Clinical trial NCT04676867
Conditions: Covid19
Keywords: COVID-19 Coronavirus disease Dalcetrapib
Sponsor: DalCor Pharmaceuticals
Start date: 2021-01-11; Completion date: 2021-05-17
Enrollment: 227 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a placebo-controlled, Phase 2a proof-of-concept clinical study which will evaluate efficacy and safety of dalcetrapib in outpatients patients with mild to moderate, symptomatic, confirmed COVID 19.

Detailed description:

Arms: arm 1: Patients will receive Dalcetrapib 900 mg for 10 days arm 2: Patients will receive Dalcetrapib 1800 mg for 10 days arm 3: Patients will receive Dalcetrapib 3600 mg for 10 days arm 4: Patients will receive Placebo for 10 days
Interventions: intervention 1: Dalcetrapib intervention 2: Placebo
Intervention descriptions: intervention 1: Dalcetrapib 300 mg Film-Coated Tablets intervention 2: Placebo Tablets

Protocol documents:
Prot_000.pdf: 
Final, 14 December 2020 
Page 1 of 59 
TITLE PAGE 
Protocol 
A Double-blind, Placebo-controlled, Phase 2a Proof-of-concept Trial of Dalcetrapib in 
Patients with Confirmed Mild to Moderate COVID-19 
Protocol Status: Final 
Protocol Date: 14 December 2020 
Protocol Version: 1.1  
Investigational Product: Dalcetrapib 
Protocol Reference Number: DAL-401 
IND Number: 152693 
 
 
Sponsor: 
DalCor Pharma UK Ltd.,  
Leatherhead, Zug Branch 
Baarerstrasse 2 
Zug, 6302 
Switzerland 
 
 
 
Sponsor Signatory: 
Dr. David Kallend, MBBS 
 
Medical Monitor: 
Patrick McLeroth, MD 
Tel: +1 609 216-4187 
Email:Patrick.McLeroth@covance.com 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 4 of 59 
Protocol 
Covance Study: 8449008 
SYNOPSIS 
 
Title of study: 
A Double-blind, Placebo-controlled, Phase 2a Proof-of-concept Trial of Dalcetrapib in 
Patients with Confirmed Mild to Moderate COVID-19 
Indication: Coronavirus disease of 2019 (COVID-19) 
Number of Investigators and study centers: 
Up to 60 sites in the United States and Canada, site distribution will depend on the pandemic 
status.  
Development Phase: 2a 
Objectives: 
The primary efficacy objective of the study is: 
 
To evaluate the time to sustained clinical resolution of symptoms in patients with 
confirmed, mild to moderate, symptomatic COVID-19 treated with dalcetrapib. 
Sustained clinical resolution is defined as occurring when no key COVID-19 related 
symptom has a score higher than 1 over a 72-hour period (as documented using an 
electronic patient-reported outcome [ePRO] instrument), except for sense of smell and 
taste (items 13 and 14) where the score should be 0 over a 72-hour period. The time to 
resolution will be taken as the time from randomization until the first day of the last 
72-hour period where the patient meets the definition of resolution within 28 days. 
Patients who do not meet the definition of resolution 28 days after randomization will 
be considered not resolved. 
The secondary efficacy objectives of the study are: 
 
To evaluate the change from baseline in COVID-19 symptom severity score at all 
collected time points 
 
To evaluate time to complete clinical resolution, defined in the same way as the 
primary endpoint, but considering that all symptoms must resolve to a score of 0 for 
72 hours 
 
To evaluate the time to viral clearance using SARS-CoV-2 polymerase chain reaction 
(PCR) 
 
To evaluate change from baseline in log10 viral load 
 
To evaluate the World Health Organization (WHO) clinical outcome scale (9-point 
scale) at Day 3, Day 5, Day 10, and Day 28 
 
Rate of hospitalization through Day 28 
 
To evaluate the rate of progression to oxygen therapy through Day 28 
 
To evaluate the duration of hospitalization 
 
To evaluate the mortality rate by Day 28 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
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Protocol 
Covance Study: 8449008 
The safety objective of the study is: 
 
To assess the safety and tolerability of dalcetrapib active doses compared to placebo in 
patients with COVID-19 
The pharmacokinetics (PK) objective of the study is: 
 
To evaluate the PK of dalcetrapib in patients with COVID-19 
Methodology/study design: 
This is a randomized, double-blind, multicenter Phase 2a proof-of-concept study in outpatients 
with confirmed, mild to moderate, symptomatic COVID-19. Electronic informed consent must 
be obtained from all patients or their legally authorized representative during screening before 
any study-related procedures are performed. The Screening/Baseline assessments may be 
performed at the study site or as a home visit. 
A total of 208 patients will be randomized to receive 900, 1800, or 3600 mg of dalcetrapib or 
placebo once daily (52 patients to each of 900 mg, 1800 mg, 3600 mg and placebo) for 
10 days. Patients will be randomized and receive first dose of study drug within 72 hours of 
receiving a positive PCR or Point-of-care test for SARS-CoV-2. Patients need to have at least 
two of the 14 common COVID-19-related symptoms described in the inclusion criteria rated as 
mild or moderate, as evaluated by ePRO assessment. Symptoms will be assessed at each study 
visit daily for the first 10 days, then at Day 14 and Day 28, and as clinically indicated. 
Symptoms will be evaluated as absent, mild, moderate, or severe depending on their impact on 
activities of daily living. SARS-CoV-2 viral loads will be obtained by both saliva (Oragene) 
collection and mid-turbinate nasal swab self-collection under supervision of a healthcare 
professional (virtual or home visit) at Screening/Baseline, Day 1, Day 3, Day 5, Day 7, Day 10, 
and Day 28. Patients who require hospitalization after initiation of study treatment will be 
followed for safety assessment through Day 28. 
The study will be overseen by an independent Data Monitoring Committee (DMC). The DMC 
will review the safety data throughout the study. The DMC and Sponsor will review efficacy 
data at the interim analysis and at the end of the study. A DMC Charter, which includes 
detailed processes, will be prepared. One interim analysis will be conducted once 97 resolution 
events have been observed. 
All patients will be closely monitored for adverse events (AEs) from informed consent for at 
least 18 days after the final dose of study treatment (until Day 28±2). Patients who withdraw 
early from the study will have follow-up phone calls to collect safety data until End of Study 
on Day 28±2. On days of laboratory assessments and PK sample collection, outpatient subjects 
may have a home visit. 
Study Visit Procedures 
Study visits (virtual, study site or home visits by a healthcare professional) will take place on 
Days 1, 3, 5, 7, 10, 14, and 28. Screening/Baseline assessments may all be performed on the 
same calendar day and may be performed at the study site or as a home visit. For visits which 
include bloodwork, sample collection may be done by a visiting healthcare professional or at 
the study site (as long as the patient has no worsening of respiratory symptoms or no fever 
within 24 hours). Other visits may be conducted remotely using telemedicine. 
The samples for viral load testing will be both saliva (Oragene) collection and mid-turbinate 
nasal swab self-collected under supervision of a healthcare professional. Telemedicine visits 
such as phone calls or other digital media are to be utilized as much as possible. 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 6 of 59 
Protocol 
Covance Study: 8449008 
Number of patients: 
It is anticipated that 208 patients will be randomized into the study in a 1:1:1:1 ratio to 900, 
1800, or 3600 mg dalcetrapib or placebo. 
Determination of Sample Size: 
The purpose of the proof-of-concept study is to identify whether there is sufficient promise of 
efficacy to justify conducting a Phase 3 study in a larger sample size and to determine 
efficacious dose to be used in Phase 3. While the entirety of data will be considered at the end 
of study, the sample size has been chosen to ensure that a positive trend will be present with 
alpha of 0.2 when considering the two highest doses combined compared to placebo. One-
hundred twenty-seven (127) resolution events provides 80% power to demonstrate a positive 
trend if the average hazard ratio (HR) of the two dalcetrapib groups is 1.4 relative to placebo. 
Allowing for 20% of patients not resolving, 156 patients (52 per treatment arm) will be 
enrolled across the two highest dose levels and placebo arms, and an additional 52 will be 
randomized to 900 mg for a total sample size of 208 patients. One interim analysis will be 
conducted once 97 resolution events have occurred to allow 73 resolution events to have 
occurred in the two highest dose levels and placebo arm. At the interim analysis, if the average 
HR of the two highest dose levels relative to placebo is greater than 1.45, the study will stop 
due to efficacy and the program will be able to proceed directly to Phase 3. At the interim 
analysis, if the average HR of the two highest dose levels relative to placebo is between 1.0 and 
1.45, the study will continue enrollment until 169 resolution events have occurred. At the 
interim analysis, if the average HR of the two highest dose levels is less than 1.0, the study will 
be stopped for lack of efficacy. The final analysis will be performed at an alpha of 0.186. These 
boundaries were determined by setting the efficacy boundary to follow the power family 
boundary with ρ=2 and the futility boundary is manually set to HR=1. 
Diagnosis and criteria for inclusion and exclusion: 
The following are the inclusion criteria: 
1. Willing and able to provide informed consent 
2. Male or female patients > 18 years of age on the day of informed consent 
3. Have received a confirmed diagnosis of COVID-19 (positive for SARS-CoV-2), as 
assessed by PCR or point-of-care within 72 hours of first dose on Day 1 
4. Have mild to moderate signs or symptoms of COVID-19 with onset within 5 days of 
first dose on Day 1, at least two of the following symptoms: 
 
stuffy or runny nose 
 
sore throat 
 
shortness of breath 
 
cough 
 
fatigue  
 
myalgia  
 
headache 
 
chills or shivering 
 
feeling hot or feverish 
 
nausea 
 
vomiting 
 
diarrhea 
 
anosmia  
 
ageusia 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
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Protocol 
Covance Study: 8449008 
5. Outpatient with COVID-19 disease (not requiring oxygen therapy [WHO COVID-19 
Clinical Improvement Ordinal Scale, score of 3]) 
6. Patient is aware of the investigational nature of this study and willing to comply with 
protocol treatments, blood tests, and other evaluations listed in the ICF. 
The following are the exclusion criteria: 
1. Females who are pregnant (negative pregnancy test required for all women of 
child-bearing potential at Screening) or breast-feeding 
2. Male patients and women of childbearing potential (women who are not surgically 
sterile or postmenopausal defined as amenorrhea for >12 months) who are not using at 
least one protocol-specified method of contraception 
3. Severe COVID-19 disease as defined by the WHO COVID-19 Clinical Improvement 
Ordinal Scale, scores of 5 (non-invasive ventilation or high-flow oxygen), 6 
(intubation and mechanical ventilation), or 7 (ventilation + additional organ support 
pressors, renal replacement therapy [RRT], extracorporeal membrane oxygenation 
[ECMO]) 
4. Expected survival less than 72 hours 
5. Peripheral capillary oxygen saturation (SpO2) <90% while breathing room air 
6. Treatment with other drugs thought to possibly have activity against SARS-CoV-2 
infection like remdesivir, favipiravir, within 7 days prior to enrollment or concurrently 
7. History of abuse of drugs or alcohol that could interfere with adherence to study 
requirements as judged by the Investigator 
8. Use of any other concurrent investigational drugs while participating in the present 
study 
9. Patient requires frequent or prolonged use of systemic corticosteroids (≥20 mg of 
prednisone/day or equivalent for >4 weeks) or other immunosuppressive drugs 
(e.g., for organ transplantation or autoimmune conditions) 
10. Known renal disease with an estimated glomerular filtration rate (eGFR) <50 mL/min 
based on local laboratory results 
11. Patients with clinically apparent liver disease, e.g., jaundice, cholestasis, hepatic 
synthetic impairment, or active hepatitis 
12. Alanine transaminase (ALT) or aspartate transaminase (AST) >3 × upper limit of 
normal (ULN) or alkaline phosphatase or bilirubin levels > 2 × ULN based on local 
laboratory results 
13. Co-administration of clinical doses of orlistat with dalcetrapib 
14. Inability to swallow oral medications or a gastrointestinal disorder with diarrhea 
(e.g., Crohn’s disease) or malabsorption at Screening 
15. Any other clinically significant medical condition or laboratory abnormality that, in the 
opinion of the Investigator, would jeopardize the safety of the patient or potentially 
impact patient compliance or the safety/efficacy observations in the study 
16. History of an allergic reaction or hypersensitivity to the study drug or any component 
of the study drug formulation. 
Test products, dose, and mode of administration: 
Dalcetrapib in a dose of 900, 1800, or 3600 mg (300 mg tablets) administered once daily, 
orally, for 10 days 
Reference therapy, dose, dose form, and mode of administration: 
Matching placebo tablets administered once daily, orally, for 10 days 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 8 of 59 
Protocol 
Covance Study: 8449008 
Duration of patient participation in study: 
Planned screening duration: 1 to 2 days 
Planned treatment duration: 10 days 
Planned follow-up duration: 18 days 
Total duration of study participation: up to 30 to 32 days 
Study populations: 
Intention-to-treat (ITT) Population: The Intent to Treat Population will include all 
participants who received at least 1 dose of study drug. Participant data will be summarized by 
treatment assigned. 
Per Protocol (PP) population: All participants from the ITT population who have no 
important study protocol deviations during the study and who received at least 1 dose of study 
drug. Patients with any important protocol deviations shall be excluded from the PP population 
prior to database lock. 
Safety Population: The Safety Population will include all participants who received at least 1 
dose of study drug. Participant data will be summarized by actual treatment received. 
Pharmacokinetic Population: The PK Population will include all participants who received at 
least 1 dose of study drug, had at least one measurable plasma concentrations, and had no 
protocol deviations thought to impact the PK of study drug. 
Evaluation: Efficacy 
Primary Endpoint: 
 
Time to sustained clinical resolution. 
Sustained clinical resolution is defined as occurring when no key COVID-19 related 
symptom has a score higher than 1 over a 72-hour period (as documented using an 
electronic patient-reported outcome [ePRO] instrument), except for sense of smell and 
taste (items 13 and 14) where the score should be 0 over a 72-hour period. The time to 
resolution will be taken as the time from randomization until the first day of the last 
72-hour period where the patient meets the definition of resolution within 28 days. 
Patients who do not meet the definition of resolution 28 days after randomization will 
be considered not resolved. 
 
Secondary endpoints: 
 
Time to complete clinical resolution  
 
Change from baseline in COVID-19 total symptom score 
 
Scoring of WHO Clinical Outcome Scale (9-point scale) 
 
Rate of hospitalization 
 
Rate of progression to oxygen therapy 
 
Duration of hospitalization 
 
Time to viral clearance based on PCR test for SARS-CoV-2 
 
Change from baseline in log10 viral load 
 
Mortality rate 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 9 of 59 
Protocol 
Covance Study: 8449008 
Evaluation: Safety 
The number and percentage of patients with treatment-emergent AEs (TEAEs), serious AEs 
(SAEs), TEAEs related to study treatment, SAEs related to study treatment, TEAEs leading to 
treatment discontinuation, and TEAEs leading to death will be summarized by system organ 
class (SOC), preferred term (PT), and treatment group. In addition, the severity of TEAEs and 
relationship to study treatment will be summarized by SOC, PT, and treatment group. 
Test values and change from baseline will be summarized descriptively by treatment group for 
specific laboratory test results and vital signs. Where applicable, shift tabulations by treatment 
group will be presented. 
Evaluation: Pharmacokinetics 
Dalcetrapib concentrations will be determined in the PK samples collected according to the 
Schedule of Assessments. 
Statistical methods: 
Continuous variables will be summarized by the standard descriptive statistics: number 
of patients (n), mean, standard deviation, median, minimum, and maximum for baseline 
variables, and n, mean, standard error, and confidence interval (CI) for outcome measures. 
Frequency of patient or events and percentages will be summarized for categorical variables. 
Time to event variables will be summarized using Kaplan-Meier methods. 
Unless otherwise specified, all regression models will be stratified by maximum symptom 
severity at baseline (presence vs absence of moderate or severe symptoms) and by age 
(≤65 years vs >65 years), and Wald p-values will be considered primary. 
Efficacy Analysis 
The analysis of treatment efficacy will be based on the Intent-to-Treat Population. The PP 
population will be used for secondary analysis. This section is a summary of the planned 
efficacy analyses of the most important efficacy endpoints including primary and key 
secondary efficacy endpoints. 
Analysis of Primary Endpoints 
Time to Sustained Clinical Resolution 
The primary endpoint is time to sustained clinical resolution as determined by symptom score. 
The primary analysis of this endpoint will be performed on the ITT population. Time to 
sustained clinical resolution will be summarized by treatment group using Kaplan-Meier 
methods. Median and associated 95% CI, 25-75 percentiles, and minimum and maximum 
values will be presented. The number and percentage of patients whose symptoms resolved, 
and patients censored will be presented. 
The differences in time to sustained clinical resolution between the treatment groups will be 
evaluated using a 2-sided log-rank test, stratified for baseline symptom severity (presence vs 
absence of moderate or severe symptoms) and by age (≤65 years vs >65 years). The combined 
two highest treatment groups will be compared to placebo in addition to the comparison of 
individual doses. 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 10 of 59 
Protocol 
Covance Study: 8449008 
Analysis of Secondary Efficacy Endpoints 
Time to Complete Clinical Resolution 
Time to complete clinical resolution will be analyzed using the same model as time to 
sustained clinical resolution, but with all symptoms required to have resolved to a score of 0 
rather than 1. 
Change from Baseline in COVID-19 Total Symptom Severity Score 
COVID-19 total symptom severity score will be summarized by treatment group using 
descriptive statistics (N, mean, median, standard deviation, minimum, and maximum) for each 
visit as well as for changes from baseline (N, mean, standard error, CI). A Mixed-Effect Model 
Repeated Measure (MMRM) will be performed to analyze the average difference between 
treatment groups over 28 days and at the designated assessment days. 
Scoring of WHO Clinical Outcome Scale (9-point scale) 
The number and percentage of patients for each WHO clinical outcome score will be 
summarized. An ordinal logistic regression analysis for the specified time points will be 
presented as odds ratio, with associated 95% CI and p-value. 
Rate of Hospitalization through Day 28 
The analysis of this endpoint will be performed on the ITT population. The number and 
percentage of patients who were hospitalized and reason for hospitalized will be presented. The 
percentage of patients who were hospitalized will be compared using a logistic regression 
analysis for specified time points. The results will be presented as odds ratios, with associated 
95% CIs and p-value. 
Rate of Progression to Oxygen Therapy through Day 28 
The analysis of this endpoint will be performed on the ITT population. The number and 
percentage of patients who progress to oxygen therapy and type of oxygen therapy will be 
presented. The percentage of patients who had progressed to oxygen therapy will be compared 
using a logistic regression analysis for specified time points. The results will be presented as 
odds ratios, with associated 95% CIs and p-value. 
Duration of Hospitalization 
The duration of hospitalization will be performed on the ITT population. Duration of 
hospitalization will be summarized by treatment group using descriptive statistics (N, mean, 
median, standard deviation, standard error, CI, minimum, and maximum). Linear regression 
will be performed to analyze the difference between treatment groups. The results will be 
presented as mean treatment difference with associated 95% CI and p-value.  
Mortality Rate 
The analysis of this endpoint will be performed on the ITT population. The number and 
percentage of patients who died and reason for death will be presented. The percentage 
of patients who died will be compared using a logistic regression analysis for specified time 
points. The results will be presented as odds ratios, with associated 95% CIs and p-values. 
Time to Viral Clearance based on PCR Test for SARS-CoV-2 
The time to viral clearance based on PCR test for SARS-CoV-2 will be performed on the ITT 
population. Time to viral clearance will be summarized by treatment group using Kaplan-
Meier methods. Median and associated 95% CI, 25-75 percentiles, and minimum and 


 
 
 
Final, 14 December 2020 
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Sponsor Reference: DAL-401 
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Protocol 
Covance Study: 8449008 
maximum values will be presented. The number and percentage of patients who do not show 
virus, show virus, and patients censored will be presented. 
Change from Baseline in log10 Viral Load 
The change from baseline in log10 viral load will be assessed at specified time points by a 
MMRM. Patients who have achieved a level below the limit of detection will be included in 
the analysis at half the lower limit of detection. For this endpoint, Last Observation Carried 
Forward (LOCF) will be used to impute values for all patients. The treatment effect for the 
difference at each time point, and the average slope up to each time point for each treatment 
group will be presented along with a 95% CI. 
Safety Analysis 
Safety variables include incidence of AEs (or TEAEs), laboratory test results, and vital signs. 
All safety analyses will be based on the Safety Population. No formal statistical analysis of the 
safety data will be performed. 
Adverse events will be coded according to MedDRA, version 23.0 dated 19 Apr 2020 
(exclusively meant for COVID-19) or later. 
The number and percentage of patients with TEAEs, SAEs, TEAEs related to study treatment, 
SAEs related to study treatment, TEAEs leading to treatment discontinuation, TEAEs leading 
to study discontinuation, and TEAEs leading to death will be summarized by SOC, PT, and 
treatment group. In addition, the severity of TEAEs and relationship to study treatment will be 
summarized by SOC, PT, and treatment group. 
Test values and change from baseline will be summarized descriptively by treatment group for 
specific laboratory test results and vital signs. Where applicable, shift tabulations will be 
presented for specific laboratory test results by treatment group. Where applicable, number and 
frequency of clinically significant abnormal values for specific laboratory test results will be 
presented. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be determined using population PK modeling approach. The 
sparse PK samples will be pooled with PK data from other clinical studies for population PK 
analysis. PK profiles will be predicted and subsequently PK parameters will be estimated. 
Correlations between PK and pharmacodynamic (efficacy or safety) may be explored, 
including the relationship between drug exposure and viral elimination dynamics, if data 
permit. The methodology for PK analysis will be documented in a PK Analysis and Reporting 
Plan outside of this protocol. 
Interim Analysis 
A single interim analysis will be conducted after 97 resolution events have occurred. 
 


 
 
 
Final, 14 December 2020 
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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................1 
SPONSOR APPROVAL .....................................................................................................2 
INVESTIGATOR AGREEMENT.......................................................................................3 
SYNOPSIS ...........................................................................................................................4 
TABLE OF CONTENTS ...................................................................................................12 
LIST OF TABLES AND FIGURES..................................................................................15 
LIST OF ABBREVIATIONS ............................................................................................16 
1. 
INTRODUCTION ...............................................................................................17 
1.1. 
Study Rationale .................................................................................................17 
1.2. 
Background .......................................................................................................17 
1.3. 
Risk-benefit Assessment ...................................................................................19 
2. 
OBJECTIVES AND ENDPOINTS .....................................................................20 
2.1. 
Objectives ..........................................................................................................20 
2.2. 
Endpoints ..........................................................................................................21 
3. 
INVESTIGATION PLAN ...................................................................................22 
3.1. 
Overall Study Design and Plan Description......................................................22 
3.1.1. 
Data Monitoring Committee .............................................................................23 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups ............23 
3.3. 
End of Study Definition ....................................................................................24 
3.4. 
Selection of Doses in the Study ........................................................................24 
4. 
SELECTION OF STUDY POPULATION .........................................................25 
4.1. 
Inclusion Criteria ...............................................................................................25 
4.2. 
Exclusion Criteria..............................................................................................25 
4.3. 
Disease Diagnostic Criteria ...............................................................................26 
4.4. 
Discontinuation Criteria ....................................................................................27 
4.4.1. 
Screen Failures ..................................................................................................27 
4.4.2. 
Discontinuation of Study Treatment .................................................................27 
4.4.2.1. 
Liver Injury .......................................................................................................28 
4.4.2.2. 
Pregnancy ..........................................................................................................28 
4.4.3. 
Lost to Follow-up ..............................................................................................28 
4.4.4. 
Replacement Procedures ...................................................................................28 
4.4.5. 
Follow-up of Patients Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study ..................................................................29 
4.5. 
Stopping Rules ..................................................................................................29 
4.6. 
Study Termination .............................................................................................29 
5. 
STUDY TREATMENTS ....................................................................................31 
5.1. 
Treatments Administered ..................................................................................31 
5.2. 
Preparation, Storage, Handling, and Accountability .........................................31 
5.3. 
Method of Treatment Assignment ....................................................................32 
5.3.1. 
Dose Modification .............................................................................................32 
5.4. 
Blinding .............................................................................................................32 
5.5. 
Treatment Compliance ......................................................................................32 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ....................34 
6.1. 
Concomitant Therapy ........................................................................................34 
6.2. 
Prohibited Medications .....................................................................................34 


 
 
 
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7. 
STUDY ASSESSMENTS AND PROCEDURES ..............................................35 
7.1. 
Efficacy Assessments ........................................................................................35 
7.1.1. 
COVID-19 Symptom Severity ..........................................................................35 
7.1.2. 
COVID-19 Clinical Outcome Scale ..................................................................36 
7.1.3. 
Hospitalization ..................................................................................................37 
7.1.4. 
Viral Clearance as Measured Based on PCR Test for SARS-CoV-2 ...............37 
7.1.5. 
Viral Load for SARS-CoV-2 ............................................................................37 
7.2. 
Safety and Tolerability Assessments ................................................................37 
7.2.1. 
Adverse Events..................................................................................................37 
7.2.2. 
Pregnancy ..........................................................................................................38 
7.3. 
Clinical Laboratory Evaluations .......................................................................38 
7.4. 
Vital Signs, Physical Examination, and Other Safety Evaluations ...................39 
7.4.1. 
Vital Signs .........................................................................................................39 
7.4.2. 
Physical Examination ........................................................................................39 
7.5. 
Pharmacokinetic Assessments ..........................................................................39 
8. 
SAMPLE SIZE AND DATA ANALYSES ........................................................40 
8.1. 
Determination of Sample Size ..........................................................................40 
8.2. 
Analysis Populations .........................................................................................40 
8.2.1. 
Intent-to-Treat Population .................................................................................40 
8.2.2. 
Per Protocol Population ....................................................................................40 
8.2.3. 
Safety Population ..............................................................................................40 
8.2.4. 
Pharmacokinetic Population .............................................................................40 
8.3. 
General Considerations .....................................................................................41 
8.4. 
Efficacy Analysis ..............................................................................................41 
8.4.1. 
Analysis of Primary Endpoints .........................................................................41 
8.4.1.1. 
Time to Sustained Clinical Resolution ..............................................................41 
8.4.2. 
Analysis of Secondary Efficacy Endpoints .......................................................41 
8.4.2.1. 
Time to Complete Clinical Resolution ..............................................................41 
8.4.2.2. 
Change from Baseline in COVID-19 Symptom Severity Score .......................42 
8.4.2.3. 
Scoring of WHO Clinical Outcome Scale (9-point Scale)................................42 
8.4.2.4. 
Rate of Hospitalization Through Day 28 ..........................................................42 
8.4.2.5. 
Rate of Progression to Oxygen Therapy Through Day 28 ................................42 
8.4.2.6. 
Duration of Hospitalization ...............................................................................42 
8.4.2.7. 
Mortality Rate ...................................................................................................42 
8.4.2.8. 
Time to Viral Clearance Based on PCR Test for SARS-CoV-2 .......................43 
8.4.2.9. 
Change from Baseline in log10 Viral Load ......................................................43 
8.5. 
Safety Analysis .................................................................................................43 
8.6. 
Pharmacokinetic Analysis .................................................................................44 
8.7. 
Interim Analysis ................................................................................................44 
8.8. 
Handling of Missing Data .................................................................................44 
8.8.1. 
Imputation .........................................................................................................44 
8.8.2. 
Censoring ..........................................................................................................44 
8.9. 
Multiplicity/Multiple Testing ............................................................................44 
9. 
REFERENCES ....................................................................................................45 
10. 
APPENDICES .....................................................................................................46 
Appendix 1 – Adverse Event Definitions ..........................................................................47 


 
 
 
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Appendix 2 – Clinical Laboratory Evaluations .................................................................51 
Appendix 3 – Regulatory, Ethical, and Study Oversight Considerations ..........................52 
Appendix 4 – Schedule of Assessments ............................................................................56 
Appendix 5 – Contraceptive Guidance ..............................................................................58 
 


 
 
 
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LIST OF TABLES AND FIGURES 
Table 1: 
Molecular Docking Data of Dal-thiol and Dal-dimer ............................................... 18 
Table 2:  
Treatment Details ...................................................................................................... 31 
Table 3: 
Assessment of 14 Common COVID-19-Related Symptoms: Items and Response .. 35 
Table 4: 
WHO Clinical Outcome Scale .................................................................................. 36 
Table 5: 
Schedule of Assessments .......................................................................................... 56 
 
Figure 1: 
Inhibition of Viral Replication in Renal Human Cell ............................................... 18 
Figure 2:  
Study Design ............................................................................................................. 23 
 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC0-24 
area under the concentration-time curve during 24 hours 
CETP 
Cholesteryl Ester transfer protein 
CFR 
Code of Federal Regulations 
CHD 
coronary heart disease 
CI 
confidence interval 
Cmax 
maximum concentration 
COVID-19 
Coronavirus Disease of 2019 
CRO 
Contract Research Organization 
CT 
computerized tomography 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic Case Report Form 
EOT 
End of treatment 
ePRO 
electronic patient-reported outcome 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL-C 
high-density lipoprotein cholesterol 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IVRS/IWRS 
Interactive Voice/Web Response System 
LOCF 
Last Observation Carried Forward 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-Effect Model Repeated Measure 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PP 
Per Protocol 
PT 
preferred term 
QTc 
corrected QT 
SAE 
serious adverse event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome CoronaVirus 2 
SOC 
system organ class (MedDRA classification) 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


 
 
 
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1. INTRODUCTION 
In 2019, an outbreak of respiratory disease caused by a novel coronavirus was first detected in 
Wuhan City, Hubei Province, China.1 The virus has been named Severe Acute Respiratory 
Syndrome COronaVirus 2 (SARS-CoV-2), and the disease it causes has been named 
Coronavirus Disease of 2019 (COVID-19). This virus has now been detected in many locations 
internationally, and COVID-19 was characterized as a pandemic by the World Health 
Organization (WHO) on 11 March 2020.2 As of 22 October 2020, WHO reported approximately 
41 million COVID-19 positive cases and included approximately 1,128,000 deaths.3 
SARS-CoV-2 can cause a potentially fatal disease. COVID-19 can range from mild to severe 
disease, the latter including pneumonia, severe acute respiratory syndrome, multi-organ failure, 
and death. FDA provided emergency use authorization to remdesivir for the treatment of 
hospitalized COVID-19 patients.4 However, there is a need for treatment, as well as to have a 
clinically effective antiviral drug for the prevention of COVID-19. Clinical management includes 
symptomatic and supportive care, such as supplemental oxygen, mechanical ventilation, and 
extracorporeal membrane oxygenation (ECMO) when indicated. There is an urgent need for safe 
and effective anti-SARS-CoV-2 drugs.1 
The main protease (Mpro) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating 
viral replication and transcription. Dalcetrapib and its metabolite dalcetrapib-thiol is known to 
covalently bind to Cysteine13 of the Cholesteryl Ester transfer protein (CETP). It is speculated 
that it may form a disulfide bond with Cysteine145 of Main Protease (3CLMpro) of 
SARS-CoV-2 and inactivate the enzyme therefore stopping the viral replication and transcription 
in cells. In vitro results are provided in Section 1.2. 
1.1. 
Study Rationale 
This placebo-controlled, Phase 2a proof-of-concept clinical study will evaluate efficacy and 
safety of dalcetrapib in outpatients patients with mild to moderate, symptomatic, confirmed 
COVID-19. 
Selection of doses in the study is discussed in Section 3.4. 
1.2. 
Background 
Dalcetrapib is being investigated for coronary heart disease (CHD) (NCT00658515) in 
CHD patients. Dalcetrapib is a compound selected for its capacity to modulate plasma CETP 
activity and increase high-density lipoprotein cholesterol (HDL‐C) levels. Dalcetrapib has been 
evaluated in several large clinical trials, most notably dal‐OUTCOMES, a 15,871 patient trial 
designed to evaluate its effect in patients with recent acute coronary syndrome. As compared 
with placebo, dalcetrapib did not alter the risk of cardiovascular morbidity and mortality or total 
mortality despite an effect on HDL‐C levels (30% increase). However, the trial demonstrated the 
safety and tolerability of dalcetrapib in this population.5 
Molecular docking investigations suggested that dalcetrapib-thiol binds to the active site of the 
SARS-CoV-2 main 3CL protease with a delta G value of -8.5 kcal/mol (Table 1). 


 
 
 
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Table 1: 
Molecular Docking Data of Dal-thiol and Dal-dimer 
MPro 
ΔG Kcal/mol 
CETP 
ΔG Kcal/mol 
Dal-ester 
-8.62 
-8.90 
Dal-Thiol 
-8.72 
-8.07 
Dal-DIMER 
-10.14 
-10.66 
Natural substrate of Main Protease 
-10.99 
- 
In vitro data from SARS-CoV-2 infected cultured cell line confirmed antiviral activity and no 
obvious toxicity was observed in the in vivo toxicity study.6 
Remdesivir, an injectable intravenous treatment for severe forms of COVID-19, is currently the 
only treatment approved by the FDA. In vitro data for remdesivir and dalcetrapib confirm the 
inhibition of viral replication in renal monkey cells with pre-incubation to achieve lower half 
maximal inhibitory concentration (IC50). Dalcetrapib inhibited main 3CL protease activity both 
in vitro and viral replication in cells with IC50 values of 14.4±3.3 μM and 17.5±3.5 μM. 
Near-complete inhibition of protease activity persisted despite elution of dalcetrapib 
approximately 100 times below its IC50, suggesting stable protease-drug interaction. 
Figure 1: 
Inhibition of Viral Replication in Renal Human Cell 
 
IC50 = half maximal inhibitory concentration 


 
 
 
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1.3. 
Risk-benefit Assessment 
Dalcetrapib is an oral, safe and generally well-tolerated drug which could target mild, moderate, 
and severe forms of the COVID-19, and possibly prevent COVID-19 in high-risk or 
exposed patients.7 
No obvious toxicity was observed in the in-vivo toxicity studies. The major dose-limiting finding 
associated with dalcetrapib in monkeys was gastrointestinal toxicity (diarrhea and loose stools). 
In general, dalcetrapib has been well-tolerated in patients with CHD. In the short-term 
(<12 weeks) Phase 1 and 2 studies, the incidence of adverse events (AEs) leading to 
discontinuation of dalcetrapib (300, 600, and 900 mg) was low across the Phase1 healthy 
volunteer and Phase 2 patient studies. The majority of the AEs were of mild or moderate 
intensity. The most frequently reported AEs were those from body system organ classes of 
gastrointestinal system and nervous system, and included diarrhea, stool abnormalities, and 
headache. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of dalcetrapib may be found in the Investigator’s Brochure. 
As the study subjects targeted are patients with limited treatment options, the study supports 
further investigation of dalcetrapib in patients with mild to moderate symptoms due to 
COVID-19 in a Phase 2a setting. 


 
 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary efficacy objective of the study is: 
 To evaluate the time to sustained clinical resolution of symptoms in patients with 
confirmed, mild to moderate, symptomatic COVID-19 treated with dalcetrapib.  
Sustained clinical resolution is defined as occurring when no key COVID-19 related 
symptom has a score higher than 1 over a 72-hour period (as documented using an 
electronic patient-reported outcome [ePRO] instrument), except for sense of smell and 
taste (items 13 and 14) where the score should be 0 over a 72-hour period. The time to 
resolution will be taken as the time from randomization until the first day of the last 
72-hour period where the patient meets the definition of resolution within 28 days. 
Patients who do not meet the definition of resolution 28 days after randomization will be 
considered not resolved. 
The secondary efficacy objectives of the study are: 
 To evaluate the change from baseline in COVID-19 symptom severity score at all 
collected time points 
 To evaluate time to complete clinical resolution, defined in the same way as the primary 
endpoint, but considering that all symptoms must resolve to a score of 0 for 72 hours 
 To evaluate the time to viral clearance using SARS-CoV-2 polymerase chain reaction 
(PCR) 
 To evaluate change from baseline in log10 viral load 
 To evaluate the WHO Clinical Outcome Scale (9-point scale) at Day 3, Day 5, Day 10, 
and Day 28 
 Rate of hospitalization through Day 28 
 To evaluate the rate of progression to oxygen therapy through Day 28 
 To evaluate the duration of hospitalization 
 To evaluate the mortality rate by Day 28 
The safety objective of the study is: 
 To assess the safety and tolerability of dalcetrapib active doses compared to placebo in 
patients with COVID-19 


 
 
 
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The pharmacokinetics (PK) objective of the study is: 
 To evaluate the PK of dalcetrapib in patients with COVID-19 
2.2. 
Endpoints 
The primary efficacy endpoint is: 
 Time to sustained clinical resolution. 
Sustained clinical resolution is defined as occurring when no key COVID-19 related 
symptom has a score higher than 1 over a 72-hour period (as documented using an 
electronic patient-reported outcome [ePRO] instrument), except for sense of smell and 
taste (items 13 and 14) where the score should be 0 over a 72-hour period. The time to 
resolution will be taken as the time from randomization until the first day of the last 
72-hour period where the patient meets the definition of resolution within 28 days. 
Patients who do not meet the definition of resolution 28 days after randomization will be 
considered not resolved. 
The secondary efficacy endpoints are: 
 Time to complete clinical resolution 
 Change from baseline in COVID-19 total symptom score 
 Score on the WHO Clinical Outcome Scale (9-point scale) 
 Rate of hospitalization 
 Rate of progression to oxygen therapy 
 Duration of hospitalization 
 Time to viral clearance based on PCR test for SARS-CoV-2 
 Change from baseline in log10 viral load 
 Mortality rate 


 
 
 
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3. INVESTIGATION PLAN 
3.1. 
Overall Study Design and Plan Description 
This is a randomized, double-blind, multicenter, Phase 2a proof-of-concept study in outpatients 
with confirmed, mild to moderate, symptomatic COVID-19. Dalcetrapib inactivates the 
3CLMpro enzyme of Corona virus and therefore stops the viral replication and transcription in 
cells. It is being planned to use for treatment in patients with COVID-19. 
Up to 60 sites in the United States and Canada, and other countries as appropriate based on the 
pandemic situation, are planned to enroll patients. 
Total duration of study participation is up to 32 days. The screening period is planned to occur 
between 48 to 24 hours prior to dosing. Randomization will occur during the Screening/Baseline 
visit in order for treatment to be dispensed in time for start of first dose on Day 1. Patients will 
either receive dalcetrapib 900, 1800, or 3600 mg or placebo for 10 days and be followed for 
18 days of follow-up. The study design is summarized in Figure 2. 
It is anticipated that 208 patients will be randomized in one of the dalcetrapib treatment arms or 
placebo (52 patients to each of 900 mg, 1800 mg, 3600 mg and placebo) for 10 days. Patients 
will be randomized and receive first dose of study drug within 72 hours of receiving a positive 
PCR or Point-of-care test for SARS-CoV-2. Patients need to have at least two of the 14 common 
COVID-19-related symptoms described in the inclusion criteria rated as mild or moderate, as 
evaluated by ePRO assessment. Symptoms will be assessed at each study visit daily for the first 
10 days, then at Day 14 and Day 28, and as clinically indicated. Symptoms will be evaluated as 
absent, mild, moderate, or severe depending on their impact on activity of daily living. 
SARS-CoV-2 viral loads will be obtained by both saliva (Oragene) collection and mid-turbinate 
nasal swab self-collected under supervision of healthcare professional (virtual or home visit) at 
Screening/Baseline, Day 1, Day 3, Day 5, Day 7, Day 10, and Day 28. Patients who require 
hospitalization after initiation of study treatment will be followed for vital status through Day 28. 
Study Visit Procedures 
Study visits (virtual, study site or home visits by a healthcare professional) will take place on 
Days 1, 3, 5, 7, 10, 14, and 28. Screening/Baseline assessments may all be performed on the 
same calendar day and may be performed at the study site or as a home visit. For visits which 
include bloodwork, sample collection may be done by a visiting healthcare professional or at the 
study site (as long as the patient has no worsening of respiratory symptoms or no fever within 24 
hours). Other visits may be conducted remotely using telemedicine. 
The samples for viral load testing will be both saliva (Oragene) collection and mid-turbinate 
nasal swab self-collected under supervision of a healthcare professional. Telemedicine visits 
such as phone calls or other digital media are to be utilized as much as possible. Study 
procedures are presented in detail in Section 7. 


 
 
 
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Figure 2:  
Study Design 
  
D=Day. 
 
3.1.1. 
Data Monitoring Committee 
The study will be overseen by an independent Data Monitoring Committee (DMC). The DMC 
will review safety data throughout the study. The DMC and Sponsor will review efficacy data at 
the interim analysis and at the end of the study. A DMC Charter, which includes detailed 
processes, will be prepared. 
One interim analysis will be conducted for efficacy once 97 resolution events have occurred to 
allow 73 resolution events to have occurred in the two highest dose levels and placebo arm. At 
the interim analysis, if the average hazard ratio (HR) of the two highest dose levels relative to 
placebo is greater than 1.45, the study will stop due to efficacy and the program will be able to 
proceed directly to Phase 3. At the interim analysis, if the HR of the two highest dose levels 
relative to placebo is between 1.0 and 1.45, the study will continue enrollment until 169 
resolution events have occurred. At the interim analysis, if the HR of the two highest dose levels 
is less than 1.0, the study will be stopped for lack of efficacy. 
The members of the committee will include appropriately qualified medical personnel, and other 
members, as required. Detailed responsibilities of the DMC will be provided in the DMC 
Charter. 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups 
This study will be double-blind and placebo-controlled to avoid bias in the collection and 
evaluation of data during its conduct. The Sponsor will remain blinded to the treatment 


 
 
 
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randomization code until after the database has locked. The Sponsor will perform ongoing 
review of blinded data. The placebo has been chosen as the control treatment to assess whether 
any observed effects are treatment-related or simply reflect the study conditions. 
3.3. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last patient in the study. 
3.4. 
Selection of Doses in the Study 
Dalcetrapib is already in clinical development (NCT02525939), and of 11,799 subjects that have 
been dosed to date, a total of 546 subjects have received single oral doses of between 100 and 
4500 mg and 467 subjects have received consecutive doses between 300 and 3900 mg. Available 
information at higher doses showed systemic exposure of 1.73-2.68, 4.30, 3.78, 3.26, 5.63, and 
7.11 µg/mL (maximum concentration [Cmax]) and 18.2-19.1, 31.3, 30.4, 25.3, 42.3, and 51.1 
µg.h/mL (area under the concentration-time curve during 24 hours [AUC0-24]) at 900, 1200, 
1800, 2100, 3000, and 3900 mg, respectively. In vitro testing showed a protease inhibition IC50 
value of 14.4 μM and inhibition of replication IC50 value of 17.8 μM. Proposed oral dose levels 
of dalcetrapib at 900, 1800, or 3600 mg for 10 days is centered on the following: 
 900 mg: based on actual Cmax values of 1.73-2.68 µg/mL = 5.4-8.37 µM which are 
2.7-1.7- and 3.3-2.1-fold lower than protease inhibition and inhibition of replication IC50 
values, respectively to establish whether that this is not an efficacious dose. 
 1800 mg: based on actual Cmax value of 3.78 µg/mL = 11.8 µM which is approximately 
0.8-fold and 0.65-fold the values for protease inhibition and inhibition of replication IC50 
values, respectively, to establish whether this is an efficacious dose. 
 3600 mg: based on actual Cmax values for the 3000 and 3900 mg doses of 5.63 and 
7.10 µg/mL = 17.6 and 22.2 µM which are at or higher the values for protease inhibition 
and inhibition of replication IC50 values, respectively, to establish whether this is an 
efficacious dose. 
 


 
 
 
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4. SELECTION OF STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
4.1. 
Inclusion Criteria 
Patients must satisfy all of the following criteria unless otherwise stated: 
1. Willing and able to provide informed consent 
2. Male or female patients > 18 years of age on the day of informed consent 
3. Have received a confirmed diagnosis of COVID-19 (positive for SARS-CoV-2), as 
assessed by PCR or point-of-care within 72 hours of first dose on Day 1 
4. Have mild to moderate signs or symptoms of COVID-19 with onset within 5 days of first 
dose on Day 1, at least two of the following symptoms: 
 stuffy or runny nose 
 sore throat 
 shortness of breath  
 cough  
 fatigue  
 myalgia  
 headache 
 chills or shivering 
 feeling hot or feverish 
 nausea 
 vomiting 
 diarrhea 
 anosmia  
 ageusia  
5. Outpatient with COVID-19 disease (not requiring oxygen therapy [WHO COVID-19 
Clinical Improvement Ordinal Scale, score of 3]) 
6. Patient is aware of the investigational nature of this study and willing to comply with 
protocol treatments, blood tests, and other evaluations listed in the ICF. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they satisfy any of the following criteria unless 
otherwise stated: 
1. Females who are pregnant (negative pregnancy test required for all women of 
child-bearing potential at Screening) or breast-feeding 
2. Male patients and women of childbearing potential (women who are not surgically sterile 
or postmenopausal defined as amenorrhea for >12 months) who are not using at least one 
protocol-specified method of contraception 


 
 
 
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3. Severe COVID-19 disease as defined by the WHO COVID-19 Clinical Improvement 
Ordinal Scale, scores of 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation 
and mechanical ventilation), or 7 (ventilation + additional organ support pressors, renal 
replacement therapy [RRT], extracorporeal membrane oxygenation [ECMO]) 
4. Expected survival less than 72 hours 
5. Peripheral capillary oxygen saturation (SpO2) <90% while breathing room air 
6. Treatment with other drugs thought to possibly have activity against SARS-CoV-2 
infection like remdesivir, favipiravir, within 7 days prior to enrollment or concurrently 
7. History of abuse of drugs or alcohol that could interfere with adherence to study 
requirements as judged by the Investigator 
8. Use of any other concurrent investigational drugs while participating in the present study 
9. Patient requires frequent or prolonged use of systemic corticosteroids (≥20 mg of 
prednisone/day or equivalent for >4 weeks) or other immunosuppressive drugs (e.g., for 
organ transplantation or autoimmune conditions) 
10. Known renal disease with an estimated glomerular filtration rate (eGFR) <50 mL/min 
based on local laboratory results 
11. Patients with clinically apparent liver disease, e.g., jaundice, cholestasis, hepatic synthetic 
impairment, or active hepatitis 
12. Alanine transaminase (ALT) or aspartate transaminase (AST) >3 × upper limit of normal 
(ULN) or alkaline phosphatase or bilirubin levels > 2 × ULN based on local laboratory 
results 
13. Co-administration of clinical doses of orlistat with dalcetrapib 
14. Inability to swallow oral medications or a gastrointestinal disorder with diarrhea 
(e.g., Crohn’s disease) or malabsorption at Screening 
15. Any other clinically significant medical condition or laboratory abnormality that, in the 
opinion of the Investigator, would jeopardize the safety of the patient or potentially 
impact patient compliance or the safety/efficacy observations in the study 
16. History of an allergic reaction or hypersensitivity to the study drug or any component of 
the study drug formulation. 
4.3. 
Disease Diagnostic Criteria 
Patients with SARS-CoV-2 infection confirmed (nasal, nasopharyngeal, oropharyngeal, or 
respiratory samples, not serology testing, or patients with pre-study confirmed PCR test) and 
mild to moderate symptoms related to COVID-19 disease are required for enrollment. 
The entry testing is performed locally based on testing methods available at the site, such as PCR 
or rapid antigen test, to confirm the presence of SARS-CoV-2 in a person with symptoms 
compatible with COVID-19. Both saliva (Oragene) collection and self-collection of 
mid-turbinate nasal swab under supervision of a healthcare professional (virtual or home visit) 
will also occur at Screening/Baseline, Day 1, Day 3, Day 5, Day 7, Day 10, and Day 28. 


 
 
 
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4.4. 
Discontinuation Criteria 
4.4.1. 
Screen Failures 
Screen failures are defined as patients who have provided informed consent to participate in the 
clinical study but are not subsequently enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse events (SAEs). 
Re-screening will be allowed in a screen failed patient if there is a change in the situation of the 
patient which allows him/her to fulfill inclusion/exclusion criteria with the permission from the 
Medical Monitor. 
4.4.2. 
Discontinuation of Study Treatment 
Study medication will be discontinued for the following reasons: 
 Patients whose screening labs indicate an eGFR <50mL/min using CKD-EPI will 
discontinue study medication and be followed for safety 
 Withdrawal by patient (patient is free to discontinue at any point of time; specify reason 
of discontinuation in the eCRF) 
 At the discretion of the Investigator for safety, behavioral, or administrative reasons 
 Lack of efficacy (e.g., patients who require nonstudy antiviral or anticytokine therapy due 
to progression of COVID-19). Note: Study medication would be discontinued upon 
worsening of symptoms requiring hospitalization, in such cases patients could receive 
remdesivir 
 Adverse event 
Study will be discontinued for the following reasons: 
 Withdrawal of consent (patient is free to discontinue at any point of time; specify reason 
of discontinuation in the eCRF) 
 Sponsor determination 
 Unexpected safety concerns 
 Medical or ethical reasons affecting the continued performance of the study 
 Difficulties in the recruitment of patients 


 
 
 
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4.4.2.1. 
Liver Injury 
Discontinuation of study treatment for abnormal liver tests should be considered by the 
Investigator when a patient meets one of the conditions mentioned below or if the Investigator 
believes that it is in the best interest of the patient. 
 Discontinue the study treatment if AST/ALT >8 × ULN 
 Discontinue the study treatment if AST/ALT >3 × ULN and serum total bilirubin 
levels >2 × ULN (Hy’s law) 
 Discontinue the study treatment if repeat AST/ALT >5 × ULN 
4.4.2.2. 
Pregnancy 
Female patients who are pregnant or are breastfeeding or who do not agree to use a reliable 
method of birth control during the study will be permanently discontinued from study drug. 
4.4.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly is unable to be contacted. 
The following actions must be taken if a patient repeatedly is unable to be contacted. 
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit schedule, 
and ascertain whether or not the patient wishes to and/or should continue in the study. 
 In cases in which the patient is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
 Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4.4.4. 
Replacement Procedures 
Patients who discontinue from the study will not be replaced. 


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4.4.5. 
Follow-up of Patients Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study 
Due to continued scientific importance of patient data even if study treatment is discontinued 
early, patients who withdraw from the study will be asked to complete all subsequent study 
procedures (Follow-up/EOS), as described in the Schedule of Assessments (Appendix 4). 
Patients who are no longer hospitalized may complete their assessments by telephone or via 
telemedicine or other means of remote communication.  
All SAEs that are ongoing at the time of discontinuation, or that develop prior to the final 
Follow-up/EOS, will be followed until resolution or stabilization, or up to 28 days (±2 days) 
following the last dose of study treatment, by Covance Patient Safety Services group. 
Steps will be taken by the sites to ascertain vital status in all randomized patients (e.g., with a 
vital records search) up to Day 28±2. 
4.5. 
Stopping Rules 
The study will enroll 208 patients (52 patients to each of 900 mg, 1800 mg, 3600 mg and 
placebo). One interim analysis will be conducted for efficacy once 97 resolution events have 
occurred to allow 73 resolution events to have occurred in the two highest dose levels and 
placebo arm. At the interim analysis, if the average HR of the two highest dose levels relative to 
placebo is greater than 1.45, the study will stop due to efficacy and the program will be able to 
proceed directly to Phase 3. At the interim analysis, if the HR of the two highest dose levels 
relative to placebo is between 1.0 and 1.45, the study will continue enrollment until 169 
resolution events have occurred. At the interim analysis, if the HR of the two highest dose levels 
is less than 1.0, the study will be stopped for lack of efficacy. The DMC will issue a 
recommendation to enroll patients, or to stop the study depending on interim analysis 
assessment. The DMC may recommend dropping one or more treatment arms. The DMC will 
continue to review safety and assess the risk/benefit profile on an ongoing basis. 
A DMC Charter, which includes detailed processes, will be prepared. 
4.6. 
Study Termination 
The study will finish when all patients have completed all study visits. 
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. Reasons for study termination may 
include, but are not limited to: 

Adverse events unknown to date (i.e., not previously reported in any similar
investigational study drug trial with respect to their nature, severity, and/or duration)

Increased frequency and/or severity and/or duration of known, anticipated, or previously
reported AEs (this may also apply to AEs defined as baseline signs and symptoms)

Medical or ethical reasons affecting the continued performance of the study


 
 
 
Final, 14 December 2020 
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 Difficulties in the recruitment of patients 
 Cancellation of drug development 
 At the recommendation of the DMC 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the Sponsor or Investigator may include, but are not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the 
Institutional Review Board (IRB)/Ethics Committee (EC) or local health authorities, the 
Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of participants by the Investigator 


 
 
 
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5. STUDY TREATMENTS 
5.1. 
Treatments Administered 
Details on the active treatment and placebo provided to patients are summarized in Table 2. 
Table 2:  
Treatment Details 
Study Treatment Name: 
 
Dalcetrapib (or matching placebo tablets) 
Dosage Formulation: 
 
Film-coated white to off-white tablets 
Unit Dose Strength(s) 
300 mg per tablet 
Route of Administration:  
Oral (recommended to be taken with the largest meal of the 
day) 
Dosing Instructions: 
 
 For 900 mg dose: 3 active tablets and 9 placebo tablets 
 For 1800 mg dose: 6 active tablets and 6 placebo tablets 
 For 3600 mg dose: 12 active tablets 
 Placebo dose: 12 placebo tablets 
Packaging and Labeling: 
The tablets can be stored in glass and plastic bottles or 
aluminum blisters. The recommended storage conditions are on 
the packaging and should be followed. For batch specific 
details and information on shelf-life, see the packaging. 
Manufacturer: 
Dalcetrapib tablets: Recipharm, Leganés, Spain  
Placebo tablets: Catalent, Kansas City, MO, United States 
 
The physicochemical properties and the pharmaceutical specifications of dalcetrapib are 
provided in the Investigator's Brochure.6 
5.2. 
Preparation, Storage, Handling, and Accountability 
The study drug will be supplied by the Sponsor (or designee), along with the batch/lot numbers 
and Certificates of Analysis. A Certificate of Release authorized by a Qualified Person in the 
European Union will also be issued for the investigational medicinal product. The study 
treatment will be provided in bottles, 10 bottles with 12 tablets per bottle, with 1 bottle to be 
taken per day. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the Investigator and authorized site staff. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply study treatment. The Investigator, institution, or the head of the medical institution 


 
 
 
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(where applicable) is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
in a separate document. 
5.3. 
Method of Treatment Assignment 
All patients will be centrally randomized using an Interactive Voice/Web Response System 
(IVRS/IWRS). Before the study is initiated, the telephone number and call-in directions for the 
IVRS and/or the log-in information and directions for the IWRS will be provided to each site. 
The study will be stratified by presence or absence of moderate or severe symptoms and by age 
(≤65 years vs >65 years). 
Patients who confirmed eligible at the screening will be assigned a patient identifier before 
having study treatment dispensed. The patient identifier will consist of the country number, site 
number, and patient number. The country number will comprise the first 2 digits, the site number 
will comprise the next 3 digits, and the patient number will comprise the final 3 digits, 
e.g., 01002003 is Country 1, Site 2, Patient 3. 
Study treatment will be dispensed to patients at the Screening/Baseline visit (see Schedule of 
Assessments, Appendix 4). 
5.3.1. 
Dose Modification 
Dose modification will not be allowed. If a dose modification is needed, the patient should be 
discontinued from treatment and all end of treatment (EOT) assessments completed. 
5.4. 
Blinding 
This is a double-blind study. 
The Sponsor and the Contract Research Organization (CRO) must be notified as soon as possible 
(e.g., within 24 hours) when the blind is broken, in the case identification of the study treatment 
is required for a medical emergency and knowledge of the specific blinded study treatment will 
affect the immediate management of the patient’s condition. The date and reason that the blind 
was broken must be recorded in the source documentation and eCRF, as applicable. 
5.5. 
Treatment Compliance 
Records shall be maintained of the delivery of study treatment to the study sites, the inventory at 
the study sites, the use for each patient, and the return to the Sponsor. 
These records shall include dates, quantities, batch/lot information, expiry dates, and the unique 
code numbers assigned to the study treatment and study patients. 


 
 
 
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The Investigator shall be responsible for ensuring that the records adequately document that 
the patients were provided the doses specified in the protocol and that all study treatment 
received from the Sponsor is reconciled. 
Site staff will monitor compliance of patients with their assigned randomized treatment 
(dalcetrapib 900, 1800, or 3600 mg or placebo) by recording the number of tablets actually used. 
For patients who are hospitalized, patients will be administered treatment by the site staff during 
hospitalization. On discharge, all patients are to be reminded of the importance of compliance 
with the treatment with an emphasis on taking their study treatment on schedule and contacting 
the study site for an appointment as soon as possible if they think they are experiencing 
worsening of condition. 
Compliance information will be captured via eSource (if a patient version is used) or 
telemedicine. Patient will return unused supply at the EOT visit. 


 
 
 
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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded in the eCRF along with: 
 reason for use 
 dates of administration including start and end dates 
 dosage information including dose and frequency 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. The Medical Monitor should be contacted if there 
are any questions regarding concomitant or prior therapy. 
Medications, other than that those listed as prohibited medications and other restrictions, which 
are considered necessary for the patient’s safety and well-being, may be given at the discretion of 
the Investigator and must be recorded in the appropriate sections of the eCRF. 
6.2. 
Prohibited Medications 
Simultaneous participation in other clinical treatment study protocols is not allowed. 
Treatment with any antiviral drugs expected to have activity against SARS-CoV-2 are not 
allowed during therapy with study treatment but may be used as rescue medications. Orlistat 
results in lowered serum levels of dalcetrapib and is not allowed as this may result in decreased 
efficacy. 
Patients who begin to receive nonstudy rescue antiviral medication for COVID-19 after the start 
of study treatment will be discontinued from study treatment, they will remain in the study and 
complete all follow-up assessments. 


 
 
 
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7. STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Assessments (Appendix 4). 
As protocol waivers or exemptions are not allowed, with the exception of immediate safety 
concerns, these should be discussed with the Sponsor immediately upon occurrence or awareness 
to determine if the patient should continue or discontinue the study drug. Adherence to the study 
design requirements, including those specified in the Schedule of Assessments, is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure 
(Section 4.4.1), as applicable. Procedures conducted as part of the patient’s routine clinical 
management (e.g., blood count) and obtained before informed consent may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified criteria and 
was performed within the timeframe defined in the Schedule of Assessments. 
7.1. 
Efficacy Assessments 
7.1.1. 
COVID-19 Symptom Severity 
COVID-19 symptoms will be evaluated by ePRO assessment on the specified days at 
approximately the same time. Symptoms are described in Table 3. 
Table 3: 
Assessment of 14 Common COVID-19-Related Symptoms: Items and 
Response 
Symptom 
Response and scoring 
1. Stuffy or runny nose  
None = 0  
Mild = 1  
Moderate = 2  
Severe = 3  
2. Sore throat  
3. Shortness of breath (difficulty breathing)  
4. Cough  
5. Low energy or tiredness 
6. Muscle or body aches 
7. Headache 
8. Chills or shivering 
9. Feeling hot or feverish 
10. Nausea (feeling like you wanted to throw 
up) 
11. How many times did you have vomiting in 
the last 24 hours? 
I did not vomit at all = 0  
1–2 times = 1  
3–4 times = 2  
5 or more times = 3  


 
 
 
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Symptom 
Response and scoring 
12. How many times did you have diarrhea 
(loose or watery stools) in the last 24 
hours? 
I did not have diarrhea at all = 0  
1–2 times = 1  
3–4 times = 2  
5 or more times = 3  
13. Rate your sense of smell in the last 24 
hours 
My sense of smell is THE SAME AS usual = 0  
My sense of smell is LESS THAN usual = 1  
I have NO sense of smell = 2  
14. Rate your sense of taste in the last 24 hours 
My sense of taste is THE SAME AS usual = 0  
My sense of taste is LESS THAN usual = 1  
I have NO sense of taste = 2  
 
Sustained clinical resolution is defined as occurring when no key COVID-19 related symptom 
has a score higher than 1 over a 72-hour period (as documented using an ePRO instrument), 
except for sense of smell and taste (items 13 and 14) where the score should be 0 over a 72-hour 
period. The time to resolution will be taken as the time from randomization until the first day of 
the last 72-hour period where the patient meets the definition of resolution within 28 days. 
Patients who do not meet the definition of resolution 28 days after randomization will be 
considered not resolved. 
7.1.2. 
COVID-19 Clinical Outcome Scale 
COVID-19 clinical outcome scale will be evaluated by a healthcare professional.  
The WHO Clinical Outcome Scale (ordinal) is a 9-point scale (Table 4). 
Table 4: 
WHO Clinical Outcome Scale 
Patient State 
Descriptor  
 Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory 
No Limitation of Activities 
1 
 
Limitation of Activities 
2 
Hospitalized, Mild Disease 
Hospitalized no oxygen therapy 
3 
 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
 
Intubation and mechanical ventilation 
6 
 
Ventilation + additional organ support -pressors, 
RRT, ECMO 
7 
Death 
Death 
8 
ECMO = extracorporeal membrane oxygenation; RRT = renal replacement therapy; WHO = World Health 
Organization 


 
 
 
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7.1.3. 
Hospitalization 
The duration of hospitalization will be from the date of first hospitalization until date of 
discharge. The duration of hospitalization will be the total number of days hospitalized. 
7.1.4. 
Viral Clearance as Measured Based on PCR Test for SARS-CoV-2 
Each patient will be tested to determine if the patient has COVID-19 by obtaining a PCR or rapid 
antigen test as long as it confirms the presence of SARS-CoV-2 per Schedule of Assessments 
(Appendix 4). Saliva and nasal secretions will be collected as noted in the schedule of 
assessments and assessed centrally by PCR for the presence or absence of SARS-CoV-2. 
A patient will be considered to no longer have COVID-19 if two consecutive PCRs do not detect 
SARS-CoV-2. Time to viral clearance using PCR test for SARS-CoV-2 will be the period 
between randomization and the date of the first negative PCR test for SARS-CoV-2. 
7.1.5. 
Viral Load for SARS-CoV-2 
SARS-CoV-2 presence or absence will be determined by PCR from both mid-turbinate nasal 
swabs and saliva. Positive results will have a quantitative viral load determined at the central 
laboratory. 
7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each patient will be monitored from the time of providing informed consent to 
completion of study participation. Patients will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as “How have you been feeling since you were 
last asked?” at each patient contact. Patients will also be encouraged to spontaneously report AEs 
occurring at any other time during the study. 
Any AEs and remedial action required will be recorded in the patient’s source data. The nature, 
time of onset, duration, and severity will be documented, together with an Investigator’s (or 
designee’s) opinion of the relationship to study drug. 
AEs recorded during the course of the study will be followed up, where possible, until resolution 
or until the unresolved AEs are judged by the Investigator (or designee) to have stabilized. This 
will be completed at the Investigator’s (or designee’s) discretion. 
For any participants who require hospitalization, if possible, study drug should be continued and 
an effort made to collect study-related data and conduct End of Study procedures. Every attempt 
should be made for a visit to be scheduled after discharge from the hospital, providing that the 
visit is within 28 days of initiation of dosing, or to visit the patient in the hospital, where 
permitted. In lieu of a study visit, study site staff should obtain equivalent data from hospital 
records. Pertinent information from hospitalization will be collected, including need for 


 
 
 
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supplemental oxygenation, mechanical ventilation, days of hospitalization and ventilation, and 
death. 
Serious AEs of worsening COVID-19, with the exception of death, will be considered disease 
progression and will not be collected for the safety database. 
7.2.2. 
Pregnancy 
Female patients of childbearing potential will have a pregnancy test during Screening/Baseline 
and at the Day 28 Follow-up/EOS. 
Urine pregnancy test must be performed but may be confirmed with a serum pregnancy test 
(screening only). The Follow-up/EOS test will be a urine pregnancy test only (pregnancy test kit 
will be provided to the patient). 
Following administration of study treatment, any pregnancy in a patient who is a female of 
childbearing potential or female partner of a male patient will be reported if known until the 
completion of pregnancy provided that the patient agrees and all the outcome are assessed. The 
pregnancy will be reported immediately by telephone and by faxing a completed pregnancy 
report to the Sponsor (or designee) within 24 hours of knowledge of the event. The pregnancy 
will not be processed as an SAE; however, the Investigator will follow the patient until 
completion of the pregnancy and must assess the outcome in the shortest possible time. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. 
The Investigator should notify the Sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy meets the criteria for 
immediate classification of an SAE (e.g., spontaneous or therapeutic abortion [any congenital 
anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, or 
congenital anomaly), the Investigator will report the event by telephone and by faxing a 
completed SAE form to the Sponsor (or designee) within 24 hours of knowledge of the event. 
7.3. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times 
indicated in the Schedule of Assessments in Appendix 4. Clinical laboratory evaluations are as 
listed in Appendix 2. Additional clinical laboratory evaluations will be performed at other times 
if judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Screening/Baseline laboratory tests will be assessed by a local laboratory for eligibility criteria 
and a central laboratory. An Investigator (or designee) will perform a clinical assessment of all 
reported clinical laboratory data. 


 
 
 
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7.4. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
7.4.1. 
Vital Signs 
Pulse oximetry will be measured as a safety assessment, with saturation <90% triggering a 
telemedicine assessment.  
7.4.2. 
Physical Examination 
Not applicable. 
7.5. 
Pharmacokinetic Assessments  
Dalcetrapib concentrations will be determined in the PK samples collected according to the 
Schedule of Assessments (Appendix 4). 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Full details of the analytical method used will be described in a separate Bioanalytical Validation 
Report. 


 
 
 
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8. SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of Sample Size 
The purpose of the proof-of-concept study is to identify whether there is sufficient promise of 
efficacy to justify conducting a Phase 3 study in a larger sample size and to determine efficacious 
dose to be used in Phase 3. While the entirety of data will be considered at the end of study, the 
sample size has been chosen to ensure that a positive trend will be present with alpha of 0.2 
when considering the two highest doses combined compared to placebo. One-hundred twenty-
seven (127) resolution events provides 80% power to demonstrate a positive trend if the average 
HR of the two dalcetrapib groups is 1.4 relative to placebo. Allowing for 20% of patients not 
resolving, 208 patients (52 per treatment arm) will be enrolled. One interim analysis will be 
conducted once 97 resolution events have occurred to allow 73 resolution events to have 
occurred in the two highest dose levels and placebo arm. At the interim analysis, if the average 
HR of the two highest dose levels relative to placebo is greater than 1.45, the study will stop due 
to efficacy and the program will be able to proceed directly to Phase 3. At the interim analysis, if 
the average HR of the two highest dose levels relative to placebo is between 1.0 and 1.45, the 
study will continue enrollment until 169 resolution events have occurred. At the interim analysis, 
if the average HR of the two highest dose levels is less than 1.0, the study will be stopped for 
lack of efficacy. The final analysis will be performed at an alpha of 0.186. These boundaries 
were determined by setting the efficacy boundary to follow the power family boundary with ρ=2 
and the futility boundary is manually set to HR=1. 
8.2. 
Analysis Populations 
8.2.1. 
Intent-to-Treat Population 
The Intent-To-Treat Population will include all participants who received at least 1 dose of study 
drug. Participant data will be summarized by treatment assigned. 
8.2.2. 
Per Protocol Population 
The Per Protocol (PP) Population will include all participants from the ITT population who have 
no important study protocol deviations during the study and who received at least 1 dose of study 
drug. Patients with any important protocol deviations shall be excluded from the PP population 
prior to database lock. 
8.2.3. 
Safety Population 
The Safety Population will include all participants who received at least 1 dose of study drug. 
Participant data will be summarized by actual treatment received. 
8.2.4. 
Pharmacokinetic Population 
The PK Population will include all participants who received at least 1 dose of study drug, had at 
least one measurable plasma concentrations, and had no protocol deviations thought to impact 
the PK of study drug. 


 
 
 
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8.3. 
General Considerations 
Continuous variables will be summarized by the standard descriptive statistics: number 
of patients (n), mean, standard deviation, median, minimum, and maximum for baseline 
variables, and n, mean, standard error, and confidence interval (CI) for outcome measures. 
Frequency of patient or events and percentages will be summarized for categorical variables. 
Time to event variables will be summarized using Kaplan-Meier methods. 
Unless otherwise specified, all regression models will be stratified by maximum symptom 
severity at baseline (presence vs absence of moderate or severe symptoms) and by age 
(≤65 years vs >65 years), and Wald p-values will be considered primary. 
The statistical analysis plan will be finalized prior to unblinding and it will include a more 
technical and detailed description of the statistical analyses. 
8.4. 
Efficacy Analysis 
The analysis of treatment efficacy will be based on the Intent-to-Treat Population. The PP 
population will be used for secondary analysis. This section is a summary of the planned efficacy 
analyses of the most important efficacy endpoints including primary and key secondary efficacy 
endpoints. 
8.4.1. 
Analysis of Primary Endpoints 
The primary analysis will be conducted when all patients have either withdrawn from the study, 
died, or been followed for at least 28 days (±2 days) since first dose on Day 1. 
8.4.1.1. 
Time to Sustained Clinical Resolution 
The primary endpoint is time to sustained clinical resolution as determined by symptom score. 
Sustained clinical resolution is defined in Section 7.1.1. The primary analysis of this endpoint 
will be performed on the ITT population. Time to sustained clinical resolution will be 
summarized by treatment group using Kaplan-Meier methods. Median and associated 95% CI, 
25-75 percentiles, and minimum and maximum values will be presented. The number and 
percentage of patients whose symptoms resolved, and patients censored will be presented. 
The differences in time to sustained clinical resolution between the treatment groups will be 
evaluated using a 2-sided log-rank test, stratified for baseline symptom severity (presence vs 
absence of moderate or severe symptoms) and by age (≤65 years vs >65 years). The combined 
two highest treatment groups will be compared to placebo in addition to the comparison of 
individual doses.  
8.4.2. 
Analysis of Secondary Efficacy Endpoints 
8.4.2.1. 
Time to Complete Clinical Resolution 
Time to complete clinical resolution will be analyzed using the same model as time to sustained 
clinical resolution, but with all symptoms required to have resolved to a score of 0 rather than 1. 


 
 
 
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8.4.2.2. 
Change from Baseline in COVID-19 Symptom Severity Score 
COVID-19 total symptom severity score will be summarized by treatment group using 
descriptive statistics (N, mean, median, standard deviation, minimum, and maximum) for each 
visit as well as for changes from baseline (N, mean, standard error, CI). A Mixed-Effect Model 
Repeated Measure (MMRM) will be performed to analyze the average difference between 
treatment groups over 28 days and at the designated assessment days. 
8.4.2.3. 
Scoring of WHO Clinical Outcome Scale (9-point Scale) 
The number and percentage of patients for each WHO clinical outcome score will be 
summarized. An ordinal logistic regression analysis for the specified time points will be 
presented as odds ratio, with associated 95% CI and p-value. 
8.4.2.4. 
Rate of Hospitalization Through Day 28 
The analysis of this endpoint will be performed on the ITT population. The number and 
percentage of patients who were hospitalized and reason for hospitalized will be presented. The 
percentage of patients who were hospitalized will be compared using a logistic regression 
analysis for specified time points. The results will be presented as odds ratios, with associated 
95% CIs and p-value. 
8.4.2.5. 
Rate of Progression to Oxygen Therapy Through Day 28 
The analysis of this endpoint will be performed on the ITT population. The number and 
percentage of patients who progress to oxygen therapy and type of oxygen therapy will be 
presented. The percentage of patients who had progressed to oxygen therapy will be compared 
using a logistic regression analysis for specified time points. The results will be presented as 
odds ratios, with associated 95% CIs and p-value. 
8.4.2.6. 
Duration of Hospitalization 
The duration of hospitalization will be performed on the ITT population. Duration of 
hospitalization will be summarized by treatment group using descriptive statistics (N, mean, 
median, standard deviation, standard error, CI, minimum, and maximum). Linear regression will 
be performed to analyze the difference between treatment groups. The results will be presented 
as mean treatment difference with associated 95% CI and p-value. 
8.4.2.7. 
Mortality Rate 
The analysis of this endpoint will be performed on the ITT population. The number and 
percentage of patients who died and reason for death will be presented. The percentage 
of patients who died will be compared using a logistic regression analysis for specified time 
points. The results will be presented as odds ratios, with associated 95% CIs and p-values. 


 
 
 
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8.4.2.8. 
Time to Viral Clearance Based on PCR Test for SARS-CoV-2 
The time to viral clearance based on PCR test for SARS-CoV-2 will be performed on the ITT 
population. Time to viral clearance will be summarized by treatment group using Kaplan-Meier 
methods. Median and associated 95% CI, 25-75 percentiles, and minimum and maximum values 
will be presented. The number and percentage of patients who do not show virus, show virus, 
and patients censored will be presented. 
8.4.2.9. 
Change from Baseline in log10 Viral Load 
The change from baseline in log10 viral load will be assessed at specified time points by a 
MMRM. Patients who have achieved a level below the limit of detection will be included in the 
analysis at half the lower limit of detection. For this endpoint, Last Observation Carried Forward 
(LOCF) will be used to impute values for all patients. The treatment effect for the difference at 
each time point, and the average slope up to each time point for each treatment group will be 
presented along with a 95% CI. 
8.5. 
Safety Analysis 
Safety variables include incidence of AEs (or TEAEs), laboratory test results, and vital signs. All 
safety analyses will be based on the Safety Population. No formal statistical analysis of the safety 
data will be performed. 
Adverse events will be coded according to MedDRA, version 23.0 released 19 Apr 2020 
(exclusively meant for COVID-19) or later. 
The number and percentage of patients with TEAEs, SAEs, TEAEs related to study treatment, 
SAEs related to study treatment, TEAEs leading to treatment discontinuation, TEAEs leading to 
study discontinuation, and TEAEs leading to death will be summarized by SOC, preferred term 
(PT), and treatment group. In addition, the severity of TEAEs and relationship to study treatment 
will be summarized by SOC, PT, and treatment group. 
The AE summary tables will include counts of patients. Therefore, if a patient experiences more 
than 1 episode of a particular AE, the patient will be counted only once for that event. If a patient 
has more than one AE that is coded to the same PT, the patient will be counted only once for that 
PT. Similarly, if a patient has more than 1 AE within a SOC, the patient will be counted only 
once in that SOC. 
Test values and change from baseline will be summarized descriptively by treatment group for 
specific laboratory test results and vital signs. Where applicable, shift tabulations will be 
presented for specific laboratory test results by treatment group. Where applicable, number and 
frequency of clinically significant abnormal values for specific laboratory test results will be 
presented. 
Pregnancy test results and patients with confirmed positive pregnancy test result will be listed. 


 
 
 
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8.6. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be determined using population PK modeling approach. The 
sparse PK samples will be pooled with PK data from other clinical studies for population PK 
analysis. PK profiles will be predicted and subsequently PK parameters will be estimated. 
Correlations between PK and pharmacodynamic (efficacy or safety) may be explored, including 
the relationship between drug exposure and viral elimination dynamics, if data permit. The 
methodology for PK analysis will be documented in a PK Analysis and Reporting Plan outside 
of this protocol. 
8.7. 
Interim Analysis 
One interim analyses will be conducted when 97 resolution events have occurred. 
8.8. 
Handling of Missing Data 
8.8.1. 
Imputation 
Severity Symptom Score: Missing values on severity symptom score will not be imputed. Where 
a patient has died, their status will not be considered missing, but will be imputed with maximum 
severity score at each timepoint. 
Clinical Outcome Scale: Missing values on clinical outcome scale will not be imputed. Where 
a patient has died, their status will not be considered missing, but will be imputed with maximum 
clinical outcome scale at each timepoint. 
8.8.2. 
Censoring 
Severity Symptom Score: For time to resolution, a patient will be censored if the patient has not 
had the required timepoint assessment if not due to death. If patient has died or received another 
antiviral therapy prior to the assessment endpoint, then the patient will be considered as having a 
moderate or severe COVID-19 symptom for all COVID-19 symptoms and imputed to maximum 
severity score at the assessment day. 
Viral Clearance: For time to viral clearance, a patient will be censored if the patient has not had 
the required timepoint assessment. 
8.9. 
Multiplicity/Multiple Testing 
The primary analysis compares the combined two highest dalcetrapib dose groups against 
placebo as well as each treatment group individually. For the purposes of inference, if the test of 
the combined two highest dose groups against placebo is significant at two-sided alpha of 0.05, 
then the individual doses will be compared against placebo following the Hochberg step-up 
procedure at two-sided alpha of 0.05. 


 
 
 
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9. REFERENCES 
1. Food and Drug Administration. Guidance for Industry, Investigators, and Institutional 
Review Boards: FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency [Internet]. Food and Drug Administration; 2020. 
Available from: https://www.fda.gov/media/136238/download. 
2. World Health Organization. WHO Director-General's opening remarks at the media 
briefing on COVID-19 - 11 March 2020. Available at: 
https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-
media-briefing-on-covid-19---11-march-2020. Accessed 31 March 2020. 
3. World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. 
Available at: 
https://covid19.who.int/?gclid=CjwKCAjwm_P5BRAhEiwAwRzSO9jpEwPeoHR8NmL
UmBMkH5BdQEdGyjVJa5ktZh6WxXPcKP3RaC2M_BoCO-UQAvD_BwE. Accessed 
22 October 2020. 
4. U.S. Department of Health and Human Services, Determination of a Public Health 
Emergency and Declaration that Circumstances Exist Justifying Authorizations Pursuant 
to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3. 
February 4, 2020. 
5. Schwartz GG, Olsson AG, Abt M, et al. Effects of Dalcetrapib in patients with a recent 
acute coronary syndrome. N Engl J Med. 2012; 367: 2089‐2099. 
6. RO4607381 (Dalcetrapib) Investigator’s Brochure, version 7.0. 21 October 2019. 
7. Dai W, et al. Structure-based design of antiviral drug candidates targeting the 
SARS-CoV-2 main protease. Science. 10.1126/science.abb4489 (2020). 
 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 46 of 59 
Protocol 
Covance Study: 8449008 
10. APPENDICES 


 
 
 
Final, 14 December 2020 
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Page 47 of 59 
Protocol 
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Appendix 1 – Adverse Event Definitions 
Definitions 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. This includes the following: 
 Any clinically significant worsening of a pre-existing condition. 
 Note: Emergence of a new pathogen associated with a clinical event during therapy at a 
site other than the initial site of infection will be considered to be an AE. 
 Any recurrence of a pre-existing condition. 
 An AE occurring from overdose of a Sponsor study drug whether accidental or 
intentional (i.e., a dose higher than that prescribed by a health care professional for 
clinical reasons). 
 An AE occurring from abuse of a Sponsor study drug (i.e., use for nonclinical reasons). 
 An AE that has been associated with the discontinuation of the use of a Sponsor study 
drug. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the patient signs the ICF and that is documented as part of the patient’s medical 
history. 
The questions concerning whether the condition existed before the start of the active phase of the 
study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is a treatment-emergent AE. An AE is considered to be treatment-emergent if 
(1) it is not present when the active phase of the study begins and is not a chronic condition that 
is part of the patient’s medical history, or (2) it is present at the start of the active phase of the 
study or as part of the patient’s medical history, but the severity or frequency increases during 
the active phase. The active phase of the study begins at the time of the first dose of the study 
drug. The active phase of the study ends at the Follow-up/EOS. 
Reporting of Adverse Events 
At each visit the Investigator, or delegate, will determine whether or not any AEs have occurred. 
Non-leading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the patient to report any possible AEs. If 
any AEs have occurred, they will be recorded in the AE section of the electronic Case Report 
Form (eCRF) and in the patient’s source documents. If known, the diagnosis should be recorded, 
in preference to listing the individual signs and symptoms. 


 
 
 
Final, 14 December 2020 
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Sponsor Reference: DAL-401 
Page 48 of 59 
Protocol 
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Adverse event reporting begins from the time of informed consent and ends 30 days after the last 
dose of study drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
 Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
 Moderate: Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the patient. 
 Severe: Interrupts usual activities of daily living, significantly affects clinical status, or 
may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The Investigator will make a determination of the relationship of the AE to the study drug using 
a four-category system according to the following guidelines: 
 Not related: when the AE is definitely caused by the patient’s clinical state, or the study 
procedure/conditions. 
 Unlikely Related: when the temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE. 
 Possibly Related: when the AE follows a reasonable temporal sequence from the time of 
drug administration but could have been produced by the patient’s clinical state or the 
study procedures/conditions. 
 Related: when the AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized cause-
effect relationship, and (if appropriate) reappears when the drug is reintroduced. 
Action Taken for Adverse Events 
The Investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
 Dose increased: The medication schedule was modified by addition, either by changing 
the frequency, strength, or amount. 
 Dose not changed: The medication schedule was not changed. 


 
 
 
Final, 14 December 2020 
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Sponsor Reference: DAL-401 
Page 49 of 59 
Protocol 
Covance Study: 8449008 
 Dose reduced: The medication schedule was modified by subtraction, either by changing 
the frequency, strength, or amount. 
 Drug interrupted: The medication schedule was modified by temporarily terminating 
the prescribed regimen of medication. 
 Drug withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication. 
 Not applicable 
 Unknown 
Follow-up of Adverse Events 
All (S)AEs that are ongoing at the time of discontinuation, or that develop prior to the final 
follow-up telephone call, will be followed for 28 days, or until resolution or stabilization. 
Adverse Drug Reactions 
All noxious and unintended responses to an investigational medicinal product (i.e., where a 
causal relationship between an investigational medicinal product and an AE is at least a 
reasonable possibility) related to any dose should be considered adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or 
for modification of physiological function, is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g., Investigator’s Brochure for 
an unapproved IMP). 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
 Results in death 
 Is life-threatening (see below) 
 Requires patient hospitalization or prolongation of an existing hospitalization (see below) 
 Results in a persistent or significant disability or incapacity (see below) 
 Results in a congenital anomaly or birth defect 
 Results in an important medical event (see below) 


 
 
 
Final, 14 December 2020 
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Page 50 of 59 
Protocol 
Covance Study: 8449008 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not require hospitalization, or development of drug dependency or drug abuse. 
A life-threatening adverse event is any AE that places the patient at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might have 
caused death had it occurred in a more severe form but that did not create an immediate risk of 
death as it actually occurred. For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening, even though drug-induced hepatitis 
of a more severe nature can be fatal. Hospitalization is to be considered only as an overnight 
admission. 
Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious. In the absence of an AE, the participating Investigator should not report hospitalization 
or prolongation of hospitalization. This is the case in the following situations: 
 Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol. Day or night survey visits for biopsy or surgery required by the protocol are 
not considered serious. 
 Hospitalization or prolongation of hospitalization is part of a routine procedure followed 
by the study center (e.g., stent removal after surgery). This should be recorded in the 
study file. 
 Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study). 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (i.e., the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the patient’s bodily function/structure, physical activities, or quality of 
life). 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life-threatening or 
result in death, hospitalization, disability, or incapacity. These include events that may jeopardize 
the patient or may require medical intervention to prevent one or more outcomes listed in the 
definition of serious. Such events should usually be considered as serious. 
 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 51 of 59 
Protocol 
Covance Study: 8449008 
Appendix 2 – Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed: 
Chemistry(Chem-20): 
Hematology (CBC): 
Albumin 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
Blood urea nitrogen 
MCV 
Calcium 
Platelet count  
Chloride 
Red blood cell (RBC) count 
Cholesterol 
White blood cell (WBC) count 
Creatinine 
WBC differential 
Gamma glutamyl transferas 
(Percent and Absolute): 
Glucose 
Basophils 
Lactate dehydrogenase 
Eosinophils 
Phosphorus 
Lymphocytes 
Potassium 
Monocytes 
Sodium 
Neutrophils 
Total Bilirubin 
 
Total CO2 (measured as bicarbonate) 
For women of childbearing potential only: 
Total Protein 
Urine Pregnancy Test  
Triglycerides 
 
Uric acid 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete 
blood count; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 52 of 59 
Protocol 
Covance Study: 8449008 
Appendix 3 – Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
 Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
 Applicable laws and regulations 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an Institutional Review 
Board (IRB)/EC by the Investigator and reviewed and approved by the IRB/EC before the study 
is initiated. 
 Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC 
 Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC 
procedures 
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each patient will be provided with a study-specific ICF 
giving details of the study drugs, procedures, and potential risks of the study. Patients will be 
instructed that they are free to obtain further information from the Investigator (or designee) and 
that their participation is voluntary and they are free to withdraw from the study at any time. 


 
 
 
Final, 14 December 2020 
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Sponsor Reference: DAL-401 
Page 53 of 59 
Protocol 
Covance Study: 8449008 
Patients will be given an opportunity to ask questions about the study prior to providing consent 
for participation. 
Electronic informed consent will be obtained from the patients or their legally authorized 
representative that meets the requirements of local regulations, ICH guidelines, and the IRB/EC 
or study center, where applicable. The patient will be given a copy of the electronic informed 
consent, and the original will be maintained with the patient’s records. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
Patient Data Protection 
Patients will be assigned a unique identifier and will not be identified by name in electronic Case 
Report Forms (eCRFs), study-related forms, study reports, or any related publications. Patient 
and Investigator personal data will be treated in compliance with all applicable laws and 
regulations. In the event the study protocol, study report, or study data are included in a public 
registry, all identifiable information from individual patients or Investigators will be redacted 
according to applicable laws and regulations. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. The patient must also be informed that his/her medical records may be examined by 
Sponsor or CRO auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/EC members, and by inspectors from regulatory authorities. 
Committees Structure 
A DMC will review safety data throughout the study. The DMC will review efficacy data as 
detailed in the protocol and DMC Charter. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
 All patient data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 


 
 
 
Final, 14 December 2020 
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Sponsor Reference: DAL-401 
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Protocol 
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 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
 The Investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. Pre-defined, agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data 
may be included in a Data Management Plan. 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including electronic informed consent, pertaining to the conduct 
of this study must be retained by the Investigator in accordance with 21 CFR 312.62(c) 
(US site) or in the study site archive for at least 5 years after the end of the study (UK 
site) unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
Investigator Documentation Responsibilities 
All individual, patient-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture system on an eCRF in a timely fashion. All data generated from external 
sources (e.g., central laboratory, pharmacokinetics, pharmacodynamics, electrocardiogram 
central readers) and transmitted to the Sponsor or designee electronically will be integrated with 
the patient’s eCRF data in accordance with the Data Management Plan. 
An eCRF must be completed for each patient who signs an ICF and undergoes any pre-screening 
or screening procedures, according to the eCRF completion instructions. The Sponsor, or CRO, 
will review the supporting source documentation against the data entered into the eCRFs to 
verify the accuracy of the electronic data. The Investigator will ensure that corrections are made 
to the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the electronic data capture system’s electronic 
signature procedure. These signatures will indicate that the Investigator reviewed and approved 
the data on the eCRF, the data queries, and the site notifications. 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 55 of 59 
Protocol 
Covance Study: 8449008 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical study 
agreement. Unless otherwise specified in the clinical study agreement, the following process 
shall occur: 
The institution and Investigator shall not publish or present data from an individual study center 
until the complete multicenter study has been presented in full or for 2 years after the termination 
of the multicenter study, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the Investigator expects to participate in the publication of 
data generated from this site, the institution and Investigator shall submit reports, abstracts, 
manuscripts, and/or other presentation materials to the Sponsor for review before submission for 
publication or presentation. The Sponsor shall have 60 days to respond with any requested 
revisions, including (without limitation) the deletion of confidential information. The 
Investigator shall act in good faith upon requested revisions, except the Investigator shall delete 
any confidential information from such proposed publications. The Investigator shall delay 
submission of such publication or presentation materials for up to an additional 90 days in order 
to have a patent application(s) filed. 
 
 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 56 of 59 
Protocol 
Covance Study: 8449008 
Appendix 4 – Schedule of Assessments 
Table 5: 
Schedule of Assessments 
Study Period 
Screening/ 
Baseline 
Treatment Period 
Follow-up 
Visit 1 
Follow-up/EOS 
Visit 2 
Study Day 
-2 to -1a 
1 
3 
5 
7 
EOT 
10 
14 ± 2 days 
28 ± 2 days 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationb 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
SARS-CoV-2 testc 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Pregnancy test (urine) 
X 
 
 
 
 
 
 
X 
COVID-19 symptoms ePRO assessmentd 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
 
 
 
 
 
 
 
 
Clinical improvement score (WHO COVID-19 Clinical 
Improvement Ordinal Scale)e 
X 
X 
X 
X 
 
X 
 
X 
Confirm setting (outpatient, in hospital) 
X 
 
X 
 
X 
 
X 
X 
Saliva (Oragene)f 
X 
X 
X 
X 
X 
X 
 
X 
Mid-turbinate nasal swabf 
X 
X 
X 
X 
X 
X 
 
X 
Safety 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory assessments 
X 
 
 
 
 
X 
 
X 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
 
 
 
 
PK samplingg 
 
 
 
 
 
X 
 
 
Other 
 
 
 
 
 
 
 
 
Patient training on use of ePRO and pulse oximeter and 
swab self-collection 
X 
 
 
 
 
 
 
 
Dispense study drug 
X 
 
 
 
 
 
 
 
Study drug administrationh 
 
X 
X 
X 
X 
X 
 
 
Return unused treatment 
 
Xi 
 
 
 
X 
 
 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 57 of 59 
Protocol 
Covance Study: 8449008 
COVID-19 = Coronavirus disease of 2019; EOS = end of study; EOT = end of treatment; PCR = polymerase chain reaction; PK=pharmacokinetic; ePRO = electronic patient-
reported outcome; SARS-CoV-2= Severe Acute Respiratory Syndrome CoronaVirus 2; WHO = World Health Organization 
Note that any visits other than Screening/Baseline may be conducted via telephone or digital media. Missed samples/assessments when phone visits occur will not be counted as 
protocol deviations. Safety laboratory samples for hematology and chemistry, and study drug accountability, are obtained via a site visit or home visit by a healthcare professional. 
a. 
Screening/Baseline assessments may all be performed on the same calendar day and should be performed at the study site or as a home visit within 72 hours of first dose. 
Baseline assessments that are also performed at Screening do not need to be repeated if on the same calendar day. Study drug should be dispensed at the Screening/Baseline 
visit and only taken after the Day 1 virtual visit confirming the positive COVID-19 test has occurred. If the PCR test is negative or laboratory results exclude the patient, they 
will not to take the first dose of study drug and be withdrawn from the study. 
b. 
Patients will be randomized to receive either 900, 1800, or 3600 mg of dalcetrapib treatment or placebo. 
c. 
The entry testing is performed locally based on testing methods available at the site, such as PCR or rapid antigen test. 
d. 
Patients must have at least two mild to moderate signs or symptoms of COVID-19, as described in the inclusion criteria, with onset within 5 days of first dose on Day 1. 
Symptoms will be assessed daily for the first 10 days, then at Day 14 and Day 28 and as clinically indicated. 
e. 
Dates of change in WHO scale status between visits will be recorded over the course of the 28-day study period. 
f. 
SARS-CoV-2 viral loads will be obtained by both saliva (Oragene) and mid-turbinate nasal swab self-collected under supervision of a healthcare professional at 
Screening/Baseline, Day 1, Day 3, Day 5, Day 7, Day 10, and Day 28. 
g. 
Two PK samples will be collected on Day 10, one at predose and one at postdose in a sampling window of 0-2, 2-4, 4-6, 6-10, or 10-24 hours postdose. Patients will be evenly 
randomized to one of the sampling windows on Day 10. 
h. 
Study drug is self-administered as once daily oral tablets on Days 1 to 10. 
i. 
In case of screen failure only. 


 
 
 
Final, 14 December 2020 
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Sponsor Reference: DAL-401 
Page 58 of 59 
Protocol 
Covance Study: 8449008 
Appendix 5 – Contraceptive Guidance 
Definitions 
Female Patients of Childbearing Potential: Premenopausal female study patients who are 
anatomically and physiologically capable of becoming pregnant following menarche. 
Female Patients of Nonchildbearing Potential: 
1. Surgically sterile: Female study patients who are permanently sterile via 
hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy by reported 
medical history and/or medical records. Surgical sterilization to have occurred a 
minimum of 6 weeks, or at the Investigator’s discretion, prior to screening. 
2. Postmenopausal: Female study patients who are at least 1 year postmenopausal. 
Fertile male: A male that is considered fertile after puberty. 
Infertile male: Permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Patients 
Female patients who are of nonchildbearing potential will not be required to use contraception. 
Female patients of childbearing potential must be confirmed as not being pregnant at 
Screening/Baseline and be willing to use an acceptable highly-effective method of birth control 
from the time of informed consent until 90 days after the last dose of study treatment. Acceptable 
methods of contraception include: 
 Hormonal injection (as prescribed) 
 Combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
 Combined hormonal patch (as prescribed) 
 Combined hormonal vaginal ring (as prescribed) 
 Surgical method performed at least 90 days prior to the screening visit: 
o Bilateral tubal ligation 
o Essure (hysteroscopic bilateral tubal occlusion) with confirmation of occlusion of 
the fallopian tubes 
 Hormonal implant 
 Hormonal or nonhormonal intrauterine device 
 Vasectomized male partner (sterilization performed at least 90 days prior to the screening 
visit) with verbal confirmation of surgical success, and the sole partner for the female 
patient. 


 
 
 
Final, 14 December 2020 
CONFIDENTIAL 
Sponsor Reference: DAL-401 
Page 59 of 59 
Protocol 
Covance Study: 8449008 
Female patients of childbearing potential should refrain from donation of ova from the first dose 
through 90 days after the last dose of study treatment. 
Male Patients 
Male patients (even with a history of vasectomy) with partners of childbearing potential must use 
a male barrier method of contraception (i.e., male condom with spermicide) in addition to a 
second highly effective method of acceptable contraception from the first dose through 90 days 
after the last dose of study treatment. Acceptable methods of contraception for female partners 
include: 
 Hormonal injection 
 Combined oral contraceptive pill or progestin/progestogen-only pill 
 Combined hormonal patch 
 Combined hormonal vaginal ring 
 Surgical method (bilateral tubal ligation or Essure [hysteroscopic bilateral tubal 
occlusion]) 
 Hormonal implant 
 Hormonal or nonhormonal intrauterine device. 
An acceptable second method of contraception for male patients is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male patients (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the first dose 
until 90 days after the last dose of study treatment. Male patients are required to refrain from 
donation of sperm from the first dose through 90 days after the last dose of study treatment. 
Sexual Abstinence and Same-sex Relationships 
Patients who practice true abstinence, because of the patient’s lifestyle choice (i.e., the patient 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a patient 
who is abstinent at the time of informed consent becomes sexually active, he or she must agree to 
use contraception as described previously. 
For patients who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a patient who is in a same-sex relationship at the time of informed consent becomes 
engaged in a heterosexual relationship, he or she must agree to use contraception as described 
previously. 

SAP_001.pdf: 
 
BS-T1-001-05 
Confidential 
Page 1 of 29 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 Protocol number: DAL-401 
 
 
A Double-blind, Placebo-controlled, Phase 2a Proof-of-concept Trial of Dalcetrapib in Patients with 
Confirmed Mild to Moderate COVID-19 
 
 
 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
30-APR-2021 
Amendment 1:  
01-JUN-2021 
 
 
Prepared by: 
Anna Nozza, M.Sc. 
Senior biostatistician 
Montreal Health Innovations Coordinating Center (MHICC) 
5000 Bélanger Street 
Montréal, QC  H1T 1C8 
Phone: 514-461-1300 ext. 2136 / Fax: 514-461-1301 
 
 
 
 
 


 
SAP: 01-JUN-2021 / Amendment 1 
Protocol Number: DAL-401 
 
BS-T1-001-05 
Confidential 
Page 2 of 29 
Signature Approval Page 
 
 
By signing below, I indicate that I have reviewed the Statistical Analysis Plan in its entirety and approve its 
contents. 
 
 
Signature: 
 
 
Date: 
 
 
Guy Boivin, MD 
Principal Investigator 
CHU de Québec-Université Laval Research 
 
 
(DD-MMM-YYYY) 
Signature: 
 
 
Date: 
 
 
David Kallend, MBBS 
Chief Scientific Officer  
DalCor Pharmaceuticals  
 
 
(DD-MMM-YYYY) 
Signature: 
 
 
Date: 
 
 
Marie-Claude Guertin, Ph. D. 
Lead, Biostatistics 
MHICC  
 
 
(DD-MMM-YYYY) 
 
 
 
 
 


 
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Revision History 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
Final 
30-APR-2021 
Anna Nozza 
Initial version 
Amendment 1 
01-JUN-2021 
Anna Nozza 
Section 3: Sentence saying that populations of 
analysis will be confirmed by the sponsor 
added, details on the per-protocol population 
added and formula for number of days on 
study medication corrected to add 1 day.  
 
Section 6.2.2.1: Maximum clinical outcome 
scale for imputation corrected to be 7 
(maximum severity if alive) or 8 (maximum 
severity if dead). Imputation method for non-
numeric viral load results added.  
 
Section 6.4.2.1: Classification of day of 
assessment into visit identifiers added.  
 
Section 6.4.2.2: Details on the calculation of 
the area under the curve added. 
 
Section 6.4.3.4: Classification of day of 
assessment into visit identifiers added.  
 
Section 6.5.1: Formula for duration of 
exposure corrected to add 1 day. 
 
Section 7: Numbering of tables corrected. 
 
Appendix 2 with the algorithm to classify day 
of assessment added. 
 
Clarifications throughout the text that Day 1 
corresponds to date of first dose and other 
minor corrections regarding visit names 
added. 
 
References to figures and listings corrected 
throughout the text. 
 
 
 


 
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TABLE OF CONTENTS  
 
1 
Introduction ......................................................................................................................................... 7 
2 
Study Description ................................................................................................................................. 7 
2.1 
Study Design ................................................................................................................................ 7 
2.2 
Study Objectives .......................................................................................................................... 8 
3 
Datasets Analyzed ................................................................................................................................ 9 
3.1 
Intent-To-Treat (ITT) Population ................................................................................................. 9 
3.2 
Per-Protocol Population .............................................................................................................. 9 
3.3 
Safety Population ........................................................................................................................ 9 
4 
Efficacy Endpoints ................................................................................................................................ 9 
4.1 
Primary Efficacy Endpoint............................................................................................................ 9 
4.2 
Secondary Efficacy Endpoints .................................................................................................... 10 
5 
Safety Parameters .............................................................................................................................. 11 
5.1 
Adverse Events .......................................................................................................................... 11 
5.2 
Serious Adverse Events.............................................................................................................. 12 
5.3 
Laboratory Parameters .............................................................................................................. 12 
5.4 
Other Safety Parameters ........................................................................................................... 13 
6 
Statistical Methodology ..................................................................................................................... 13 
6.1 
Determination of Sample Size ................................................................................................... 13 
6.2 
Statistical Considerations .......................................................................................................... 13 
6.2.1 
Interim Analysis ..................................................................................................................... 14 
6.2.2 
Handling of Missing Data ...................................................................................................... 14 
6.2.2.1 
Imputation .................................................................................................................... 14 
6.2.2.2 
Censoring ...................................................................................................................... 14 
6.2.3 
Multiplicity/Multiple Testing ................................................................................................. 15 
6.3 
Study Subjects ........................................................................................................................... 15 
6.3.1 
Subject Disposition ................................................................................................................ 15 
6.3.2 
Protocol Deviations ............................................................................................................... 15 
6.3.3 
Datasets Analyzed ................................................................................................................. 15 
6.3.4 
Demographic and Baseline Characteristics ........................................................................... 15 
6.3.5 
Treatment Compliance .......................................................................................................... 16 
6.3.6 
Prior and Concomitant Medications ..................................................................................... 16 
6.4 
Efficacy Analysis ......................................................................................................................... 17 
6.4.1 
Primary Analysis .................................................................................................................... 17 
6.4.2 
Key Secondary Analysis ......................................................................................................... 17 
6.4.2.1 
Change from Baseline in log10 Viral Load .................................................................... 18 
6.4.2.2 
AUC in log10 Viral Load ................................................................................................ 18 
6.4.2.3 
Time to Sustained Clinical Resolution .......................................................................... 18 
6.4.3 
Other Secondary Analysis ..................................................................................................... 18 
6.4.3.1 
Time to Viral Clearance Based on PCR Test for SARS-CoV-2 ........................................ 19 
6.4.3.2 
Time to Complete Clinical Resolution (excluding cough, sense of taste and smell) .... 19 
6.4.3.3 
Time to Complete Clinical Resolution .......................................................................... 19 
6.4.3.4 
Change from Baseline in COVID-19 Total Symptom Score ........................................... 19 
6.4.3.5 
Scoring of WHO Clinical Outcome Scale (9-point Scale) .............................................. 20 
6.4.3.6 
Rate of Hospitalization Through Day 28 ....................................................................... 20 


 
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6.4.3.7 
Rate of Progression to Oxygen Therapy Through Day 28 ............................................ 20 
6.4.3.8 
Duration of Hospitalization .......................................................................................... 20 
6.4.3.9 
Mortality Rate ............................................................................................................... 21 
6.4.4 
Sensitivity Analysis ................................................................................................................ 21 
6.4.5 
Subgroup Analysis ................................................................................................................. 21 
6.5 
Safety Analysis ........................................................................................................................... 21 
6.5.1 
Treatment Exposure .............................................................................................................. 21 
6.5.2 
Adverse Events and Serious Adverse Events ......................................................................... 22 
6.5.2.1 
Adverse Events ............................................................................................................. 22 
6.5.2.2 
Serious Adverse Events ................................................................................................ 22 
6.5.3 
Laboratory Parameters ......................................................................................................... 23 
6.5.4 
Other Safety Parameters ....................................................................................................... 23 
7 
Summary Tables, Figures and Listings ................................................................................................ 23 
8 
References .......................................................................................................................................... 27 
9 
Appendices ......................................................................................................................................... 28 


 
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LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area under the curve 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
eCRF 
Electronic Case Report Form 
ECMO 
Extracorporeal Membrane Oxygenation  
ePRO 
Electronic Patient Reported Outcome 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma Glutamyl Transferase 
ITT 
Intent To Treat 
LDH 
Lactate Dehydrogenase 
LOCF 
Last Observation Carried Forward 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MHICC 
Montreal Health Innovations Coordinating Center 
PCR 
Polymerase Chain Reaction 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome CoronaVirus 2 
SOC 
System Organ Class (MedDRA classification) 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


 
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1 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to present the statistical methodology that will be 
used for the final analysis of DalCor Pharmaceuticals DAL-401. This plan also provides a description of 
the tables, figures and listings that will be included in the final statistical report. It is based on the 
protocol dated 22-OCT-2020 and on the annotated case report form (CRF) version 1.0. In case of 
differences in terms of descriptions or explanations between the SAP and the clinical protocol, the SAP 
will supersede the protocol. Any deviation to this SAP would be reported in the statistical report. 
 
Since the protocol was developed and discussed with the regulatory authorities, a greater understanding 
of COVID-19 and clinical trials in COVID-19 has emerged. New variants have also been observed and their 
clinical course needs to be taken into consideration. Based on this emerging knowledge, a higher emphasis 
will be placed on viral load analyses when interpreting the data and deciding on POC in this study. Less 
emphasis will therefore be placed on the current primary endpoint of Patient Reported Outcomes and 
endpoints that look at changes in symptoms of COVID-19. Certain symptoms such as loss of taste and loss 
of smell as well as cough are chronic symptoms which may not resolve over the course of a 28-day study. 
In view of this the endpoints evaluating symptoms will not include taste, smell or cough in some analyses. 
 
2 
STUDY DESCRIPTION 
 
2.1 
Study Design 
 
This is a randomized, double-blind, multicenter Phase 2a proof-of-concept study in outpatients with 
confirmed, mild to moderate, symptomatic COVID-19. Electronic informed consent must be obtained 
from all patients or their legally authorized representative during screening before any study-related 
procedures are performed. The Screening/Baseline assessments may be performed at the study site or 
as a home visit. 
A total of 208 patients will be randomized to receive 900, 1800, or 3600 mg of dalcetrapib or placebo 
once daily (52 patients to each of 900 mg, 1800 mg, 3600 mg and placebo) for 10 days. Patients will be 
randomized and receive first dose of study drug within 72 hours of receiving a positive PCR or Point-of-
care test for SARS-CoV-2. Patients need to have at least two of the 14 common COVID-19-related 
symptoms described in the inclusion criteria rated as mild or moderate, as evaluated by ePRO 
assessment or eCRF. Symptoms will be assessed at each study visit daily for the first 10 days, then at 
Day 14 and Day 28, and as clinically indicated. Symptoms will be evaluated as absent, mild, moderate, or 
severe depending on their impact on activities of daily living. SARS-CoV-2 viral loads will be obtained by 
both saliva (Oragene) collection and mid-turbinate nasal swab self-collection under supervision of a 
healthcare professional (virtual or home visit) at Screening/Baseline, Day 1, Day 3, Day 5, Day 7, Day 10, 
and Day 28. Patients who require hospitalization after initiation of study treatment will be followed for 
safety assessment through Day 28. 
The study will be overseen by an independent Data Monitoring Committee (DMC). The DMC will review 
the safety data throughout the study. The DMC and Sponsor will review efficacy data at the interim 
analysis and at the end of the study. A DMC Charter, which includes detailed processes, will be 
prepared. One interim analysis will be conducted once 120 patients have a follow-up time of 28 days. 
All patients will be closely monitored for adverse events (AEs) from informed consent for at least 
18 days after the final dose of study treatment (until Day 28±2). Patients who withdraw early from the 


 
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study treatment will have follow-up phone calls to collect safety data until End of Study on Day 28±2. 
On days of laboratory assessments and PK sample collection, outpatient subjects may have a home visit. 
 
2.2 
Study Objectives 
 
The primary efficacy objective of the study is: 
• 
To evaluate the time to sustained clinical resolution of symptoms (excluding cough, sense of smell 
and taste) in patients with confirmed, mild to moderate, symptomatic COVID-19 treated with 
dalcetrapib. 
The key secondary efficacy objectives of the study are: 
• 
To evaluate change from baseline in log10 viral load 
• 
To evaluate the time to sustained clinical resolution of symptoms in patients with confirmed, mild 
to moderate, symptomatic COVID-19 treated with dalcetrapib. 
Other secondary efficacy objectives of the study are: 
• 
To evaluate the time to viral clearance using SARS-CoV-2 polymerase chain reaction (PCR) 
• 
To evaluate time to complete clinical resolution of symptoms (excluding cough, sense of smell 
and taste), defined in the same way as the primary endpoint, but considering that all symptoms  
must resolve to a score of 0 for 72 hours 
• 
To evaluate time to complete clinical resolution of symptoms considering that all symptoms 
must resolve to a score of 0 for 72 hours 
• 
To evaluate the change from baseline in COVID-19 total symptom score at all collected time 
points 
• 
To evaluate the WHO Clinical Outcome Scale (9-point scale) at Day 3, Day 5, Day 10, Day 14 and 
Day 28 
• 
To evaluate the rate of hospitalization through Day 28 
• 
To evaluate the rate of progression to oxygen therapy through Day 28 
• 
To evaluate the duration of hospitalization 
• 
To evaluate the mortality rate by Day 28 
The safety objective of the study is: 
• 
To assess the safety and tolerability of dalcetrapib active doses compared to placebo in patients 
with COVID-19 


 
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The pharmacokinetics (PK) objective of the study is: 
• 
To evaluate the PK of dalcetrapib in patients with COVID-19. The methodology for PK analysis 
will not be documented in this SAP but in a separate PK plan.   
 
3 
DATASETS ANALYZED 
 
Subjects who were not eligible for randomization but who have been erroneously randomized into the 
study will be excluded from all datasets analyzed, if they did not receive study product.  
 
The populations of analysis will be reviewed and confirmed by the sponsor prior to database lock. 
 
3.1 
Intent-To-Treat (ITT) Population  
The Intent-To-Treat Population will include all participants who were randomized [a randomization 
number is provided in the eCRF Form “Randomization”] and received at least 1 dose of study drug [as 
confirmed in the eCRF Form “Study Drug Administration”] and not reported as a screen failure [in the 
eCRF Form “Disposition-Study Completion” ]. Participant data will be summarized by treatment 
assigned. 
 
3.2 
Per-Protocol Population 
 
The Per Protocol (PP) Population will include all participants from the ITT population who have no 
important study protocol deviations during the study. Because the number of days on study medication 
is likely to impact the efficacy endpoints, patients who will deviate from the protocol by not taking study 
medication at least 5 days (as assessed by the difference between date of study treatment last dose – 
date of study treatment first dose + 1 day) will be excluded. These patients shall be excluded from the 
PP population prior to database lock. 
 
3.3 
Safety Population 
 
The Safety Population will include all participants who received at least 1 dose of study drug. Participant 
data will be summarized by actual treatment received. 
 
4 
EFFICACY ENDPOINTS 
 
 
4.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is: 
• 
Time to sustained clinical resolution of symptoms (excluding cough, sense of smell and taste) 


 
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Sustained clinical resolution is defined as occurring when no key COVID-19 related symptom (excluding 
cough, sense of smell and taste) has a score higher than 1 over a 72-hour period (as documented using 
an electronic patient-reported outcome [ePRO] instrument or in the eCRF),. The time to resolution will 
be taken as the time from randomization until the first day of the last 72-hour period where the patient 
meets the definition of resolution within 28 days. Patients who do not meet the definition of resolution 
28 days after randomization will be considered not resolved.   
The classification of sustained clinical resolution of symptoms (excluding cough, sense of smell and 
taste) follows similar steps as the algorithm presented in Appendix 1. 
 
4.2 
Secondary Efficacy Endpoints 
 
The key secondary efficacy endpoints are: 
• 
Change from baseline in log10 viral load, as measured using saliva and as measured using nasal 
swab. Changes will be calculated as value at follow-up visits – value at baseline. 
• 
Time to sustained clinical resolution of symptoms. 
Sustained clinical resolution is defined as occurring when no key COVID-19 related symptom has 
a score higher than 1 over a 72-hour period (as documented using an electronic patient-
reported outcome [ePRO] instrument or in the eCRF), except for sense of smell and taste (items 
13 and 14) where the score should be 0 over a 72-hour period. The time to resolution will be 
taken as the time from randomization until the first day of the last 72-hour period where the 
patient meets the definition of resolution within 28 days. Patients who do not meet the 
definition of resolution 28 days after randomization will be considered not resolved.  
Refer to the algorithm in Appendix 1 for the derivation of this endpoint. 
Other secondary efficacy endpoints are: 
• 
Time to viral clearance based on PCR test for SARS-CoV-2, as measured using saliva and as 
measured using nasal swab 
• 
Time to complete clinical resolution of symptoms (excluding cough, sense of smell and taste) 
Clinical resolution is defined in the same way as the primary endpoint, but considering that all 
symptoms (excluding cough, sense of smell and taste) must resolve to a score of 0 for 72 hours.  
• 
Time to complete clinical resolution of symptoms 
Clinical resolution is defined as occurring when all key COVID-19 related symptom must resolve 
to a score of 0 for 72 hours.  
The derivation of this endpoint follows similar steps as the algorithm presented in Appendix 1. 
• 
Change from baseline in COVID-19 total symptom score 


 
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Total symptom score is defined as the sum [range 0-42] of the scores of all 14 common COVID-
19 symptoms. 
• 
Score on the WHO Clinical Outcome Scale (9-point scale) [as collected on eCRF Form “WHO 
COVID-19 Clinical Improvement Score”] 
• 
Rate of hospitalization [hospitalization will be identified in the eCRF Form “Adverse Event” if 
adverse event is serious and serious category is Hospitalization or prolonged hospitalization] 
• 
Rate of progression to oxygen therapy [progression to oxygen therapy will be identified in the 
eCRF Form “Adverse Event” if event requires supplemental oxygenation or mechanical 
ventilation or extracorporeal membrane oxygenation] 
• 
Duration of hospitalization [duration will be identified in the eCRF Form “Adverse Event” as the 
difference between date of discharge and date of admission] 
• 
Mortality rate [death will be identified in the eCRF Form “Adverse Event” if outcome of adverse 
event is fatal] 
 
5 
SAFETY PARAMETERS 
 
Safety variables include incidence of AEs (or TEAEs), laboratory test results and vital signs.  
 
5.1 
Adverse Events 
 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. This includes the following: 
• 
Any clinically significant worsening of a pre-existing condition. 
• 
Note: Emergence of a new pathogen associated with a clinical event during therapy at a site 
other than the initial site of infection will be considered to be an AE. 
• 
Any recurrence of a pre-existing condition. 
• 
An AE occurring from overdose of a Sponsor study drug whether accidental or intentional (i.e., a 
dose higher than that prescribed by a health care professional for clinical reasons). 
• 
An AE occurring from abuse of a Sponsor study drug (i.e., use for nonclinical reasons). 
• 
An AE that has been associated with the discontinuation of the use of a Sponsor study drug. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is diagnosed 
before the patient signs the ICF and that is documented as part of the patient’s medical history. 


 
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The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is 
a treatment-emergent AE. An AE is considered to be treatment-emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the Follow-up/EOS. 
 
Treatment-emergent AEs will be identified in the eCRF Form “Adverse Event” if the answer to the question 
“Did the AE start after the patient took the first dose?” is answered as Yes. 
 
The Investigator will make a determination of the relationship of the AE to the study drug using a four-
category system according to the following guidelines: 
• 
Not related: when the AE is definitely caused by the patient’s clinical state, or the study 
procedure/conditions. 
• 
Unlikely Related: when the temporal association between the AE and the drug is such that the 
drug is not likely to have any reasonable association with the AE. 
• 
Possibly Related: when the AE follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by the patient’s clinical state or the study 
procedures/conditions. 
• 
Related: when the AE follows a reasonable temporal sequence from administration of the drug, 
abates upon discontinuation of the drug, follows a known or hypothesized cause-effect 
relationship, and (if appropriate) reappears when the drug is reintroduced. 
Related to study treatment will be identified as possibly related or related as per reported on eCRF Form 
“Adverse Event”.  
5.2 
Serious Adverse Events 
 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria:  
 
• 
Results in death,  
• 
Is life-threatening;  
• 
Requires patient hospitalization or prolongation of an existing hospitalization;  
• 
Results in persistent or significant disability or incapacity;  
• 
Results in a congenital anomaly or birth defect;  
• 
Results in an important medical event.  
 
 
5.3 
Laboratory Parameters 
 


 
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Laboratory evaluations are done at screening, Day 10 and follow-up visit 2 (Day 28). Additional clinical 
laboratory evaluations will be performed at other times if judged to be clinically appropriate or if the 
ongoing review of the data suggests a more detailed assessment of clinical laboratory safety evaluations 
is required.  
 
Hematology laboratory tests include: hematocrit (L/L), hemoglobin (g/L), MCH (pg), MCHC (g/L), MCV (fL), 
Platelet count (GI/L), RBC count (TI/L), WBC count (GI/L) and WBC differentials (Neutrophils, Eosinophils, 
Basophils, Lymphocytes and Monocytes) in both percent (%) and absolute (GI/L). 
 
Biochemistry laboratory tests include: albumin (g/L), alkaline phosphatase (U/L), ALT (U/L), AST (U/L), 
bicarbonate (mmol/L), BUN (mmol/L), calcium (mmol/L), chloride (mmol/L), cholesterol (mmol/L), 
creatinine (umol/L), GFR CKD-EPI (mL/min/1.73m2) , GGT (U/L), glucose (mmol/L), LDH (U/L), phosphorus 
(mmol/L), potassium (mmol/L), sodium (mmol/L), total bilirubin (umol/L),  total protein (g/L), triglycerides 
(mmol/L) and uric acid (umol/L). 
 
5.4 
Other Safety Parameters 
 
Pulse oximetry and saturation measurements will take place on screening, Days 1, 3, 5, 7, 10, follow-up 
visit 1 (Day14) and follow-up visit 2 (Day28/EOS).   
 
6 
STATISTICAL METHODOLOGY 
 
6.1 
Determination of Sample Size 
 
As per protocol, it was anticipated that 208 patients will be randomized into the study in a 1:1:1:1 ratio 
to 900, 1800, or 3600 mg dalcetrapib or placebo.The original sample size was calculated for the 
sustained resolution endpoint and was described in the protocol as follows: The purpose of the proof-of-
concept study is to identify whether there is sufficient promise of efficacy to justify conducting a Phase 3 
study in a larger sample size and to determine efficacious dose to be used in Phase 3. While the entirety 
of data will be considered at the end of study, the sample size has been chosen to ensure that a positive 
trend will be present with alpha of 0.2 when considering the two highest doses combined compared to 
placebo. One-hundred twenty-seven (127) resolution events provides 80% power to demonstrate a 
positive trend if the average hazard ratio (HR) of the two dalcetrapib groups is 1.4 relative to placebo. 
Allowing for 20% of patients not resolving, 156 patients (52 per treatment arm) will be enrolled across 
the two highest dose levels and placebo arms, and an additional 52 will be randomized to 900 mg for a 
total sample size of 208 patients. 
6.2 
Statistical Considerations 
 
Continuous variables will be summarized by the standard descriptive statistics: number of patients (n), 
mean, standard deviation, median, Q1, Q3, minimum, and maximum, along with confidence interval (CI) 
for outcome measures when appropriate. Frequency of patient or events and percentages will be 
summarized for categorical variables, again with CI when appropriate. Time to event variables will be 
summarized using Kaplan-Meier methods. 
All statistical tests will be conducted at a two-sided 0.20 significance level. 


 
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Statistical analyses will be performed using SAS Version 9.4 or higher.  
 
6.2.1 
Interim Analysis 
 
The study will be overseen by an independent Data Monitoring Committee (DMC). The DMC will review 
safety data throughout the study. The DMC will review efficacy data at the interim analysis and at the 
end of the study. A DMC Charter, which includes detailed processes, will be prepared. 
One interim analysis will be conducted for efficacy once 120 patients with a follow-up of 28 days have 
occurred. No decision to stop the trial will be made based on these efficacy findings as the review of 
data will occur around the time the last patients enrolled in the study complete the treatment period.  
The members of the committee will include appropriately qualified medical personnel, and other 
members, as required. Detailed responsibilities of the DMC will be provided in the DMC Charter. 
6.2.2 
Handling of Missing Data 
 
6.2.2.1 
Imputation 
 
Severity Symptom Score: Missing values on severity symptom score will not be imputed. However, 
where a patient has died, their symptom score will not be considered missing, but will be imputed with 
the maximum severity score (3) for each symptom at each time point. 
Clinical Outcome Scale: Missing values on clinical outcome scale will not be imputed. However, where 
a patient has died, their clinical outcome scale will not be considered missing, but will be imputed with 
maximum clinical outcome scale (7 [maximum severity if alive] or 8 [maximum severity if dead]) at each 
time point. 
Viral load: Prior to the log 10 transformation, non-numeric viral load results reported as below the limit 
of detection will be replaced by the limit of detection divided by 2. As an example, results reported as 
“<2228cp/mL SARSCoV2 detected” will be replaced by 1114 cp/mL. Non-numeric viral load results 
reported as “No SARS-CoV2 detected” will be replaced by 1 cp/mL. Replacing by 1 (instead of by zero) 
will be done so that the log 10 of viral load will be defined in all subjects (and equal to zero when no 
SARS-CoV2 is detected). 
 
6.2.2.2 
Censoring 
 
Severity Symptom Score: For time to resolution, a patient will be censored if the patient has not had the 
required time point assessment if not due to death. If patient has died or received another antiviral 
therapy prior to the assessment endpoint, then the patient will be considered as having a moderate or 
severe COVID-19 symptom for all COVID-19 symptoms and imputed to maximum severity score at the 
assessment day. 
Viral Clearance: For time to viral clearance, a patient will be censored if the patient has not had the 
required time point assessment. 


 
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6.2.3 
Multiplicity/Multiple Testing 
 
The primary analysis compares the combined two highest dalcetrapib dose groups against placebo as 
well as each treatment group individually. No adjustments will be made for multiple testing. 
 
6.3 
Study Subjects 
 
6.3.1 
Subject Disposition  
 
Number of subjects randomized, number of subjects who took at least one dose of study medication, 
number of subjects completing the study and reasons for not completing the study will be summarized by 
randomized treatment group, for all randomized subjects as well as for the ITT population.  
 
A listing of subject disposition will be presented (Section 7, Listing 1). 
 
Subject disposition will also be presented with a flow chart reporting the following information: subjects 
who signed informed consent, subjects who are screen failures, subjects randomized (excluding screening 
failures that were randomized), subjects who took at least one dose of study medication, subjects 
completing the study and reasons for study discontinuation (Section 7, Figure 1). 
 
Which visits were done will also be summarized overall and by treatment group, for the ITT population. 
 
 
6.3.2 
Protocol Deviations  
 
Protocol deviations will be summarized overall and by treatment group for the ITT population.  
 
A listing will also be provided (Section 7, Listing 3).  
 
6.3.3 
Datasets Analyzed 
 
The number of subjects in the ITT population, PP population and Safety population will be summarized 
overall and by treatment group.  
 
A listing of datasets analyzed will be presented and will include subject ID, randomization group, ITT 
population (Yes/No), reason for exclusion from the ITT population, PP population, reason for exclusion 
from the PP population, Safety population (Yes/No) and reason for exclusion from the Safety population 
(Section 7, Listing 2). 
 
 
6.3.4 
Demographic and Baseline Characteristics 
 
Demographic data such as age, sex, ethnicity, race and smoker will be summarized overall and by 
treatment group for the ITT population.  
 
In case the date of birth is incomplete [in the eCRF Demographics], the following imputation will be done: 


 
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• 
the partial date will be replaced by the fifteenth day of the month if month and year are known; 
• 
the partial date will be replaced by the first day of July if only the year is known. 
 
A listing of demographic data will be provided (Section 7, Listing 4).  
 
Medical and surgical history such as diabetes, hypertension, prior cardiovascular disease, respiratory 
disease, renal disease and liver disease will also be summarized overall and by treatment group for the 
ITT population. 
 
Delays since first symptoms of COVID-19 will be summarized overall and by treatment group, for the ITT 
population. The number of days between the date of first symptom of COVID-19 and the following dates 
will be presented in this table: date of positive diagnosis for COVID-19, date of randomization and date of 
first dose of study medication. In addition, the number of days between the date of positive diagnosis of 
COVID-19 and the date of randomization will be presented, as well as how the diagnosis of COVID-19 was 
established. 
 
Delays will be calculated as: 
 
• 
Date of positive diagnosis for COVID-19 - Date of first COVID-19 symptoms 
• 
Date of randomization - Date of first COVID-19 symptoms 
• 
First treatment start date - Date of first COVID-19 symptoms 
• 
Date of randomization - Date of positive diagnosis for COVID-19 
 
 
6.3.5 
Treatment Compliance  
 
Compliance will be assessed if subject took all the pills at each study visit and will be summarized using 
frequencies and percentages, by treatment group, for the subjects of the ITT population.  If subject did 
not take all the pills, then the number of missed pills will be reported as number of patients (n), mean, 
standard deviation, median, Q1, Q3, minimum, and maximum.  
 
6.3.6 
Prior and Concomitant Medications 
 
Prior and concomitant medications will be coded with respect to indication and generic name using the 
WHO drug dictionary (version MAR2021).   
 
Frequency of use of medications at randomization will be presented for the subjects of the ITT population 
by therapeutic class and preferred term, overall and for each treatment group. 
 
A medication will be flagged as being ongoing at the time of randomization if: 
• 
Medication start date < randomization date 
AND 
• 
(Medication end date ≥ randomization date OR Medication is ongoing) 
 
In case of missing or incomplete medication start / end dates, the following rules will be applied: 


 
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• 
If 1) the medication start date is completely missing, or 2) only the year is specified, it is the same 
as the randomization year and randomization did not occur the first day of the year or 3) only the 
month/year are specified, they are the same as the randomization month/year, then the 
medication will be assumed to have started before randomization. 
• 
If 1) the medication end date is completely missing, or 2) only the year is specified and it is the 
same as the randomization year or 3) only the month/year are specified and they are the same 
as the randomization month/year, then the medication will be assumed to have ended after 
randomization. 
• 
Otherwise, partial medication start / end dates (month/year or year only) will be compared to 
the randomization date and the medication will be classified accordingly. 
 
Frequency of use of prior and concomitant medications will also be presented for the subjects of the ITT 
population by therapeutic class and preferred term, overall and for each treatment group. 
 
A listing of concomitant medication(s) taken by the subject will be provided (Section 7, Listing 5).  
 
6.4 
Efficacy Analysis 
 
The analysis of treatment efficacy will be based on the Intent-to-Treat Population. The PP population 
will be used for sensitivity analysis. This section is a summary of the planned efficacy analyses of the 
most important efficacy endpoints including primary and key secondary efficacy endpoints. 
 
6.4.1 
Primary Analysis 
 
The primary endpoint is time to sustained clinical resolution of symptoms (excluding cough, sense of 
smell and taste) as determined by symptom score. Sustained clinical resolution of symptoms (excluding 
cough, sense of smell and taste) is defined in Section 4.1. Time to sustained clinical resolution will be 
calculated as date of resolution – date of randomization + 1. Subjects who did not resolve will be 
censored at the last time point where they were not resolved [see Section 9 Appendix 1]. The number 
and percentage of patients whose symptoms resolved will be presented, and to summarize the time to 
resolution, censored subjects will be imputed with a time to resolution of 29 days and simple medians 
with 80% confidence intervals will be provided. 
The differences in time to sustained clinical resolution of symptoms (excluding cough, sense of smell and 
taste) between the treatment groups will be evaluated using 2-sided log-rank tests, The combined two 
highest treatment groups will be compared to placebo in addition to the comparison of individual doses.  
The cumulative incidence curve for sustained clinical resolution (excluding cough, sense of smell and 
taste) will also be presented using 1 – Kaplan-Meier estimates(Section 7, Figure 2). Should there be 
several deaths, the cumulative incidence curve will be presented under a competing risk model. 
A listing with the score of each symptom at each time point will be provided (Section 7, Listing 7).  
 
6.4.2 
Key Secondary Analysis 
 


 
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6.4.2.1 
Change from Baseline in log10 Viral Load 
 
Log10 viral load, as assessed using the saliva and as assessed using the nasal swab, will be summarized 
by treatment group using descriptive statistics (N, mean, median, standard deviation, minimum, and 
maximum) for each visit as well as for changes from baseline where an 80% CI will also be presented.  
Mean changes from baseline will be analyzed using a repeated measures ANCOVA model including 
effects of treatment, visit (Day 3, Day 5, Day 10 and Day 28/EOS), and treatment-by-visit interaction, as 
well as baseline value of log10 viral load and baseline value of log10 viral load-by-visit-interaction.  An 
unstructured covariance structure will be used to model the within-patient errors and the Kenward-
Roger approximation will be used to estimate denominator degrees of freedom.  The combined two 
highest treatment groups will be compared to placebo in addition to the comparison of individual doses 
at the following study visits (Day 3, Day 5, Day 10 and Day 28/EOS). 
 
Since oragene and nasal samples are collected by the subjects themselves (visit identifiers may be 
unreliable), an algorithm (presented in Appendix 2) was developed to classify the day of assessment into 
their respective visit identifiers. This algorithm is based on the fact that Day 1 corresponds to the date of 
the first dose and as such, will be used as baseline when available. This is in alignment with the study 
protocol that identifies Day 1 as the date of first dose. It is understood that all protocol assessments 
collected on Day 1 were to be done PRIOR to the first dose. Therefore, Day 1 will correspond to baseline 
when available. Please refer to Appendix 2 for more details.   
 
A plot of mean change from baseline in log10 viral load with 80% CI at each study visit will also be 
presented (Section 7, Figure 4). 
6.4.2.2 
AUC in log10 Viral Load 
 
The area under the curve (AUC) of log10 viral load, as assessed using the saliva and as assessed using the 
nasal swab, will be calculated from randomization to Day 10 and summarized by treatment group using 
descriptive statistics (N, mean, median, standard deviation, Q1, Q3, minimum, and maximum). The AUC 
will be calculated using the trapezoidal rule on the period from baseline to Day 10. In subjects who will 
not have a viral load assessment up to Day 10, the last observation carried forward will be used so that 
the AUC is calculated on 10 days in all subjects. An ANOVA model will be performed to analyze the 
difference between treatment groups. The model will include only the treatment group. Contrasts under 
this model will allow for the comparisons across treatment groups. The results will be presented as 
mean treatment difference with associated 80% CI and p-value. 
6.4.2.3 
Time to Sustained Clinical Resolution 
 
Sustained clinical resolution is defined in Section 4.2. 
Same statistical methods as those described in section 6.4.1 will be used to analyze the time to 
sustained clinical resolution.  
 
6.4.3 
Other Secondary Analysis 
 


 
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6.4.3.1 
Time to Viral Clearance Based on PCR Test for SARS-CoV-2 
 
Each subject will be tested to determine if the subject has COVID-19 by obtaining a PCR or rapid antigen 
test as it confirms the presence of SARS-CoV-2. A subject will be considered to no longer have COVID-19 
if two consecutive PCRs do not detect SARS-CoV-2. Time to viral clearance using PCR test for SARS-CoV-
2, as assessed using the saliva and using the nasal swab, will be calculated as date of the first negative 
PCR test for SARS-CoV-2 – date of randomization + 1. Subjects who did not obtain two consecutive 
negative PCRs will be censored at the date of study completion. 
Same statistical methods as those described in section 6.4.1 will be used to analyze the time to viral 
clearance.  
6.4.3.2 
Time to Complete Clinical Resolution (excluding cough, sense of taste and smell)  
 
Complete clinical resolution (excluding cough, sense of taste and smell) is defined in Section 4.2. 
Same statistical methods as those described in section 6.4.1 will be used to analyze the time to 
complete clinical resolution (excluding cough, sense of taste and smell).  
6.4.3.3 
Time to Complete Clinical Resolution   
 
Time to complete clinical resolution is defined in Section 4.2 
Same statistical methods as those described in section 6.4.1 will be used to analyze the time to 
complete clinical resolution.  
6.4.3.4 
Change from Baseline in COVID-19 Total Symptom Score 
 
COVID-19 total symptom score will be summarized by treatment group using descriptive statistics (N, 
mean, median, standard deviation, minimum, and maximum) for each visit as well as for changes from 
baseline where an 80% CI will also be presented.  
Mean changes from baseline will be analyzed using a repeated measures ANCOVA model including 
effects of treatment, visit (Day5, Day10, Day14 & Day28/EOS), and treatment-by-visit interaction, as well 
as baseline value of total symptom score and baseline value of total symptom score-by-visit-
interaction.  An unstructured covariance structure will be used to model the within-patient errors and 
the Kenward-Roger approximation will be used to estimate denominator degrees of freedom. The 
combined two highest treatment groups will be compared to placebo in addition to the comparison of 
individual doses at the following study visits (Day5, Day10, Day14 and Day 28/EOS).   
 
Symptom scores were either reported electronically by the subject or by the site through telephone 
calls. Except for the assessments done at screening reported in the eCRF, no visit identifiers were 
attached to these evaluations, only the date of the assessment. Therefore, similar to viral load, the day 
of assessment of the symptom scores will be classified into visit identifiers as per the algorithm 
presented in Appendix 2.  This will ensure that Day X for symptom score will correspond to Day X for 
viral load.  
 


 
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A plot of mean change from baseline in COVID-19 total symptom score with 80% CI at each study visit on 
the ITT population will be presented (Section 7, Figure 6). 
6.4.3.5 
Scoring of WHO Clinical Outcome Scale (9-point Scale) 
 
The number and percentage of patients for each WHO clinical outcome score will be summarized.  
The combined two highest treatment groups will be compared to placebo in addition to the comparison 
of individual doses at the following visits (Baseline, Day3, Day5, Day10, Day14 and Day 28/EOS) using the 
Mann-Whitney-Wilcoxon test. Since Day 1 corresponds to the date of first dose, Day 1 will be used for 
baseline. A frequency distribution plot of WHO clinical outcome scale at each study visit on the ITT 
population will also be presented (Section 7, Figure 9). 
A listing of the WHO clinical outcome scale score at each time point will be provided (Section 7, Listing 8).  
 
6.4.3.6 
Rate of Hospitalization Through Day 28 
 
The number and percentage of patients who were hospitalized will be presented. The percentage 
of patients who were hospitalized will be compared using a binary logistic regression analysis. The 
model will include only the treatment group. Contrasts under this model will allow for the comparisons 
across treatment groups. The results will be presented as odds ratios, with associated 80% CIs and p-
value. The period will cover from the time of randomization to 28 days after, any hospitalization for 
which date of hospitalization > date of randomization + 28 would be excluded. 
A listing with details on hospitalizations will be incorporated as part of the AE listing (Section 7, Listing 
9). 
6.4.3.7 
Rate of Progression to Oxygen Therapy Through Day 28 
 
The analysis of this endpoint will be performed on the ITT population. The number and percentage of 
patients who progress to oxygen therapy and type of oxygen therapy will be presented. The percentage 
of patients who had progressed to oxygen therapy will be compared using a binary logistic regression 
analysis. The model will include only the treatment group. Contrasts under this model will allow for the 
comparisons across treatment groups. The results will be presented as odds ratios, with associated 80% 
CIs and p-value. The period will cover from the time of randomization to 28 days after, any progression 
to oxygen therapy for which date of progression > date of randomization + 28 would be excluded. 
6.4.3.8 
Duration of Hospitalization 
 
The duration of hospitalization will be from the date of first hospitalization until date of discharge [(Date 
of hospitalization – date of discharge) in the eCRF Form “Adverse Event”]. The duration of 
hospitalization will be the total number of days hospitalized in case of more than one hospitalization. 
The duration of hospitalization will be analyzed on the ITT population in subjects who were hospitalized. 
Duration of hospitalization will be summarized by treatment group using descriptive statistics (N, mean, 
median, standard deviation, Q1, Q3, minimum, and maximum). An ANOVA model will be performed to 
analyze the difference between treatment groups. The model will include only the treatment group. 


 
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Contrasts under this model will allow for the comparisons across treatment groups. The results will be 
presented as mean treatment difference with associated 80% CI and p-value. 
6.4.3.9 
Mortality Rate 
 
The analysis of this endpoint will be performed on the ITT population. The number and percentage of 
patients who died will be presented. The percentage of patients who died will be compared using a 
binary logistic regression. The model will include only the treatment group. Contrasts under this model 
will allow for the comparisons across treatment groups. The results will be presented as odds ratios, 
with associated 80% CIs and p-values. The period will cover from the time of randomization to 28 days 
after, any death for which date of death > date of randomization + 28 would be excluded. 
A listing with details on deaths will be provided (Section 7, Listing 10). 
 
6.4.4 
Sensitivity Analysis 
 
As a sensitivity analysis, the primary analysis described in section 6.4.1 will be repeated on the PP 
population. 
 
As an additional sensitivity analysis, the primary endpoint will be derived using the algorithm of Appendix 
1, but prior to applying the algorithm, the last observation carried forward will be used in alive patients 
with no assessment at Day 28. In other words, in alive patients, the missing assessment at Day 28 will be 
imputed as the last available assessment.  
 
 
6.4.5 
Subgroup Analysis 
 
A subgroup analysis for the variants might be done on the primary endpoint, time to sustained clinical 
resolution of symptoms (excluding cough, sense of smell and taste). The analysis described in section 6.4.1 
would be repeated in subjects presenting a specific variant. These analyses would however be done at a 
later time point when the information on the variants become available. 
 
6.5 
Safety Analysis 
 
The safety analyses described in this section will be conducted on the safety population.  No formal 
statistical testing is planned for the safety parameters. 
 
6.5.1 
Treatment Exposure 
 
Duration of exposure will be defined as number of days on treatment for each subject.  Duration will be 
calculated as:  [treatment end date – treatment start date + 1] from the eCRF Form “Study Drug 
Administration”.  
 
Duration of exposure will be summarized by treatment arm using N, mean, median, standard deviation, 
Q1, Q3, minimum and maximum.   
 


 
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Duration of exposure will also be categorized according to day intervals ([1-3], [4-5], [6-7], [8-9], [10], 
[>10]) and summarized using frequencies and percentages, overall and by treatment group.   
 
In addition, if subject interrupted/discontinued the study medication, then the reason will also be 
reported using frequencies and percentages overall and by treatment group. 
 
Duration of exposure will be presented for the safety population. 
 
A listing with details on the administration of study medication will be provided (Section 7, Listing 6). 
6.5.2 
Adverse Events and Serious Adverse Events 
 
6.5.2.1 
Adverse Events 
 
AEs will be coded by system organ class and preferred term according to the MedDRA dictionary (version 
24). 
 
Treatment-emergent AEs (TEAEs) will be summarized. Number and proportion of subjects experiencing a 
treatment-emergent AE will be presented by system organ class and preferred term overall and for each 
treatment group. 
 
An overall summary of TEAEs that includes the total number of TEAEs reported, the number and 
proportion of subjects experiencing at least one TEAE, at least one severe TEAE, at least one TEAE related 
to the study treatment, at least one TEAE leading to treatment discontinuation and a TEAE leading to 
death will also be presented. 
 
TEAEs related to study treatment will also be summarized. Number and proportion of subjects 
experiencing a treatment-emergent AE related to study treatment will be presented by system organ class 
and preferred term overall and for each treatment group. 
 
An overall summary of TEAEs related to study treatment that includes the total number of TEAEs reported, 
the number and proportion of subjects experiencing at least one TEAE, at least one severe TEAE, at least 
one TEAE leading to treatment discontinuation and a TEAE leading to death will also be presented. 
 
TEAEs leading to treatment discontinuation will also be summarized. Number and proportion of subjects 
experiencing a treatment-emergent AE leading to treatment discontinuation will be presented by system 
organ class and preferred term overall and for each treatment group. Severe TEAEs will be presented 
similarly. 
 
All AEs will also be listed (Section 7, Listing 9).  
 
 
6.5.2.2 
Serious Adverse Events 
 
Treatment-emergent serious AEs (TESAE) will be summarized. Number and proportion of subjects 
experiencing a treatment-emergent serious AE will be presented by system organ class and preferred 
term overall and for each treatment group. 


 
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An overall summary of the total number of TESAEs reported, the number and proportion of subjects 
experiencing at least one TESAE, at least one severe TESAE, at least one TESAE related to the study 
treatment, at least one TESAE leading to treatment discontinuation, a TESAE leading to death, at least one 
TESAE requiring supplemental oxygenation, at least one TESAE requiring mechanical ventilation and at 
least one TESAE requiring ECMO will also be presented. 
 
Treatment-emergent serious AEs (TESAE) related to study treatment will also be summarized. Number 
and proportion of subjects experiencing a treatment-emergent serious AE related to study treatment will 
be presented by system organ class and preferred term overall and for each treatment group. 
 
An overall summary of TESAEs related to study treatment that includes the total number of TESAEs related 
to study treatment reported, the number and proportion of subjects experiencing at least one TESAE 
related to study treatment, at least one severe TESAE related to study treatment, at least one TESAE 
related to study treatment leading to treatment discontinuation, a TESAE related to study treatment 
leading to death, at least one TESAE related to study treatment requiring supplemental oxygenation, at 
least one TESAE related to study treatment requiring mechanical ventilation and at least one TESAE 
related to study treatment requiring ECMO will also be presented. 
 
All SAEs will also be listed (Section 7, Listing 9).  
  
A separate listing for deaths will be also provided (Section 7, Listing 10).  
 
6.5.3 
Laboratory Parameters 
 
Laboratory data will be transferred electronically by Covance central lab.  For all laboratory parameters, 
results at each visit and change from screening will be summarized overall and by treatment group using 
descriptive statistics (N, mean, median, standard deviation, Q1, Q3, minimum and maximum).   
  
 
6.5.4 
Other Safety Parameters 
 
Vital signs [pulse oximetry and peripheral oxygen saturation] at each visit will be summarized overall and 
by treatment group using descriptive statistics (N, mean, median, standard deviation, Q1, Q3, minimum 
and maximum). Change from Day 1 will also be presented similarly using descriptive statistics since Day 1 
corresponds to the date of first dose. 
 
In addition, saturation will be characterized as: [<90%], [91%-95%], [>95%] at each visit overall and by 
treatment group.  Number and proportion of subjects within each category will be provided. 
 
 
7 
SUMMARY TABLES, FIGURES AND LISTINGS 
 
 
1 Study subject 
1.1 Subject disposition 


 
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Table 1.1.1 
Subject disposition 
Table 1.1.1b 
Subject disposition, ITT population 
Table 1.1.2 
Visits done, ITT population 
Table 1.1.3 
Protocol deviations, ITT population 
Table 1.1.4 
Datasets analyzed 
 
 
1.2 Demographic and baseline characteristics 
Table 1.2.1 
Summary of demographics, ITT population 
Table 1.2.2 
Summary of medical and surgical history,  ITT population 
Table 1.2.3 
Summary of additional medical or surgical conditions, ITT population 
Table 1.2.4 
Summary of COVID-19 diagnosis, ITT population 
 
 
1.3 Prior and concomitant medication 
Table 1.3.1 
Summary of medication at randomization, ITT population 
Table 1.3.2 
Summary of concomitant medication, ITT population 
 
 
1.4 Treatment compliance 
Table 1.4.1 
Summary of treatment compliance, ITT population 
 
2 Efficacy analysis 
2.1 Primary analysis 
Table 2.1.1 
Summary of and statistical analysis for sustained clinical resolution (excluding 
cough, sense of smell and taste), ITT population 
Table.2.1.2 
Summary of and statistical analysis for sustained clinical resolution (excluding 
cough, sense of smell and taste), PP population – Sensitivity analysis 
Table 2.1.3 
Summary of and statistical analysis for sustained clinical resolution (excluding 
cough, sense of smell and taste) with last observation carried forward, ITT 
population – Sensitivity analysis 
 
 
2.2 Key secondary analysis 
Table 2.2.1 
Summary of and statistical analysis for log10 viral load (saliva), ITT population 
Table 2.2.2 
Summary of and statistical analysis for log10 viral load (nasal swab), ITT 
population 
Table 2.2.3 
Summary of and statistical analysis for area under the curve of log10 viral load 
(saliva), ITT population 
Table 2.2.4 
Summary of and statistical analysis for area under the curve of log10 viral load 
(nasal swab), ITT population 
Table 2.2.5 
Summary of and statistical analysis for sustained clinical resolution of 
symptoms, ITT population  
2.3 Other secondary analysis 
Table 2.3.1 
Summary of and statistical analysis for viral clearance (saliva), ITT population  
Table 2.3.2 
Summary of and statistical analysis for viral clearance (nasal swab), ITT 
population  
Table 2.3.3 
Summary of and statistical analysis for complete clinical resolution (excluding 
cough, sense of smell and taste), ITT population  


 
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Table 2.3.4 
Summary of and statistical analysis for complete clinical resolution, ITT 
population  
Table 2.3.5 
Summary of and statistical analysis for COVID-19 total symptom severity 
score, ITT population  
Table 2.3.6 
Summary of and statistical analysis for WHO clinical outcome scale, ITT 
population  
Table 2.3.7 
Summary of and statistical analysis for proportion of subjects with 
hospitalizations, ITT population  
Table 2.3.8 
Summary of and statistical analysis for proportion of subjects who progress to 
oxygen therapy, ITT population  
Table 2.3.9 
Summary of and statistical analysis for duration of hospitalization, ITT 
population 
Table 2.3.10 
Summary of and statistical analysis for death, ITT population 
 
3 Safety analysis 
3.1 Treatment exposure 
Table 3.1.1 
Summary of treatment exposure, safety population 
 
 
3.2 Adverse events and serious adverse events 
Table.3.2.1 
Overall summary of treatment emergent adverse events (TEAE), Safety 
population 
Table 3.2.2 
Summary of treatment emergent adverse events (TEAE) by preferred term and 
system organ class, Safety population 
Table 3.2.3 
Overall summary of treatment emergent adverse events (TEAE) related to 
study treatment, Safety population 
Table 3.2.4 
Summary of treatment emergent adverse events (TEAE) related to study 
treatment by preferred term and system organ class, Safety population 
Table 3.2.5 
Summary of treatment emergent adverse events (TEAE) leading to treatment 
discontinuation by preferred term and system organ class, Safety population 
Table 3.2.6 
Summary of severe treatment emergent adverse events (TEAE) by preferred 
term and system organ class, Safety population 
Table 3.2.7 
Overall summary of treatment emergent serious adverse events (TESAE), 
Safety population 
Table 3.2.8 
Summary of treatment emergent serious adverse events (TESAE) by preferred 
term and system organ class, Safety population 
Table 3.2.9 
Overall summary of treatment emergent serious adverse events (TESAE) 
related to study treatment, Safety population 
Table 3.2.10 
Summary of treatment emergent serious adverse events (TESAE) related to 
study treatment by preferred term and system organ class, Safety population 
 
 
3.3 Laboratory variables 
Table 3.3.1 
Summary of hematology, Safety population 
Table 3.3.2 
Summary of biochemistry, Safety population 
 
 
3.4 Other safety parameters 


 
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Table 3.4.1 
Summary of vital pulse rate (bmp), Safety population 
Table 3.4.1 
Summary of vital SpO2 (%), Safety population 
Table 3.4.2 
Summary of vital SpO2 (%) in categories, Safety population 
 
Figures 
Figure 1 
Subject Disposition (flow chart) 
Figure 2 
Cumulative incidence curve for sustained clinical resolution (excluding cough, 
sense of smell and taste), ITT population 
Figure 3 
Cumulative incidence curve for sustained clinical resolution (excluding cough, 
sense of smell and taste), PP population – Sensitivity analysis 
Figure 4 
Cumulative incidence curve for sustained clinical resolution (excluding cough, 
sense of smell and taste) with last observation carried forward, ITT population 
– Sensitivity analysis 
Figure 5 
Plot of mean change from baseline in log10 viral load (saliva) with 80% CI at 
each study visit, ITT population 
Figure 6 
Plot of mean change from baseline in log10 viral load (nasal swab) with 80% 
CI at each study visit, ITT population 
Figure 7 
Cumulative incidence curve for sustained clinical resolution, ITT population 
Figure 8 
Plot of mean change from baseline in COVID-19 total symptom score with 
80% CI at each study visit, ITT population 
Figure 9 
Frequency distribution plot of WHO clinical outcome scale at each study visit, 
ITT population 
 
Listings 
Listing 1 
Subject disposition 
Listing 2 
Datasets analyzed 
Listing 3 
Protocol deviations 
Listing 4 
Demographics 
Listing 5 
Concomitant medications 
Listing 6 
Study medication administration 
Listing 7 
COVID-19 related symptoms and endpoints 
Listing 8 
WHO clinical outcome scale 
Listing 9 
Adverse events and serious adverse events 
Listing 10 
Deaths 
 
 


 
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8 
    REFERENCES 
 
NA 
 


 
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9 
  APPENDICES 
 
APPENDIX 1 
 
Algorithm used to classify sustained clinical resolution: 
 
For each subject, all ePRO records will be sorted by the date/time. For each assessment, we characterize 
the record as clinically resolved (i.e., score of 0 for taste and smell and all other symptoms, a score of 0 
or 1) or not.  
 
From Day1 to Day10 (or last ePRO assessment before Day14) 
 
a) 
If resolved at Day 10 (or last ePRO assessment), identify first date when resolution occurred 
with no relapse. This is the tentative date of resolution to be confirmed at Day 14 and Day 
28. 
b) 
If not resolved at Day 10 (or last ePRO assessment), re-assess at Day 14. 
 
At Day14:  
 
c) 
If resolved for the first time at Day 14 (i.e. was not resolved at Day 10 or before), use date of 
Day 14 as the tentative date of resolution to be confirmed at Day 28.  
d) 
If still resolved at Day 14 (i.e. was already resolved at Day10 or before), use date of 
resolution identified in step a). This is the tentative date of resolution to be confirmed at 
Day 28.  
e) 
If not resolved at Day 14, re-assess at Day28.      
 
At Day28:  
 
f) 
If resolved for the first time at Day 28 (i.e., was not resolved at Day 14), subject will be 
classified as resolved within 28 days and date of resolution will be the date of Day 28.  
 
g) 
If still resolved at Day 28 (i.e. was already resolved at Day 14), subject will be classified as 
resolved within 28 days and date of resolution will be the date of resolution identified in 
step c) or d).  
 
h) 
If not resolved at Day 28, subject will be classified as not resolved within 28 days and the 
date of censoring will be the date of Day 28. 
 
It should also be noted that subjects who do not have an assessment at Day 28 will be classified as non-
resolved REGARDLESS if symptoms were resolved up to their last assessment. Date of censoring will be 
the date of study discontinuation.   
 
 


 
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APPENDIX 2 
 
To classify the symptom score and viral load assessments to their appropriate visit identifier, the 
difference in days between the date of the assessment and the date of the first dose will be calculated, 
and this difference will be classified according to the reporting windows below. This algorithm will 
ensure that Day X for symptom score will correspond to Day X for viral load. As per the study protocol, 
Day 1 corresponds to the date of 1st dose in which all assessments were to be done PRIOR to first dose. 
 
Once the visit identifiers are sorted out, Day 1 will be used to establish a baseline visit. If a subject has 
no Day 1 assessment but a screening one, then the screening assessment is chosen.   
 
In cases where more than one assessment falls within the same reporting window, the first assessment 
will be chosen. 
 
Note: For the symptom score, if both ePRO and eCRF assessments were done on the same day, then the 
ePRO was favored.   
 
Reporting windows for the classification of the visit identifiers for symptom score and viral load* 
VISIT** 
SCHEDULED 
WINDOW  
(± DAYS) 
DIFFERENCE BETWEEN DATE OF 
ASSESSMENT AND DATE OF 1ST 
DOSE  
*Screening 
--- 
<0 
*DAY 1 
--- 
0 
DAY 2 
--- 
1 
DAY 3 
--- 
2 
DAY 4 
--- 
3 
DAY 5 
--- 
4 
DAY 6 
--- 
5 
DAY 7 
--- 
6 
DAY 8 
--- 
7 
DAY 9 
--- 
8 
DAY 10 
--- 
9 
Follow-up visit 1 (DAY 14) 
±2 
11 to 15 
Follow-up visit 2 (DAY 28/EOS) 
±2 
25 to 29 
*Screening and Day 1 will not be reported separately but will be used to classify the baseline visit as 
detailed above. 
 
**Viral loads are presented ONLY at baseline, Day 3, Day 5, Day 7, Day 10 & Day 28/EOS.