP 
Per Protocol 
PO (po) 
Per os 
PRN 
pro re nata (as necessary) 
SAE 
Serious Adverse Event 
SOPs 
 
Standard operating procedures 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TESS 
Treatment-Emergent Signs and Symptoms 
WMA  
World Medical Association 
 
 
 


 
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1 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to present the statistical methodology that will be used 
for the final analysis of Montreal Heart Institute protocol MHICC-2020-003.  This plan also provides a 
description of the tables, figures and listings that will be included in the final statistical report. It is based 
on the protocol dated 17FEV2021 and on the annotated case report form (CRF) version 2.0. In case of 
differences in terms of descriptions or explanations between the SAP and the clinical protocol, the SAP 
will supersede the protocol. Any deviation to this SAP would be reported in the statistical report. 
 
2 
STUDY DESCRIPTION 
 
2.1 
Study Design 
 
This will be a randomized, double-blind, placebo-controlled study. The study will include subjects from 
Quebec diagnosed with COVID-19 infections. Following informed consent, 216 subjects meeting all 
inclusion and no exclusion criteria will be randomized to receive either hesperidin (1000 mg q.d.) or 
placebo (1:1 allocation ratio) for 14 days. Investigational drug will be delivered to the patients’ homes. In 
addition, patients will be provided with an oral electronic thermometer as well as a daily symptoms diary 
(see Appendix A). Follow-up phone assessments will occur after 3 7, 10, and 14 days following 
randomization for evaluation of the occurrence of any trial endpoints or other adverse events. Electronic 
CRF (eCRF) will be completed by the research personnel over the phone with the patients. 
 
 
The schedule of visits for this study is outlined in Appendix B. However, a patient may be evaluated at any 
time for safety concerns.  
 
2.2 
Study Objectives 
 
The primary objective of the study is to determine the effect of hesperidin therapy on the presence of 
selected COVID-19 symptoms (fever, cough, shortness of breath or anosmia) at 3, 7, 10, and 14 days 
following randomization. 
 
The secondary objectives are: 
1- To determine the effect of hesperidin therapy on the mean number of COVID-19 symptoms at 3, 
7, 10, and 14 days following randomization. 
2- To determine the effect of hesperidin therapy on the duration of COVID-19 symptoms. 
3- To determine the effect of hesperidin therapy on the presence of each individual COVID-19 
symptoms at 3, 7, 10, and 14 days following randomization. 
 
The exploratory objectives are: 
1- To evaluate the effect of hesperidin therapy on the presence of each individual COVID-19 
symptoms on a daily basis based on a patient symptoms’ diary. 
2- To evaluate the effect of hesperidin therapy on COVID-19-related hospitalization, mechanical 
ventilation and death in the 14 days following randomization. 
 
 


 
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3 
Datasets Analyzed 
 
Subjects who were not eligible for randomization but who have been erroneously randomized into the 
study will be excluded from all datasets analyzed, if they did not take study medication. In this study, 
pregnancy tests are shipped with the medication at randomization. In case of positive pregnancy test, 
women will not be eligible and will also be excluded from all datasets analyzed, if they did not take study 
medication.  
 
3.1 
Intent-To-Treat (ITT) Population  
 
All patients randomized that have been delivered study medications will be included in the ITT population 
(i.e. subjects having a randomization number on the Randomization Form of the electronic case report 
form (eCRF)), excluding randomized women whose pregnancy test is positive. In the ITT population, 
subjects allocated to a treatment group by randomization will be followed up, assessed and analyzed as 
members of that group irrespective of their compliance to the planned course of treatment. ITT 
population will be approved by the sponsor prior to database lock. 
 
3.2 
Safety Population 
 
All patients who took at least one dose of study medication will be included in the safety population. 
Patients will be assigned according to the true treatment received for analysis purposes. If a patient 
receives hesperidin at randomization or as supplemental bottle, the true treatment received will be 
imputed as hesperidin. The subjects of the safety population will be identified using the variable MEDIC 
of the Study Medication Administration Form of the eCRF. If a woman with a positive pregnancy test 
took at least one dose of study medication even it is not recommended, she will be included in the 
safety population. The same will apply if the unlikely case of a subject erroneously randomized who took 
at least one dose of study medication.  Safety population will be approved by the sponsor prior to 
database lock. 
 
 
4 
EFFICACY ENDPOINTS 
 
4.1 
Primary Efficacy Endpoint 
 
The primary endpoint will be the proportion of subjects with any of the following COVID-19 symptoms: 
fever, cough, shortness of breath or anosmia, at day 3, 7, 10 and 14 of the patient’s symptoms diary. 
Presence of these symptoms (Yes/No) will be identified using the Covid-19 Symptoms Form of the eCRF 
(variables COUGH, FEVER [considered a symptom if greater than 38⁰], SBREATH and ANOS respectively) 
at DAY 3, DAY 7, DAY 10 and DAY 14. 
 
4.2 
Secondary Efficacy Endpoints 
 
 
Mean number of COVID-19 symptoms (range 0 – 13) at day 3, 7, 10 and 14 of the patient 
symptoms’ diary. This endpoint will be derived using the Covid-19 Symptoms Form of the eCRF at 


 
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DAY 3, DAY 7, DAY 10 and DAY 14. For each subject, the number of symptoms reported as ‘Yes’ 
will be calculated, adding one if the symptom “Fever” is greater than 38⁰. 
 
 
Duration of COVID-19 symptoms, defined as the number of days between randomization and 
complete disappearance of symptoms. More specifically, duration of COVID-19 symptoms will be 
taken as day of complete disappearance (because randomization is DAY 0). Subjects who will still 
have at least one symptom at their last assessment will be censored at the day of this last 
assessment. 
 
To determine day of complete disappearance of symptoms, all symptom assessments from the 
patient’s diary will be sorted by day (variable DAYPARM). At each time point, the assessment will 
be categorized as complete disappearance of symptoms (if number of symptoms = 0) or no 
complete disappearance of symptoms (if number of symptoms > 0).  
 
 If there is complete disappearance of symptoms at Day 14 (or last assessment), day of 
complete disappearance is the first day when complete disappearance occurred with no 
relapse. 
 If there is no complete disappearance of symptoms at Day 14 (or last assessment), the 
day of this last assessment will be the censoring day. 
 
It should also be noted that subjects who do not complete the study will be classified as still 
having symptoms (i.e. no complete disappearance) REGARDLESS if symptoms disappeared 
earlier. Date of censoring will be the date of study discontinuation.  
 
 
For each of the 13 COVID-19 symptoms listed in the appendix, proportion of subjects with the 
symptom at day 3, 7, 10 and 14 of the patient symptoms’ diary. Presence of these symptoms 
(Yes/No) will be identified using the Covid-19 Symptoms Form of the eCRF (variables COUGH, 
FEVER [considered a symptom if greater than 38⁰], FEVERISH, STHROAT, …, ANOS) at DAY 3, DAY 
7, DAY 10 and DAY 14. 
 
4.3 
Tertiary (or Exploratory) Efficacy Endpoints 
 
 
For each of the 13 COVID-19 symptoms listed in the appendix, proportion of subjects with the 
symptom on a daily basis based on patient’s diary. Presence of these symptoms (Yes/No) will be 
identified using the Covid-19 Symptoms Form of the eCRF (variables COUGH, FEVER [considered 
a symptom if greater than 38⁰], FEVERISH, STHROAT, …, ANOS) at DAY 1 to DAY 14. 
 
 
Composite of COVID-19-related hospitalization, mechanic ventilation or death in the 14 days 
following randomization. These events will be identified using the Adverse Events Form of the 
CRF:  
 COVID-19 related hospitalization: AECOVID=YES and AESER=YES and AESHOSP=YES; date 
of hospitalization = ADMDAT 
 COVID-19 related mechanic ventilation: AECOVID=YES and AEVENT=YES; date of 
mechanic ventilation = AEVSDTA  
 COVID-19 death: AECOVID=YES and AEOUT=Fatal; date of death = AEENDAT1 
 


 
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5 
SAFETY PARAMETERS 
 
Safety will be assessed through adverse events (AEs) and serious adverse events (SAEs). 
 
5.1 
Adverse Events 
 
Information regarding AEs will be collected at day 3, 7, 10 and 14 after randomization. Any AEs prior to 
randomization will be recorded in the medical history and kept in the patients’ chart. Information 
collected will include the onset, end date (if applicable), severity, relationship to study drug, and the 
management. 
 
A treatment-emergent AE is an AE which started on or after the date of the first dose of study medication. 
In case the date of first dose of study medication is unknown, the AE will be assumed to be treatment-
emergent if it started on or after the study medication delivery date. 
 
In case the day the AE started is unknown (month and year are required fields for the AE start date), the 
AE will be assumed to be treatment-emergent if it started on the same month and year as the date of first 
dose of study medication (or study medication delivery date); otherwise the partial AE start date will be 
compared to the date of first dose of study medication (or study medication delivery date) and the AE will 
be classified accordingly. 
 
A related AE is one where, according to the investigator, there is a reasonable possibility that the event 
may have been caused by the study drug. They will be identified from the Adverse Events Form of the 
eCRF as AEs that are possibly or probably related to study drug.  
 
5.2 
Serious Adverse Events 
 
Serious Adverse Events (SAE) are those that meet any of the following International Council for 
Harmonisation (ICH) criteria: 
 
 
Is fatal or immediately life-threatening (NOTE: the term "Life-Threatening" refers to an event in 
which the patient was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused death had it been more severe); 
 
Results in persistent or significant disability/incapacity; 
 
Requires or prolongs patient hospitalization; 
 
Is a congenital anomaly/birth defect in the offspring of the patient; 
 
Is a cancer; 
 
Is an overdose (intentional or accidental); 
 
Is judged to be medically important. 
 
Medically important events may not be immediately life-threatening, result in death or hospitalization, 
but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the 
definition above. Serious adverse events are to be reported if they are known to occur within 21 days 
after randomization. 
 


 
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6 
STATISTICAL METHODOLOGY 
 
6.1 
Determination of Sample Size 
 
Sample size is based on the proportion of subjects with any of the following COVID-19 symptoms: fever, 
cough, shortness of breath or anosmia at day 7 since this time point will be the primary focus. Using a 
two-sided 0.05 significance level, sample sizes of 91 in both groups (182 total) will achieve 80% power to 
detect an absolute between groups difference of 20% in the proportion of subjects with the above COVID-
19 symptoms at day 7. This is assuming that the proportions of patients with the above COVID-19 
symptoms at day 7 will be 50% in the placebo group and 30% in the active treatment group. Factoring in 
a 15% drop out rate, a total of 216 patients will be randomized in the study (108 per group). 
 
6.2 
Statistical Considerations 
 
Baseline, efficacy and safety data will be reported using descriptive statistics. N, mean, standard deviation, 
median, Q1, Q3, minimum and maximum will be provided for continuous variables. Count and frequency 
will be provided for categorical variables. 
 
Basic assumptions of the proposed analyses will be verified prior to the analyses. Subject disposition, 
datasets analyzed, baseline characteristics and efficacy analyses will be carried out on the ITT population 
defined in Section 3.1 according to the intent to treat principle. Safety analyses will be done on the safety 
population defined in Section 3.2.  
 
All statistical tests will be two-sided and conducted at the 0.05 significance level. Statistical analyses will 
be done using SAS version 9.4 or higher. 
 
A fully independent 3-member Data and Safety Monitoring Board (DSMB) will be established and will 
review unblinded data as detailed in the DSMB charter after randomization of 50, 100 and possibly 150 
subjects. The DSMB charter will pre-specify the rules for early study termination, approved by all board 
members. 
 
6.2.1 
Handling of Missing Data  
 
Subjects will be asked to assess daily the presence (Yes/No) of 13 COVID-19 symptoms for a duration of 
14 days. Most efficacy endpoints rely heavily on the assessment of these symptoms so a rule has to be 
defined in case the symptoms are reported as ‘Not Done’ or are missing.   
 
At any given day (DAY 1 to DAY 14), if some symptoms among the 13 symptoms are reported as ‘Not 
Done’ or are missing, these symptoms will be imputed as the last observation carried forward.   
 
On the other hand, if, at any given day, all symptoms are reported as ‘Not Done’ or are missing, the 
following will be done:  
 
 
If the subject has died, then all symptoms will be imputed as ‘Yes’ (and symptom “Fever” as 
greater than 38⁰) if that day is prior to date of death. 
 


 
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 
Otherwise, the symptoms will not be imputed and the assessment on that day will be 
considered missing. 
 
6.3 
Study Subjects 
 
6.3.1 
Subject Disposition  
 
Number of subjects randomized, number of subjects who took at least one dose of study medication, 
number of randomized subjects completing the study and reasons for discontinuation will be summarized 
overall and by treatment group.  A listing of subject disposition will be provided and will include subject 
ID, date of informed consent, date of randomization, randomized treatment group, result of the 
pregnancy test, day of first dose, day of last dose, completion (Yes/No), date of discontinuation and reason 
for discontinuation. Subject disposition will also be presented with a flow chart. 
 
 
The number of days between the positive diagnosis for COVID-19 infection and the date of randomization 
will be summarized overall and by treatment group for the ITT population. The same will be done for the 
number of days between the first COVID-19 symptoms prior to randomization and the date of 
randomization. The first COVID-19 symptoms prior to randomization will also be displayed.   
 
6.3.2 
Protocol Deviations  
 
Protocol deviations, as collected on the Protocol Deviation Form of the eCRF, will be summarized overall 
and by treatment group for the ITT population. Major protocol deviation will be summarized similarly. A 
listing will also be provided.  
 
6.3.3 
Datasets Analyzed 
 
The number of subjects in each datasets will be summarized overall and by treatment group. A listing, 
including reason for being excluded from a given dataset, will be provided as well. 
 
6.3.4 
Demographic and Baseline Characteristics 
 
Demographic data (age at informed consent, sex, ethnicity, race) and baseline characteristics such as 
physical appearance (height weight, waist circumference), medical and surgical history (smoking, 
diabetes, hypertension, dyslipidemia, myocardial infarction, percutaneous coronary intervention, 
coronary artery bypass graft surgery, stroke, heart failure, respiratory disease) as well as other past or 
present clinically significant medical or surgical conditions will be summarized using descriptive statistics, 
overall and by treatment group for the ITT population.   
 
A listing will be presented for demographic data. 
 
6.3.5 
Prior and Concomitant Medications 
 
Prior and concomitant medications will be coded with respect to indication and generic name using the 
WHO Drug dictionary (version C March 2018).   
 


 
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Frequency of use of medications at randomization will be presented for the subjects of the ITT population 
by therapeutic class and preferred term, overall and for each treatment group.   
 
A medication will be flagged as being ongoing at the time of randomization if: 
 
Medication start date < randomization date 
AND 
 
Medication end date ≥ randomization date OR Medication is ongoing 
 
In case of missing or incomplete medication start / end dates, the following rules will be applied: 
 
If 1) the medication start date is completely missing or 2) only the year is specified and it is the 
same as the randomization year or 3) only the month/year are specified and they are the same 
as the randomization month/year, then the medication will be assumed to have started before 
randomization. 
 
If 1) the medication end date is completely missing or 2) only the year is specified and it is the 
same as the randomization year or 3) only the month/year are specified and they are the same 
as the randomization month/year, then the medication will be assumed to have ended after 
randomization. 
 
Otherwise, partial medication start / end dates will be compared to the randomization date and 
the medication will be classified accordingly. 
 
Frequency of use of prior and concomitant medications will also be presented for the subjects of the ITT 
population by therapeutic class and preferred term, overall and for each treatment group. 
 
6.3.6 
Study Medication Administration 
 
Number and proportion of subjects who received study medication, who took study medication and for 
whom the blinded was maintained will be provided, overall and by treatment group, for the ITT 
population. Number and proportion of subjects for whom study medication was prematurely 
discontinued, along with reason, will be displayed as well, overall and by treatment group.  
 
Information on study medication administration will be listed. 
 
6.4 
Efficacy Analysis 
 
All efficacy analyses will be conducted on the ITT population.  
 
6.4.1 
Primary Analysis 
 
Number and proportion of patients with fever, cough, shortness of breath or anosmia will be 
summarized at 3, 7, 10 and 14 days, overall and by treatment group.  
 
The primary analysis will compare the proportions of subjects with these symptoms between the two 
treatment groups using a generalized linear mixed model (GLMM), more precisely a repeated binary 
logistic regression model, with terms for treatment group (placebo, hesperidin), time (3, 7, 10 and 14 
days) and treatment group x time interaction. Contrasts under this model will allow for the comparisons 
of the proportions at each time point. The primary analysis will be the comparison between treatment 


 
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groups at day 7, although treatment groups will also be compared at the other time points. Odds ratios 
will be provided at each time point with 95% confidence intervals and p-values. 
 
Data for the primary endpoint will be listed. 
 
6.4.2 
Secondary Analysis 
 
 
Number of COVID-19 symptoms (range 0 – 13) will be summarized using descriptive statistics at 
3, 7, 10 and 14 days, overall and by treatment group. 
 
Mean number of COVID-19 symptoms will be compared between treatment groups using a 
repeated measures analysis of variance (ANOVA) model with terms for treatment group 
(placebo, hesperidin), time (3, 7, 10 and 14 days) and treatment group x time interaction. 
Contrasts under this model will allow for the comparisons of the mean number of symptoms at 
each time point. Mean differences will be presented with 95% confidence intervals and p-
values. If more appropriate given the distribution of the data, a Poisson regression model for 
repeated measures could be used.  
 
 
Number and proportion of subjects with complete disappearance of COVID-19 symptoms after 
randomization will be provided overall and by treatment group. In those subjects, duration of 
symptoms will be summarized using descriptive statistics. 
 
Duration of COVID-19 symptoms will be compared between treatment groups using a log rank 
test and Kaplan-Meier curves will be presented.  
 
 
Individual COVID-19 symptoms over time (3, 7, 10 and 14 days) will be presented and analyzed 
as the primary endpoint, using the statistical approach described in section 6.4.1.  
 
6.4.3 
Exploratory Analysis 
 
 
The number and proportion of subjects with each individual COVID-19 symptom will be 
summarized on a daily basis, i.e. at 1, 2, 3, …, 14 days, overall and by treatment group.  
 
 
In each treatment group, the incidence of the composite of COVID-19-related hospitalization, 
mechanic ventilation or death in the 14 days following randomization will be calculated as the 
number of subjects who either died, were hospitalized or required mechanic ventilation in the 
14 days following randomization, divided by the number of subjects randomized to that 
treatment group. Number and proportion of subjects with this composite endpoint will be 
presented, overall and by treatment group. The incidence will be compared between treatment 
groups using a chi-square test. If the number of events is low, Fisher’s exact test could be used.  
 
Since this endpoint is defined in the 14 days following randomization, the delay between an 
event and randomization will be calculated as date of the event (date of death, date of 
hospitalization or date of mechanic ventilation) – date of randomization (in days), and any event 
for which the delay is > 14 days will be excluded from the analysis. In case the date of the event 
is incomplete (the exact day could be unknown, but the month and year should be known as 


 
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they are required fields), the missing event will be assumed to occur the first day of the month, 
unless the randomization date is after, in which case the event will be assumed to occur the day 
of the randomization.  
 
6.5 
Safety Analysis 
 
The safety analyses described in this section will be conducted on the safety population (patients who 
took at least one dose of study medication). Safety of hesperidin will be evaluated by presenting 
descriptive statistics on adverse events and serious adverse events broken down by group. No formal 
statistical testing is planned for the safety parameters. 
 
6.5.1 
Treatment Exposure 
 
Duration of exposure will be defined as number of days on treatment (computed as date of last dose – 
date of first study drug dispensed + 1) for each subject of the safety population.  Duration of exposure will 
be summarized overall and by treatment group.  Duration of exposure will also be categorized according 
to 3 days intervals ([1-3], [4-6], [7-9], etc.) and summarized accordingly using frequencies and 
percentages, overall and by treatment group.   
 
6.5.2 
Adverse Events and Serious Adverse Events 
 
6.5.2.1 
Adverse Events 
 
AEs will be coded by system organ class and body system according to the MedDRA dictionary (version 
23.1).  
 
The total number of TEAEs reported, the number and proportion of subjects experiencing at least one 
TEAE, at least one severe TEAE, at least one TEAE related to the study treatment, and at least one TEAE 
leading to drug withdrawal will be presented. In addition, number and proportion of subjects experiencing 
a treatment-emergent AE will be presented by system organ class, preferred term and severity overall 
and for each treatment group. 
 
All AEs will be listed but only treatment-emergent AEs will be summarized. Listing will include Subject ID, 
age, gender, date of beginning of treatment, name and preferred term of AE, start and stop date, severity, 
relationship to study drug and outcome.   
 
6.5.2.2 
Serious Adverse Events 
 
Serious adverse events will be presented similarly to AEs as described in section 6.5.2.1.  
 
A separate listing for deaths will be provided. This listing will include subject ID, age, gender, date of 
beginning of treatment, date of death, phase of the study during which death occurred as well as the 
cause of death. 
 
 


 
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7 
SUMMARY TABLES, FIGURES AND LISTINGS 
 
1 Study subject 
1.1 Subject disposition 
Table 1.1.1 
Subject Disposition 
Table 1.1.2 
COVID-19 Symptoms Prior to Randomization, ITT Population 
Table 1.1.3 
Protocol Deviation, ITT population 
Table 1.1.4 
Datasets Analyzed 
 
 
1.2 Demographic and baseline characteristics 
Table 1.2.1 
Summary of Demographics, ITT Population 
Table 1.2.2 
Summary of physical Appearance, ITT Population 
Table 1.2.3 
Summary of Medical and Surgical History, ITT Population 
Table 1.2.4 
Summary of Other Clinically Significant Surgical or Medical Conditions, ITT 
Population 
 
 
1.3 Prior and concomitant medication 
Table 1.3.1 
Summary of Medication at Randomization, ITT Population 
Table 1.3.2 
Summary of Prior and Concomitant Medication, ITT Population 
 
 
1.4 Treatment compliance 
Table 1.4.1 
Summary of Study Medication Administration, ITT Population 
 
2 Efficacy analysis 
2.1 Primary analysis 
Table 2.1.1 
Summary of and statistical analysis for proportion of subjects with selected 
COVID-19 symptoms at day 3, 7, 10 and 14, ITT population 
 
 
2.2 Secondary analysis 
Table 2.2.1 
Summary of and Statistical Analysis for Mean Number of COVID-19 Symptoms 
at Day 3, 7, 10 And 14, ITT Population 
Table 2.2.2 
Summary of and Statistical Analysis for Duration of COVID-19 Symptoms, ITT 
Population 
Table 2.2.3a 
Summary of and Statistical Analysis for Proportion of Subjects With Cough at 
Day 1 To 14, ITT Population 
Table 2.2.3b 
Summary of and Statistical Analysis For Proportion of Subjects With Fever At 
Day 1 To 14, ITT Population 
… 
… 
Table 2.2.3m 
Summary of and Statistical Analysis for Proportion of Subjects With Anosmia 
at Day 1 To 14, ITT Population 
 
 
2.3 Exploratory analysis 
Table 2.3.1 
Summary of and Statistical Analysis for Composite of Hospitalization, 
Mechanic Ventilation or Death due to COVID-19 Infection, ITT Population 
 


 
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3 Safety analysis 
3.1 Treatment exposure 
Table 3.1.1 
Summary of Extent of Exposure, Safety Population 
 
 
3.2 Adverse events and serious adverse events 
Table.3.2.1 
Overall Summary of Treatment Emergent AEs, Safety Population 
Table 3.2.2 
Summary of Treatment Emergent AEs by Preferred Term, System Organ Class 
and Severity, Safety Population 
Table 3.2.3 
Overall Summary of Treatment Emergent SAEs, Safety Population 
Table 3.2.4 
Summary of Treatment Emergent SAEs by Preferred Term, System Organ Class 
and Severity, Safety Population 
 
Figures 
Figure 1 
Subject Disposition (Flow Chart) 
Figure 2 
Kaplan-Meier Survival Curves for Duration of COVID-19 Symptoms, ITT 
Population  
 
Listings 
Listing 1 
Subject Disposition 
Listing 2 
Datasets Analyzed 
Listing 3 
Protocol Deviations 
Listing 4 
Demographics 
Listing 5 
Study Medication Administration 
Listing 6 
Daily Symptom Assessments 
Listing 7 
AEs 
Listing 8 
SAEs 
Listing 9 
Deaths 
 
 
 
 


 
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8 
APPENDICES 
 
APPENDIX A COVID-19_ SYMPTOMS LOG 
 
Symptoms 
Day 1 
 
Yes  No 
Day 2 
 
Yes  No 
Day 3 
 
Yes  No 
Day 4 
 
Yes  No 
Day 5 
 
Yes  No 
Day 6 
 
Yes  No 
Day 7 
 
Yes  No 
Recent cough or aggravation of chronic 
cough 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Fever (enter temperature) 
  
  
  
  
  
   
  
Feverish/chills (temperature not taken) 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Sore throat 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Runny nose 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Shortness of breath/difficulty breathing 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Nausea/vomiting  
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Headache 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
General weakness 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Pain (muscular, chest, abdominal, joint, 
etc.) 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Irritability/confusion 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Diarrhea  
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
Sudden Loss of smell (anosmia) 
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 
    
   
 Comment or other, specify: 
 
 
 
 
 
 
 
 
 
 
 
Reminder: Please have the completed diary on hand at each phone call or video contact follow up. 
 
 
Symptoms 
Day 8 
 
Yes  No 
Day 9 
 
Yes  No 
Day 10 
 
Yes  No 
Day 11 
 
Yes  No 
Day 12 
 
Yes  No 
Day 13 
 
Yes  No 
Day 14 
 
Yes  No 
Recent cough or aggravation of chronic 
cough 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Fever (enter temperature) 
 
 
 
 
 
 
 
Feverish/chills (temperature not taken) 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Sore throat 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Runny nose 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Shortness of breath/difficulty breathing 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Nausea/vomiting  
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Headache 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
General weakness 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Pain (muscular, chest, abdominal, joint, 
etc.) 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Irritability/confusion 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Diarrhea  
    
 
    
 
    
 
    
 
    
 
    
 
    
 
Sudden Loss of smell (anosmia) 
    
 
    
 
    
 
    
 
    
 
    
 
    
 
 Comment or other, specify: 
 
 
 
 
 
 
 
 
 
 
 
Reminder: Please have the completed diary on hand at each phone call or video contact follow up. 
 


 
SAP: 29-APR-2021  
Protocol number: MHICC-2020-003 
 
BS-T1-001-05 
Confidential 
Page 18 of 18 
APPENDIX B TIMETABLE OF VISITS AND PROCEDURES 
 
Visits 
1.  Screening / 
randomization  
(Phone call) 
2.  Contact 
Point 
(Phone) 
–
no window 
3. 
Contact 
Point 
(Phone ) (± 1 
day) 
4. 
Contact 
Point (Phone) 
(± 3 days) 
5. Contact Point 
(Phone call)  
(± 3 days)  
 
Days 
0 
3 
7 
10 
14 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
Review concomitant medication 
X 
X 
X 
X 
X 
Covid-19 symptoms (including 
date of onset) 
X 
X 
X 
X 
X 
Review Inclusion/Exclusion 
criteria 
X 
 
 
 
 
Urinary pregnancy test* 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Record potential study endpoints 
and other AEs  
 
X 
X 
X 
X 
Study medication dispensing  
X 
 
  
 
 
Study medication compliance 
 
X 
X 
X 
X 
*For women of childbearing potential 
**If day 3 occurs on the weekend, contact point will be done on previous Friday or following Monday, whichever is closer to day 3.