Conditions: COVID 19
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 215
Healthy volunteers: no

Brief summary:
The CONTAIN (CiclesOnide cliNical TriAl covId-19 treatmeNt) is a randomized control study of ciclesonide vs placebo for mild covid-19 disease. The need for potential therapy for COVID-19 patients is urgent. Ciclesonide has shown encouraging in vitro results, is easy to be used and is readily available. It has a low rate of side effects and few interactions with other drugs. It is unusual to use an inhaled steroid drug for COVID-19 but there has been new data suggesting steroids may have an antiviral effect in addition to an anti-inflammatory effect. Investigators propose to use inhaled and nasal ciclesonide to stop viral replication in the nose and airways. Investigators hope this will accelerate recovery from COVID-19 illness in individuals who are not admitted to hospital at time of diagnosis of COVID-19.

Detailed description:

Arms:
arm 1: Intranasal ciclesonide BID 50mcg BID to each nostril and inhaled ciclesonide 600mcg BID x 14 days arm 2: Normal Saline intranasal BID and Placebo 3 puff MDI inhaled BID

Interventions: intervention 1: Normal Saline intranasal and placebo inhaler intervention 2: Ciclesonide intervention 3: Ciclesonide nasal
Intervention descriptions: intervention 1: Normal Saline intranasal BID and Placebo 3 puff MDI inhaled BID intervention 2: Ciclesonide 600mcg BID inhaled with aero chamber intervention 3: intranasal ciclesonide 200 mcg DIE

Protocol document:
Prot_SAP_000.pdf: 
Version 6.1 
August 23, 2021 
1 
MILD- CONTAIN CICLESONIDE CLINICAL TRIAL COVID-19 TREATMENT 
 
2021-6696 
 
Short Title: Mild-CONTAIN 
Health Canada Submission Protocol – Version 5.2 July 27, 2021 
Canadian Sponsor: 
Research Institute of the McGill University Health Centre 
 
 
Canadian Principal Investigator: 
 
Nicole Ezer MD MPH 
Assistant Professor of Medicine, McGill University 
 
Draft or Version Number: 6.1 
August 23, 2021 
 
 


Version 6.1 
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2 
STATEMENT OF COMPLIANCE 
This protocol will receive independent institutional review board (IRB) permission in each 
participating province. For the purposes of regulatory compliance, the sponsor institution is the 
Research Institute of the McGill University Health Center for the operations in Canada. 
 
 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable Canadian law and ICH guidelines. 
 
Principal Investigator: 
 
Signed: 
Date: 
August 23, 2021 
 
Nicole Ezer 
Assistant Professor of Medicine, Research Institute of 
the McGill University Health Center 
 
 
 


Version 6.1 
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TABLE OF CONTENTS 
 
Page 
MILD- CONTAIN CiclesOnide cliNical TriAl covId-19 treatmeNt 
1 
1 
Key Roles – McGill University Health Centre 
10 
2 
Background Information and Scientific Rationale 
12 
2.1 
Background Information 
12 
2.2 
Rationale 
15 
2.3 
Potential Risks and Benefits 
17 
2.3.1 
Potential Risks 
17 
2.3.2 
Known Potential Benefits 
18 
3 
Objectives 
18 
3.1 
Study Objectives 
18 
3.2 
Study Outcome Measures 
18 
3.2.1 
Primary Outcome Measures 
18 
3.2.2 
Secondary Outcome Measures 
18 
4 
Study Design 
19 
4.1 
Design 
20 
4.2 
Study participant duration 
20 
4.3 
Study procedures 
20 
4.5 
Substudies (if applicable) 
21 
5 
Study Enrollment and Withdrawal 
22 
5.1 
Subject Inclusion Criteria 
22 
5.2 
Subject Exclusion Criteria 
22 
5.3 
Treatment Assignment Procedures 
23 
5.3.1 
Randomization Procedures 
23 
5.3.2 
Masking Procedures 
23 
5.3.3 
Subject withdrawal criteria 
23 
5.3.4 
Handling of Withdrawals 
23 
5.3.5 
Termination of Study 
23 
6 
Study Intervention/Investigational Product 
24 
6.1 
Study Product Description 
24 
6.1.1 
Acquisition 
24 
6.1.2 
Formulation, Packaging, and Labeling 
24 
6.1.3 
Drug Description: 
24 
6.1.4 
Formulation: 
24 
6.1.5 
Product Storage and Stability 
25 
6.2 
Dosage, Preparation, and Administration of Investigational Product 
25 
6.3 
Modification of Investigational Product for a Participant 
25 


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6.4 
Accountability Procedures for the Investigational Product: 
25 
6.5 
Assessment of Subject Compliance 
25 
6.6 
Concomitant Medications/Treatments 
25 
7 
Study Schedule 
26 
7.1 
Screening 
27 
7.2 
Enrollment/Baseline 
27 
7.3 
Follow-up 
27 
7.4 
Final Study Visit 
28 
7.5 
Early Termination Visit 
28 
7.6 
Unscheduled/Sick Visit 
28 
8 
Study Procedures/Evaluations 
30 
8.1 
Clinical Evaluations 
30 
8.2 
Laboratory Evaluations 
30 
9 
Assessment of Safety 
31 
9.1 
Specification of Safety Parameters 
31 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
 
31 
9.2.1 
Adverse Events 
31 
9.2.2 
Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
31 
9.2.3 
Serious Adverse Events (SAEs) 
31 
9.2.4 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal Clinical 
Findings 31 
9.3 
Reporting Procedures 
32 
9.3.1 
Serious Adverse Events 
32 
9.3.2 
Regulatory Reporting 
33 
9.3.3 
Reporting of Pregnancy 
33 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
33 
9.5 
Safety Oversight (DSMB) 
33 
10 
Clinical Site Monitoring 
34 
11 
Statistical Considerations 
35 
11.1 
Study Hypotheses 
35 
11.2 
Sample Size Considerations 
35 
11.3 
Planned Interim Analyses 
36 
11.4 
Primary Analysis 
36 
12 
Source Documents and Access to Source Data/Documents 
37 
13 
Quality Control and Quality Assurance 
37 


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14 
Ethics/Protection of Human Subjects 
37 
14.1 
Ethical Standard 
37 
14.2 
Institutional Review Board 
37 
14.3 
Informed Consent Process 
37 
14.4 
Exclusion of Women, Minorities, and Children 
38 
14.5 
Subject Confidentiality 
38 
14.6 
Future Use of Stored Specimens 
38 
15 
Data Handling and Record Keeping 
39 
15.1 
Data Management Responsibilities 
39 
15.2 
Data Capture Methods 
39 
15.3 
Types of Data 
39 
15.4 
Timing/Reports 
39 
15.5 
Study Records Retention 
39 
15.6 
Protocol Deviations 
39 
16 
Publication Policy 
40 
17 
Literature References 
40 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
SRS-CoV 
SARS coronavirus                      
(i.e. circa 2003) 
SARS-CoV-2 
SARS coronavirus 2                   
(i.e. circa 2019) 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
MUHC 
McGill University Health Center 
N 
Number (typically refers to subjects) 
PHI 
Protected Health Information 
PI 
Principal Investigator 
RI-MUHC 
Research Institute of the McGill University Health Centre 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization 
 
 
 
 
 
 


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Summary 
Full Title: 
Mild - CONTAIN CiclesOnide cliNical TriAl covId-19 
treatmeNt 
Short Title: 
Mild - CONTAIN  
Clinical Phase: 
II 
Sponsor: 
Research Institute of the McGill University Health Centre 
Principal Investigator: 
Nicole Ezer MDCM, MPH, FRCPC 
Co-Investigators 
James Martin, MD; Todd Lee, MD; Emily McDonald, MD; 
Andrea Benedetti, PhD Statistician; Ben Smith, MD, PhD; 
Susan Barlett, PhD, Sara Belga, MD; Shay Daniels, MD; Nick 
Daneman, MD; Adrienne Chan, MD 
Study Population 
>=18 years of age 
Laboratory confirmed COVID-19 as determined by PCR within 
5 days of enrolment  
 
Early mild symptomatic patients: Non-hospitalized adults or 
health care workers with COVID-19 (n= 159 per arm) 
Objective 
Evaluate whether early treatment with inhaled and nasal 
ciclesonide improves symptoms at day 7 in early mild to 
moderate symptomatic patients 
Study Design 
Adaptive, Double-blind, randomized placebo-controlled clinical 
trial 
Pragmatic trial with internet based self-referral, electronic 
consent, virtual online follow-up and self-reported outcomes. 
Study medicine delivered by courier to consented participants. 
Follow up through 7 days and 14 days and 30 days after 
randomization.  
 


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Intervention Arm: 
Ciclesonide (600mcg BID inhaled with aerochamber) plus nasal 
ciclesonide (200 mcg DIE) for 14 days  
Control Arm: 
Placebo (delivered by metered dose inhaler BID with 
aerochamber) plus intranasal saline DIE for 14 days.  
Primary Endpoint  
Proportion of participants with no symptoms of cough, fever or 
dyspnea at day 7. 
Secondary Endpoints 
 
• Hospitalization for SARS-CoV-2 related illness at day 14 
• Primary outcome (proportion of patients with no cough 
fever or dyspnea) measured at day 14 
• Mortality at day 14 and 29  
• Ordinal Scale for Evaluating subject Clinical Status  
• PROMIS dyspnea, anxiety and sleep at day 7 and 14.   
• Visual Analog scale from 0-10 indicating improvement in 
symptoms at day 7 and 14. 
• Time to symptom resolution (post-hoc) 
Duration of 
Participation 
● Recruitment and follow up will be internet-based. 
● Clinical Assessment: 14 days post ciclesonide initiation 
to assess final outcome  
● Clinical assessment at Day 29: Clinical assessment, 
Follow up vital status, self reported hospitalization 
Inclusion Criteria 
Symptomatic adult patients positive by PCR for COVID-19 
within 5 days of enrollment with fever, cough or shortness of 
breath (day 6 if shipped same day). Provision of Informed 
Consent 
 
At Day 0, patients should be at home 


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Exclusion Criteria 
● Already on inhaled corticosteroid medication  
● Currently using systemic steroids (oral or intravenous or 
intramuscular such as Prednisone) or use of steroids 7 
days prior to enrolment 
● Severely ill patients at enrollment (i.e., admitted to ICU 
at admission) 
● Unable to self-administer the inhaler 
● Known or suspected pregnancy and breastfeeding  
● Known allergy to study medication or its components 
(non-medicinal ingredients; including lactose allergy 
(type I)) 
● Patients with untreated fungal, bacterial or tubercular 
infections of the respiratory tract 
● Current hospitalization 
● Current use of oxygen at home or in hospital 
● Vaccinated for COVID-19 
Stratification 
Randomization will be stratified by sex  
Statistical 
Assumptions 
With 159 subjects per arm we will be able to detect an absolute 
increase of 15%  in the number of patients with resolved 
symptoms at day 7. 
Safety 
Safety of the intervention will be assessed by the cumulative 
incidence of Grade 3 and 4 AE and SAEs using the Division of 
AIDS Table for Grading Severity of Adult and Pediatric 
Adverse Events version 2.1  


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Schematic of Study Design: 
 
 
 
 
 
 
 
1 
KEY ROLES – MCGILL UNIVERSITY HEALTH CENTRE 
Individuals: 
 
 
Principal Investigator:  Nicole Ezer MDCM, MPH, FRCPC 
 
Co-Investigator: Emily G. McDonald MDCM MSc 
Co-Investigator: Todd C. Lee MD MPH FIDSA  
Co-Investigator: James Martin MDCM 
Co-Investigator: Ben Smith MD 
Mild/Moderate COVID-19 confirmed patients with 
positive PCR in the last 5 days before recruitment
Treatment arm:
Inhaled Ciclesonide 600 mcg BID with 
spacer (aerochamber) AND 
ciclesonide nasal spray 200 mcg by day 
(2 sprays in each nostril once daily) for 
14 days
Placebo arm: 
2 inhalations BID with spacer AND 
placebo nasal spray 2 sprays in 
each nostril once daily) for 14 days
Severity of overall symptom
COVID-19 MESSA symptom checklist
PROMIS scales (Dyspnea, sleep, anxiety)
Visual analogue scale
Day 0
Day 7
Day 29
Day 14
Primary outcome
End of treatment
Day 1
Day 3,5
Start study 
drug
Day 10
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Dyspnea severity
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Dyspnea severity
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
Randomization
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Dyspnea severity
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
If hospitalization occur, patient will be followed up at  Day 29
*Wording of column a, b and c will be simplified to access 
symptom evolution over time


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Co-Investigator: Sara Belga MD 
Co-Investigator: Shay Daniels, MD 
Co-Investigator: Nick Daneman, MD 
Co-Investigator: Adrienne Chan, MD 
Medical Monitor: Richard Menzies MD 
Research Pharmacist: Kathleen Normandin B. Pharm MSc  
Database Management: Alek Lefebvre  
 
Institutions:  
Division of Respiratory Medicine, Department of Medicine, McGill 
University Health Centre (Research Institute), Montreal, QC 
University of British Columbia, Vancouver General Hospital, 
Vancouver, BC  
Sunnybrooke Hospital, Toronto, Ontario   
 
 
 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
Significance of Research Question/Purpose: 
Coronaviruses are a large family of viruses that usually cause mild to moderate respiratory illness. 
However, three major coronaviruses capable of causing serious disease have been identified in the 
last two decades, namely SARS-CoV, MERS-CoV and most recently, the novel SARS-CoV-2. 
First identified in December 2019 in the province of Wuhan, China, SARS-CoV-2 has rapidly 
emerged as a highly transmissible and potentially fatal virus, causing COVID-19. It has shown to 
be capable of causing mild to severe disease, requiring oxygen therapy, hospitalization, intensive 
care, mechanical ventilation, and has led to widespread illness and death.  
 
The number of global COVID-19 cases has rapidly progressed in the last few months. The outbreak 
was declared a Public Health Emergency of International Concern on January 30, 2020, and on 
March 11th, the World Health Organization declared COVID-19 a global pandemic.  
 
As of April 20, 2020, there were 2.36 million confirmed COVID-19 cases worldwide, and 164 656 
deaths related to COVID-19. In Canada, there were 34 777 cases and 1580 deaths(1). In an effort 
to prevent disease progression and overload of healthcare systems, provincially and 
internationally, authorities have held multiple public services and public spaces, postponed various 
in and out-hospital services and have imposed travel restrictions.  
 
Only one antiviral therapy is currently approved in Canada for patients with mild to moderate 
symptoms of COVID-19 (Bamlanivimab) (2) however it is not widely available due to costs and 
the need for IV infusion.  The standard of care remains supportive measures and quarantine of 
infected persons for a minimum of 14 days. 
 
Global efforts to evaluate novel antivirals and therapeutic strategies to treat COVID-19 have 
intensified and there is an urgent public health need for rapid development of novel interventions.  
Preliminary Data: 
Like MERS-CoV and SARS-CoV (3), SARS-CoV-2 virus is a betacoronavirus. It has 79.5% 
sequence identity with that of human SARS-CoV (4). 
 
Ciclesonide has shown in vitro activity against MERS-CoV, SARS-CoV and SARS-CoV-2. In 
vitro, the viral replication of SARS-COV-2 showed 2-fold reduction at 27 hours post infection. 
(5) In Vero cells, the half maximal inhibitory concentration (IC50) of ciclesonide against SARS-
CoV-2 was 4.33 mcM (5).  The NSP15 homo-hexamer was possibly the target of ciclesonide. 
Other steroids tested (cortisone, prednisolone, fluticasone, dexamethasone) showed no 
significant effect on viral replication suggesting the ciclesonide effect is drug specific and not a 
steroid class effect (6). Subsequently, reduced viral load of SARS-CoV-2 has been shown to be 
associated with reduced clinical disease severity (7). 
 


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Existing Literature: 
In February 2020, 5406 compounds (including 2069 FDA approved drugs) were tested for anti-
MERS-CoV activity by determining viral spike protein expression in infected Vero cells and 12 
compounds were selected for having demonstrated a greater than 70% anti MERS-CoV activity. 
Ciclesonide was identified as one of the drugs that inhibit MERS-CoV replication, similar to 
chloroquine (8).  
 
The in vitro effect of different steroids on MERS-COV, SARS-CoV and SARS-CoV-2 showed 
that ciclesonide was suppressing the viral replication of those 3 coronaviruses with low 
cytotoxicity. For SARS-CoV-2, the viral replication was reduced 2-fold at 27 hours post infection 
(Figure 1). The NSP15 homo-hexamer was possibly the target of ciclesonide. Other steroids tested 
against MERS-CoV (cortisone, prednisolone, fluticasone, dexamethasone, mometasone) showed 
no significant effect on viral replication (except for mometasone) suggesting the ciclesonide effect 
is drug specific and not a steroid class effect, so these steroids were not tested against SARS-CoV-
2 (Figure 2) (6). 
 
Figure 1. -  Antiviral effects of steroids on SARS-CoV-2. (a) Intracellular SARS-CoV-2 
RNA (6 hpi). VeroE6/TMPRSS2 cells were infected with SARS-CoV-2 at MOI = 1 in the 
presence of 10μM compounds for 6 h. Cellular viral RNA was quantified by real-time PCR 
using the E gene primer/probe set. (b) Culture Medium SARS-CoV-2 RNA (27 hpi). 
VeroE6/TMPRSS2 cells were infected with SARS-CoV-2 at MOI = 0.01 in the presence of 
ciclesonide for 27 h. Viral RNA in culture medium was quantified by real-time PCR using the 
E gene primer/probe set. Cell viability in the presence of ciclesonide was quantified at 27 hpi 
by WST assay (1). 
 
 


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14 
 
 
Figure 2- Antiviral effects of steroids on SARS-CoV-2. (a) Intracellular SARS-CoV-2 
RNA (6 hpi). VeroE6/TMPRSS2 cells were infected with SARS-CoV-2 at MOI = 1 in the 
presence of 10μM compounds for 6 h. Cellular viral RNA was quantified by real-time PCR 
using the E gene primer/probe set. 
 
 
In order to determine drug antiviral activity specific to SARS-CoV-2, 3000 FDA and IND-
approved drugs were screened and ciclesonide showed a potent antiviral effect (IC50=4.33 mcM; 
Figure 3) in addition to its intrinsic anti-inflammatory function (5). 
 
 
 


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Figure 3 - (part of Figure 1B from reference 5) Dose response 
curve analysis by immunofluorescence for 45 drugs that were tested in this study. The 
blue squares represent inhibition of virus infection (%) and the red triangles represent cell viability 
(%). Means ± SD were calculated from duplicate experiments 
 
Subsequently, reduced viral load of SARS-CoV-2 has been shown to be associated with 
reduced clinical disease severity (7). 
 
2.2 
Rationale 
 
Current standard of care is supportive care after the diagnosis of COVID-19. 
 
Ciclesonide is a corticosteroid currently used for asthma (in its inhaled form) and nasal rhinitis (in 
its spray form). It has a very good safety profile. Much higher doses of ciclesonide (up to a single 
inhalation of 3200 mcg) have been administered to healthy volunteers and were well tolerated (9). 
As such, inhaled and nasal ciclesonide at the doses of 600mcg BID for 2 weeks will have few 
adverse events.  The usual doses for ciclesonide are: 
 
 


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Standard asthma treatment (ciclesonide, Alvesco): 
● The recommended dose range for ciclesonide in inhalation is 100 to 800 mcg daily (9). 
● The recommended starting dose for most asthmatic patients is 200 mcg daily in Canada 
(10). 
● The maximum dose of 800 mcg daily should be administered as 400 mcg twice daily (9). 
 
Standard allergic rhinitis treatment (ciclesonide, Omnaris) (11): 
● The recommended dose of OMNARIS is 200 mcg per day administered as 2 sprays (50 
mcg/spray) in each nostril once daily. 
● The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day) 
 
As the specific dose of ciclesonide to decrease SARS-CoV-2 is unknown, we planned to give a 
higher dose than the maximum approved dose for asthma of inhaled ciclesonide (1200 mcg daily 
administered as 600 mcg twice daily) plus the usual dose of intranasal ciclesonide (200 mcg/day) 
for 14 days. Given viral replication begins in the nasal cavity and then progress to the lungs, we 
have chosen to administer ciclesonide both intranasally and inhaled. This dose has been chosen in 
order to maximize deposition of the study drug in the lower airways. Although the usual dose of 
ciclesonide for asthma is 400 mcg twice daily (for a total of 800 mcg/day), single doses (up to 
3200 mcg) have been administered to healthy subjects without significant side effects (9).   
 
The in vitro replication of SARS-CoV-2 was reduced by twice in 27h, so we expect the effect of 
ciclesonide to be rapid. Moreover, as we hypothesize its antiviral effects will affect the nasal/upper 
airways replication of the virus, it should be more effective at the beginning of the disease 
compared to when the virus has spread to the lung. Therefore, we aim to recruit patients at the 
beginning of their disease (within 5 days of positive SARS-CoV-2 PCR) and to have a rapid benefit 
on symptom severity (at 7 days of enrollment). However, multiple complications of COVID-19 
appear after the first 7 days (Zhou and al., 2020) so we will continue our treatment for a total of 
14 days (4).    
 
The proposed treatment will allow faster symptom resolution of COVID-19 symptoms in mildly 
symptomatic outpatients and return to work for healthcare workers and essential workers.  
In Canada we will be using DIN 02285614 / Alvesco) and intranasal Ciclesonide (DIN 
02303671/ Omnaris) as the active drug and a placebo inhaler (NDC 70515-710-01) as the 
placebo.  
 
 


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2.3 
Potential Risks and Benefits 
2.3.1  Potential Risks 
Ciclesonide is a drug currently used for asthma maintenance treatment (in its inhaled form) 
and nasal rhinitis. It has been approved by Health Canada in 2008 in this setting. It has a 
very good safety profile with mainly local possible side effects. The principal sides effects 
as listed on the monograph are:  
 
Common Clinical Trial Adverse Drug Reactions (≥1% - <10%)  
Respiratory: Paradoxical bronchospasm (1.6%), Dysphonia (1.0%).  
 
Uncommon Clinical Trial Adverse Drug Reactions (≥0.1% to <1%)  
Cardiovascular: Palpitations (0.1%).  
Eye: Cataract subcapsular (0.1%).  
Gastrointestinal: Nausea (0.2%), Dry mouth (0.1%), Dyspepsia (0.1%) 
Infections: Oral candidiasis (0.6%), Candidiasis (0.1%), Oral fungal infection (0.1%), 
Pharyngitis (0.1%).  
Injury: Contusion (0.1%).  
Investigations: ALT increased (0.1%), Gamma-glutamyltransferase increased (0.1%) 
Weight increased (0.1%) 
Nervous System: Headache (0.4%), Dysgeusia (0.3%), Dizziness (0.1%).  
Respiratory, thoracic and mediastinal disorders: Pharyngolaryngeal pain (0.4 %), Throat 
irritation (0.3%), Dry throat (0.1%).  
Skin: Rash (0.1%).  
The incidence of local oropharyngeal adverse reactions in ALVESCO-treated patients was 
low and comparable to placebo. 
 
The risk of thrush (appearance of Candida albicans in the mouth and throat) is rare but can 
be further reduced by the use of an aerochamber and a proper mouth rinsing after using 
Ciclesonide.  
 
The contraindications to Ciclesonide, as listed on the monograph: 
 
CONTRAINDICATIONS ALVESCO (ciclesonide) is contraindicated in patients with 
known hypersensitivity to any of the ingredients.  
 
ALVESCO is not to be used in the primary treatment of status asthmaticus or other acute 
episodes of asthma, or in patients with moderate to severe bronchiectasis.  
 
OMNARIS (ciclesonide) is contraindicated in patients with hypersensitivity to any of the 
ingredients. 
 
OMNARIS should be used with caution, if at all, in patients with active or quiescent 
tuberculosis infections of the respiratory tract. 
 


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2.3.2 Known Potential Benefits 
● There are no proven benefits in humans for treatment of COVID-19 
● At the Kanagawa Prefectural Ashigarakami Hospital, in Japan, three 
patients with COVID-19 were treated with inhaled Alvesco and clinically 
improved (12).  
● In vitro antiviral activity against SARS-CoV and SARS-CoV-2 viruses 
● Ciclesonide both in inhalation and spray have a long history of safe, 
effective use is asthma and allergic rhinitis, both acutely and long-term. 
● 2 randomized clinical trials on Ciclesonide for COVID-19 are about to start, 
one in mild patients taking place in Korea (13) and one pre-symptomatic 
patients, taking place in Japan (14).  
● Recent studies have shown potential direct-acting antiviral activity in 
addition to its intrinsic anti-inflammatory function (5). 
 
3 
OBJECTIVES 
3.1 
Study Objectives 
 
To evaluate whether early treatment with inhaled and nasal ciclesonide results in symptom 
resolution at day 7 in early mild symptomatic patients (particularly dyspnea) 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
 
Primary outcome is defined as the proportion of patients with resolved respiratory 
symptoms (fever, cough, shortness of breath, chest congestion or chest tightness) at day 7. 
3.2.2 Secondary Outcome Measures 
 
a) Hospitalization for SARS-CoV-2 related illness at day 14  
b) Primary outcome (proportion of patients with no cough, fever or dyspnea) measured at day 
14 
c) Mortality at day 14 and 29  
d) Ordinal Scale for Evaluating subject Clinical Status (overall feeling) (see Appendix 2) 
measured on day 0, 1, 3, 5, 7, 14 and 29: We will evaluate the proportion who are reporting 
that they are “very much improved” or “much improved” by day 7 and day 14 (vs. not).  
e) PROMIS dyspnea, anxiety and sleep (respectively).  We will look at the questionnaires at 
day 7 and at day 14 and compare the proportions between groups with a 3 point or higher 
change (compared to day 0 and using the t-score adjusted for population).  We will also 
report the mean T scores. Raw scores are converted to standardized T scores using 


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calibrated algorithms for the general population. They are standardized scores with a mean 
of 50 and SD of 10; 45 to 55 on a PROMIS T score is considered the normal range. 55-60 
is mild levels of symptoms (anxiety, sleep, dyspnea), 60-70 is moderate, and 70+ is 
severe. A meaningful change will be considered a 3 point change on the T score.  
f) Visual Analog scale from 0-10 indicating improvement in symptoms measured at day 0, 1, 
3, 5, 7, 10, 14 and 29; analysis will look at resolution of symptoms at day 7 and day 14, 
and resolution of cough at day 7 and 14. 
g) Time to symptom resolution (post-hoc) 
 
Assessment of outcome measures will be primarily by self-report.  As necessary, COVID-19 
disease will be verified from public health records, medical records, or death certificates. The 
primary analysis will use PCR+ confirmed disease.  
4 
STUDY DESIGN 
 
 
 
 
 
Mild/Moderate COVID-19 confirmed patients with 
positive PCR in the last 5 days before recruitment
Treatment arm:
Inhaled Ciclesonide 600 mcg BID with 
spacer (aerochamber) AND 
ciclesonide nasal spray 200 mcg by day 
(2 sprays in each nostril once daily) for 
14 days
Placebo arm: 
2 inhalations BID with spacer AND 
placebo nasal spray 2 sprays in 
each nostril once daily) for 14 days
Severity of overall symptom
COVID-19 MESSA symptom checklist
PROMIS scales (Dyspnea, sleep, anxiety)
Visual analogue scale
Day 0
Day 7
Day 29
Day 14
Primary outcome
End of treatment
Day 1
Day 3,5
Start study 
drug
Day 10
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Dyspnea severity
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Dyspnea severity
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
Randomization
Severity of overall symptom
COVID-19 MESSA symptom checklist*
PROMIS scales (Dyspnea, sleep, anxiety)
Dyspnea severity
Visual analogue scale
Hospitalization/oxygen use questions
Medication side effects, adverse events
If hospitalization occur, patient will be followed up at  Day 29
*Wording of column a, b and c will be simplified to access 
symptom evolution over time


Version 6.1 
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20 
4.1 
DESIGN 
Randomized, double-blind, placebo-controlled clinical trial, parallel design 
 
• Intervention Arm: Ciclesonide 600mcg BID inhaled with aero chamber plus intranasal 
ciclesonide 200 mcg DIE for 14 days. The aerochamber is Respichamber from the 
hospital which will be discarded after the 14 days. For information on how to use the 
aerochamber please refer to: 
https://www.youtube.com/watch?time_continue=1&v=O92_Ftf6Wnk&feature=emb_title 
 
• Control Arm: Placebo inhaled BID with respichamber (same as above) plus intranasal 
saline DIE for 14 days.  
 
In Canada we will be using inhaled Ciclesonide (DIN 02285614 / Alvesco) and intranasal 
Ciclesonide (DIN 02303671/ Omnaris) as the active drug and a placebo inhaler (NDC 
70515-710-01) as the placebo.  
At present, all these products are sourced from Canadian wholesale distributors. 
4.2 
Study participant duration 
● 14 days consisting of internet-based virtual visits 
● Observational follow up at day 29 to assess final outcome status of hospitalization 
and SAE. 
4.3 
Study procedures 
● All procedures will consist of internet-based questionnaires completed by self-
report. 
● Informed consent is provided to access medical records to verify information, as 
necessary and in accordance with individual provincial laws. 
 
 
4.4 
Individually identifiable health information:  
 
Name, date of birth,  phone number and address will be collected centrally at the RI-MUHC 
to prescribe study medication. These names and addresses will be communicated to 
approved study sites in other provinces to facilitate timely prescription and local shipping 
in each participating province. Email addresses will be collected for communication. If 
participants are hospitalized, the hospitalization date will be collected. NO 
IDENTIFIABLE 
HEALTH 
INFORMATION 
WILL 
BE 
TRANSMITTED 
OUTSIDE OF CANADA. 


Version 6.1 
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21 
4.5 
Substudies (if applicable)  
Additional sub-studies will undergo separate IRB approval, and these studies will involve 
separate informed consent. Consented participants will be queried as to if they wish to 
participate in future research. 
 
4.6 
Participation in concomitant clinical trials 
 
Because of unknown potential drug-drug interactions between ciclesonide and other 
investigational products we will ask participants not to enroll in other clinical trials for the 
study duration.   
 


Version 6.1 
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22 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
Participants will undergo screening via REDCap.. The screening and inclusion criteria will 
be based on self-report.  
 
5.1 
Subject Inclusion Criteria 
 
● Symptomatic COVID-19 disease (fever, cough OR shortness of breath) AND confirmed 
diagnosis with PCR+ SARS-CoV-2 within <= 6 days of enrolment (day 6 if same day 
shipping geographically permits) 
● Shortness of breath is defined by self report as “ shortness of breath”, “chest tightness” or 
“chest congestion” 
● Cough is defined as “dry cough” or “wet cough” by self report  
● >= 18 years of age 
● Provision of informed consent 
● Mild symptomatic SARS-CoV-2 disease is defined as individuals who are SARS-CoV-2 
PCR positive AND present with more than one symptom listed on the symptom checklist 
developed by the National Institute of Health MESA COVID-19 questionnaire (Version 
dated 04/10/2020; symptom checklist page 8) at study entry (see Appendix 2). 
5.2 
Subject Exclusion Criteria 
 
 
Rationale for inclusion / exclusion criteria: 
Mean Incubation period is ~5.2 days, thus we wish to limit enrollment such that delivery 
of the study medicine occurs in the time period in which it can ameliorate disease (i.e. start 
● Already on inhaled corticosteroid medication  
● Currently using systemic steroids (oral or intravenous or intramuscular such as Prednisone) 
or use of steroids 7 days prior to enrolment 
● Severely ill patients at enrollment (i.e., admitted to ICU at admission) 
● Unable to self-administer the inhaler 
● Anticipated transfer to another hospital within 72 hours which is not a study site  
● Known or suspected pregnancy and breastfeeding 
● Known allergy to study medication or its components (non-medicinal ingredients; 
including lactose allergy (type I)) 
● Patients with untreated fungal, bacterial or tubercular infections of the respiratory tract 
● Current hospitalization 
● Current use of oxygen at home or in hospital 
● Vaccinated for COVID-19 


Version 6.1 
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23 
of study medicine by <=6 days after positive PCR). Day 6 only if able to ship the drug and 
commence it the same day as receiving it. 
In clinical practice, oral and nasal ciclesonide is prescribed without any baseline laboratory 
testing or monitoring.  
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Participants will be randomized via permuted block randomization. Randomization 
will be created and recorded on an electronic log. Study investigators and subjects 
will be blinded.  
 
5.3.2 Masking Procedures 
Participants will be provided masked study medicine, shipped by courier (e.g. 
FedEx). The intervention vs. placebo will not be identical; however, participants 
and outcome assessors will be masked to their assignment. 
5.3.3 Subject withdrawal criteria 
 
Participants may withdraw at any time point at their discretion. Subject withdrawal 
is defined as decision to terminate trial treatment. Subject will be replaced until the 
targeted 318 patients required for our power calculation. Study recruitment will be 
on a rolling basis. Our accrual ceiling is 2 times the required number of participants 
for the study. Based an alpha of 0.05 and a 15% subject dropout rate, we require 
159 participants per arm. Our current power calculations account for a 25% subject 
dropout rate. As such, should individuals drop out (ie. be lost to follow up), it is 
unlikely to affect the study error.   
  
5.3.4 Handling of Withdrawals 
 
Patients who discontinue the study drug will be encouraged to stay on study and 
will continue to be followed for safety and efficacy endpoints, unless they have 
withdrawn consent.  
 
5.3.5 Termination of Study 
 
This study may be prematurely terminated if there is sufficient reasonable cause, 
including but not limited to: 


Version 6.1 
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24 
● Unexpected, significant, or unacceptable risk to subjects 
● Regulatory authorities decide that study should be terminated 
● Insufficient compliance with protocol requirements 
● Data are not sufficiently complete and/or not evaluable 
 
 
6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
6.1.1 Acquisition 
Omnaris (aqueous nasal ciclesonide) and Alvesco (aerosol oral ciclesonide) will be 
supplied free of charge by Covis Pharma 
6.1.2 Formulation, Packaging, and Labeling 
The study medicines will be packaged in 
GCP appropriate packaging/labelling by 
the Research Pharmacies at each of the 
approved provincial centers. RI-MUHC 
will do this for the province of Quebec. 
Dispensed medications will be delivered by 
courier (e.g. Fedex) to study participants 
directly from the research pharmacies in 
packaging which obscures the content. At 
the end of the treatment period, patients 
will be asked to safely dispose of their 
unused medication by going to the nearest 
pharmacy or ecocenter. Due to the COVID-
19 pandemic, pateints will not be allowed to send back their unsed medication to 
the study site due to risk of fomites.  
 
6.1.3 Drug Description:  
Drug name: [11 beta, 16 alpha (R)]-16, 17-[(Cyclohexylmethylene)-bis(oxy)]-
11- hydroxy-21-(2-methyl-1-oxopropoxy) pregna-1,4-diene-3,20-dione 
6.1.4 Formulation:  
Oral: 100 or 200mcg/actuation (ex-valve) 
Nasal: 50mcg/metered spray 
 


Version 6.1 
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25 
6.1.5 Product Storage and Stability 
Omnaris: Store at room temperature up to 30°C 
Alvesco: Cannister contains pressurized liquid. Store at room temperature 15-25°C and 
protect from temperatures above 50°C.  Do not freeze. 
 
6.2 
Dosage, Preparation, and Administration of Investigational Product 
 
6.2.1 Drug/Device Handling: Omnaris (aqueous nasal ciclesonide) and Alvesco 
(aerosol oral ciclesonide) or placebo will be dispensed by the Research 
Pharmacy in each approved center. The RI-MUHC will do this for the 
province of Quebec. To do so, the study investigators will send a prescription 
to the Pharmacy, the pharmacy will  dispense the appropriate study medicine. 
The medicine will then be provided to research volunteers via FedEx / 
courier delivery in the province of approval (e.g. within Quebec for RI-
MUHC). 
6.3 
Modification of Investigational Product for a Participant 
In the event of substantial side effects, participants may discontinue the study medication 
and stay in the study to complete follow up. 
6.4 
Accountability Procedures for the Investigational Product: 
 
Accountability will be via self-report at the day 14 virtual questionnaire. 
6.5 
Assessment of Subject Compliance 
 
Adherence will be via self-report at day 14 virtual questionnaire.  
6.6 
Concomitant Medications/Treatments 
Participants may receive other concomitant medications or therapies and will be asked to 
report these in regard to other therapies received on day 1, 3, 5, 7, 10, 14 and in the event 
of hospitalization. Participants will be recommended not to continue the study drug if 
hospitalized. 
 
 
 
 


Version 6.1 
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26 
7 
STUDY SCHEDULE 
 
 
 
 
Questionnaire 
Day 0 
Day1 
Day 3 
Day 5 
Day 7 
Day 
10 
Day 
14 
Day 
29 
Eligibility (screening 
form) 
x 
 
 
 
 
 
 
 
Enrolment form (for 
eligible patients) 
x 
 
 
 
 
 
 
 
Follow up 
questionnaire (MESA 
COVID 19) 
x 
x 
x 
x 
x 
x 
x 
x 
Severity of overall 
symptoms 
x 
x 
x 
x 
x 
x 
x 
x 
Dyspnea characteristics x 
x 
x 
x 
x 
x 
x 
x 
Dyspnea severity 
x 
x 
x 
x 
x 
x 
x 
x 
Visual analog scale for 
individual symptoms  
x 
x 
x 
x 
x 
x 
x 
x 
Sleep PROMIS scale 
x 
x 
x 
x 
x 
x 
x 
x 
Anxiety PROMIS scale x 
x 
x 
x 
x 
x 
x 
x 
Screening online questionnaire
Email study email if you have been tested positive for COVID-19 and experienced 
symptoms within the past 5 days
You will be sent an email with information about our study
A URL link will be provided for you to take the online screening survey
Medication shipped
Study medicine will be shipped overnight to your address
Study medication should arrive by 10:30 am
Take inhaler twice a day using aerochamber and administer 2 nasal sprays in each 
nostril
Online survey (Day 1)
You will receive an email with a link to online survey
Take the second dose exactly as the day 1
Study days 2 to 14
You should continue taking your medication the same way as day 1
Online survey (Day3,5,7,10)
You will receive an email with a link to an online survey
End of study survey(Day 14)
You will receive an email with a link to an online survey
This marks the end of the study. We will ask if you would like to participate in the 
future studies
If you were hospitalised we will reach out by 2 weeks.


Version 6.1 
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27 
WHO ordinal scale  
x 
x 
x 
x 
x 
x 
x 
x 
Hospitalization/Oxygen 
use query  
 
x 
x 
x 
x 
x 
x 
x 
Side effects query 
 
x 
x 
x 
x 
x 
x 
x 
Mortality 
 
 
 
 
 
 
x 
x 
Subject orientation of 
the type of the study 
drug (placebo or active 
drug) 
 
 
 
 
 
 
x 
 
 
7.1 
Screening  
● Baseline screening for eligibility through online questionnaire 
● Informed consent by electronic consent form in REDCap  
● Participant answers comprehension questions to ensure understands study protocol  
● This will be performed via a web-based form. Eligibility criteria will be by self-
report. 
7.2 
Enrollment/Baseline 
7.2.1 Randomization (Day 0) 
● Medication list and screening form will be reviewed by central physician using the 
doctor review function in REDCap.  
○ If there are any doubts about the subject’s appropriateness, the patient will 
be called by telephone to obtain more details.  The medication list provided 
by the patient will be specifically reviewed by an expert physician in 
Internal Medicine who is aware of issues surrounding polypharmacy.  
Patients who have an unacceptable medical review will be excluded prior 
to randomization and the reason noted. 
● Participants will be randomized by a computer-generated algorithm using a 
permuted block randomization sequence 
● Randomization will be stratified by study site and sex  
● Investigational pharmacy will dispense the masked study medicine  
● Study personnel will then courier study medicine to the participant 
● Participant will be sent an email about when to expect medication to arrive  
7.3 
Follow-up 
 
Day 0 Virtual questionnaire 
● Query for symptom status 
 
Day 1 Virtual questionnaire 
● Verify receipt of study medicine 
● Clinical status check-in 
● Participant starts study medicine Ciclesonide 600mcg BID inhaled with aero 
chamber plus intranasal ciclesonide 200 mcg DIE 


Version 6.1 
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28 
● Confirm the positive SARS-CoV-2 test result 
● Query for symptom status 
● Assess other medicines used during study period 
● self reported hospitalization and oxygen use 
 
 
Day 3, 5, 7, 10 Virtual questionnaires   
● Clinical status check-in 
● Query for symptom status 
● Query for medication-related side effects / AEs 
● Assess other medicines used during study period 
● self reported hospitalization and oxygen use 
 
7.4 
Final Study Visit 
● Day 14 Visit 
● Clinical status check-in 
○ Query for study medicine side effects since enrollment 
○ Query for hospitalization or SAEs 
● Final outcome assessment 
● Completion of study medicine, which has a ~6-hour half-life 
●  Assessment of adherence by self-report 
● Assess whether or not the patient believes they received study drug or placebo 
● Assess other medicines used during study period 
 
● Day 29: Vital Status, clinical status, self reported hospitalization and oxygen use 
7.5 
Early Termination Visit 
If patients feel they are worsening they will need to see their healthcare providers to be 
medically assessed. They are to notify us via email or phone and case report forms will be 
generated. If patients are admitted to hospital, study drug will be stopped.  
7.6 
Unscheduled/Sick Visit  
Subjects will be provided a central email contact (info@contain-covid19.com). This is 
their central electronic point of contact and will be regularly responded to 7 days a week 
in a timely fashion.  The person monitoring that account will either be a physician or will 
be someone who can contact a physician.  
Patients will also receive phone numbers which will be manned but also have voicemail 
and will be responded to in a timely fashion.  
All such interactions which may be due to coronavirus or a SAE will trigger a new daily 
CRF to be sent manually to log the patient’s issue in the core dataset.  


Version 6.1 
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29 
As this is a distance study, patients who are significantly unwell and who need urgent or 
emergent care will need to access regular channels for healthcare (e.g. doctors office, 
emergency room, etc.)  
Additionally, those who have symptoms at baseline, or those who have developed NEW 
symptoms will be sent a follow-up eCRF on Day 10.  
 
 


Version 6.1 
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30 
8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
 
Clinical evaluations are by self-report 
8.2 
Laboratory Evaluations 
There are no laboratory evaluations in the protocol.  
SARS-CoV2 positivity is laboratory-confirmed and self-reported. Informed consent asks 
for access to medical records in case this needs to be verified. 
Informed consent will request permission to contact local public health authorities or their 
medical provider in the event of loss to follow up or COVID-19 disease. 
 
8.3 
Subject Recruitment  
• List of outpatients with COVID positive test will be contacted by research assistants by 
phone using script in appendix 3. They will ask patients for their email. If patients 
demonstrate interest in participation, research assistants will send them a link to study 
website. Study website has a link to REDCap portal for enrollment (www.contain-
covid19.com). Participants will only have data saved in REDCap. Research assistants will 
not enter any data from COVID list into REDCap.  
• Flyers will be left at the testing center for interested participants to visit the study website. 
See appendix 4 for flyers  
 
 
 


Version 6.1 
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31 
9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Ciclesonide has a years-long track record of safety in Canada and the USA. As an already, 
Health Canada-approved medicine, this trial is designed as a pragmatic trial in the setting 
of a public health emergency. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
9.2.1 Adverse Events 
Minor Adverse events will not be captured, unless they result in hospitalization. See 
Serious Adverse Events below.   
Expected adverse events would include normal events within the general population as 
well COVID-19-related disease events which may include need for hospitalization, 
pneumonia, respiratory failure, sepsis, and death.  
9.2.2 Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
 
Not applicable  
9.2.3 Serious Adverse Events (SAEs) 
 
SAEs (e.g. hospitalization) will be followed for up to 29 days to assess final outcome. 
A patient who reports hospitalization and/or an adverse effect of the study drug on a CRF 
who has not reached out to the team by phone or email will be contacted in a timely fashion 
and the site doctor made aware.  We will review the “positive” CRFs to detect these.  We 
also collect details about the hospitalization. 
Patients who do not complete their day 14 CRF will receive reminder emails and, if they 
do not respond to that, they will be telephoned.  Patients must provide an alternate contact 
at enrollment. If they do not respond to the above means, we will call that contact to find 
out what has happened.  If that person does not know or is not available, we will send 
registered mail to the address of the patient before concluding loss to follow-up.  A 
sensitivity analysis of the mortality outcome will be performed assuming patients lost to 
follow-up despite these means have died. 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings 
 
Not applicable 


Version 6.1 
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32 
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
 
 
An AE or suspected adverse reaction is considered a serious adverse event (SAE) if it 
results in any of the following outcomes:  
● Death, 
● life-threatening adverse event (as below),  
● Hospitalization 
● Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
● Important medical events that may not result in death, but are life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.   
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
Life-threatening adverse events: An AE is considered “life-threatening” if, in the view of 
either the site principal investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death.  It does not include an AE that, had it occurred in a more severe 
form, might have caused death. For life threatening AEs, subjects would be recommended 
/expected to be hospitalized.  
 
Based on the known safety track record of ciclesonide, this pragmatic protocol will focus on 
death, life-threatening AEs, and hospitalizations.  Incapacity / permanent disability is a 
possibility with COVID-19, but this is not associated with ciclesonide. In the event of 
incapacity, the subject would be expected to be hospitalized.   
 
Ciclesonide can be used in asthmatic pregnant women. However, as per product monograph; 
‘’There are no adequate and well controlled studies in pregnant women. However, serum 
concentrations of ciclesonide are generally very low following inhaled administration; thus, 
fetal exposure is expected to be negligible and the potential for reproductive toxicity low. 
As with other inhaled corticosteroids, ciclesonide should only be used during pregnancy 
when the potential benefit to the mother justifies the potential risk to the mother, fetus or 
infant. Infants born to mothers who received corticosteroids during pregnancy should be 
observed carefully for hypoadrenalism.’’ As we don’t know the potential benefit of 
ciclesonide in COVID-19 patients, we will exclude pregnant women for our trial.  
  
Thus, the hospitalization or death secondary endpoint will capture relevant SAEs for those 
with ongoing hospitalization at the day 14 study visit, participants will be queried in 14-days 
with the hospital eCRF to assess their final outcome. 


Version 6.1 
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33 
9.3.2 Regulatory Reporting  
As ciclesonide is a Health Canada-approved medicine being used at standard dosing, 
reporting to regulatory authorities will occur as standard and at a frequency of at least 
annually. 
Serious unexpected suspected adverse reactions (SUSARs) which are not expected with 
COVID-19 nor listed in the Health Canada package insert will be reported to the IRB. 
  
Those SUSARS which are deemed by an independent medical monitor to be related to the 
study medicine will be reported to Health Canada and the IRB. 
9.3.3 Reporting of Pregnancy 
We are excluding women who are pregnant, and we will ask child-bearing age women 
participants to use a contraceptive measure during the trial. Methods of contraception 
include hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, 
injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS), and/or 
barrier methods of contraception while on the study drug.  
 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Participants who are hospitalized for COVID-19 or SAEs will have up to 29 day follow 
up conducted to assess their final outcome.  As this is a distance study, management or 
complications of COVID-19 will need to be as per the participant’s local healthcare 
provider. 
9.5 
Safety Oversight (DSMB) 
A DSMB was formed and met at 50% enrolment and when trial enrolment dropped off. 
There were no early stopping criteria defined. Members included: Richard Menzies MD, 
Faiz Khan MD and Sandra Dial MD.  
 
 


Version 6.1 
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34 
10 
CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 
subjects are protected and that the reported trial data are accurate, complete, and verifiable. 
Clinical monitoring also ensures that conduct of the trial is in compliance with the currently 
approved protocol/ amendment(s), ICH, GCP, and with applicable regulatory 
requirement(s) and Sponsor requirements. Clinical monitoring will also verify that any 
critical study procedures are completed following specific instructions. Monitoring in 
Canada will be the responsibility each Site PI under the overall responsibility of Nicole 
Ezer, RI-MUHC. 
  
The automated logic of the REDCap database system will enable complete records. All 
data are by self-report.   
 
 
 
 
 


Version 6.1 
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35 
11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
We hypothesize that ciclesonide is superior to placebo for reducing dyspnea due to COVID-19 
disease among who are symptomatic.  
11.2 Sample Size Considerations 
 
Our primary outcome is the proportion of patients with resolved respiratory symptoms (fever, 
cough, shortness of breath, chest congestion or chest tightness) at day 7. 
 
This study is powered based on determining if there is a 15% increase in our primary outcome, the 
proportion of participants with no symptoms of shortness of breath (including chest congestion 
and chest tightness), cough or fever at Day 7. Based on the assumption that, by Day 7, 65% of 
untreated subjects, and 80% of treated subjects, will have resolved their symptoms, we will need 
159 subjects per group to detect this difference with 80% power (5% alpha). This analysis has been 
adjusted to include a 15% dropout rate.  The total number of study participants required is 318.  
These assumptions were made based on another outpatient RCT evaluating symptoms in COVID-
19(15). 
 
% Resolved 
by Day 7- 
Placebo arm 
% Resolved 
by Day 7- 
Treatment 
arm 
Proportion 
difference 
Nominal 
Power, 
p=0.05 
Total 
participants 
Total 
participants 
including 
15% drop 
out 
75% 
85% 
10% 
0.8 
250 
 
75% 
90% 
15% 
0.8 
200 
 
75% 
95% 
20% 
0.8 
98 
 
70% 
80% 
10% 
0.8 
586 
 
70% 
85% 
15% 
0.8 
240 
 
70% 
90% 
20% 
0.8 
124 
 
70% 
95% 
25% 
0.8 
70 
 
65% 
75% 
10% 
0.8 
656 
 
65% 
80% 
15% 
0.8 
276 
318 
(159 
per arm) 
65% 
80% 
15% 
0.9 
368 
 
65% 
85% 
20% 
0.8 
144 
 
65% 
90% 
25% 
0.8 
86 
 
60% 
70% 
10% 
0.8 
712 
 
60% 
75% 
15% 
0.8 
304 
 
60% 
75% 
15% 
0.9 
406 
 
60% 
80% 
20% 
0.8 
162 
 
60% 
85% 
25% 
0.8 
98 
 
60% 
90% 
30% 
0.8 
62 
 


Version 6.1 
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36 
 
11.3 Planned Interim Analyses 
 
No interim analyses are planned. 
11.4 Primary Analysis 
 
Primary outcome analyses: 
 
A modified intention to treat approach will be used where subjects will be analyzed according to 
the group they were randomized provided they have been shipped the drug, taken one dose and 
completed at least one follow-up assessment.  
 
The proportion of patients who meet the primary outcome will be compared by binomial 
regression adjusting for stratification and the difference will be reported as an absolute risk 
difference and 95% CI.  
Secondary Analyses: 
Proportions meeting each secondary outcome will be analyzed by binomial regression adjusting 
for stratification and the differences will be reported as an absolute risk difference and 95% CI.  
 
The post-hoc analysis of time to symptom resolution will use the Kaplan Meier plot. 
 
 
Handling of withdrawn subjects. 
 
If there is a large lost to follow up / study discontinue rate, then the primary endpoint would have 
a secondary analysis to assess incidence as a 3-category analysis of: i) increase in disease 
symptoms, ii) decrease in disease symptoms, iii) no change in disease symptoms or iiii) unknown.   
 
Participants who stop taking the study medicine but who agree to be followed for the duration of 
the study will be assessed as intent-to-treat. On Day 1, 3, 5, 7, 14 and 29, we will ask for other 
medications or vitamins that were taken during the study period. 
 


Version 6.1 
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37 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Source documents will include internet forms self-completed by participants directly entered into 
a REDCap database.   
This protocol is based on self-report. 
This internet-based protocol is meant to enable a large number of participants to be recruited, 
quickly as well as maintain the safety of the research staff.  In person visits, create a public health 
risk due to transmission of COVID-19 from unrecognized cases. Likewise, paper documents and 
consent forms also carry this risk (as fomites) and so all consent documentation will be recorded 
electronically with an online signature.  
Participants will be asked to provide consent to obtain medical records from their healthcare 
provider or public health official, if there is the need to verify outcomes – for SARS-CoV-2 test 
results or hospitalizations.  
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study medications will be Health Canada-approved following Good Manufacturing Practice. 
14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
This study is to be conducted in the spirit of Canadian and international standards of Good Clinical 
Practice (International Conference on Harmonization guidelines), Declaration of Helsinki, and 
International Ethical Guidelines for Biomedical Research Involving Human Subjects, applicable 
provincial regulations and institutional research policies and procedures. All investigators must 
have received ethics and GCP training prior to human subject involvement. 
14.2 Institutional Review Board 
Prior to the initiation of the study, the protocol, all informed consent forms, and the participant 
Information materials will be submitted to and approved by the RI-MUHC. For outside of Quebec, 
other REBs will take responsibility for their provinces using this master protocol.  Likewise, any 
future amendments to the study protocol will be submitted and approved by the IRB before 
implementation.  This protocol and any amendments will undergo review and approval.  
14.3 Informed Consent Process 
● Written informed consent will be obtained via an English or French-language, internet-
based web form. If potential participants have questions, they may contact a study staff 


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member in their province to answer their questions about the research, either via email or 
phone call. Participants will electronically sign the consent form.  
● Participants will be asked to upload a photo ID (provincial health card) to confirm their 
identification. 
● After completion of reading the form, participants will be assessed for comprehension, 
querying: 
○ Concept of Randomization to ciclesonide or placebo 
○ Whether ciclesonide is known to be effective in preventing disease 
○ Duration of the study? (14 days) 
○ Duration of taking the study medicine (14 days) 
○ When follow up surveys will be sent (Days 1, 3, 5, 7, 10, and 14) 
○   If ciclesonide can be shared? (No) 
14.4 Exclusion of Women, Minorities, and Children  
● Persons under 18 years of age are not eligible to participate. 
● Women who are pregnant or breastfeeding are excluded because the safety data is 
inadequately known for this study.  
● Non-English or French speaking adults are not eligible as the webpage and consents 
will only be available in English or French. 
14.5 Subject Confidentiality 
● Interaction will be via internet-based REDCap eCRFs conforming to required 
Canadian privacy and server security standards. 
● Clinical data will be entered into a study specific database by designated staff on a 
regular basis from completed electronic Case Record Forms (eCRF). Access to 
database will be given to authorized personnel only (members of the immediate 
study team). eCRF and trial documents will be kept in a secure database.  
● Documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to 
any unauthorized third party, without prior written approval of the participant 
except as necessary for monitoring by the IRB or public health authorities  
● No participant identifying information will be disclosed in any publication or at 
any conference activities arising from the study. 
● Anonymized data on demographics, survey responses and outcomes will be 
pooled with international collaborators subject to inter-institutional agreements. 
14.6 Future Use of Stored Specimens 
● No specimens are to be collected.  
 
 


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15 
DATA HANDLING AND RECORD KEEPING 
15.1 Data Management Responsibilities 
15.2 Data Capture Methods 
● Data will be obtained via internet-based REDCap forms. 
15.3 Types of Data 
● Participants will be asked to provide data regarding COVID-19 exposure timing 
and location. They will also be asked to provide ongoing symptom reports during 
the follow-up period. 
15.4 Timing/Reports 
● An enrollment progress report will be generated monthly 
○ Participants Enrolled 
○ Participants on study 
○ Participants completed the study 
○ Lost to Follow Up 
○ Cumulative Hospitalizations (pooled, both arms) 
○ Cumulative mortality 
 
● De-identified data will be shared with the research team members for analysis. 
15.5 Study Records Retention 
● No paper documents will be retained or stored. 
● Digital records will be kept in a secure server setting. 
15.6 Protocol Deviations 
Protocol violations will be reported to the IRB of record in each province and forwarded to the 
main Canadian PI.  
 
 


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16 
PUBLICATION POLICY 
Publication will be expeditiously made with a full, de-identified data made available. 
17 
LITERATURE REFERENCES 
1. 
Roser M, Ritchie, H., Ortiz-Ospina, E., & Hasell, J. (2020). 
https://ourworldindata.org/coronavirus Coronavirus Disease (COVID-19), Retrieved 20 April 
2020. 
2. 
Health CANADA AdfC.  [Available from: https://www.canada.ca/en/health-
canada/services/drugs-health-products/covid19-industry/drugs-vaccines-
treatments/authorization/applications.html#wb-auto-4. 
3. 
Coronavirus Disease 2019 (COVID-19) Situation Summary. (2020). Retrieved 20 April 
2020, from https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/summary.html. 
4. 
Zhou Pea. A pneumonia outbreak associated with a new coronavirus of probable bat 
origin. Nature. 2020. 
5. 
Sangeun Jeon MK, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, 
Seungtaek Kim,. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-
approved drugs. BioRxiv. 2020. 
6. 
Shutoku Matsuyama MK, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru 
Kamitani, Masayuki Shimojima, Shuetsu Fukushi. The inhaled corticosteroid ciclesonide blocks 
coronavirus RNA replication by targeting viral NSP15. BioRxiv. 2020. 
7. 
Yang Liu L-MY, Lagen Wan, Tian-Xin Xiang, Aiping Le, Jia-Ming Liu, Malik Peiris, 
*Leo L M Poon, *Wei Zhang. Viral dynamics in mild and severe cases of COVID-19. The 
Lancet Infectious Diseases. 
8. 
Meehyun Ko SYC, Soo Young Byun, Inhee Choi, Anne-Laure Pham Hung d’Alexandry 
d’Orengiani, David Shum, Ji-Young Min, Marc P. Windisch. Screening of FDA-approved drugs 
using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for 
COVID-19. BioRxiv (preprinted). 2020. 
9. 
Alvesco. [2006; revised 2017 January 17]. In:[database?]. AstraZeneca. Available from: 
https://www.astrazeneca.ca/content/dam/az-ca/downloads/productinformation/alvesco-product-
monograph-en.pdf. 
10. 
Lougheed M, Lemiere, C., Ducharme, F., Licskai, C., Dell, S., & Rowe, B. et al. 
Canadian Thoracic Society 2012 Guideline Update: Diagnosis and Management of Asthma in 
Preschoolers, Children and Adults. Canadian Respiratory Journa. 2012. 
11. 
Omnaris. [2007: revised 2017 January 19]. In:[databse?]. AstraZeneca. Available from: 
https://www.astrazeneca.ca/content/dam/az-ca/downloads/productinformation/omnaris-product-
monograph-en.pdf. 
12. 
(https://mainichi.jp/english/articles/20200317/p2a/00m/0na/026000c). 
13. 
(https://clinicaltrials.gov/ct2/show/NCT04330586). 
14. 
(https://pj.jiho.jp/article/241752). 
15. 
Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. 
Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial. 
Ann Intern Med. 2020;173(8):623-31. 


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SUPPLEMENTS/APPENDICES 
 
 
APPENDIX A: SCHEDULE OF EVENTS 
 
Overview of Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participants with ongoing hospitalization at day 14 will be followed with an additional eCRF 
after 14 days.  
 
Screen
•Research Assistant  emails RECRUITMENT EMAIL
•Auto-Response Study Info Sheet/Website
•URL links to Screening eCRF
Consent
•Screening for Inclusion/Exclusion 
•If eligible -> Informed Consent Form
•Assessment of Comprehension
•Signing online consent form
Rando
mize
•Prescription order sent to Pharmacy
•pharmacy dispence the study drug 
•Study Staff to Ship Study Medicine
Day +1
•Email with URL to eCRF to verify:
•Receipt of med
•Symptom status / AEs
Day 
+3,5,7,
10
•Email with URL link to eCRF to verify:
•Symptom status
•Hospitalization status; AEs 
Day 
+14
•Email with URL link to eCRF to verify:
•Symptom status
•Hospitalization status; AEs
•Inquiry if future contact for research? 


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APPENDIX B: LOGIC 
 
1) Must have all inclusion criteria as defined.   
 
2) Must not have any exclusion criteria. 
 
3) Patients who are not in the study provinces will receive a message saying the study is not 
available in their province (this is not counted as being formally ineligible).