Clinical trial NCT04377711
Conditions: COVID-19
Sponsor: Covis Pharma S.à.r.l.
Start date: 2020-06-08; Completion date: 2021-01-05
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of Alvesco (ciclesonide) Inhalation Aerosol in non hospitalized patients with symptomatic COVID-19 infection in a multicenter, randomized, double-blind, placebo controlled study

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy, and safety study of ciclesonide MDI for the treatment of symptomatic COVID-19 infection. Enrolled patients were male and female adults and adolescents 12 years of age or older with confirmed COVID-19 infection who were currently exhibiting symptoms of the disease and who were not currently hospitalized or under immediate consideration for hospitalization at the time of enrollment. The study consisted of an initial screening/enrollment/randomization visit, a 30-day treatment period, and a follow-up period.

Arms: arm 1: Participants receive Alvesco 320mcg, twice daily for 30 days via pMDI arm 2: Participants receive Placebo matching Alvesco , twice daily for 30 days via pMDI
Interventions: intervention 1: Ciclesonide intervention 2: Placebo
Intervention descriptions: intervention 1: 160mcg Inhaler intervention 2: Matching Placebo Inhaler

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
Covis Pharma B.V. 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Assess the Safety and Efficacy of Ciclesonide Metered-Dose 
Inhaler in Non-Hospitalized Patients 12 Years of Age and Older 
With Symptomatic COVID-19 Infection 
Protocol Number: 
ALV-020-001 
Investigational Product: 
Alvesco® (ciclesonide) Inhalation Aerosol 
IND Number: 
 
Development Phase: 
Phase 3 
Sponsor Name and Address: 
Covis Pharma B.V. 
Grafenauweg 12 
Zug Branch 
Zug, CH-6300 
Switzerland 
Sponsor Protocol Approver: 
 
 
Responsible Medical Officer: 
 
Protocol Date and Version: 
December 21, 2020; Version 4.0 (Protocol Amendment 3) 
August 31, 2020; Version 3.0 (Protocol Amendment 2) 
May 18, 2020; Version 2.0 (Protocol Amendment 1) 
May 1, 2020; Version 1.0 (Original Protocol) 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and 
regulations.  In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them.  These restrictions on 
disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


Investigator’s Statement 
I understand that all information concerning the product supplied to me by Covis Pharma B.V. 
and 
 in connection with this study and not previously 
published, is confidential information.  This information includes the protocol (and applicable 
amendments), case report forms, assay methods, technical methodology, and basic scientific 
data. 
I will conduct the study according to the protocol, and I understand that any changes to the 
protocol must be approved in writing by Covis Pharma B.V., 
 
 and the institutional review board/independent ethics committee before 
implementation, except where necessary to eliminate apparent immediate hazards to the subjects. 
I confirm that I will report all adverse events following the regulations referenced in the protocol. 
I confirm that I will conduct this study in conformance with the principles of the Declaration of 
Helsinki, Good Clinical Practice, and United States law and regulations. 
I confirm that I am informed of the need for records retention and that no data will be destroyed 
without the written consent of Covis Pharma B.V. 
By my signature below, I hereby attest that I have read, understood, and agree to abide by all 
conditions, instructions, and restrictions contained in this protocol, dated December 21, 2020. 
 
Investigator’s Signature:  
 
 
Name (printed): 
 
 
Date 
 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


1 PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Covis Pharma B.V. 
Name of Product: 
Alvesco® Inhalation Aerosol 
Name of Active Ingredient: 
ciclesonide 
Title of Study: 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and 
Efficacy of Ciclesonide Metered-Dose Inhaler in Non-Hospitalized Patients 12 Years of Age and Older 
With Symptomatic COVID-19 Infection 
Study Sites: 
Up to 15 sites in the United States 
Protocol Number: 
ALV-020-001 
Development Phase: 
Phase 3 
Primary Objective: 
The primary study objective is to assess whether treatment with ciclesonide metered-dose inhaler (MDI) 
plus standard supportive care results in improved time to alleviation of Coronavirus Disease 2019 
(COVID-19)-related symptoms of cough, dyspnea, chills, feeling feverish, repeated shaking with chills, 
muscle pain, headache, sore throat, and new loss of taste or smell compared with placebo plus standard 
supportive care in non-hospitalized patients with symptomatic COVID-19 infection. 
Secondary Objectives: 
The secondary study objectives are: 
• 
to assess whether treatment with ciclesonide MDI plus standard supportive care reduces the 
incidence of hospital admissions or death compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• 
to assess whether treatment with ciclesonide MDI plus standard supportive care reduces all-cause 
mortality compared with placebo plus standard supportive care in non-hospitalized patients with 
symptomatic COVID-19 infection 
• 
to assess whether treatment with ciclesonide MDI plus standard supportive care reduces 
COVID-19-related mortality compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• 
to assess whether treatment with ciclesonide MDI plus standard supportive care reduces the 
incidence of subsequent emergency department visits or hospital admissions for reasons attributable 
to COVID-19 compared with placebo plus standard supportive care in non-hospitalized patients 
with symptomatic COVID-19 infection 
• 
to assess whether treatment with ciclesonide MDI plus standard supportive care increases the 
percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, chills, 
feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of 
taste or smell compared with placebo plus standard supportive care in non-hospitalized patients with 
symptomatic COVID-19 infection 
• 
to assess whether treatment with ciclesonide MDI plus standard supportive care increases the time 
to hospital admission or death compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• 
to assess the impact of treatment with ciclesonide MDI plus standard supportive care on oxygen 
saturation levels compared with placebo plus standard supportive care in non-hospitalized patients 
with symptomatic COVID-19 infection 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


Name of Sponsor/Company: 
Covis Pharma B.V. 
Name of Product: 
Alvesco® Inhalation Aerosol 
Name of Active Ingredient: 
ciclesonide 
• 
to assess the impact of treatment with ciclesonide MDI plus standard supportive care on COVID-19 
viral load compared with placebo plus standard supportive care in non-hospitalized patients with 
symptomatic COVID-19 infection 
• 
to assess the safety of ciclesonide MDI plus standard supportive care compared with placebo plus 
standard supportive care in non-hospitalized patients with symptomatic COVID-19 infection 
Methodology: 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety 
study of ciclesonide MDI for the treatment of symptomatic COVID-19 infection.  Enrolled patients will 
be male and female adults and adolescents ≥ 12 years of age with confirmed COVID-19 infection who 
are currently exhibiting symptoms of the disease and who are not currently hospitalized or under 
immediate consideration for hospitalization at the time of enrollment.  The study will consist of an initial 
screening/enrollment/randomization visit, a 30-day treatment period, and a follow-up period. 
Following signature of the informed consent form, patients meeting inclusion/exclusion criteria will be 
randomly assigned (1:1) to treatment with ciclesonide MDI 320 µg twice daily (BID) (morning [AM] 
and evening [PM]) plus standard supportive care (hereafter referred to as the ciclesonide arm) or placebo 
MDI BID (AM and PM) plus standard supportive care (hereafter referred to as the placebo arm).  During 
the initial screening/enrollment/randomization visit, patients will be instructed on how to self-administer 
a MDI and will be discharged home with a 30-day supply of investigational product (ie, either 
ciclesonide MDI or placebo MDI), standard supportive care, a pulse oximeter for at-home oxygen 
saturation level monitoring, and an electronic diary (eDiary).  A nasopharyngeal sample for viral load 
analysis will also be obtained at the initial screening/enrollment/randomization visit.  Patients will be 
instructed to record self-administration of investigational product and oxygen saturation levels in the 
eDiary.  Prior to self-administration of the investigational product (ie, within 1 hour of administration), 
patients will also complete and record assessments in the eDiary of severity of COVID-19-related 
symptoms of cough, dyspnea, chills, and feeling feverish (based on a 4-point scale where 0 = absent, 
1 = mild, 2 = moderate, and 3 = severe) and the presence/absence of COVID-19-related symptoms of 
repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell.  
Qualified healthcare providers will contact patients on days 2, 4, 6, 8, 10, 12, 14, 21 ± 2 days, and 
30 ± 2 days for a health status check, to collect adverse event and concomitant medication information, 
and to confirm/clarify information recorded in the eDiary.  During these patient contacts, medical advice 
commensurate with standard of care for reported symptoms or adverse events will be provided.  On 
day 30 (window of + 2 days), the patient will return to the study site for collection of a nasopharyngeal 
sample for viral load analysis and to return the eDiary and investigational product (ie, used and unused 
MDIs).  Qualified healthcare providers will contact patients on day 37 ± 4 days and day 60 ± 7 days to 
collect follow-up safety and outcome data (the follow-up period). 
Patients (or their representatives) will be asked to notify study personnel directly in the event they visit 
an emergency department or are hospitalized during their participation in the study. 
Patient duration on study is expected to be approximately 60 days, including the 
screening/enrollment/randomization visit, the 30-day treatment period and the subsequent follow-up 
period.  In the event the patient requires hospitalization during the 30-day treatment period, the patient 
will discontinue investigational product and scheduled follow-up procedures but will continue to be 
followed for the outcome of hospitalization and ongoing adverse events. 
An independent and appropriately constituted Data Monitoring Committee (DMC) will be organized for 
this study.  A charter detailing the purpose of the committee as well as their roles and responsibilities 
will be put into place and will guide and direct their actions. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


Name of Sponsor/Company: 
Covis Pharma B.V. 
Name of Product: 
Alvesco® Inhalation Aerosol 
Name of Active Ingredient: 
ciclesonide 
Number of Patients: 
Approximately 400 patients (200 in each arm) will be randomized. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
Patients eligible for enrollment in the study must meet all the following criteria: 
1. Male and female adults and adolescents ≥ 12 years of age. 
2. Positive SARS-CoV-2 molecular or antigen diagnostic test within 72 hours prior to enrollment.  
3. Patient is not currently hospitalized or under immediate consideration for hospitalization at the time 
of enrollment. 
4. Patient is currently experiencing symptoms of fever, cough, and/or dyspnea. 
5. Patient has an oxygen saturation level > 93%. 
6. Ability to show adequate use of MDI, including inhalation technique. 
7. Patient, parent/legal guardian, or legally-authorized representative must have signed a written 
informed consent before administration of any study-specific procedures. 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for participation in the study: 
1. Existence of any life-threatening co-morbidity or any other medical condition which, in the opinion 
of the investigator, makes the patient unsuitable for inclusion. 
2. History of hypersensitivity to ciclesonide. 
3. Treatment with inhaled or intranasal corticosteroids within 14 days of the screening/ 
enrollment/randomization visit. 
4. Treatment with oral corticosteroids within 90 days of the screening/enrollment/randomization visit. 
5. Participation in any other clinical trial or use of any investigational agent within 30 days of the 
screening/enrollment/randomization visit. 
6. Currently receiving treatment with hydroxychloroquine/chloroquine. 
7. Patients with cystic fibrosis. 
8. Patients with idiopathic pulmonary fibrosis. 
9. Pregnancy (for females of childbearing potential). 
Test Product, Dose, and Mode of Administration: 
Ciclesonide 160 µg/actuation MDI, 320 µg BID (2 actuations in the AM and 2 actuations in the PM), oral 
inhalation 
Reference Therapy, Dose, and Mode of Administration: 
Placebo MDI, BID (2 actuations in the AM and 2 actuations in the PM), oral inhalation  
Duration of Treatment: 
30 days 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


Name of Sponsor/Company: 
Covis Pharma B.V. 
Name of Product: 
Alvesco® Inhalation Aerosol 
Name of Active Ingredient: 
ciclesonide 
Criteria for Evaluation: 
Efficacy: 
Primary Efficacy Endpoint 
•  Time to alleviation of COVID-19-related symptoms of cough, dyspnea, chills, feeling feverish, 
repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell, 
defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by 
day 30 
Secondary Efficacy Endpoints 
• Percentage of patients with hospital admission or death by day 30 
• All-cause mortality by day 30 
• COVID-19-related mortality by day 30 
• Percentage of patients with subsequent emergency department visit or hospital admission for reasons 
attributable to COVID-19 by day 30 
• Percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, chills, 
feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of 
taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM 
assessments) by day 7, by day 14, and by day 30 
• Time to hospital admission or death 
• Change from baseline in oxygen saturation levels 
• Change from baseline in COVID-19 viral load in nasopharyngeal sample at day 30 
Safety: Safety will be assessed based on adverse events. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


Name of Sponsor/Company: 
Covis Pharma B.V. 
Name of Product: 
Alvesco® Inhalation Aerosol 
Name of Active Ingredient: 
ciclesonide 
Statistical Methods: 
Efficacy 
The primary efficacy variable is time to alleviation of COVID-19-related symptoms of cough, dyspnea, 
chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of 
taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM 
assessments) by day 30.  The primary analysis will be based on the intent-to-treat population 
(all randomized patients).  To increase precision of treatment effect estimation and inference, a Cox 
proportional hazards model will be used to allow for inclusion of additional prespecified prognostic 
baseline covariates.  The median time to event and 95% confidence intervals will be summarized by 
treatment arm, and Kaplan-Meier estimates of the survival curves will also be generated.  The secondary 
efficacy endpoints of percentage of patients with hospital admission or death by day 30; all-cause 
mortality by day 30; COVID-19-related mortality by day 30; percentage of patients with subsequent 
emergency department visit or hospital admission for reasons attributable to COVID-19 by day 30; and 
percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, chills, 
feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste 
or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by 
day 7, by day 14, and by day 30 will be analyzed using a logistic regression model.  This will improve 
the precision of treatment effect estimation and inference by allowing for baseline covariate adjustments 
to be included in the model.  Analysis of the secondary efficacy endpoint of time to hospital admission 
or death will be performed using the same method as that used for the primary efficacy endpoint.  The 
secondary efficacy endpoint of change from baseline in oxygen saturation levels will be summarized 
descriptively at all timepoints captured in the eDiary.  The secondary efficacy endpoint of change from 
baseline in COVID-19 viral load in nasopharyngeal sample at day 30 will be summarized descriptively. 
Safety 
The safety population will include all randomized patients who receive at least 1 dose of double-blind 
study medication.  Safety will be evaluated by summarizing the incidence of adverse events.  
Comparative analyses will be done on adverse events of special interest (eg, oral candidiasis). 
Interim Safety Review  
The DMC will conduct a review of blinded safety data once 100 subjects have been enrolled.  Details of 
the interim safety review will be described in detail in the DMC charter. 
Sample Size and Power: 
This study is designed to assess the efficacy and safety of ciclesonide MDI plus standard supportive care 
compared with placebo MDI plus standard supportive care.  The primary endpoint is time to alleviation 
of COVID-19-related symptoms of cough, dyspnea, chills, feeling feverish, repeated shaking with chills, 
muscle pain, headache, sore throat, and new loss of taste or smell, defined as symptom-free for a 
continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by day 30.  Assuming a median time to 
alleviation of 7 days for the ciclesonide arm and 11 days for the placebo arm (hazard ratio of 
approximately 1.58) with a total study duration of 30 days and a total of 201 events observed in the 
2 arms combined, a sample size of approximately 232 patients (116 in each arm) is required to achieve 
90% power at α = 0.05 for the study.  To account for an unknown drop-out rate in this patient 
population as well as other factors that may impact the overall power of the study, the planned sample 
size was increased to 400 patients (200 in each arm) for this study.  Note that these are best estimates at 
this point as there is still much uncertainty regarding COVID-19. 
 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


 
TABLE OF CONTENTS 
Description 
Page 
1 Protocol Synopsis .....................................................................................................................3 
2 List of Abbreviations and Definition of Terms ...................................................................11 
3 Introduction ............................................................................................................................12 
3.1 
Background Information on Coronavirus Disease 2019 (COVID-19) .............................12 
3.2 
Background Information on Ciclesonide and Rationale for Use in COVID-19 ...............12 
3.3 
Rationale for Dose Selection and Treatment Duration .....................................................13 
3.4 
Rationale for Subject Population ......................................................................................14 
4 Study Objectives.....................................................................................................................15 
4.1 
Primary Objective .............................................................................................................15 
4.2 
Secondary Objectives ........................................................................................................15 
4.3 
Estimands ..........................................................................................................................16 
4.3.1 
Primary Endpoint Estimand ......................................................................................16 
4.3.2 
Key Secondary Endpoint Estimand ..........................................................................17 
5 Study Description ...................................................................................................................18 
5.1 
Study Design .....................................................................................................................18 
5.2 
Study Schedule ..................................................................................................................19 
5.3 
Study Visits and Procedures .............................................................................................22 
5.3.1 
Screening/Enrollment/Randomization Visit .............................................................22 
5.3.2 
Double-blind Treatment Period ................................................................................23 
5.3.3 
Follow-up Period ......................................................................................................24 
5.3.4 
Early Termination Procedures ..................................................................................24 
6 Patient Eligibility and Withdrawal Criteria........................................................................25 
6.1 
Number of Patients ...........................................................................................................25 
6.2 
Inclusion Criteria ..............................................................................................................25 
6.3 
Exclusion Criteria .............................................................................................................25 
6.4 
Withdrawal Criteria ..........................................................................................................26 
7 Study Assessments and Procedures ......................................................................................27 
7.1 
Efficacy .............................................................................................................................27 
7.1.1 
Efficacy Endpoints ....................................................................................................27 
7.1.2 
Efficacy Assessments ...............................................................................................27 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


7.2 
Safety ................................................................................................................................28 
7.2.1 
Safety Endpoint.........................................................................................................28 
7.2.2 
Safety Assessments ...................................................................................................28 
7.3 
Data Monitoring Committee .............................................................................................29 
8 Study Conduct ........................................................................................................................30 
8.1 
Treatments to be Administered .........................................................................................30 
8.2 
Method of Assigning Patients to Treatment Groups .........................................................30 
8.3 
Blinding .............................................................................................................................30 
8.4 
Treatment Compliance ......................................................................................................30 
8.5 
Investigational Product Materials and Management .........................................................31 
8.5.1 
Description of Investigational Product .....................................................................31 
8.5.2 
Investigational Product Packaging and Labeling......................................................31 
8.5.3 
Investigational Product Storage ................................................................................31 
8.5.4 
Investigational Product Handling and Disposal........................................................31 
8.6 
Procedure for Breaking the Randomization Code ............................................................32 
8.7 
Investigational Product Accountability .............................................................................32 
8.8 
Concomitant and Prohibited Medications .........................................................................32 
9 Adverse Events .......................................................................................................................34 
9.1 
Adverse Event Definition .................................................................................................34 
9.2 
Reporting of Adverse Events ............................................................................................34 
9.2.1 
Severity of Adverse Events.......................................................................................34 
9.2.2 
Relationship to Investigational Product ....................................................................35 
9.2.3 
Action Taken with Investigational Product ..............................................................35 
9.2.4 
Outcome ....................................................................................................................35 
9.3 
Serious Adverse Event Definition ....................................................................................36 
9.4 
Reporting Serious Adverse Events ...................................................................................36 
10 Statistical Evaluation .............................................................................................................38 
10.1 Sample Size and Power .....................................................................................................38 
10.2 Statistical Analysis Sets ....................................................................................................38 
10.3 Statistical Methods ............................................................................................................38 
10.3.1 General Principles .....................................................................................................38 
10.3.2 Missing Data .............................................................................................................39 
10.4 Demographic and Baseline Characteristics ......................................................................39 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


10.5 Patient Disposition ............................................................................................................39 
10.6 Concomitant Medications .................................................................................................39 
10.7 Analysis of Efficacy Data .................................................................................................39 
10.7.1 Primary Efficacy Endpoint .......................................................................................39 
10.7.2 Secondary Efficacy Endpoints ..................................................................................40 
10.7.3 Multiple Comparisons...............................................................................................40 
10.8 Analysis of Safety Data ....................................................................................................41 
10.9 Interim Safety Review ......................................................................................................41 
11 Quality Control and Quality Assurance ..............................................................................42 
11.1 Conduct of the Study ........................................................................................................42 
11.2 Study Monitoring ..............................................................................................................42 
12 Ethics .......................................................................................................................................44 
12.1 Independent Ethics Committee/Institutional Review Board .............................................44 
12.2 Written Informed Consent and Assent ..............................................................................44 
13 Data Handling and Record Keeping ....................................................................................45 
13.1 Case Report Forms/Source Data Handling .......................................................................45 
13.2 Retention of Essential Documents ....................................................................................46 
14 Financing and Insurance .......................................................................................................47 
15 Publication Policy...................................................................................................................48 
16 References ...............................................................................................................................49 
 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AM 
morning 
BID 
twice daily 
CDC 
Centers for Disease Control and Prevention 
Cmax 
maximum concentration  
COVID-19 
coronavirus disease 2019 
DDC 
direct data capture 
DMC 
data monitoring committee 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonization  
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board  
ITT 
intent-to-treat 
MDI 
metered-dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities  
PM 
evening 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
WHO 
World Health Organization  
 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


3 INTRODUCTION 
3.1 
Background Information on Coronavirus Disease 2019 (COVID-19) 
There is currently an outbreak of respiratory disease caused by a novel coronavirus that was first 
detected in Wuhan City, Hubei Province, China, and that has now been detected in many 
locations internationally, including cases in the United States.  The virus has been named Severe 
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the disease it causes has been 
named Coronavirus Disease 2019 (COVID-19).  On January 31, 2020, the Department of Health 
and Human Services issued a declaration of a public health emergency related to COVID-19 and 
on March 13, 2020, the President declared a national emergency in response to COVID-19. 
The United States Centers for Disease Control and Prevention (CDC) has stated that symptoms 
compatible with COVID-19 include subjective or measured fever, cough, or difficulty breathing, 
and may present within 2 to 14 days after exposure.  Reported illnesses have ranged from mild 
symptoms to severe illness and death for confirmed COVID-19 cases. 
Currently there are no approved treatments for COVID-19.  Innovators are looking at products in 
a variety of areas, including the assessment of antiviral drugs that might treat the specific virus, 
as well as host targets, such as interleukin-6 receptor inhibitors that may be helpful in reducing 
lung inflammation and improving lung function in COVID-19 patients, thereby potentially 
slowing the progression of severe respiratory symptoms. 
3.2 
Background Information on Ciclesonide and Rationale for Use in COVID-19 
Alvesco® (ciclesonide) Inhalation Aerosol is an inhaled corticosteroid that has been approved in 
the United States for the indication of maintenance treatment of asthma as prophylactic therapy 
in adult and adolescent patients 12 years of age and older (Alvesco® Inhalation Aerosol US 
prescribing information, 2019).  Alvesco (ciclesonide) Inhalation Aerosol is administered by oral 
inhalation employing a pressurized metered-dose inhaler (MDI) and is available in 2 strengths 
(80 µg/actuation and 160 µg/actuation).  Additional summary information regarding Alvesco 
(ciclesonide) Inhalation Aerosol is provided in the product labeling (Alvesco® Inhalation Aerosol 
US prescribing information, 2019). 
Systemic glucocorticoid therapy is not currently indicated in patients with pneumonia or 
COVID-19 because of the potential for prolonging viral replication, as observed in patients with 
Middle East Respiratory Syndrome Coronavirus (CDC, 2020).  However, inhaled 
glucocorticoids, such as ciclesonide, may demonstrate clinical benefit in patients with less severe 
symptoms of COVID-19 (Fu et al, 2020; Zhai et al, 2020). 
Institut Pasteur Korea has recently identified ciclesonide as a potential candidate against 
COVID-19 infection based on a screening of approximately 3000 drugs.  A total of 48 drugs 
were initially pre-selected based on an assay of SARS-CoV and were further tested for antiviral 
activity against SARS-CoV-2.  Of these, 24 drugs (including ciclesonide) showed antiviral 
activity against SARS-CoV-2 (Jeon et al, 2020).  This finding was corroborated in a recent 
publication by Matsuyama et al, 2020, in which it was reported that ciclesonide blocked 
SARS-CoV-2 replication in cultured cells at low concentrations.  Furthermore, a small number 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


(n = 3) of patients in Japan with confirmed COVID-19 infection, all over 65 years of age and 
receiving supplemental oxygen, were treated with ciclesonide and demonstrated clinical 
improvement in 2 days (Puiu, 2020), providing additional support for continued study of 
ciclesonide in the treatment of COVID-19.  Interestingly, an underlying mechanism for the 
suppression of viral infection by ciclesonide has been revealed by the isolation of a drug-resistant 
mutant.  Isolation of this mutant indicated that NSP15, a viral riboendonuclease, is a molecular 
target of ciclesonide (Matsuyama et al, 2020).  Thus, it is reasonable to consider that ciclesonide 
may exhibit a direct-acting antiviral activity in addition to its intrinsic anti-inflammatory function 
and, therefore, has the potential to manifest dual roles (antiviral and anti-inflammatory) in the 
treatment of COVID-19 infection. 
The systemic bioavailability is low for inhaled glucocorticoids (mean maximum concentration 
[Cmax] of des-ciclesonide [pharmacologically active metabolite of ciclesonide prodrug] in plasma 
following once daily 320 µg inhaled ciclesonide was 0.369 ng/mL), whereas oral glucocorticoids 
such as prednisone and prednisolone have a mean Cmax of 2.4 and 18.1 µg/L/1 mg dose, 
respectively (Czock et al, 2005).  Therefore, it is hypothesized that use of Alvesco (ciclesonide) 
Inhalation Aerosol will reduce inflammation and viral replication in the lung in patients with 
COVID-19 while limiting the risk of systemic toxicities.  These effects have the potential to 
decrease symptom burden and shorten disease duration. 
From data available to date, it appears that patients with comorbidities of hypertension 
and diabetes mellitus are at most risk when exposed to COVID-19 (Yang et al, 2020;  
Zhang et al, 2020).  There is currently limited data describing how COVID-19 affects people 
with asthma.  In a study of 140 cases of COVID-19 patients no link to asthma was observed 
(Zhang et al, 2020).  The data reported thus far may support the hypothesis that inhaled 
corticosteroids could provide a protective effect for these patients against COVID-19. 
Covis Pharma B.V. (Covis) is assessing the safety and efficacy of Alvesco (ciclesonide) 
Inhalation Aerosol in non-hospitalized patients with symptomatic COVID-19 infection in this 
multicenter, randomized, double-blind, placebo-controlled study. 
3.3 
Rationale for Dose Selection and Treatment Duration 
The dose of ciclesonide selected for use in this study is 320 µg twice daily (BID), which is the 
currently approved highest recommended starting dose for Alvesco Inhalation Aerosol 
(Alvesco® Inhalation Aerosol US prescribing information, 2019).  Patients will be instructed to 
self-administer Alvesco Inhalation Aerosol (hereafter referred to as ciclesonide MDI) or placebo 
MDI at a frequency of BID concurrently with standard supportive care for 30 days.  The duration 
of treatment is consistent with the limited information available regarding time to discharge for 
patients in China without hypoxemia or respiratory distress (mean time to discharge 17 ± 4 days) 
(Pan et al, 2020). 
Because there are no proven or approved treatments for COVID-19, all patients will also receive 
standard supportive care according to the treating facility’s standard. 
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3.4 
Rationale for Subject Population 
Patients with confirmed COVID-19 infection who are not hospitalized and presenting with mild 
to moderate disease represent the largest population (80%; Verity et al, 2020) and have been 
determined as the population with the highest likelihood of benefit from ciclesonide treatment 
due to earlier intervention potentially decreasing viral replication and, therefore, viral load.  It is 
hypothesized that treatment with ciclesonide will decrease duration of clinical symptoms, 
thereby decreasing the severity of disease. 
The study will enroll male and female patients 12 years of age or older, the population for which 
Alvesco has been determined to be safe.  Furthermore, patients who have been treated with 
inhaled or intranasal corticosteroids within 14 days of screening/enrollment/randomization or 
any patient who has received oral corticosteroids within 90 days of screening/enrollment/ 
randomization will be excluded from the study in order to minimize potential confounding of 
data from background steroid use. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


4 STUDY OBJECTIVES 
4.1 
Primary Objective 
The primary study objective is to assess whether treatment with ciclesonide MDI plus standard 
supportive care results in improved time to alleviation of COVID-19-related symptoms of cough, 
dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, 
and new loss of taste or smell compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection. 
4.2 
Secondary Objectives 
The secondary study objectives are: 
• to assess whether treatment with ciclesonide MDI plus standard supportive care reduces the 
incidence of hospital admissions or death compared with placebo plus standard supportive 
care in non-hospitalized patients with symptomatic COVID-19 infection 
• to assess whether treatment with ciclesonide MDI plus standard supportive care reduces 
all-cause mortality compared with placebo plus standard supportive care in non-hospitalized 
patients with symptomatic COVID-19 infection 
• to assess whether treatment with ciclesonide MDI plus standard supportive care reduces 
COVID-19-related mortality compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• to assess whether treatment with ciclesonide MDI plus standard supportive care reduces the 
incidence of subsequent emergency department visits or hospital admissions for reasons 
attributable to COVID-19 compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• to assess whether treatment with ciclesonide MDI plus standard supportive care increases the 
percentage of patients with alleviation of COVID 19-related symptoms of cough, dyspnea, 
chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and 
new loss of taste or smell compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• to assess whether treatment with ciclesonide MDI plus standard supportive care increases the 
time to hospital admission or death compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• to assess the impact of treatment with ciclesonide MDI plus standard supportive care on 
oxygen saturation levels compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
• to assess the impact of treatment with ciclesonide MDI plus standard supportive care on 
COVID-19 viral load compared with placebo plus standard supportive care in 
non-hospitalized patients with symptomatic COVID-19 infection 
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• to assess the safety of ciclesonide MDI plus standard supportive care compared with placebo 
plus standard supportive care in non-hospitalized patients with symptomatic COVID-19 
infection 
4.3 
Estimands 
The International Council for Harmonization (ICH) Guidance: Addendum on Estimands and 
Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials 
E9(R1) was adopted on 20 November 2019.  This section will describe the planned analyses for 
this protocol in the context of this guideline.   
An estimand is a description of the treatment effect to address the clinical/scientific question of 
interest posed by the trial objective.   
4.3.1 
Primary Endpoint Estimand 
The attributes of the estimand for the primary endpoint of this trial are: 
1. Treatment regimens: ciclesonide and placebo 
2. Populations of interest: patients meeting inclusion/exclusion criteria grouped according to 
randomized treatment assignment reflect the target population 
3. Patient-level outcome: time to alleviation of COVID-19-related symptoms of cough, 
dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore 
throat, and new loss of taste or smell, defined as symptom-free for a continuous period of 
≥ 24 hours (ie, ≥ 3 AM/PM assessments) by day 30 
4. Intercurrent events: regardless of the use of rescue medications, protocol violations, or 
investigational product discontinuation 
5. Population-level summary measure: difference in survival distributions between treatment 
regimens 
The treatment-policy strategy for this estimand is the difference in survival distributions of 
time to alleviation of COVID-19-related symptoms of cough, dyspnea, chills, feeling feverish, 
repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell, 
defined as symptom-free for a continuous period of  ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by 
day 30 between those assigned to ciclesonide and those assigned to placebo, regardless of 
patient’s use of rescue medications, protocol violations, or investigational product 
discontinuation.  Therefore, for all patients in the intent-to-treat (ITT) analysis set, all observed 
on-study data will be analyzed in accordance with the definition set forth above for intercurrent 
events. 
Since death and hospitalization are not part of the primary endpoint patient level-outcome 
definition, a composite strategy will be used to handle these situations.  If a patient dies or is 
hospitalized, regardless of when it occurs, the value attributed in that scenario would be a failure 
to respond or achieve alleviation of COVID-19-related symptoms by the end of the study 
(day 30).  This ascribes a sufficiently unfavorable outcome under these scenarios. 
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4.3.2 
Key Secondary Endpoint Estimand 
The attributes of the estimand for the key secondary endpoint included in the multiplicity control 
procedure of this trial are: 
1. Treatment regimens: ciclesonide and placebo 
2. Populations of interest: patients meeting inclusion/exclusion criteria grouped according to 
randomized treatment assignment reflect the target population 
3. Patient-level outcome: binary indicator of alleviation of COVID-19-related symptoms of 
cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, 
sore throat, and new loss of taste or smell, defined as symptom-free for a continuous period 
of ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by day 14 
4. Intercurrent events: regardless of the use of rescue medications, protocol violations, or 
investigational product discontinuation 
5. Population-level summary measure: difference in response probabilities between treatment 
regimens 
The treatment-policy strategy for this estimand is the difference in probabilities of alleviation 
of COVID-19-related symptoms of cough, dyspnea, chills, feeling feverish, repeated shaking 
with chills, muscle pain, headache, sore throat, and new loss of taste or smell, defined as 
symptom-free for a continuous period of  ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by day 14 
between those assigned to ciclesonide and those assigned to placebo, regardless of patient’s use 
of rescue medications, protocol violations, or investigational product discontinuation.  Therefore, 
for all patients in the ITT analysis set, all observed on-study data will be analyzed in accordance 
with the definition set forth above for intercurrent events. 
Since death and hospitalization are not part of this key secondary endpoint patient level-outcome 
definition, a composite strategy will be used to handle these situations.  If a patient dies or is 
hospitalized, then the value attributed in that scenario would be failure to achieve alleviation of 
COVID-19-related symptoms which ascribes the most unfavorable value. 
Estimands for other secondary efficacy endpoints included in the multiplicity control procedure 
(section 10.7.3) will be described in the Statistical Analysis Plan (SAP). 
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5 STUDY DESCRIPTION 
5.1 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy, and 
safety study of ciclesonide MDI for the treatment of symptomatic COVID-19 infection.  Enrolled 
patients will be male and female adults and adolescents ≥ 12 years of age with confirmed 
COVID-19 infection who are currently exhibiting symptoms of the disease and who are not 
currently hospitalized or under immediate consideration for hospitalization at the time of 
enrollment.  The study will consist of an initial screening/enrollment/randomization visit, a 
30-day treatment period, and a follow-up period. 
Following signature of the informed consent form (ICF), patients meeting inclusion/exclusion 
criteria will be randomly assigned (1:1) to treatment with ciclesonide MDI 320 µg BID (AM and 
PM) plus standard supportive care (hereafter referred to as the ciclesonide arm) or placebo MDI 
BID (AM and PM) plus standard supportive care (hereafter referred to as the placebo arm).  
During the initial screening/enrollment/randomization visit, patients will be instructed on how to 
self-administer a MDI and will be discharged home with a 30-day supply of investigational 
product (ie, either ciclesonide MDI or placebo MDI), standard supportive care, a pulse oximeter 
for at-home oxygen saturation level monitoring, and an electronic diary (eDiary).  
A nasopharyngeal sample for viral load analysis will also be obtained at the initial 
screening/enrollment/randomization visit.  Patients will be instructed to record 
self-administration of investigational product and oxygen saturation levels in the eDiary.  
Prior to self-administration of the investigational product (ie, within 1 hour of administration), 
patients will also complete and record assessments in the eDiary of severity of 
COVID-19-related symptoms of cough, dyspnea, chills, and feeling feverish (based on a 
4-point scale where 0 = absent, 1 = mild, 2 = moderate, and 3 = severe) and the presence/absence 
of COVID-19-related symptoms of repeated shaking with chills, muscle pain, headache, sore 
throat, and new loss of taste or smell.  Qualified healthcare providers will contact patients on 
days 2, 4, 6, 8, 10, 12, 14, 21 ± 2 days, and 30 ± 2 days for a health status check, to collect 
adverse event and concomitant medication information, and to confirm/clarify information 
recorded in the eDiary.  During these patient contacts, medical advice commensurate with 
standard of care for reported symptoms or adverse events will be provided.  On day 30 
(window of + 2 days), the patient will return to the study site for collection of a nasopharyngeal 
sample for viral load analysis and to return the eDiary and investigational product (ie, used and 
unused MDIs).  Qualified healthcare providers will contact patients on day 37 ± 4 days and day 
60 ± 7 days to collect follow-up safety and outcome data (the follow-up period). 
Patients (or their representatives) will be asked to notify study personnel directly in the event 
they visit an emergency department or are hospitalized during their participation in the study. 
Patient duration on study is expected to be approximately 60 days, including the screening/ 
enrollment/randomization visit, the 30-day treatment period and the subsequent follow-up 
period.  In the event the patient requires hospitalization during the 30-day treatment period, the 
patient will discontinue investigational product and scheduled follow-up procedures but will 
continue to be followed for the outcome of hospitalization and ongoing adverse events 
(see section 5.3.4). 
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5.2 
Study Schedule 
The time and events schedule for this study is provided in Table 1. 
 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


 
 
Table 1. 
Schedule of Events 
 
Screening/Enrollment/Randomization 
Visit (Day 1) 
Treatment Period 
(Day 1 through Day 30) 
Follow-up Period 
(Through Day 60) 
Early 
Termination 
Informed consent 
X (before administration of any 
study-specific procedures) 
 
 
 
Inclusion/exclusion criteria review 
X (predose) 
 
 
 
Prior/concomitant medication review 
X (predose) 
X (collected during patient contacts) 
 
 
Demographic data and medical historya 
X (predose) 
 
 
 
Physical examination, vital signs, height, 
weight, and calculation of body mass index 
X (predose) 
 
 
 
Urine pregnancy test (for females of 
childbearing potential only) 
X (predose, within 48 hours prior to 
enrollment) 
 
 
 
Confirm positive COVID-19 diagnostic 
testb 
X (predose) 
 
 
 
Randomization 
X (predose) 
 
 
 
Dispensing of IP, eDiary, and pulse 
oximeter 
X (predose) 
 
 
 
Training on MDI inhalation technique 
(including rinsing of mouth with water 
following inhalation of IP), use of eDiary, 
and use of pulse oximeter 
X (predose) 
 
 
 
Assess severity of COVID-19-related 
symptoms of cough, dyspnea, chills, and 
feeling feverish using a 4-point scale 
X (predose) 
X (BID [AM and PM] ≤ 1 hour prior to IP 
administration, record in eDiary)c 
 
 
Assess presence/absence of COVID-19-
related symptoms of repeated shaking with 
chills, muscle pain, headache, sore throat, 
and new loss of taste or smell 
X (predose) 
X (BID [AM and PM] ≤ 1 hour prior to IP 
administration, record in eDiary)c 
 
 
Oxygen saturation levels 
X (predose) 
X (BID [AM and PM] ≤ 1 hour prior to IP 
administration, record in eDiary)c 
 
 
Collection of nasopharyngeal sample for 
viral load analysis 
X (predose) 
X (day 30 [window of + 2 days])d 
 
 
IP administration 
X 
X (BID [AM and PM], record in eDiary)c 
 
 
Adverse events 
X (record any adverse events that occur 
following signing of informed consent) 
X (collected during patient contacts) 
X (collected during 
patient contacts) 
Xf 
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Table 1. 
Schedule of Events 
 
Screening/Enrollment/Randomization 
Visit (Day 1) 
Treatment Period 
(Day 1 through Day 30) 
Follow-up Period 
(Through Day 60) 
Early 
Termination 
HCP to contact patient for health status 
check, to collect adverse event and 
concomitant medication information, and to 
confirm/clarify information recorded in 
eDiarye 
 
X (days 2, 4, 6, 8, 10, 12, 14, 21 ± 2 days, 
and 30 ± 2 days) 
 
 
Return of eDiary and investigational 
product (ie, used and unused MDIs) 
 
X (day 30 [window of + 2 days])d 
 
X 
HCP to contact patient to collect follow-up 
safety and outcome data 
 
 
X (day 37 ± 4 days 
and day 60 ± 7 days) 
Xf 
AM = morning (prior to noon); BID = twice a day; COVID-19 = coronavirus disease 2019; eDiary = electronic diary; HCP = healthcare provider; IP = investigational 
product; MDI = metered-dose inhaler; PM = evening (prior to midnight); SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2. 
a 
= 
To include date of onset of COVID-19 symptoms. 
b 
= 
To meet criteria for inclusion, patient must have a positive SARS-CoV-2 molecular or antigen diagnostic test within 72 hours prior to enrollment. 
c 
= 
Note on day 1 dosing: In the event the patient receives the initial dose of IP at or before noon during the screening/enrollment/randomization visit, this will be 
considered to be the day 1 AM dose and the patient will be instructed to perform symptom assessments and oxygen saturation level monitoring, and to self-
administer the day 1 PM dose prior to midnight.  In the event the patient receives the initial dose of IP any time after noon during the 
screening/enrollment/randomization visit, this will be considered to be the day 1 PM dose and the patient will be instructed to wait until morning to perform 
symptom assessments, oxygen saturation level monitoring, and to self-administer the next dose (ie, day 2 AM dose). 
Note on day 30 dosing: Patients will be instructed to continue dosing through day 30.  In the event the patient has their day 30 (window of + 2 days) visit on 
day 30, they will be instructed to perform symptom assessments and oxygen saturation level monitoring, and to self-administer the day 30 doses as per their 
typical schedule/routine.  Thus, depending upon the time of day that the day 30 visit occurs, patients may or may not receive both doses on day 30.  For patients 
that have their day 30 visit on day 31 or day 32, they will be instructed to complete through the day 30 PM dose and then discontinue investigational product 
dosing, symptom assessments, and oxygen saturation level monitoring. 
d 
= 
On day 30 (window of + 2 days) the patient will return to the study site for collection of a nasopharyngeal sample for viral load analysis and to return the eDiary 
and investigational product (ie, used and unused MDIs). 
e 
= 
During these patient contacts, medical advice commensurate with standard of care for reported symptoms or adverse events will be provided. 
f 
= 
In the event of early termination, all ongoing non-serious adverse events will be followed until resolution, stabilization, or study day 60, whichever comes first; 
all ongoing serious adverse events will be followed until resolution or resolution with sequelae. 
Note: Patients (or their representatives) will be asked to notify study personnel directly in the event they visit an emergency department or are hospitalized during their 
participation in the study. 
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5.3 
Study Visits and Procedures 
For each patient, 3 study periods are planned:  the screening/enrollment/randomization visit, the 
30-day treatment period, and the follow-up period.  The procedures and assessments to be 
performed during each study period are indicated in Table 1.  Further relevant details of the 
evaluations to be performed at each study period are described below. 
5.3.1 
Screening/Enrollment/Randomization Visit 
Before any study-specific activities/procedures, the appropriate written informed consent must 
be obtained (see section 12.2). 
The following procedures will be conducted prior to administration of investigational product 
(ie, predose): 
• Review inclusion/exclusion criteria. 
• Confirm positive SARS-CoV-2 molecular or antigen diagnostic test (Note: patient must have 
a positive SARS-CoV-2 molecular or antigen diagnostic test within 72 hours prior to 
enrollment). 
• Review demographics, medical history, and medication history (including prior [within 
90 days before screening/enrollment/randomization visit] and current medications).  Date of 
onset of COVID-19 symptoms should be recorded. 
• Perform full physical examination, including measurements of vital signs (blood pressure 
[mm Hg], respiratory rate [breaths per minute], temperature [°F], and heart rate [beats per 
minute]), oxygen saturation level, height, weight, and calculation of body mass index. 
• Perform urine pregnancy test for females of childbearing potential within 48 hours prior to 
enrollment. 
• Collect nasopharyngeal sample for COVID-19 viral load analysis. 
• Provide patient with the eDiary and instruct on usage. 
• Provide patient with pulse oximeter and instruct on usage.  Instruct patient to seek medical 
attention immediately should oxygen saturation levels fall to 93% or below. 
• Instruct patient on recording severity of COVID-19-related symptoms of cough, dyspnea, 
chills, and feeling feverish using a 4-point scale where 0 = absent, 1 = mild, 2 = moderate, 
and 3 = severe, and have patient record baseline results in the eDiary. 
• Instruct patient on recording presence/absence of COVID-19-related symptoms of repeated 
shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell, and 
have patient record baseline results in the eDiary. 
• Provide patient with study personnel contact information and instruct patient (or their 
representative) to notify study personnel directly in the event they visit an emergency 
department or are hospitalized during their participation in the study. 
• Dispense investigational product according to treatment assignment. 
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• Train patient on appropriate MDI inhalation technique and instruct patient to rinse their 
mouth with water following inhalation of investigational product. 
Following completion of the above procedures, study personnel will observe patient 
self-administration of the first dose of investigational product, and the patient will record 
administration in the eDiary. 
Study personnel will record any adverse events occurring following signing of the informed 
consent in the eSource direct data capture (DDC) system. 
Patients will be instructed to seek medical attention immediately in the event they 
experience any of the emergency warning signs for COVID-19 as listed on the CDC 
website. 
5.3.2 
Double-Blind Treatment Period 
• Patient to self-administer investigational product at a frequency of BID (AM [prior to noon] 
and PM [prior to midnight]) and record in the eDiary. 
• Patient to assess severity of COVID-19-related symptoms of cough, dyspnea, chills, and 
feeling feverish using a 4-point scale at a frequency of BID (AM and PM) ≤ 1 hour prior to 
investigational product administration and record results in the eDiary. 
• Patient to assess presence/absence of COVID-19-related symptoms of repeated shaking with 
chills, muscle pain, headache, sore throat, and new loss of taste or smell at a frequency of 
BID (AM and PM) ≤ 1 hour prior to investigational product administration and record results 
in the eDiary. 
• Patient to check oxygen saturation levels using provided pulse oximeter at a frequency of 
BID (AM and PM) ≤ 1 hour prior to investigational product administration and record in the 
eDiary. 
• Qualified healthcare providers will contact each patient on days 2, 4, 6, 8, 10, 12, 14, 
21 ± 2 days, and 30 ± 2 days for a health status check, to collect adverse event and 
concomitant medication information, and to confirm/clarify information recorded in the 
eDiary.  During these patient contacts, medical advice commensurate with standard of care 
for reported symptoms or adverse events will be provided. 
• Patient to return to the study site on day 30 (window of + 2 days) for collection of 
nasopharyngeal sample for viral load analysis and to return the eDiary and investigational 
product (ie, used and unused MDIs). 
Note on day 1 dosing: In the event the patient receives the initial dose of investigational product 
at or before noon during the screening/enrollment/randomization visit, this will be considered to 
be the day 1 AM dose and the patient will be instructed to perform symptom assessments and 
oxygen saturation level monitoring, and to self-administer the day 1 PM dose prior to midnight.  
In the event the patient receives the initial dose of investigational product any time after noon 
during the screening/enrollment/randomization visit, this will be considered to be the day 1 
PM dose and the patient will be instructed to wait until morning to perform symptom 
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assessments, oxygen saturation level monitoring, and to self-administer the next dose 
(ie, day 2 AM dose). 
Note on day 30 dosing: Patients will be instructed to continue dosing through day 30.  In the 
event the patient has their day 30 (window of + 2 days) visit on day 30, they will be instructed to 
perform symptom assessments and oxygen saturation level monitoring, and to self-administer the 
day 30 doses as per their typical schedule/routine.  Thus, depending upon the time of day that the 
day 30 visit occurs, patients may or may not receive both doses on day 30.  For patients that have 
their day 30 visit on day 31 or day 32, they will be instructed to complete through the day 30 PM 
dose and then discontinue investigational product dosing, symptom assessments, and oxygen 
saturation level monitoring. 
5.3.3 
Follow-Up Period 
• Qualified healthcare providers to contact patient to collect follow-up safety and outcome data 
on day 37 ± 4 days and day 60 ± 7 days. 
5.3.4 
Early Termination Procedures 
In the event of early termination, all ongoing non-serious adverse events will be followed until 
resolution, stabilization, or study day 60, whichever comes first; all ongoing serious adverse 
events will be followed until resolution or resolution with sequelae.  Patients should be instructed 
to return the eDiary and investigational product (ie, used and unused MDIs) to the study site in a 
timely manner. 
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6 PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA 
6.1 
Number of Patients 
Approximately 400 patients (200 in each arm) will be randomized.  A sample size justification is 
provided in section 10.1. 
It is anticipated that patients will be enrolled at up to 15 study sites in the United States. 
6.2 
Inclusion Criteria 
Patients eligible for enrollment in the study must meet all the following criteria: 
1. Male and female adults and adolescents ≥ 12 years of age. 
2. Positive SARS-CoV-2 molecular or antigen diagnostic test within 72 hours prior to 
enrollment. 
3. Patient is not currently hospitalized or under immediate consideration for hospitalization at 
the time of enrollment. 
4. Patient is currently experiencing symptoms of fever, cough, and/or dyspnea. 
5. Patient has an oxygen saturation level > 93%. 
6. Ability to show adequate use of MDI, including inhalation technique. 
7. Patient, parent/legal guardian, or legally-authorized representative must have signed a written 
informed consent before administration of any study-specific procedures.  In the event the 
patient is a minor under the age of 18, assent by the patient to participate in the study must 
also be obtained. 
6.3 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for participation in the study: 
1. Existence of any life-threatening co-morbidity or any other medical condition which, in the 
opinion of the investigator, makes the patient unsuitable for inclusion. 
2. History of hypersensitivity to ciclesonide. 
3. Treatment with inhaled or intranasal corticosteroids within 14 days of the screening/ 
enrollment/randomization visit. 
4. Treatment with oral corticosteroids within 90 days of the screening/enrollment/ 
randomization visit. 
5. Participation in any other clinical trial or use of any investigational agent within 30 days of 
the screening/enrollment/randomization visit. 
6. Currently receiving treatment with hydroxychloroquine/chloroquine. 
7. Patients with cystic fibrosis. 
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8. Patients with idiopathic pulmonary fibrosis. 
9. Pregnancy (for females of childbearing potential). 
6.4 
Withdrawal Criteria 
Patients have the right to withdraw from the study at any time for any reason.  Patients may also 
be withdrawn by the investigator at any time during the study for any of the following reasons: 
• Patient, parent/legal guardian, or legally-authorized representative requests withdrawal. 
• Patient experiences an adverse event requiring withdrawal from the study. 
• Patient is noncompliant with the study schedule. 
• Investigator believes it is in the best interest of the patient’s health. 
The medical monitor must be notified immediately for any of these instances to discuss 
follow-up plans.  The data monitoring committee (DMC) (see section 7.3) should also be notified 
of patient withdrawals for any reason.  When a patient withdraws before completing the study, 
the reason for withdrawal is to be documented in the eSource.  Early termination procedures 
should be completed (see section 5.3.4). 
Patients who are withdrawn from the study will not be replaced. 
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7 STUDY ASSESSMENTS AND PROCEDURES 
7.1 
Efficacy 
7.1.1 
Efficacy Endpoints 
The primary efficacy endpoint is: 
• Time to alleviation of COVID-19-related symptoms of cough, dyspnea, chills, feeling 
feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of 
taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM 
assessments) by day 30 
The secondary efficacy endpoints for the study are: 
• Percentage of patients with hospital admission or death by day 30 
• All-cause mortality by day 30 
• COVID-19-related mortality by day 30 
• Percentage of patients with subsequent emergency department visit or hospital admission for 
reasons attributable to COVID-19 by day 30 
• Percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, 
chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and 
new loss of taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, 
≥ 3 AM/PM assessments) by day 7, by day 14, and by day 30 
• Time to hospital admission or death 
• Change from baseline in oxygen saturation levels 
• Change from baseline in COVID-19 viral load in nasopharyngeal sample at day 30 
7.1.2 Efficacy Assessments 
7.1.2.1 
Assessment of COVID-19-Related Symptoms of Cough, Dyspnea, Chills, and 
Feeling Feverish 
Patients will assess severity of COVID-19-related symptoms of cough, dyspnea, chills, and 
feeling feverish using a 4-point scale where 0 = absent, 1 = mild, 2 = moderate, and 3 = severe.  
Assessment of these symptoms will be performed predose during the screening/enrollment/ 
randomization visit.  During the 30-day treatment period, patients will be instructed to assess 
these 4 symptoms using a 4-point scale at a frequency of BID prior to self-administration of the 
investigational product (ie, within 1 hour of administration).  The patient will record results in 
the eDiary. 
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7.1.2.2 
Presence/Absence of COVID-19-Related Symptoms of Repeated Shaking with 
Chills, Muscle Pain, Headache, Sore Throat, and New Loss of Taste or Smell 
Patients will assess the presence/absence of COVID-19-related symptoms of repeated shaking 
with chills, muscle pain, headache, sore throat, and new loss of taste or smell.  Assessment of 
these symptoms will be performed predose during the screening/enrollment/randomization visit.  
During the 30-day treatment period, patients will be instructed to assess presence/absence of 
these symptoms at a frequency of BID prior to self-administration of the investigational product 
(ie, within 1 hour of administration).  The patient will record results in the eDiary. 
7.1.2.3 
Oxygen Saturation Levels 
Oxygen saturation levels will be measured predose during the screening/enrollment/ 
randomization visit.  During the 30-day treatment period, patients will be instructed to measure 
oxygen saturation levels (using the provided pulse oximeter) at a frequency of BID.  The patient 
will record results of all assessments in the eDiary.  The patient will be instructed to seek 
medical attention immediately should oxygen saturation levels fall to 93% or below. 
7.1.2.4 
Viral Load Analysis 
A nasopharyngeal swab for viral load analysis will be collected by study personnel predose 
during the screening/enrollment/randomization visit and on day 30 (window of + 2 days).  For 
each patient, the same nostril should be used for collection of samples at both time points, if 
possible.  Sample collection, handling, labeling, storage, shipping, and methods of analysis will 
be performed according to procedures specified in separate documents. 
7.2 
Safety 
7.2.1 
Safety Endpoint 
Safety will be assessed based on adverse events. 
7.2.2 
Safety Assessments 
Adverse events will be recorded starting with the signing of the ICF.  Adverse events occurring 
during the screening/enrollment/randomization visit will be recorded by study personnel in the 
eSource.  Information regarding adverse events occurring during the 30-day treatment period and 
post-treatment adverse events occurring during the follow-up period will be collected by 
qualified healthcare providers during the scheduled patient contacts and recorded in the eSource. 
Any new infection that occurs on study, regardless of the infecting agent (ie, viral or non-viral) 
should be captured as an adverse event.  In these cases, the site of infection and source of culture 
(eg, bronchoalveolar lavage, tracheal aspirate, sputum, blood, urine) should be recorded. 
Section 9 contains additional information regarding to adverse events. 
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7.3 
Data Monitoring Committee 
An independent and appropriately constituted DMC will be organized for this study.  A charter 
detailing the purpose of the committee as well as their roles and responsibilities will be put into 
place and will guide and direct their actions. 
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8 STUDY CONDUCT 
8.1 
Treatments to be Administered 
The investigational product in this study is ciclesonide MDI (supplied as Alvesco Inhalation 
Aerosol, 160 µg) or a matching placebo MDI; all patients will also receive standard supportive 
COVID-19 care.  The investigational product will be self-administered by the patient BID 
(2 actuations in the AM and 2 actuations in the PM) for 30 days.  During the initial 
screening/enrollment/randomization visit, patients will be provided with investigational product 
for the duration of the 30-day treatment period and will be instructed on how to appropriately 
self-administer a MDI.  For patients in the ciclesonide arm, the total daily dose will be 640 µg 
(320 µg BID).  Patients will be instructed to rinse their mouth with water following inhalation of 
investigational product. 
8.2 
Method of Assigning Patients to Treatment Groups 
Following signature of the ICF, patients meeting inclusion/exclusion criteria will be randomly 
assigned (1:1) to treatment with ciclesonide MDI 320 µg BID plus standard supportive care or 
placebo MDI BID plus standard supportive care.  The randomization schedule will be generated 
by the contract manufacturing organization and incorporated into the labeling of kits.  
Randomization will be done in blocks of 6 with 3 active and 3 placebo kits randomized within 
each block.  Sites will be supplied with kits in groups of 6 according to these predetermined 
blocks.  Assignment of kits to patients at a site will be done sequentially with patients receiving 
the next available kit in the block of kits when they have met the necessary criteria and are ready 
to be randomized. 
All patients will be assigned a unique patient number during the 
screening/enrollment/randomization visit.  After a patient number has been assigned, the 
number will not be reused even if the patient withdraws before receiving any study drug. 
8.3 
Blinding 
Patients and investigators/study personnel will be blinded to study treatment assignment. 
8.4 
Treatment Compliance 
The first dose of investigational product will be administered following randomization during the 
screening/enrollment/randomization visit and recorded by the patient in the eDiary.  During the 
30-day treatment period, patients will enter the dosing regimen taken (number of actuations, 
date, and time) BID in the eDiary.  Patients should make every attempt to maintain consistency 
in the dosing schedule. 
Qualified healthcare providers will contact patients on days 2, 4, 6, 8, 10, 12, 14, 21 ± 2 days, 
and 30 ± 2 days for a health status check, to collect adverse event and concomitant medication 
information, and to confirm/clarify information recorded in the eDiary (including treatment 
compliance).  Based on these compliance checks, the patient may be counseled about the 
importance of taking the investigational product as instructed. 
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8.5 
Investigational Product Materials and Management 
8.5.1 
Description of Investigational Product 
Ciclesonide is a white to yellow-white powder.  It is soluble in dehydrated alcohol, acetone, 
dichloromethane, and chloroform.  The molecular formula of ciclesonide is C32H44O7. 
Ciclesonide will be supplied by the sponsor as commercially available Alvesco Inhalation 
Aerosol, 160 µg.  Alvesco 160 µg Inhalation Aerosol is a pressurized, metered-dose aerosol unit 
fitted with a dose indicator.  The 160 µg/actuation strength contains 60 actuations fill/canister.  
Alvesco is intended for oral inhalation only.  Each unit contains a solution of ciclesonide in 
propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol.  After priming, Alvesco 160 µg 
delivers 160 µg of ciclesonide from the actuator.  The actual amount of drug delivered to the 
lung may depend on patient factors, such as the coordination between the actuation of the device 
and inspiration through the delivery system. 
A matching placebo MDI will also be provided. 
8.5.2 
Investigational Product Packaging and Labeling 
Investigational product will be supplied as commercially available Alvesco Inhalation Aerosol, 
160 µg or a matching placebo MDI.  Two inhalers will be provided per patient in a patient kit.  
The investigational product label will include the protocol number and notice that the contents 
are for research use only.  A unique identifier on the label will provide traceability of the 
investigational product to the lot number, batch number, and retest date. 
8.5.3 
Investigational Product Storage 
Investigational product should be stored per Alvesco Inhalation Aerosol labeling (ie, 25°C 
[77°F] with excursions permitted between 15°C and 30°C [59°F to 86°F]) 
(Alvesco Inhalation Aerosol US prescribing information, 2019). 
Until dispensing, investigational products must be stored in a securely locked area, accessible 
only to authorized site personnel and the study monitor. 
8.5.4 
Investigational Product Handling and Disposal 
The sponsor will supply investigational products only to the investigator or designee.  
The investigator or designee (eg, site pharmacist) is responsible for inventory, storage, and 
dispensing of investigational products.  The investigator will not allow use of the investigational 
products other than as directed by this protocol. 
The patient will return investigational product (ie, used and unused MDIs) to the study site 
during their visit on day 30 (window of + 2 days).  In the event the patient is withdrawn from the 
study, they should be instructed to return the investigational product to the study site in a timely 
manner. 
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All used and unused MDIs must be returned to the sponsor according to instructions provided to 
the site by the sponsor, site monitor, or designee. 
8.6 
Procedure for Breaking the Randomization Code 
Under normal circumstances, the blind will not be broken.  In the event of a medical emergency, 
when management of a patient’s condition requires knowledge of the treatment assignment, the 
blind may be broken.  Should emergency unblinding be necessary, the investigator will contact 
the contract manufacturing organization for unblinding information and will notify the sponsor 
immediately.  
 
 
 
 
 
 
 
 
 
 
Reasons for unblinding will be documented in the eSource.  The date and the identity of the 
person responsible for breaking the blind must be also documented. 
8.7 
Investigational Product Accountability 
The investigator must ensure that all investigational product supplies are kept in a secure locked 
area, under controlled temperature, with access limited to those authorized by the investigator.  
The investigator must maintain accurate records of the receipt of all investigational product 
shipped by the sponsor or the sponsor’s representative, including but not limited to the date 
received, lot number, expiration date, amount received, and the disposition of all investigational 
product. 
8.8 
Concomitant and Prohibited Medications 
Investigators may prescribe concomitant medications as standard supportive COVID-19 care. 
Concomitant medications (including prescription medications, over-the-counter medications, 
herbal medications, vitamins, and nutritional supplements) taken by the patient and the reasons 
for use will be recorded during the screening/enrollment/randomization visit.  Patients should 
continue to take these medications as directed during their participation in the study. 
Concomitant medication use occurring during the 30-day treatment period will be collected by 
qualified healthcare providers during the scheduled patient contacts on days 2, 4, 6, 8, 10, 12, 
14 , 21 ± 2 days, and 30 ± 2 days and recorded in the eSource. 
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Patients who received treatment with inhaled or intranasal corticosteroids within 14 days or oral 
corticosteroids within 90 days of the screening/enrollment/randomization visit are excluded from 
study participation.  Patients are also excluded from study participation if they are participating 
in any other clinical study or have used any investigational agent within 30 days of the 
screening/enrollment/randomization visit or if they are currently receiving treatment with 
hydroxychloroquine/chloroquine.  These medications are also prohibited for the duration of the 
study. 
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9 ADVERSE EVENTS 
9.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product that does not necessarily have to have a causal relationship with the pharmaceutical 
product.  An adverse event can, therefore, be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related to the 
medicinal product.  Any worsening of the patient’s disease under study or other medical 
conditions will also be considered to be an adverse event, unless it is within the normal range of 
disease fluctuation for that patient. 
Any new infection that occurs on study, regardless of the infecting agent (ie, viral or non-viral) 
should be captured as an adverse event.  In these cases, the site of infection and source of culture 
(eg, bronchoalveolar lavage, tracheal aspirate, sputum, blood, urine) should be recorded. 
9.2 
Reporting of Adverse Events 
Adverse events will be recorded starting with the signing of the ICF.  Adverse events occurring 
during the screening/enrollment/randomization visit will be recorded by study personnel in the 
eSource.  Information regarding adverse events occurring during the 30-day treatment period and 
post-treatment adverse events occurring during the follow-up period will be collected by 
qualified healthcare providers during the scheduled patient contacts and recorded in the eSource. 
Investigators will review the reported adverse events on a regular basis during the course of the 
study.  A DMC will conduct a review of blinded safety data once 100 subjects have been 
enrolled (see section 10.9). 
9.2.1 
Severity of Adverse Events 
Adverse events will be graded for severity as follows: 
• Mild is defined as causing no limitation of usual activities. 
• Moderate is defined as causing some limitation of usual activities. 
• Severe is defined as causing inability to carry out usual activities. 
Severity of adverse events occurring during the screening/enrollment/randomization visit will be 
recorded by study personnel in the eSource.  Severity information for each adverse event 
occurring during the 30-day treatment period and post-treatment adverse events occurring during 
the follow-up period will be obtained by qualified healthcare providers during the scheduled 
patient contacts and recorded in the eSource. 
It should be noted that a severe adverse event need not be serious in nature and that a serious 
adverse event need not, by definition, be severe. 
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9.2.2 
Relationship to Investigational Product 
The investigator will be asked to document his/her opinion of the relationship of the adverse 
event to the investigational product as follows: 
• Not related - The event can be readily explained by the patient’s underlying medical 
condition or concomitant therapy, and no relationship exists between the investigational 
product and the event. 
• Unlikely related - The temporal relationship between the event and the administration of the 
investigational product is uncertain, and the event can most likely be explained by the 
patient’s medical condition or other therapies. 
• Possibly related - There is some logical temporal relationship between the event and the 
administration of the investigational product, and the event is unlikely to be explained by the 
patient’s medical condition or other therapies. 
• Related - The temporal relationship is compelling between the administration of the 
investigational product, and the event cannot be explained by the patient’s medical condition 
or other therapies. 
9.2.3 
Action Taken with Investigational Product 
For each recorded adverse event, the action taken with investigational product will be 
documented as follows: 
• No change 
• Drug interrupted 
• Drug withdrawn 
• Not applicable 
• Unknown 
9.2.4 
Outcome 
The outcome of the adverse event will be documented as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal 
• Unknown 
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Outcome data will be obtained by qualified healthcare providers during the scheduled patient 
contacts and recorded in the eSource. 
9.3 
Serious Adverse Event Definition 
A serious adverse event is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
• Requires patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability and/or incapacity 
• Results in a congenital anomaly or birth defect 
The term “life-threatening” in the definition of “serious” refers to an event in which the patient 
was at immediate risk of death at the time of the serious adverse event.  It does not refer to a 
serious adverse event that hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that 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 other outcomes listed in the definition above.  These 
should also be considered to be serious adverse events. 
9.4 
Reporting Serious Adverse Events 
All serious adverse events that occur during the course of the study from the time informed 
consent is signed and up to the patient’s study completion or discontinuation, whether or not the 
event is considered causally related to the investigational product, must be reported by the 
investigator to the sponsor’s safety reporting group as described in the Safety Reporting 
Instructions.  In the event that the investigator becomes aware of a serious adverse event that 
occurred after the patient completes or discontinues from the study, and the serious adverse event 
is suspected to be related to investigational product, it must be reported to the sponsor’s safety 
reporting group.  Any special reporting requirements are described in the Safety Reporting 
Instructions. 
All serious adverse events must be reported within 24 hours from the time when the investigator 
first becomes aware of the event.  Serious Adverse Event Report Forms will be provided to each 
study site.  Details on the process of reporting can be found in the Safety Reporting Instructions.  
The completed Serious Adverse Event Form should be sent to Premier Research by one of the 
following methods: 
 
 
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For all serious, unexpected adverse events potentially related to the use of the investigational 
product, Covis or its designee will notify the appropriate regulatory authorities and all 
participating investigators in accordance with ICH guidelines and local safety reporting 
requirements.  It is the responsibility of the investigator to notify the Institutional Review 
Board (IRB) of all unexpected serious adverse drug reactions involving risk to human subjects in 
compliance with their IRB reporting requirements. 
Each serious adverse event must be followed until its resolution or its resolution with sequelae.  
Any follow-up information to a serious adverse event must be reported to the sponsor within 
24 hours of receipt of the new information. 
The investigator must determine whether the clinical seriousness of the event warrants removal 
of the patient from the study.  The investigator should, in any case, institute appropriate 
diagnostic and therapeutic measures and keep the patient under observation for as long as is 
medically indicated. 
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10 STATISTICAL EVALUATION 
As a companion to this protocol and in an effort to provide a more detailed explanation of the 
statistical methodology to be used for this study, a SAP will be finalized prior to locking the 
database and before unblinding the randomization.  Any changes in the statistical methods 
described in this protocol that occur prior to unblinding will be documented in the SAP and will 
not require a protocol amendment. 
10.1 Sample Size and Power 
This study is designed to assess the efficacy and safety of ciclesonide MDI plus standard 
supportive care compared with placebo MDI plus standard supportive care.  The primary 
endpoint is time to alleviation of COVID-19-related symptoms of cough, dyspnea, chills, feeling 
feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste 
or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM 
assessments) by day 30.  The Cox proportional hazards model will be used to compare treatment 
arms with respect to time to alleviation (or recovery) of COVID-19-related symptoms as defined 
in the primary endpoint.  Total number of events (recoveries) as well as the expected rate of 
recovery (or hazard ratio) for treatment compared to placebo are key determinants of power.  
The expected median survival time is approximately 7 days for the ciclesonide arm and 
approximately 11 days for the placebo arm (hazard ratio of approximately 1.58) with a total 
study duration of 30 days.  For 90% power, approximately 201 events (recoveries) are required 
to detect this anticipated increase in rate of recovery between ciclesonide and placebo.  A sample 
size of 232 patients (116 per arm) is required to achieve the specified 90% power at an α = 0.05 
for this study.  To account for an unknown drop-out rate in this patient population as well as 
other factors that may impact the overall power of the study, the planned sample size was 
increased to 400 patients (200 in each arm) for this study.  Note that these are best estimates at 
this point as there is still much uncertainty regarding COVID-19. 
10.2 Statistical Analysis Sets 
The safety population will include all patients who received at least 1 dose of investigational 
product (either ciclesonide MDI or placebo MDI).  Safety analyses will compare groups defined 
by the treatment they received.  The ITT population will include all randomized patients.  
Analyses conducted on the efficacy dataset will be on an ITT basis where the treatment groups 
are defined by the treatment to which patients were randomized. 
Any additional analysis sets will be defined in the SAP. 
10.3 Statistical Methods 
10.3.1 General Principles 
Summary statistics will be presented by treatment group.  For continuous variables, unless 
otherwise stated, the number of available observations (n), mean, standard deviation, median, 
and range will be provided.  For categorical variables, the number and percentage in each 
category will be determined. 
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10.3.2 Missing Data 
All attempts will be made to minimize the amount of missing data.  Sensitivity analyses may be 
conducted to evaluate the potential impact of the missing data. 
10.4 Demographic and Baseline Characteristics 
Demographics and baseline characteristics, medical history, baseline physical examination 
findings, baseline vital sign data, baseline height, baseline weight, and baseline body mass index 
will be summarized descriptively by treatment group. 
10.5 Patient Disposition 
Patient disposition will be summarized, including the reasons for discontinuation.  The number 
of patients in each analysis population will be displayed and an accounting of exclusions from 
each study population will be provided. 
10.6 Concomitant Medications 
Concomitant medications will be tabulated by Anatomical and Therapeutic Class of World 
Health Organization (WHO) drug, preferred term, and treatment group.  A medication’s usage 
will be considered concomitant if it was started or continued after administration of 
investigational product.  If the start date is missing, it will be assumed that the medication was 
used concomitantly. 
10.7 Analysis of Efficacy Data 
10.7.1 Primary Efficacy Endpoint 
The primary efficacy variable is time to alleviation of COVID-19-related symptoms of cough, 
dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, 
and new loss of taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours 
(ie, ≥ 3 AM/PM assessments) by day 30.  The primary analysis will be based on the ITT 
population (all randomized patients).  To improve the precision of treatment effect estimation 
and inference, baseline covariate adjustments will be made for gender, age, race, and body mass 
index, as these are known COVID-19 risk factors.  A Cox proportional hazards model will be 
used to allow for inclusion of these additional covariates.  The median time to event and 
95% confidence intervals will be summarized by treatment arm, and Kaplan-Meier estimates of 
the survival curves will also be generated. 
The SAP will describe how missing data will be handled in the primary analysis.  In addition, a 
sensitivity analysis for the primary endpoint will be conducted using a tipping point analysis that 
will systematically and comprehensively vary assumptions about the missing outcomes on the 
treatment arms.  Details will be provided in the SAP. 
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10.7.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints of percentage of patients with hospital admission or death by 
day 30; all-cause mortality by day 30; COVID-19-related mortality by day 30; percentage of 
patients with subsequent emergency department visit or hospital admission for reasons 
attributable to COVID-19 by day 30; and percentage of patients with alleviation of 
COVID-19-related symptoms of cough, dyspnea, chills, feeling feverish, repeated shaking with 
chills, muscle pain, headache, sore throat, and new loss of taste or smell, defined as symptom-
free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM assessments) by day 7, by day 14, and 
by day 30 will be analyzed using a logistic regression model.  To improve the precisions on 
treatment effect estimation and inference, baseline covariate adjustments will be made for 
gender, age, race, and body mass index, as these are known COVID-19 risk factors.  Analysis of 
the secondary efficacy endpoint of time to hospital admission or death will be performed using 
the same method as that used for the primary efficacy endpoint.  The secondary efficacy 
endpoint of change from baseline in oxygen saturation levels will be summarized descriptively at 
all time points captured in the eDiary.  The secondary efficacy endpoint of change from baseline 
in COVID-19 viral load in nasopharyngeal sample at day 30 will be summarized descriptively. 
10.7.3 Multiple Comparisons 
In order to control the overall Type I error rate for the analyses of the planned primary and 
secondary endpoints, a fixed-sequence method will be utilized.  Under this methodology, all 
endpoints will be ordered sequentially; testing will begin with the first endpoint (primary 
endpoint) at the full alpha level and continue through the sequence only until an endpoint is not 
statistically significant.  The sequence of testing will be as follows: 
1. Time to alleviation of COVID-19-related symptoms of cough, dyspnea, chills, feeling 
feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of 
taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours (ie, ≥ 3 AM/PM 
assessments) by day 30 
2. Percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, 
chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and 
new loss of taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours 
(ie, ≥ 3 AM/PM assessments) by day 14 
3. Percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, 
chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and 
new loss of taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours 
(ie, ≥ 3 AM/PM assessments) by day 7 
4. Percentage of patients with alleviation of COVID-19-related symptoms of cough, dyspnea, 
chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and 
new loss of taste or smell, defined as symptom-free for a continuous period of ≥ 24 hours 
(ie, ≥ 3 AM/PM assessments) by day 30 
5. Change from baseline in oxygen saturation levels at day 7 
6. Change from baseline in COVID-19 viral load in nasopharyngeal sample at day 30 
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7. Percentage of patients with subsequent emergency department visit or hospital admission for 
reasons attributable to COVID-19 by day 30 
8. Time to hospital admission or death 
9. Percentage of patients with hospital admission or death by day 30 
10. All-cause mortality by day 30 
11. COVID-19-related mortality by day 30 
 
10.8 Analysis of Safety Data 
The incidence of adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) body system classification and preferred term.  All treatment-emergent 
adverse events will be summarized overall and for each body system and preferred term by 
treatment group, relationship to investigational product, and severity.  For tabulations by 
severity, only a patient’s most severe event within the category (eg, overall, body system, or 
preferred term) will be counted.  “Treatment-emergent” will be defined as starting or worsening 
after the first dose of investigational product.  If the start date is missing, the event is assumed to 
be treatment-emergent.  All serious adverse events will be tabulated. 
In order to understand specific adverse events of special interest (eg, oral candidiasis), analyses 
will be conducted to compare the treatment arms with respect to differences in cumulative 
incidence rates with accompanying confidence intervals.  Details will be provided in the SAP. 
10.9 Interim Safety Review  
The DMC will conduct a review of blinded safety data once 100 subjects have been enrolled.  
Details of the interim safety review will be described in detail in the DMC charter. 
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Conduct of the Study 
Covis shall implement and maintain quality control and quality assurance procedures with 
written Standard Operating Procedures to ensure that the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, ICH Good Clinical 
Practice (GCP), and applicable regulatory requirements. 
This study is to be conducted according to globally accepted standards of GCP (as defined in the 
ICH E6 Guideline for GCP, 1 May 1996), in agreement with the latest revision of the 
Declaration of Helsinki and in keeping with local regulations. 
The investigator should ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties. 
The investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate Independent Ethics Committee (IEC)/IRB, 
except when necessary to eliminate immediate hazards to the patient or when the change(s) 
involve(s) only logistical or administrative aspects of the study.  Any deviations may result in the 
patient having to be withdrawn from the study and render that patient nonevaluable. 
11.2 Study Monitoring 
Monitoring and auditing procedures, developed or endorsed by the sponsor, will be followed to 
comply with GCP guidelines.  Access to the study documentation and medical records will be 
ensured. 
The study will be monitored by the sponsor or its designee.  Throughout the course of the study, 
the study monitor will make frequent contact with the investigator.  This will include 
telephone/web calls, e-mails, and video conferences, if appropriate.  During the remote interim 
monitoring visits, the status of the site will be discussed including, but not limited to the 
following:  enrollment status, review of study data, and ICF process for newly enrolled patients. 
As part of the data monitoring, source documents must be made available to the study monitor 
for remote review.  Remote source data verification will be performed as specified in the clinical 
monitoring plan.  The study monitor will also perform remote investigational product drug 
accountability and will perform reviews of the electronic investigator study file to ensure 
completeness of documentation in all respects of clinical study conduct and safety oversight. 
Upon completion of the study, the study monitor will conduct a final review of the study files, 
after which the files should be secured for the appropriate time period.  The investigator, or 
appointed delegate, will make themselves available over the phone or web, if needed, and will 
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cooperate in making documents available for inspection and responding to inquiries.  In addition, 
the investigator will permit inspection of the study files by authorized representatives of the 
sponsor or regulatory agencies. 
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12 ETHICS 
12.1 Independent Ethics Committee/Institutional Review Board 
Prior to initiation of the study, the investigator will submit the study protocol, sample ICF, and 
any other documents that pertain to patient information, recruitment methods, and 
advertisements, to the IRB/IEC.  The investigator must also submit any other information that 
may be requested to the IRB/IEC for review and approval.  The investigator will request that the 
IRB/IEC provide written approval of the study and will keep on file records of approval of all 
documents pertaining to this study.  A letter confirming the approval must be forwarded to the 
study monitor prior to initiation of this study.  This letter will be forwarded to the sponsor prior 
to the initiation of the study. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC for all 
subsequent protocol amendments and changes to the ICF.  The investigator should notify the 
IRB/IEC of deviations from the protocol or serious adverse events occurring at the site, as well 
as other adverse event reports received by the sponsor, in accordance with local procedures. 
The investigator will be responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study. 
12.2 Written Informed Consent and Assent 
Potential patients, their parent/legal guardian, or their legally-authorized representative must 
provide written consent to participate after the nature, scope, and possible consequences of the 
clinical study have been explained in a form understandable to them. 
An ICF that includes information about the study will be prepared and given to the patient.  This 
document will contain all the elements required by the ICH Guidance: Integrated Addendum to 
ICH E6(R1), Guideline for Good Clinical Practice E6(R2) (2016).  The document must be in a 
language understandable to the patient and must specify who informed the potential patient.  
After reading the ICF, the potential patient must give consent in writing.  The patient’s consent 
must be confirmed at the time of consent by the personally dated signature of the patient and by 
the personally dated signature of the person conducting the informed consent discussions. 
A copy of the signed ICF must be given to the patient.  The original signed ICFs will be retained 
by the Investigator. 
The investigator will not undertake any measures specifically required only for the clinical study 
until valid consent has been obtained. 
In the event the patient is a minor under the age of 18, assent by the patient to participate in the 
study must also be obtained. 
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13 DATA HANDLING AND RECORD KEEPING 
13.1 Case Report Forms/Source Data Handling 
Source documents and source data will be captured electronically in this trial and will meet the 
same fundamental elements of data quality (eg, attributable, legible, contemporaneous, original, 
and accurate) as paper records.  These data will be collected into a DDC system also known as 
the eSource that is fully validated according to 21 Code of Federal Regulations Part 11.  Changes 
to the data will be captured by an automatic audit trail.  The study site will be given a tablet to 
directly record subject data and clinical observations on electronic forms.  Designated trial site 
staff will not be given access to the system until they have been appropriately trained.  
Information to be originally captured and reviewed electronically shall include details of the 
subject visit and the protocol required assessments performed as a part of these visits, medical 
history, adverse events, and concomitant medications.  Because this trial is using an electronic 
source record as the original point of data capture, there is no additional data entry step for the 
study site for data collected directly into the application; rather, the electronic source record 
directly populates the trial database.  At the end of the study, the investigator must certify that 
the data entered into the eSource system are complete and accurate.  After database lock, the 
investigator will receive an electronic copy of the subject data. 
The investigator, or designee, will enter study data required by the protocol into the eSource 
system.  The eSource system has a variety of validations programmed which direct the site user 
to collect clean and complete data in the moment as well as clear indicators of incomplete forms 
so that they can be followed up on in a timely manner.  Clinical research associates will also 
remotely monitor the collected data via an online portal to review for completeness and 
accuracy.  Any questions about the collected data can be queried within the eSource system by 
the clinical research associate or data manager.  Appropriate study site personnel should then 
address those queries within the eSource system which will maintain a comprehensive audit trail.  
Uniform procedures for addressing queries will be discussed during system training as well as 
the study site initiation visits and will be documented in a data management plan. 
Designated data captured in the eSource system will automatically be included into the clinical 
database as specified in the data management plan.  Quality control and data validation 
procedures will be applied to ensure the validity and accuracy of the clinical database. 
Computerized and manual procedures should be used to review and check data within the 
eSource system for omissions, apparent errors, and values that may require further clarification.  
Data queries requiring clarification should be initiated within the eSource system for the study 
site to review and resolve.  Only authorized personnel can make corrections to the clinical 
database, and all corrections will be documented in the system audit trail. 
Adverse events will be coded using the most current MedDRA version.  Prior and concomitant 
medications will be coded according to the WHO Drug Dictionary. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


 
13.2 Retention of Essential Documents 
The following records must be retained by the investigator for a minimum of 2 years after the 
sponsor has notified FDA that investigations have been discontinued, or after FDA has approved 
the new drug application: 
• Signed ICFs for all patients 
• Patient identification code list, screening log (if applicable), and enrollment log 
• Record of all communications between the investigator and the IRB/IEC 
• Composition of the IRB/IEC or other applicable statement 
• Record of relevant communications between the investigator and sponsor (or contract 
research organization) 
• List of sub-investigators and other appropriately qualified persons to whom the investigator 
has delegated significant study-related duties, together with their roles in the study and their 
signatures 
• Copies of the eSource records and of documentation of corrections for all patients 
• Drug accountability records 
• Record of any body fluids or tissue samples retained 
• All other source documents (eDiaries, patient records, hospital records, laboratory records, 
etc.) 
• All other documents as listed in section 8 of the ICH Guidance: Integrated Addendum to ICH 
E6(R1), Guideline for Good Clinical Practice E6(R2) (2016) (Essential Documents for the 
Conduct of a Clinical Trial) 
However, due to international regulatory requirements, the sponsor may request retention for a 
longer period of time.  The investigator must therefore obtain approval in writing from the 
sponsor prior to destruction of any records. 
Normally, these records will be held in the investigator's archives.  If the investigator is unable to 
meet this obligation, he or she must ask the sponsor for permission to make alternative 
arrangements.  Details of these arrangements should be documented. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


 
14 FINANCING AND INSURANCE 
 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


 
15 PUBLICATION POLICY 
The sponsor will retain the ownership of all data.  When the study is complete, the sponsor will 
arrange the analysis and tabulation of data.  A clinical study report will then be prepared, which 
may be used for publication, presentation at scientific meetings, or submission to regulatory 
authorities.  All proposed publications based on this study must be subject to the sponsor’s 
approval requirements. 
Covis Pharma GmbH, Ciclesonide Inhalation Aerosol


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Covis Pharma GmbH, Ciclesonide Inhalation Aerosol