Clinical trial NCT04604184
Conditions: COVID-19
Sponsor: Boehringer Ingelheim
Start date: 2020-11-03; Completion date: 2021-05-31
Enrollment: 133 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with COVID-19 infection who are in hospital and receive oxygen. Participants need to be 50 years of age or older and need to be at risk of further worsening of their condition.

The purpose of the study is to find out whether a medicine called BI 764198 helps people with COVID-19 infection and breathing problems. BI 764198 may prevent cell death and swelling of the lung tissue and therefore help patients with COVID-19 infection.

Participants are put into 2 groups by chance. One group of participants gets BI 764198 capsules and the other group gets placebo capsules. The placebo capsules look exactly like the BI 764198 capsules but do not contain any medicine. Participants take 1 capsule per day.

Participants are in the study for about a month. At study end, doctors compare the 2 groups for the number of patients that are alive and do not need mechanical breathing support. During the study, the doctors collect information on any health problems of the participants.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 764198 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 764198 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c32418694-02
EudraCT No.
EU Trial No.
2020-003211-96
BI Trial No.
1434-0009
BI Investigational
Medicinal Product
BI 764198
Title
BI 764198 efficacy and safety in prevention/progression of ARDS 
and ARDS-related complications secondary to COVID-19
(ACTION ON COVID-19)
Lay Title
ACTION ON COVID-19: A study to test whether BI 764198 helps 
lung health of people hospitalised with COVID-19 
Clinical Phase
Phase II
Clinical Trial 
Leader
Phone:  
Fax:  
Coordinating 
Investigator
Phone 
Version and Date
Version: 2.0
Date: 08 Jan 2021
Page 1 of 58
Proprietary confidential information.
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
18 Sep 2020
Revision date
08 Jan 2021
BI trial number
1434-0009
Title of trial
BI 764198 efficacy and safety in prevention/progression of ARDS 
and ARDS-related complications secondary to COVID-19 (ACTION 
ON COVID-19)
Coordinating 
Investigator
Phone 
Trial site(s)
Multi-centre trial
Clinical phase
Phase II
Trial rationale
TRPC6 inhibition should reduce pulmonary endothelial and epithelial 
cell apoptosis thereby improve lung edema and clinical outcomes in 
patients with severe SARS-CoV-2 infection.. 
Trial objective(s)
To evaluate the efficacy and safety of 
 BI 764198, an inhibitor 
of the transient receptor potential subtype C6 (TRPC6), compared to 
placebo in reducing risk or severity of acute respiratory distress 
syndrome (ARDS) in patients hospitalised for COVID-19. 
Trial endpoints
Primary endpoint 

Patients alive and free of mechanical ventilation at Day 29
Secondary endpoints 

Patients alive and discharged free of oxygen at Day 29

Patients with occurrence of any component of composite: In-
hospital mortality or intensive care unit (ICU) admission or 
mechanical ventilation at Day 29

Time to response, defined as clinical improvement of at least 2 
points (from randomisation) on the World Health Organization
Clinical Progression Scale, discharge from the hospital, or 
considered fit for discharge (a score of 0, 1, 2, or 3 on the 
Clinical Progression Scale), whichever comes first, by Day 29

Number of ventilator free days by Day 29

Mortality at Day 15, 29, 60, and 90
Trial design
This is a multi-centre, randomised, double-blind, placebo-controlled 
trial of BI 764198 in the treatment of COVID-19 disease. 
Total number of patients
randomised
130 patients
Number of patients on 
each treatment
65 patients placebo and 65 patients 
BI 764198
Diagnosis
Hospitalised with a diagnosis of COVID-19 at risk of developing or 
diagnosed with ARDS


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Main in- and exclusion 
criteria

Adults (≥50 years) hospitalised for SARS-CoV-2 infection 
confirmed by PCR or approved point-of-care test. 

Women of childbearing potential (WOCBP) and men able to 
father a child must abstain from male female sex or must use 
highly effective methods of birth control per ICH M3 (R2) that 
result in a low failure rate of less than 1% per year when used 
consistently and correctly during hospitalisation and for at least 7
days after last trial drug intake.

A score of 5 (hospitalised; oxygen by mask or nasal prongs) or 6
(hospitalised; oxygen by non-invasive ventilation or high flow) on 
the World Health Organization Clinical Progression Scale (no 
previous score of 7 or above).

Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.

No relevant end-organ failure or other medical conditions (e.g. 
active cancer, renal, cardiac, gastrointestinal) which based on 
investigator judgement would interfere with the conduct of this 
study. 

Not previously on long-term oxygen therapy.
Test product(s)
BI 764198
dose
 per day
mode of 
administration
Oral (p.o.) or, only if needed, nasogastric intubation
Comparator product(s)
Placebo to BI 764198
dose
Not applicable
mode of
administration
Oral (p.o.) or, only if needed, nasogastric intubation
Duration of treatment
Up to 28 days
Statistical methods
The primary endpoint will be analysed with a logistic regression 
model using covariates of treatment, severity grade at baseline, age, 
creatinine at baseline, and duration of symptoms before 
hospitalisation, to evaluate the absolute difference in proportions of 
patients alive and free of mechanical ventilation at Day 29 with BI 
764198 and placebo. Patients who terminate the study medication 
prematurely will be followed and the events which occur after 
premature discontinuation of medication and before the time point of 
interest will be included in the analysis using the Full Analysis Set 
(FAS).
The logistic regression for the primary endpoint analysis will be used 
for other binary endpoint(s) and time-to-event endpoints will be 
analysed using Cox regression including covariates used for the 
primary analysis. Ventilator free days will be analysed using 
ANCOVA including the same covariates as in the primary analysis.


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FLOW CHART
Trial Periods
Screening 
Treatment
Follow-up
(telephone visits onlyb)
Visit
1
2
3 through 29
EOTa
FUPb
1
FUPb
2, 3, 4
EOSb
Day
-1
1
Daily Day 2
through
discharge -1 
day (maximum
Day 28)
dis-
charge/
day 
after 
last dose
EOT +4
days
15, 29, 
60
(from 
Day 1)
90
(from 
Day 1)
Time window for visits (days)
-3 to 1c
+2
±3
±6
Informed Consent
X
Demographics
X
Medical History
X
Baseline Conditions
X
Clinical Frailty Scale (CFS)
X
SARS-CoV-2 PCR test c,h
X
Review of inclusion/exclusion criteriac
X
X
Randomisation
X
Concomitant Therapy and Procedures
X
X
X
X
X
X
X
Adverse event evaluation
X
X
X
X
X
X
X
Hospitalisation Status
X
X
X
X
X
X
X
World Health Organization (WHO)
Clinical Progression Scale
X
X
X
X
Xf
Xf
Ventilation and oxygen parameters; 
respiratory rate, FiO2, SpO2
X
X
X
X
Xf
Xf
Vital signs (refer to Section 5.2.2) 
X
X
X
X
Blood Gases/PaO2 data capture if 
performed as part of routine care
X
X
X
X
12-lead ECGc,g
X
X
(+1 
day)
Day 3,7,14,21
(±1 day)
X
Physical Exam (refer to Section 5.2.1)
X
X
(±1 
day)
Day 3,7,14,21
(±1 day)
X
Safety Laboratory Samples (refer to 
Section 5.2.3)c,d
X
X
(±1 
day)
Day 3,7,14,21
(±1 day)
X
Pregnancy test (blood) for WOCBPc,d
X
Day 7,14
(±1 day)
X
Administration of trial medicatione
X
X
Xi
Termination of trial medication 
X
Trial Completion  
X
Vital Status
X
X
X
EOT=End of Treatment; EOS=End of Study; FiO2=fraction of inspired oxygen; FUP=Follow-up; PCR=polymerase chain 
reaction; PO2=partial pressure of oxygen; SARS-CoV-2= severe acute respiratory syndrome coronavirus 2.
Footnotes:
a EOT visit should be completed the day after the last dose of study drug is administered for all
patients. EOT visit should occur no later than Day 29.
b FUP 1 should be performed 4 days after EOT visit for all patients. FUP 2 and FUP 3 which 
correspond to study Day 15 and Day 29 after start of therapy, should be performed if the time point is 
applicable after drug discontinuation. FUP 2 and FUP 3 visits should not be conducted within +/- 2 
days of EOT or FUP 1. FUP 4 and EOS which correspond to study Day 60 and Day 90 will be 
performed for all patients. If a patient remains hospitalized after EOT visit, applicable FUP visits and 


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the EOS visit will be conducted in hospital until discharge and thereafter by telephone. Refer to 
Section 6.2.3. 
c Laboratory tests and ECG performed up to 72 hours prior to enrolment will be accepted for 
determination of eligibility and the screening visit date may be the same day as Visit 2 or up to 3 
days prior to Visit 2.
d Results from laboratory tests performed as part of routine clinical care within the specified visit 
window may be used. 
e Interactive Response Technology (IRT) will be used to allocate a 10 day supply of study drug at 
Visit 2 (or at the conclusion of Visit 1 after all eligibility criteria are confirmed to be met to allow 
time to prepare the study drug prior to day of randomization (first administration of study drug) and, 
if applicable per an individual patient’s treatment duration, at Visit 12 and Visit 22. 
f If the patient discontinues treatment and is not discharged prior to Day 29, collect ventilation and 
oxygen parameters daily up to Day 29, respiratory rate, FiO2, SpO2, if applicable, at Day 29, and 
WHO Clinical Progression Scale score at Day 29. If patient is on oxygen therapy at discharge, 
collect end date of that oxygen therapy when available during the Follow-up visit telephone call(s).
g ECG should be performed 0.5-4 hours after drug administration.
h SARS-CoV-2 PCR test to be performed as visit procedure and an approved SARS-CoV-2 point-of-
care test may be used to evaluate inclusion criterion 2, refer to Section 3.3.2.  
i Dosing should be stopped the day prior to EOT.  However, if it is uncertain whether a patient is fit 
for discharge, and the patient has not yet completed the allowed treatment duration of 28 days, 
administer study drug and perform all study procedures per the planned treatment period visit. If later 
that day the PI makes the decision that patient will discharge, perform any additional EOT visit 
procedures, if applicable, per Flow Chart and record visit in the eCRF as EOT visit.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................6
ABBREVIATIONS..................................................................................................................9
1.
INTRODUCTION...............................................................................................12
1.1
MEDICAL BACKGROUND.............................................................................12
1.2
DRUG PROFILE................................................................................................13
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................15
1.4
BENEFIT - RISK ASSESSMENT.....................................................................16
1.4.1
Benefits.................................................................................................................16
1.4.2
Risks .....................................................................................................................16
1.4.3
Discussion.............................................................................................................17
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................18
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........18
2.1.1
Main objectives....................................................................................................18
2.1.2
Primary endpoint(s)............................................................................................18
2.1.3
Secondary endpoints...........................................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
3.1
OVERALL TRIAL DESIGN.............................................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................20
3.3
SELECTION OF TRIAL POPULATION .......................................................21
3.3.1
Main diagnosis for trial entry ............................................................................22
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................22
3.3.4
Withdrawal of patients from treatment or assessments..................................23
3.3.4.1
Discontinuation of trial treatment .........................................................................23
3.3.4.2
Withdrawal of consent to trial participation .........................................................24
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................24
4.
TREATMENTS...................................................................................................25
4.1
INVESTIGATIONAL TREATMENTS ...........................................................25
4.1.1
Identity of the Investigational Medicinal Products..........................................25
4.1.2
Selection of doses in the trial and dose modifications......................................25
4.1.3
Method of assigning patients to treatment groups...........................................26
4.1.4
Drug assignment and administration of doses for each patient......................26


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4.1.5
Blinding and procedures for unblinding...........................................................27
4.1.5.1
Blinding.................................................................................................................27
4.1.5.2
Unblinding and breaking the code ........................................................................27
4.1.6
Packaging, labelling, and re-supply...................................................................28
4.1.7
Storage conditions...............................................................................................28
4.1.8
Drug accountability.............................................................................................28
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................29
4.2.1
Other treatments and emergency procedures..................................................29
4.2.2
Restrictions ..........................................................................................................29
4.2.2.1
Restrictions regarding concomitant treatment ......................................................29
4.2.2.2
Restrictions on diet and life style..........................................................................30
4.2.2.3
Contraception requirements..................................................................................30
4.3
TREATMENT COMPLIANCE........................................................................30
5.
ASSESSMENTS..................................................................................................31
5.1
ASSESSMENT OF EFFICACY........................................................................31
5.1.1
Proportion of patients alive and free of mechanical ventilation at Day 29....31
5.1.2
Improvements on the WHO Clinical Progression Scale..................................31
5.1.3
Other efficacy assessments.................................................................................31
5.2
ASSESSMENT OF SAFETY.............................................................................32
5.2.1
Physical examination ..........................................................................................32
5.2.2
Vital signs and blood gases.................................................................................32
5.2.3
Safety laboratory parameters ............................................................................32
5.2.4
Electrocardiogram ..............................................................................................35
5.2.5
Other safety parameters.....................................................................................35
5.2.6
Assessment of adverse events.............................................................................35
5.2.6.1
Definitions of AEs ................................................................................................35
5.2.6.2
Adverse event collection and reporting ................................................................38
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................39
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................39
5.5
BIOBANKING ....................................................................................................39
5.6
OTHER ASSESSMENTS...................................................................................39
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................40
6.
INVESTIGATIONAL PLAN.............................................................................41
6.1
VISIT SCHEDULE.............................................................................................41
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................41
6.2.1
Screening and run-in period(s)..........................................................................41
6.2.2
Treatment period(s)............................................................................................42
6.2.3
Follow-up period and trial completion..............................................................42
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................43
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................43
7.2
PLANNED ANALYSES.....................................................................................43
7.2.1
General considerations .......................................................................................43


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7.2.2
Primary endpoint analyses.................................................................................43
7.2.3
Secondary endpoint analyses .............................................................................44
7.2.5
Safety analyses.....................................................................................................44
7.2.6
Interim Analyses .................................................................................................45
7.3
HANDLING OF MISSING DATA ...................................................................45
7.4
RANDOMISATION ...........................................................................................45
7.5
DETERMINATION OF SAMPLE SIZE .........................................................46
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........47
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................47
8.2
DATA QUALITY ASSURANCE ......................................................................48
8.3
RECORDS...........................................................................................................48
8.3.1
Source documents ...............................................................................................48
8.3.2
Direct access to source data and documents.....................................................49
8.3.3
Storage period of records ...................................................................................49
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................49
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........49
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................50
8.6
TRIAL MILESTONES.......................................................................................50
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................51
9.
REFERENCES....................................................................................................52
9.1
PUBLISHED REFERENCES............................................................................52
9.2
UNPUBLISHED REFERENCES......................................................................53
10.
APPENDICES.....................................................................................................54
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................55
11.1
GLOBAL AMENDMENT 1 ..............................................................................55


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ARDS
Acute Respiratory Distress Syndrome
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
Ca2+
Calcium
CFS
Clinical Frailty Scale
CKD-EPI
Chronic Kidney Disease-Epidemiology Collaboration 
Cmax
Maximum Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
ECMO
Extracorporeal Membrane Oxygenation
EOS
End of Study
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FiO2
Fraction of inspired Oxygen


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FUP
Follow-up
GCP
Good Clinical Practice
gRT
Global Randomization Team
GMP
Good Manufacturing Practice
HA
Health Authority
HR
Hazard Ratio
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
iSTAT
Independent Statistician
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLVPE
Last Patient Last Visit Primary Endpoint 
LPLT
Last Patient Last Treatment
LPS
Lipopolysaccharide
MedDRA
Medical Dictionary for Drug Regulatory Activities
MPC
Mutant Prevention Concentration
NOAEL
No-Observable-Adverse-Effect-Level
OPU
Operative Unit
PaO2
Partial pressure of Oxygen
PCR
Polymerase Chain Reaction
p.o.
per os (oral)
q.d.
quaque die (once a day)
RA
Regulatory Authority
RNA
Ribonucleic Acid
REP
Residual Effect Period
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SoC
Standard of Care


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SpO2
Oxygen Saturation
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TRPC6
Transient Receptor Potential subtype C6
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
VFD
Ventilator Free Days
WHO
World Health Organization
WOCBP
Woman Of Child Bearing Potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Coronaviruses are single-stranded ribonucleic acid (RNA) viruses. In humans, infection with 
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to the syndrome 
known as COVID-19 which is associated with a wide spectrum of symptoms and symptom 
severities. The respiratory system is a key organ affected.
Many individuals, in particular younger patients, with COVID-19 experience only mild upper 
respiratory tract symptoms. Severe illness occurs more frequently in people over the age of 
60 years and in those with co-morbidities. In some cases, dyspnoea and progressive 
hypoxemia may necessitate the use of mechanical ventilation. Upwards of 15% of patients 
with SARS-CoV-2 require hospitalisation and many of these patients need some form of 
oxygen support. 
Many of the COVID-19 cases which require hospitalisation are complicated by acute 
respiratory distress syndrome (ARDS), an injurious and potentially fatal lung condition [R20-
1310, R20-1309]. ARDS has no effective specific treatment besides supportive care, which 
includes conservative fluid strategies, early empirical antibiotics for suspected bacterial co-
infection, and importantly the use of ventilation strategies, and prone positioning in severe 
disease. The mortality rate for severely affected patients with ARDS is between 25% and 
60% with the current standard of care [R20-1652]. Histological hallmarks in the early stages 
of ARDS include diffuse alveolar damage followed by oedema, haemorrhage, and subsequent
intra-alveolar fibrin deposition [R20-1812]. Thus, preventing or reducing the severity of the 
‘exudative’ phase of ARDS may delay the onset and/or severity of the injurious 
‘proliferative’ and potentially the ‘fibrotic’ stages of disease in some patients [R20-1815].
Transient Receptor Potential (TRP) channels have been shown to act as chemosensors in 
stress-induced signal transduction cascades [P20-05219]. In the human lung, TRPC6 is the 
most abundantly expressed TRP channel. It is highly expressed on bronchial epithelial cells, 
alveolar type II cells, and endothelial cells. There is evidence that TRPC6 channels are 
indirectly activated by hypoxia and reactive oxygen species, resulting in channel-induced 
Ca2+-influx. Increased calcium influx in smooth muscle cells causes cellular contraction and 
increased epithelial and endothelial cell damage which lead to increased endothelial 
permeability and lung oedema in pathological conditions. Pharmacological inhibition of 
TRPC6 in mouse models of lung injury has been shown to markedly reduce alveolar leakage, 
endothelial cellular damage and cell death.
Due to the rapid global spread of SARS-CoV-2, there is an urgent need to develop efficacious 
treatments for the disease and its complications. While the investigation of anti-viral 
treatment strategies for COVID-19 continues, and in anticipation of a potential future safe 
and effective vaccine, therapies aimed at preventing or slowing down the progression and/or 
intensity of the exudative phase of ARDS secondary to COVID-19 may provide a 
complementary means of reducing morbidity and mortality in patients with lung 


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complications. Targeted inhibition of TRPC6 in this context might therefore be of benefit to 
patients with SARS-CoV-2 at risk of lung complications.
1.2
DRUG PROFILE
BI 764198 is an oral, small-molecule inhibitor of TRPC6. It is being developed for the 
treatment of advanced chronic kidney disease on top of standard of care. Because of the 
potential effect of TRPC6 inhibition in the lungs with regard to formation of lung edema and 
endothelial and epithelial cell apoptosis, BI 764198 is also being investigated for the 
treatment of patients hospitalised for COVID-19. 
Mode of action
BI 764198 is a potent inhibitor of human TRPC6 
, rat TRPC6 
, mouse 
 dog TRPC6 
 and 
cynomolgus monkey 
 in in vitro manual patch clamp assays using 
human HEK293 cells with inducible TRPC6 expression. 
Inhibition of channel-induced Ca2+-influx is believed to prevent smooth muscle cell 
contraction and reduce endothelial cell permeability and damage. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug interactions
To date, no human drug-drug interaction studies have been conducted.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
TRPC6 inhibition should slow or prevent the progression of pulmonary endothelial and 
epithelial cell apoptosis and lung edema in patients with SARS-CoV-2 infection, improving 
the outcome for patients. There is an urgent public health need for rapid development of 
interventions to treat COVID-19 and its complications. Patients to be included in this trial 
will be hospitalised and may require either supplemental oxygen, non-invasive ventilation or 
high-flow oxygen devices. The trial will investigate the efficacy and safety of BI 764198 in 
patients with SARS-CoV-2.


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
The TRPC6 channel is the most abundantly expressed member of the TRP family on human
lung cells. In pulmonary endothelial cells, calcium (Ca2+) influx through TRPC6 increases 
cellular permeability induced by hypoxia/reactive oxygen species generation. Therefore, 
inhibition of channel-induced Ca2+-influx in this context may prevent smooth muscle cell 
contraction and reduce endothelial cell permeability and damage. These dysregulated 
pathophysiological events are postulated to contribute to COVID-19 induced lung 
injury/ARDS. 
 
 
 
 
The intended target indication for BI 764198 is the reduction of ARDS risk or severity in 
hospitalised patients with SARS-CoV-2 infection. TRPC6 inhibition in this patient 
population is expected to improve lung associated morbidity and mortality on top of 
supportive standard of care oxygen therapy, antiviral therapy, or anti-inflammatory therapies. 
The medication is to be administered orally or via nasogastric tube as needed. 
 
 
Risks
Procedure-related risks
The use of an indwelling venous catheter for blood sampling may be accompanied by mild 
bruising and in rare cases, by transient inflammation of the wall of the vein. In addition, in 
rare cases a nerve might be injured while inserting the venous catheter, potentially resulting 
in paraesthesia, reduced sensibility, and/or pain for an indefinite period. The same risks apply 
to venipuncture for blood sampling. 
In most cases, the total volume of blood withdrawn during the entire study per subject will 
likely not exceed the volume of a normal blood donation (500 mL). 
Drug-related risks and measures
Non-clinical safety data is summarized in Section 1.2 above. 
 
 
 


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Taken together, no specific drug-related risks are anticipated. Nevertheless, the following 
safety measures in this study will minimize the risk for the participating patients:

As all patients in the study are hospitalised, they will undergo close medical surveillance 

Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters 
to ensure subjects´ safety, see also Section 5.2.6.1.4, adverse events of special interest
(AESI).
1.4.3
Discussion
BI 764198 has the potential to become an oral treatment for patients hospitalised with SARS-
CoV-2 at risk of respiratory complications, an area of urgent unmet medical need. Based 
upon preclinical and first clinical data for BI 764198, as well as the close medical monitoring 
in this study, medical risks are minimized in relation to the important information expected to 
be gained from this trial. Considering the medical need for effective treatments in patients
hospitalised for COVID-19, the sponsor considers that the potential benefits of therapy in this 
context will outweigh potential risks, which justifies the treatment of patients with BI 764198 
who are hospitalized with severe SARS-CoV-2 and are at high risk of lung complications.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
To evaluate the efficacy and safety of
 BI 764198, an inhibitor of the transient receptor 
potential subtype C6 (TRPC6), compared to placebo in hospitalised patients at risk of 
developing ARDS or diagnosed with ARDS secondary to COVID-19 infection.
The primary comparison of interest is the absolute difference in proportion of patients alive 
and free of mechanical ventilation by Day 29. The primary trial objective is to estimate the 
treatment effect between BI 764198 and placebo. The primary comparison will be made as 
randomised, without regard to any treatment changes.
2.1.2
Primary endpoint(s)

Patients alive and free of mechanical ventilation at Day 29
2.1.3
Secondary endpoints

Patients alive and discharged free of oxygen at Day 29

Patients with occurrence of any component of composite: In-hospital mortality or 
intensive care unit (ICU) admission or mechanical ventilation at Day 29

Time to response, defined as clinical improvement of at least 2 points (from 
randomisation) on the World Health Organization Clinical Progression Scale, 
discharge from the hospital, or considered fit for discharge (a score of 0, 1, 2, or 3 on 
the Clinical Progression Scale), whichever comes first, by Day 29
World Health Organization (WHO) Clinical Progression Scale [R20-2002]:
0. Uninfected; no viral RNA detected
1. Asymptomatic; viral RNA detected
2. Symptomatic; independent
3. Symptomatic; assistance needed
4. Hospitalised; no oxygen therapy
5. Hospitalised; oxygen by mask or nasal prongs
6. Hospitalised; oxygen by non-invasive ventilation or high flow
7. Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200
8. Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors
9. Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or
extracorporeal membrane oxygenation (ECMO)
10. Death

Number of ventilator free days by Day 29

Mortality at Day 15, 29, 60, and 90


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a multi-centre, randomised, double-blind, placebo-controlled trial of BI 764198 in the 
treatment of COVID-19. 
The study will include adult patients (≥50 years) who are hospitalised for infection with 
SARS-CoV-2, the virus that causes COVID-19, as confirmed by PCR (approved point-of-
care test may be used to evaluate inclusion criterion 2 (Section 3.3.2). For inclusion, patients 
will need to have clinical status of Grade 5 (hospitalised; oxygen by mask or nasal prongs) or 
Grade 6 (hospitalised; oxygen by non-invasive ventilation or high flow), as defined by the 
WHO Clinical Progression Scale (Section 2.1.3).
Patients will be enrolled (screened) in the trial once the appropriate informed consent has 
been obtained. Patients who successfully complete screening and still meet the 
inclusion/exclusion will be randomised in a 1:1 ratio to receive either placebo or 
 
BI 764198 per day stratified by baseline severity grade. Dosing with study medication will 
commence on Day 1. The treatment duration is anticipated to last up to 28 days. Refer to 
Flow Chart for EOT, FUP, and EOS visit schedule. The study schematic is shown in 
Figure 3.1: 1 below.
Day 1, randomisation
EOT
Figure 3.1: 1 Study schematic
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
There is an urgent public health need for development of treatments for COVID-19. This trial 
is designed to assess BI 764198 as a potential treatment for respiratory disease associated 
with COVID-19. Patients to be initiated in the study will be those hospitalised for COVID-
19, but not yet needing tracheal intubation and mechanical ventilation.
The primary endpoint (patients alive and free of mechanical ventilation at Day 29) is a 
clinically meaningful outcome measure for an acute condition in which most patients will 
either die or substantially recover within a short time period.


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The secondary endpoint of improvement on the WHO Clinical Progression Scale is an 
internationally recommended endpoint for assessing the efficacy of new treatments for 
patients with SARS-CoV-2 [R20-2002]. As patients may continue to worsen despite therapy, 
the study will also capture disease worsening prior to, or in the absence of, disease 
improvement.
A parallel group, randomized, double-blind, placebo-controlled trial is considered the most 
appropriate design to assess the efficacy and safety BI 764198. Therapy will be on top of 
usual care for COVID-19, so all patients will receive usual care.
A Data Monitoring Committee (DMC), which is independent of the sponsor except for the 
iSTAT, will be established for this study to assess safety on an ongoing basis throughout the 
study (see Section 8.7). The DMC members will perform ongoing safety surveillance and 
provide recommendations to the sponsor regarding study conduct. Further details are
provided in the DMC charter. 
3.3
SELECTION OF TRIAL POPULATION
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
Patients over the age of 50 years are included as these patients have higher risk of developing 
severe lung complications or potentially dying as result of SARS-CoV-2 infection. Hence, the 
evaluation of the potential beneficial effects of TRPC6 inhibition in this high risk population 
would expose a smaller number of patients to this investigational compound in this clinical 
proof of concept study.
Patients are selected because they have been hospitalised for COVID-19 and are at risk of 
developing ARDS. Efforts should be made to minimize the time from patient identification to 
treatment, as TRPC6 inhibition is expected to provide benefit early in the course of disease.  
Patients that do not have the potential for key outcomes or are already improving should not 
be included.
A sufficient number of patients hospitalised for COVID-19 will be screened in multiple 
countries from approximately 40 trial sites to ensure the randomisation of approximately 130
eligible patients.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.


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3.3.1
Main diagnosis for trial entry
Adult patients (≥50 years) hospitalised for COVID-19 requiring non-mechanical (ventilator) 
oxygen therapy and who comply with eligibility requirements may qualify for participation in 
this trial.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Age ≥50 years 
2. SARS-CoV-2 infection positive confirmed by PCR or approved point-of-care test.
3. A score of 5 (hospitalised; oxygen by mask or nasal prongs) or 6 (hospitalised; 
oxygen by non-invasive ventilation or high flow), but not previously ≥7, on the 
WHO Clinical Progression Scale.
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
5. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must abstain from male female sex or must use highly effective methods 
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly during hospitalisation for at least 7 days after 
last trial drug intake. A list of contraception methods meeting these criteria is provided 
in Section 4.2.2.3.
3.3.3
Exclusion criteria
1.
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >5 × the upper 
limit of normal (ULN).
2.
Known active infection with HIV or hepatitis B or C.
3.
Pulmonary oedema/respiratory failure due to cardiogenic insult.
4.
Long-term oxygen therapy prior to current hospitalisation. 
5.
A confirmed baseline prolongation of QTc interval to greater than 450 ms in males or 
470 ms in females, or any other relevant ECG finding at screening, or continued use of 
agents known to prolong the QT interval (refer to listing provided in ISF).
6.
Stage 4 kidney disease or requiring dialysis (i.e., eGFR <30 mL/min/1.73 m2).
7.
History of the following cardiac conditions:
a)
Myocardial infarction within 3 months prior to the first dose
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 2 years without an alternative medical cause.


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b)
Unstable angina
c)
Clinically significant long QT features on electrocardiogram (ECG) or history of 
familial long QT
8.
Anticipated transfer/discharge to another hospital or care facility other than their place 
of residence.
9.
Not committed to full support or intubation (do not resuscitate/do not intubate wishes)
10. Allergy to study medication.
11. Relevant end-organ failure or other medical conditions (e.g. active cancer, cardiac, 
gastrointestinal) which based on investigator judgement would interfere with the 
conduct of this study.
12. Experimental, or off-label usage of medicinal products as specific treatments for 
COVID-19.
13. Currently enrolled in another investigational device or drug trial, or less than 30 days or 
5 half-lives (whichever is shorter) since ending another investigational device or drug 
trial(s), or receiving other investigational treatment(s).
14. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Section 3.3.4.1 and 
Section 3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.6.2.1 and 
5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).


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
The patient experiences renal impairment based on clinical judgement (e.g. sustained 
eGFR <30 mL/min/1.73 m2).

The patient experiences hepatic impairment based on clinical judgement (e.g. ALT/AST 
>5 × ULN.

The patient experiences QT prolongation of the QTc interval of either >60 ms change 
from baseline or greater than 500 ms during the study.
Should a patient become pregnant during the trial, study medication will be stopped and the 
patient will be followed up until birth or otherwise termination of the pregnancy. The data of 
the patient will be collected until Last Patient Completed and reported in the clinical trial 
report. Any events thereafter will be reported in the BI Pharmacovigilance database. For 
further details on pregnancy reporting, refer to Section 5.2.6.2.3.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation, follow-up, and 
vital status collection as outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of patients affected will occur as described in Section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 764198 and placebo to match BI 764198
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 Test product 1
Substance:
BI 764198
Pharmaceutical formulation:
Capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
 
Posology
q.d.
Route of administration:
Oral (p.o.) or, only if needed, nasogastric intubation
Table 4.1.1: 2 Test product 2
Substance:
Placebo to match BI 764198
Pharmaceutical formulation:
Capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
Not applicable
Posology
q.d.
Route of administration:
Oral (p.o.) or, only if needed, nasogastric intubation
4.1.2
Selection of doses in the trial and dose modifications
The proposed therapeutic dose in patients hospitalised with COVID-19 is
 once daily; a 
dose expected to achieve maximal therapeutic benefits. The rationale for the selection of this 
dose is based on the following considerations (refer to Section 1.2):


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4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomised to treatment groups according to a randomisation plan in a 1:1 ratio at Visit 2 via
Interactive Response Technology (IRT). Note that the medication number is different from 
the patient number (the latter is generated during screening via the IRT System).
4.1.4
Drug assignment and administration of doses for each patient
Study medication will be administered, according to the Flow Chart, by a member of the site 
staff that is qualified and licensed to administer the study drug. During the treatment period,
patients are hospitalised and study medication will be administered once daily after the other 
visit procedures have been performed. Study drug should be administered after at least 6 
hours fasting (no food, water is allowed). Patients should remain fasted for 1.5 hours after 
study drug administration. Therefore, it is recommended to dose patients after overnight fast, 
1.5 hours prior to breakfast meal intake.
For administration of study medication on Day 1, the following guidance may be followed to 
allow flexibility in the emergency care setting to begin treatment as soon as feasibility after 
study qualification: 

While 6 hours of fasting is preferred, a minimum of 2 hours is allowed in order to 
dose an eligible patient as soon as feasible following completion of screening

It would be preferred to maintain a 12-18 hour interval between the doses

If the patient is dosed before 18:00, the next dose should be a morning fasted dose the 
next day (followed by morning dosing thereafter)

If the patient is dosed before midnight, the next dose should be at about noon the next 
day (followed by morning dosing thereafter)
The route of administration is oral (p.o.) or, only if needed, nasogastric intubation (refer to 
investigator site file (ISF) for dissolution preparation and administration instructions). If a 
patient is on continuous nasogastric feeding, the need to meet caloric requirements should be 
prioritized and it is recommended that feeding only be interrupted for the duration needed to 
administer the drug.


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Trial treatment may be restarted after a temporary reason for treatment discontinuation. Dose 
reductions or down-titrations are not allowed.
Patients will be administered one capsule per day from Visit 2 until the visit prior to EOT
Visit. Patients may receive treatment with study drug for up to 28 days. In Table 4.1.4: 1, the 
medication schedule for each treatment group is listed.
Table 4.1.4: 1
Dosage and treatment schedule
or matching placebo capsule
 treatment group
1 active
Placebo group
1 placebo
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis
or with any other interest in this double-blind trial will remain blinded with regard to the 
randomised treatment assignments until a snapshot after Last Patient Last Visit Primary 
Endpoint is taken. This snapshot will be taken after the last patient completes the EOT Visit, 
and will be used to obtain efficacy results, to guide further development plans for BI 764198.
At the timepoint of unblinding of this snapshot, patients and investigators will continue to be 
blinded and will remain so until after database lock after Last Patient Completed. 
The access to the randomisation codes will be kept restricted by the global Randomization 
Team (gRT) until the last patient has completed their End of Treatment (EOT) visit and all 
data up until that time point should be entered and cleaned and in preparation for unblinding
according to the sponsor’s Standard Operating Procedures (SOPs).
To ensure that all members of the Trial Team remain blinded, a trial independent statistician 
(iSTAT) will be appointed for the DMC. The iSTAT is involved neither in the conduct of the 
trial(s) the DMC Charter refers to, nor in any other project activities. The iSTAT is not 
allowed to disclose any unblinded trial data to anyone else other than the DMC members and 
is also not allowed to disclose any of the proceedings of the closed DMC session to non-
DMC members. In order to unblind the data for the DMC, the randomization codes will be 
submitted to the iSTAT by the gRT according to the sponsor’s SOPs.
Refer to Section 4.1.5.2 for rules of breaking the code for an individual or for all patients in 
emergency situations.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator


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in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from
to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated clinical 
research organization (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed 
via an IRT system, which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. Where 
necessary, a temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (for US sites).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use for each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 


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These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were administered the doses specified by the Clinical Trial Protocol (CTP) and 
reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor and/or appointed CRO, the investigator or designee must verify that all 
unused or partially used drug supplies have been returned and that no remaining supplies are 
in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Study medication will be administered as an add-on to standard of care (SoC). The SoC will 
be based on appropriate guidelines in place at the time of treatment and may change during the 
course of the study as new information becomes available about treating COVID-19.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications listed under the exclusion criteria (Section 3.3.3), are restricted during the 
trial (refer to ISF for further details).


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4.2.2.2
Restrictions on diet and life style
Patients are hospitalised during the treatment period and study drug should be administered 
after at least 6 hours fasting (no food, water allowed). Patients should remain fasted for 1.5
hours after study drug administration.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to Section 3.3.3) and men able to father a child must 
abstain from male-female sex or must use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and 
correctly during hopsitalisation and for a period of at least 7 days after last trial drug intake.
Men (trial participant or partner of a trial participant) must be vasectomised with documented 
absence of sperm or use a condom if their sexual partner is a WOCBP.
WOCBP (trial participant or partner of a trial participant) must use a highly effective method 
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly if their sexual partner is a man able to father a child.

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion
Or WOCBP and men able to father a child must abstain from male-female sex. This is 
defined as being in line with the preferred and usual lifestyle of the patient or, per 
investigator judgement, relevant to the patient during hospitalisation through 7 days after last 
trial drug intake. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation 
methods; declaration of abstinence for the duration of exposure to study drug; and withdrawal 
are not acceptable.
4.3
TREATMENT COMPLIANCE
For each dose of study medication administered, the date, time, and route will be entered into 
the electronic case report forms (eCRFs). Any missed doses must be recorded in the eCRFs.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Proportion of patients alive and free of mechanical ventilation at Day 29
Patients who are alive and free of mechanical ventilation at Day 29 is defined as those who 
have not died at Day 29 and those who do not depend on mechanical ventilation for breathing
at Day 29.
5.1.2
Improvements on the WHO Clinical Progression Scale
The condition of each potential participant in the study will be assessed using the WHO 
Clinical Progression Scale at the time points specified in the Flow Chart, prior to study drug 
administration as applicable.
WHO Clinical Progression Scale [R20-2002]:
0. Uninfected; no viral RNA detected
1. Asymptomatic; viral RNA detected
2. Symptomatic; independent
3. Symptomatic; assistance needed
4. Hospitalised; no oxygen therapy
5. Hospitalised; oxygen by mask or nasal prongs
6. Hospitalised; oxygen by non-invasive ventilation or high flow
7. Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200
8. Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors
9. Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or 
extracorporeal membrane oxygenation (ECMO)
10. Death
To be considered for inclusion in the study, patients must be Grade 5 or 6 on this scale.
To be considered a “responder” to treatment with a target candidate, a patient needs to show a 
response defined by time to an improvement of at least 2 points (from randomisation) on this 
scale by Day 29. For example, a patient who is Grade 5 (hospitalised; oxygen by mask or 
nasal prongs) at randomisation but improves to Grade 3 (symptomatic; assistance needed) 
would be considered to be a responder. A patient with a discharge from hospital or who is 
considered fit for discharge (a score of 0, 1, or 2 on the Clinical Progression Scale) by Day 29 
will also be considered to be a responder.
5.1.3
Other efficacy assessments
The duration of, and time to, ICU admission, the number of ventilator-free and oxygen-free
days, the initiation of new ventilation use, and duration of hospitalisation will be derived 
from source documents. The date of discharge from hospital and/or death will be recorded on 
the eCRF. 


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The Clinical Frailty Scale (CFS) [R20-2080] will be determined at the time point indicated on 
the Flow Chart. The CFS is a means of summarising the overall level of fitness or frailty of 
an individual. It comprises a 9-point scale with categories ranging from 1 (very fit) to 9 
(terminally ill).
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination, including an assessment of presenting symptoms, will be 
performed at the time points specified in the Flow Chart. It includes at a minimum general 
appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin. 
Height and weight will be recorded at screening.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs and blood gases
Vital signs and blood gases will be evaluated at the time points specified in the Flow Chart, 
prior to study drug administration as applicable.
Temperature, pulse rate, blood pressure, and respiratory rate will be assessed. SpO2 will also 
be assessed. The results must be included in the source documents available at the site.
Blood gases (oxygen and carbon dioxide), when available as part of routine care, and 
respiratory support will be recorded. FiO2 will also be recorded.
Measurements will be taken in line with standard practices for the study centre.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time 
points please see the Flow Chart. All analyses will be performed by a local hospital 
laboratory, the respective reference ranges will be provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
It is the responsibility of the investigator to evaluate the local laboratory results. Clinically 
relevant abnormal findings as judged by the investigator will be reported as adverse events 
(please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.


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The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula will be used 
to estimate eGFR (R12-1392) using serum creatinine in mg/dL (Conventional Unit)* [R12-
1392]:
eGFR = 141 × minS/κ, 1
 × maxS/κ, 1
. × 0.993$%& × 1.018 [if female] x 1.159 [if Black]0, 
where:
S is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of S/κ or 1, and
max indicates the maximum of S/κ or 1
The equation does not require weight because the results are reported normalized to 1.73 m² 
body surface area, which is an accepted average adult surface area.
Note * when serum creatinine is reported in SI unit (µmol/L), the value must be multiplied by 
0.0113 to obtain the value in Conventional Unit (mg/dL).


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Table 5.2.3: 1 
Safety laboratory tests
Laboratory 
Assessments
Parameters
Haematology
Blood Typing (only at screening)
Reticulocyte Count (absolute)
Complete blood count:
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential
Platelet count
Coagulation
D-dimer test 
Fibrinogen
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
International Normalised Ratio (INR)
Protein C (activity as well as antigen, if available)
Plasminogen activator inhibitor-1 (PAI-1) (activity)
Clinical Chemistry
Potassium 
Sodium 
Calcium
Magnesium
Phosphate
Alkaline phosphatase
Bicarbonate
Creatinine
Creatine kinase (MB fraction)
eGFR (estimated by the CKD-EPI formula)
Glucose
Total bilirubin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Gamma-glutamyl transferase (GGT) 
C-reactive protein (regular test)
Ferritin 
Triglycerides
Lactate dehydrogenase (LDH)
Troponin (I)


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5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. ECGs should be performed 0.5-4 hours after drug 
administration. The investigator or a designee will evaluate whether the ECG is normal or 
abnormal and assess clinical relevance. ECGs may be repeated for quality reasons and a 
repeated recording used for safety evaluation. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record. The aggregate PR, QRS, 
QT, RR, QTcF, and QTcB interval data, as available, from the local ECG readout will be 
recorded in the eCRF for safety evaluation.   
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.  
Refer to Section 3.3.4.1 for treatment discontinuation criteria regarding QT prolongation.
5.2.5
Other safety parameters
Not applicable
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions.
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.


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5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture system. A 
copy of the latest list of “Always Serious AEs” will be provided upon request. These events 
should always be reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 


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
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 


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of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the follow-up Visit 1: 
all AEs (non-serious and serious) and all AESIs.
•
After follow-up Visit 1 until the individual patient’s end of trial: cancers of new histology 
and exacerbations of existing cancers, all trial treatment related SAEs and all trial 
treatment related AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
Section 5.2.6.2.2), but not on the CRF.
Vital Status Data Collection
Patients who discontinue trial medication prematurely, who agree to be contacted further, but 
do not agree to physical visits, should be followed up as described in Section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report all deaths/fatal AEs regardless of relationship, and trial treatment 
related SAEs and trial treatment related AESIs the investigator becomes aware of.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs (including “Always serious” events, even though they 
may not have met the criteria of an SAE), AESIs, and non-serious AEs which are relevant for 
the reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific reporting process will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.


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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable
5.4
ASSESSMENT OF BIOMARKER(S)
No exploratory biomarkers are planned. Established biomarkers of efficacy and safety are 
described and discussed in Sections 5.1 and 5.2.
5.5
BIOBANKING
Not applicable
5.6
OTHER ASSESSMENTS
Not applicable


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5.7
APPROPRIATENESS OF MEASUREMENTS
The primary endpoint measurements will be consistent with the recognized standard for 
patients hospitalised with SARS-CoV-2.
All other measurements performed during this trial are standard measurements and will be 
performed in order to determine the efficacy and safety in an appropriate way. 
Therefore, all measurements performed in this trial are considered by the sponsor to be 
appropriate.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The visit schedule is to be adhered to as specified in the Flow Chart. Each visit date (with its 
window) is to be counted from Day 1. 
If any visits cannot be performed while the patient is hospitalised, subsequent visits should 
follow the original visit date schedule. Blood sampling for safety laboratories and pregnancy
testing is marked with a window of +/- 1 day in the Flow Chart and should be performed 
accordingly when a daily visit cannot be done.
If any Follow-up (FUP) visits have to be rescheduled, subsequent visits should follow the 
original visit date schedule. 
Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may 
be included as deemed necessary by the investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and explanations 
provided in Section 5. Additional details on procedures at selected visits are provided below.
At all applicable visits vital signs, blood gases and WHO Clinical Progression Scale 
assessment should be done prior to study drug administration. 
6.2.1
Screening and run-in period(s)
Screening Period
The Screening period is defined as the period from the screening visit to randomization (first 
study drug administration). 
All patients (or the patient’s legally accepted representative) must sign an Informed Consent 
consistent with ICH-GCP guidelines and the local legislation prior to any study specific 
procedures (refer to Section 8.1). Once consented, the patient is considered to be enrolled in 
the trial and have started screening. The patient should be recorded on the enrolment log and 
registered in IRT as a screened patient. Patients will be assigned a patient number and 
enrolment must be recorded in eCRF pages.
Patients who do not meet eligibility criteria should be documented as a screen failure. Re-
screening will not be permitted. Procedures can be retested as necessary per investigator 
judgement to confirm eligibility prior to randomization.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.


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Medical History:
Medical history includes estimated date and time of first SARS-CoV-2 infection symptoms as 
well as symptom details.
Baseline Conditions:
Baseline conditions include number of co-morbidities (e.g., respiratory, cardiovascular, 
metabolic, malignancy, endocrine, gastrointestinal, immunologic, and renal).
6.2.2
Treatment period(s)
The treatment period starts with Visit 2 (Day 1, randomization) and ends with the EOT visit
(possible Day 2 through Day 29). Patients will remain hospitalised during the treatment
period and daily protocol visits will be conducted to complete procedures according the Flow 
Chart. Patients may receive treatment with study drug for up to 28 days, however if a patient 
is well enough to be discharged, then study drug may be stopped before the maximum 
treatment duration (i.e. 28 days).
EOT visit should be completed the day after the last dose of study drug is administered for all 
patients regardless of discharge status. EOT visit is expected to align with day of discharge, 
unless it is planned for a patient to remain hospitalised after treatment with study drug is 
stopped. EOT visit should occur no later than Day 29.
6.2.3
Follow-up period and trial completion
For all randomised patients, termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.
Applicable FUP visits and EOS visits will be conducted remotely by a phone contact for all 
patients that have completed treatment, EOT visit, and discharge. Each of these visits 
includes vital status.
FUP visits should be conducted as follows:

FUP 1 should be performed 4 days after EOT visit for all patients. 

FUP 2 and FUP 3 which correspond to study Day 15 and Day 29 after start of therapy, 
should be performed if the time point is applicable after drug discontinuation. FUP 2 
and FUP 3 visits should not be conducted within +/- 2 days of EOT or FUP 1. 

FUP 4 and EOS which correspond to study Day 60 and Day 90 will be performed for 
all patients.
If a patient remains hospitalized after EOT visit, applicable FUP visits and the EOS visit will 
be conducted in hospital until discharge and thereafter by telephone. 
If a patient withdraws participation from the study, it may be agreed to collect vital status per 
the remaining originally planned visit schedule according to the Flow Chart. 
Trial completion is defined as patients completing the FUP and EOS visits according to the 
Flow Chart.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This is a randomized, double-blind, placebo-controlled, parallel group trial with an
anticipated treatment period of 4 week and a follow up period of up to 90 days from 
randomisation. BI 764198 will be compared to placebo in hospitalised patients at risk of 
developing ARDS or diagnosed with ARDS secondary to COVID-19 infection.
The primary endpoint is patients alive and free of mechanical ventilation at Day 29 and will 
be analysed using a logistic regression model to compare the absolute difference in 
proportions of patients alive and free of mechanical ventilation at Day 29 with BI 764198 and 
placebo. Detailed specifications are provided in Section 7.2.2.
The primary endpoint and secondary endpoints are defined in Section 2.1.
7.1
NULL AND ALTERNATIVE HYPOTHESES
No formal testing will be performed and hence no null and alternative hypotheses are defined 
since this is an exploratory study.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The efficacy analysis will be performed in all randomized patients who documented to have 
received at least one dose of trial medication. This set will be called Full Analysis Set (FAS).
Patients will be analysed as randomised, without regard to any treatment changes. The intent-
to-treat (ITT) principle will be applied to the randomized set including all observed data in 
the primary analysis regardless of treatment discontinuation. Baseline refers to the last 
measurement prior to randomisation.
7.2.2
Primary endpoint analyses
To evaluate the difference in proportions of patients alive and free of mechanical ventilation 
at Day 29 with BI 764198 and placebo, the analysis of the primary endpoint will be 
performed with a logistic regression model including covariates of treatment, severity grade 
at baseline, age, creatinine at baseline, and duration of symptoms before hospitalisation. The 
point estimates, standard errors and confidence intervals for the difference in proportions will 
be derived based on the estimates from the logistic regression model. Patients who terminate 
the study medication prematurely will be followed and the events which occur after 
premature discontinuation of medication and before the time point of interest will be included 
in the analysis using Full Analysis Set (FAS). Patients will be analysed according to their 
assessed severity grade on the WHO Clinical Progression Scale recorded at baseline (last 
assessment prior to administration of study drug).


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A sensitivity analysis will be conducted with a logistic regression model including covariates 
of treatment, severity grade at baseline, age, creatinine at baseline, D-dimer at baseline, and 
duration of symptoms before hospitalisation with patients who don’t miss D-dimer at 
baseline. Details will be defined in TSAP.
Subgroup analysis will be performed using descriptive statistics/figures by subgroup e.g., age 
category, race, baseline severity grade, categorized duration of symptoms before 
hospitalisation, etc. Details will be defined in TSAP.
7.2.3
Secondary endpoint analyses
Analysis of patients alive and discharged free of oxygen at Day 29 and mortality at Day 15, 
29, 60, and 90 will be conducted using the same model used for the primary endpoint, to 
assess the difference in proportions of patients with BI 764198 and placebo . 
The difference of ventilator free days between BI 764198 and placebo group will be analysed 
using an ANCOVA model including treatment, age, creatinine at baseline, and duration of 
symptoms before hospitalisation.
Time to response, defined as clinical improvement of at least 2 points (from randomisation) 
on the World Health Organization Clinical Progression Scale, discharge from the hospital, or 
considered fit for discharge (a score of 0, 1, 2, or 3 on the Clinical Progression Scale), 
whichever comes first, by Day 29, will be analysed using a Cox proportional-hazards model 
including covariates of treatment, age, creatinine at baseline, and duration of symptoms 
before hospitalisation will be performed. Hazard ratio and Kaplan-Meier curves will be 
provided. Patients who do not respond will be censored at Day 29.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. 
 


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All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.2.6
Interim Analyses
No interim analysis is planned, but a Data Monitoring Committee (DMC) will be in place 
with tasks as described in Section 8.7.
7.3
HANDLING OF MISSING DATA
All attempt will be made to collect all data per protocol.
For patients who miss Clinical Progression Scales, imputation will be performed using data 
from other sources if available, e.g., oxygen use, ventilation use, etc.
For patients who miss start date and/or end data of hospitalisation, ventilator use and oxygen 
use, data will be imputed based on available Clinical Progression Scales. If a patient dies 
while hospitalised, the number of days of hospitalisation will be imputed as 28 days.
Further details will be specified in the TSAP.
7.4
RANDOMISATION
Patients will be randomised in blocks at a 1:1 ratio to double-blind treatment stratified by 
baseline disease severity based on scores in the Clinical Progression Scale (5 vs. 6). 
Approximately equal numbers of patients will be randomised to each treatment group.


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BI will arrange for the randomisation, packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history


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
Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site


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as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection and future use of 
biological samples and clinical data, in particular

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Visit Primary Endpoint” is defined as the date at which the last 
patient in the whole trial is examined for the purpose of final collection of data for the 
primary endpoint.
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site. Early termination of the trial is 
defined as the premature termination of the trial due to any reason before the end of the trial
as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 
The DMC will evaluate safety data and efficacy data. While DMC members may be 
unblinded, measures are in place to ensure the blinding for everyone else involved in the trial. 
Regular DMC meetings will be held at specified intervals. The DMC will recommend 
continuation, modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
An IRT vendor will be used in this trial. Details will be provided in the IRT Manual, 
available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P20-05219
Dietrich A. Modulators of transient receptor potential (TRP) channels as 
therapeutic options in lung disease. Pharmaceuticals 2019;12:23.
R20-1309
Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al, China Medical Treatment 
Expert Group for Covid-19. Clinical characteristics of coronavirus disease 
2019 in China. N Engl J Med 2020;382(18):1708-1720.
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
KusekJW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med 2009; 150(9) ; 604-612
R20-1310
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and 
outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, 
China: a single-centered, retrospective, observational study. Lancet 
Respiratory Medicine, Published Online February 21, 2020, doi: 
10.1016/S2213-2600(20)30079-5; 2020.
R20-1652
Aranda-Valderrama P, Kaynar AM. The basic science and molecular 
mechanisms of lung injury and acute respiratory distress syndrome. Int 
Anesthesiol Clin 2017;56(1):1-25.
R20-1812
Katzenstein ALA, Bloor CM, Leibow AA. Diffuse alveolar damage – the 
role of oxygen, shock, and related factors: a review. Am J Pathol 
1976;85(1):210-228.
R20-1815
Thompson BT, Chambers RC, Liu KD. Acute respiratory distress 
syndrome. N Engl J Med 2017;377(6):562-572.
R20-1823
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et 
al. Remdesivir for the treatment of Covid-19 - preliminary report. New 
England Journal of Medicine, published on May 22, 2020, doi: 
10.1056/NEJMoa2007764; 2020.
R20-3802
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et 
al. Remdesivir for the treatment of Covid-19 - final report. New England 
Journal of Medicine, 383(19)1813-1826; 2020.
R20-2001
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-
ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 
2020;382(19):1787-1799.
R20-2002 
WHO Working Group on the Clinical Characterisation and Management of 
COVID-19 infection. A minimal common outcome measure set for 
COVID-19 clinical research. Lancet Infectious Diseases, Published Online 
June 12, 2020, doi: 10.1016/S1473-3099(20)30483-7; 2020.


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R20-2080
Juma S, Taabazuing MM, Montero-Odasso M. Clinical frailty scale in an 
acute medicine unit: a simple tool that predicts length of stay. Can J Geriatr 
2016;19(2):34-39.
9.2
UNPUBLISHED REFERENCES
c29080032
Safety, tolerability and pharmacokinetics of BI 764198 in healthy male 
subjects (single-blind, partially randomised, placebo-controlled, parallel 
group design). 1434-0001. 09 April 2020.
c32296993
Investigator’s Brochure BI 764198 for the treatment of COVID-19 related 
ARDS.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
08 Jan 2021
EudraCT number
EU number
2020-003211-96
BI Trial number
1434-0009
BI Investigational Medicinal 
Product
BI 764198
Title of protocol
BI 764198 efficacy and safety in 
prevention/progression of ARDS and ARDS-
related complications secondary to COVID-19
(ACTION ON COVID-19)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Synopsis, Flow Chart, 3.1, 3.3.2, 
Description of change
Addition of point-of-care SARS-CoV-2 testing.
Rationale for change
To allow use of point-of-care testing to evaluate 
inclusion criterion 2.
Section to be changed
Flow Chart
Description of change
Specified allowed time window for screening 
ECG, Visit 2 safety laboratories, and physical 
examinations.
Addition to footnote “f” to collect oxygen therapy 
end date during Follow-up, if unknown at 
discharge.
Clarified IRT randomisation call timing.
Added footnote “i” to cover potential dosing on 
EOT Visit, if treatment is less than 28 days.
Rationale for change
To add further instructions to Flow Chart 
procedures.
Section to be changed
Flow Chart, 5.2.4
Description of change
 
 
 


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Section to be changed
Description of change
Rationale for change
Section to be changed
3.3
Description of change
Addition of paragraph to guide patient selection 
and timing of trial entry.
Rationale for change
To message on selection of patients that will help 
better evaluate the study drug and trial endpoints. 
Section to be changed
3.3.3
Description of change
Removed “renal” from exclusion criterion 11.
Rephrased exclusion criterion 4.
Rationale for change
To eliminate redundancy, as already covered by
exclusion criterion 6.
To clarify exclusion criterion 4.
Section to be changed
3.3.3, 3.3.4.1, 4.2.2.1: 1, 5.2.4
Description of change
 
 
 
   
 
 
Rationale for change
 
Section to be changed
4.1.4
Description of change
Addition of guidance for the administration of the 
first dose of study drug and continuous nasogastric 
feeding. 
Rationale for change
To provide study drug administration instructions 
around scenarios that may arise during emergency 
care.
Section to be changed
4.2.2.1, 4.2.2.1: 1
Description of change
 
 


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Rationale for change
 
Section to be changed
5.1.2, 6.2
Description of change
Specified that WHO Clinical Progression Scale 
should be performed prior to dosing.
Rationale for change
To clarify time point of assessment.
Section to be changed
5.2.2, 6.2, 6.2.2
Description of change
Updated text for requirement of vital signs and 
blood gases to be done prior to dosing and 
removed text stating that dosing must be last.
Rationale for change
To remove unnecessary ordering of procedures for 
an inpatient study and clarify that vital signs and 
blood gases, if applicable, are to be assessed for 
eCRF data entry once pre-dose.
Section to be changed
5.2.3, 9.1
Description of change
Addition of CKD-EPI formula and the associated 
reference
Rationale for change
Formula needed for site calculation.
Section to be changed
5.2.3: 1
Description of change
Clarified safety laboratory parameters.
Rationale for change
To provide sites a clearer description of local 
laboratory assessments.
Section to be changed
5.2.6.2.2
Description of change
Addition of “The investigator must report SAEs 
(including “Always serious” events, even though 
they may not have met the criteria of an SAE)…”
Rationale for change
To clarify SAE reporting requirements for 
“Always serious” events.
Section to be changed
7.2.2
Description of change
Addition of text to define that patients will be 
analysed according to their assessed severity grade 
on the WHO Clinical Progression Scale recorded 
at baseline.
Addition of race as a subgroup analysis.
Rationale for change
To specify analysis rules and provide a rationale 
for collection of race data in eCRF.


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BI Trial No.: 1434-0009
c32418694-02
Clinical Trial Protocol
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Section to be changed
7.2.3
Description of change
Removed further endpoint mistakenly placed in 
this section.
Rationale for change
To correct the section to contain secondary 
endpoints only. 
Section to be changed
7.5, 3.3, Synopsis
Description of change
Updated sample size and probabilities for decision 
making
Rationale for change
To increase sample size and give additional 
information on the rationale used for the 
calculation.
Section to be changed
Synopsis, Flow Chart, 1.1, 1.4.1, 2.2.2, 3.3, 3.3.3, 
4.1.4
Description of change
Minor formatting and editorial corrections.
Rationale for change
To improve readability. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32418694
2.0
clinical-trial-protocol-revision-01
BI 764198 efficacy and safety in prevention/progression of ARDS and ARDS-related
complications secondary to COVID-19 (ACTION ON COVID-19)
Approval-Therapeutic Area 
11 Jan 2021 09:49 CET
Author-Trial Statistician
11 Jan 2021 15:18 CET
Approval-Team Member Medicine
11 Jan 2021 15:23 CET
Author-Clinical Trial Leader
11 Jan 2021 18:04 CET
Verification-Paper Signature
Completion
11 Jan 2021 19:08 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32418694
2.0

SAP_001.pdf: 
Boehringer 
lngelheim 
TRIAL STATISTICAL ANALYSIS PLAN 
c35421742-01 
BI Trial No.: 
Title: 
BI Investigational 
. Product(s): 
Responsible trial 
statistician( s): 
Date of statistical 
analysis plan: 
Version: 
1434-0009 
BI 764198 efficacy and safety in prevention/progression of ARDS 
and ARDS-related complications secondary to COVID-19 (ACTION 
ON COVID-19) 
BI 764198 
08 APR 2021 
Page 1 of 28 
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□ 2021 Boehringer lngelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated 
companies 


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1. 
TABLE OF CONTENTS
TITLE PAGE ........................................................................................................................... 1 
1. 
TABLE OF CONTENTS .............................................................................................. 2 
LIST OFT ABLES ................................................................................................................... 4 
2. 
3. 
4. 
5. 
5.1 
5.2 
5.2.1 
5.2.2 
6. 
6.1 
6.Z 
6.3 
6.5 
6.6 
6.7 
7. 
7.1 
7.2 
7.3 
7.4 
7.4.1 
7.4.2 
7.5 
7.5.1 
7.5.2 
7.7 
7.8 
7.8.1 
7.8.2 
7.8.3 
LIST OF ABBREVIATIONS ....................................................................................... 5 
INTRODUCTION ......................................................................................................... 7 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY .............................. 8 
ENDPOINTS .................................................................................................................. 8 
PRIMARY ENDPOINTS ............................................................................................. 8 
SECONDARY ENDPOINTS ....................................................................................... 8 
Key secondary endpoints .......................................................................................... 8 
Secondary endpoints .................................................................................................. 8 
GENERAL ANALYSIS DEFINITlONS ..................................................................... 9 
TREATMENTS ............................................................................................................. 9 
IMPORTANT PROTOCOL DEVIATION ................................................................ 9 
SUBJECT SETS ANALYSED ................................................................................... 10 
POOLING OF CENTRES .......................................................................................... 12 
HANDLING OF MISSING DATA AND OUTLIERS ............................................ 12 
BASELINE, TIME WINDOWS AND CALCULATED VISITS ............................ 13 
PLANNED ANALYSIS .............................................................................................. 14 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................. 14 
CONCOMITANT DISEASES AND MEDICATION .............................................. 15 
TREATMENT COMPLIANCE ................................................................................ 15 
PRIMARY ENDPOINTS ........................................................................................... 15 
Primary Analysis ....................................................................................................... 15 
Subgroup analysis .................................................................................................... 17 
SECONDARY ENDPOINTS ..................................................................................... 17 
Key secondary endpoints ........................................................................................ 17 
(Other) Secondary endpoints .................................................................................. 17 
EXTENT OF EXPOSURE ......................................................................................... 19 
SAFETY ANALYSIS .................................................................................................. 20 
Adverse events .......................................................................................................... 20 
Laboratory data ....................................................................................................... 21 
Vital signs ................................................................................................................. 21 


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7.8.4 
7.8.5 
8. 
9. 
11. 
ECG ........................................................................................................................... 21 
Others ........................................................................................................................ 21 
TIME POINT OF RELEASE OF TREATMENT INFORMATION ..................... 22 
REFERENCES ............................................................................................................ 23 
HISTORY TABLE ...................................................................................................... 28 


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LIST OF TABLES 
Table 6.1: l 
Definition of treatment periods .......................................................................... 9 
Table 6.3: l 
Patient sets analysed ...................................................................................... 11 
Table 11: 1 
History table ..................................................................................................... 28 


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2. 
Term 
AE 
BRPM 
BES 
CTC 
CTP 
CTR 
DM&SM 
DRA 
DM 
DMG 
EDC 
EMEA 
FAS 
HPT 
ICH 
IPD 
LOCF 
MedDRA 
MCPMod 
MQRM 
MMRM 
PASI 
PCR 
PK 
PKS 
PPS 
PSTAT 
PT 
PV 
·QI 
LIST OF ABBREVIATIONS 
Definition / description 
Adverse Event 
Blinded Report Planning Meeting 
Biopsy Evaluable Set 
Common Terminology Criteria 
Clinical Trial Protocol 
Clinical Trial Report 
Boehringer Ingelheim Data Management And Statistics Manual 
Drug Regulatory Affairs 
Diabetes mellitus 
Dictionary Maintenance Group 
Electronic Data Capture 
European Agency For The Evaluation Of Medicinal Products 
Full Analysis Set 
Hypertension 
International Conference On Harmonisation 
Important Protocol Deviation 
Last Observation Carried Forward 
Medical Dictionary For Regulatory Activities 
Multiple Comparison Procedure and Modelling 
Medical Quality Review Meeting 
Mixed Effect Model Repeated Measurement 
Psoriasis Area Severity Index 
Poly m erase Chain Reaction 
Pharmacokinetics 
Pharmacokinetics Set 
Per Protocol Set 
Project Statistician 
Preferred Term 
Protocol Violation 
Lower Quartile 


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companies 
Term 
Q3 
REP 
RS 
SA 
SD 
SMQ 
soc 
sPGA 
TOM 
ToC 
TS 
TSAP 
Definition / description 
Upper Quartile 
Residual Effect Period 
Randomised Set 
Statistical Analysis 
Standard Deviation 
Standardised MedDRA Query 
System Organ Class 
Static Physician's Global Assessment 
Trial Oversight Meeting 
Table of Contents 
Treated Set 
Trial Statistical Analysis Plan 


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3. 
INTRODUCTION
As per ICH E9 ill, the purpose of this document is to provide a more technical and 
detailed elaboration of the principal features of the analysis described in the protocol, and 
to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data. 
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 "Statistical Methods and Determination of Sample Size". 
Therefore, TSAP readers may consult the CTP for more background information on the 
study, e.g., on study objectives, study design and population, treatments, definition of 
measurements and variables, planning of sample size, randomization. 
The trial data is stored in the BI Rave (BRA VE) database system. 
S A S ®  Version 9.4 will be used for analyses. 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
This section is not applicable as no change has been made. 
5. 
ENDPOINTS
5.1 
PRIMARY ENDPOINTS 
Please refer to protocol. 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Key secondary endpoints 
This section is not applicable as no key secondary endpoint has been specified in the 
protocol 
5.2.2 
Secondary endpoints 
Please refer to CTP. 


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· 6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
Patients will be randomised l: l to BI 764198 treatment group or placebo. 
The assignment of treatment groups will be based on randomization for randomized patient 
set as defined in Section 6.3. 
The following study periods based on actual start and stop dates of study treatment 
administration are defined: 
Table 6.1: 1 Definition of treatment periods 
Analysing Treatment 
Start Date (including) 
Period 
Screening 
Day of informed consent 
On-treatment period 
Post-treatment 
Day of first administration of 
study medication 
Stop Date (including) 
Date of first administration 
of study medication -1 day 
(It could be the same day of 
informed consent) 
Last contact date 
For detailed rules for assigning AEs to these time periods, please refer to Section 7.8. l. 
6.2 
IMPORTANT PROTOCOL DEVIATION 
A protocol deviation (PD) is important if it affects the rights or safety of the study subjects, 
or if it can potentially influence the primary outcome measurement(s) in a non-negligible 
way. Patients with important PDs that could potentially impact the evaluation of the 
primary endpoint(s) will be excluded from PPS, if applicable. 
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. Important PDs will be reviewed at Medical Quality Review Meetings 
(MQRMs) conducted periodically during the trial. A list of protocol deviations will be 
discussed at the Blinded Report Planning Meetings (BRPMs). 
If the data show other important PDs, this table will be supplemented accordingly at 
BRPMs or through team review of the manual PD log. The decision whether a subject will 


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be excluded from the analysis will be made at the final BRPM prior to Database Lock 
(DBL). 
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. 
6.3 
SUBJECT SETS ANALYSED 
There are 4 patient sets defined in this trial: 
•
Screened Set (SCR)
This set includes all patients with signed informed consent. The screened set will be 
used for disposition summaries.
•
Randomised Set (RS) 
The RS includes all patients who signed the informed consent form and were also 
randomised, regardless whether the patient was treated with trial medication or not. 
The randomized set will be used for analysis of important protocol deviations (IPDs). 
•
Full Analysis Set (FAS)
The FAS includes all patients in the RS who received at least l dose of trial
medication. The FAS is used for efficacy and safety analyses.
•
Per Protocol Set (PPS)
The PPS includes all patients from the FAS without IPDs leading to exclusion from per
protocol analysis. The PPS is used for efficacy sensitivity analyses only if the number
of patients with IPDs is> 10% of total number of patients in FAS. 
Analyses will be performed as outlined in Table 6.3: 1. 


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Table 6.3: 1 Patient sets analysed 
Class of 
Screened set 
endpoint 
Efficacy 
analysis 
Safety 
analysis 
Patients 
X 
disposition 
1 S = Sensitivity analyses 
2 0 : Optional 
Patient set 
Full analysis set 
Randomised set 
Per Protocol Set 
X 
si 
02 
X 
The FAS will be used for the efficacy analyses following the intention-to-treat (ITT) 
principle in assigning patients to treatment groups, i.e., efficacy analyses will be analysed 
as randomised using the FAS. 
If a patient receives incorrect medication for the entire treatment period, efficacy will be 
analysed as randomized and safety will be analysed as treated. If a patient receives 
incorrect medication for part of the treatment period, such cases will be discussed in the 
RPM. 


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6.5 
POOLING OF CENTRES 
This section is not applicable because centre/country is not included in the statistical 
model. 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
All patients will be followed to collect necessary efficacy and safety information, even if 
patients discontinue study medication prematurely. 
For patients who miss WHO clinical progression scales, imputation will be performed 
using data from other sources if available, e.g., oxygen use, ventilation use, etc. 
For patients who miss start date and/or end data of hospitalisation, ventilator use and 
oxygen use, data will be imputed based on available information on the eCRF page of 
WHO Clinical Progression Scales. 


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If a patient dies while hospitalised, the number of days of hospitalisation will be imputed 
until day 29 (i.e, 28 days of hospitalisation). If a patient dies while in ICU, the duration of 
ICU stay will be imputed until day 29. For patients who die before day 29, WHO 
progression scale will be imputed as 10 for all remaining visits: in addition, duration of 
oxygen (or ventilation) use will be imputed until day 29. 
For patients who are discharged before day 29, WHO progression scale will be imputed 
using the last available observation if no additional data is available after discharge. 
For patients who discontinue treatment early, if the patient is on oxygen/ventilation before 
discontinuation, the number of days on oxygen/ventilation will be imputed until day 29. If 
the patient is not on mechanical ventilator at the last observed assessment, the number of 
ventilator free days will be imputed until day 29. 
For missing or incomplete AE dates, BI internal procedures and guidelines will be 
followed Q.,_]J_. The same philosophy will be applied to missing concomitant medication 
dates (where applicable), and dates of study medication discontinuation, and trial 
completion date. 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
For efficacy endpoints, baseline is defined as the pre-treatment observation at Visit 2. If 
Visit 2 is missing, then Visit 1 will be used for baseline. 
For laboratory safety measurements, the last measurements taken prior to the treatment 
start will be considered as baseline. 
The visit schedule with accompanying details can be found in Flow Chart 1 in CTP. 
Measurements taken after start of treatment will be considered either on- or off-treatment 
values based on definition in Table 6.1: l. 


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7. 
PLANNED ANALYSIS
Descriptive statistics for continuous variables will be N (number of patients with non-
m1ssmg 
values), mean, standard deviation (SD), minimum, median, and maximum. In general, 
means, 
medians, SDs, will be presented to one more decimal place than the raw data. Minimums 
and 
maximums will be presented to the same number of decimal places as the raw data. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage(%) relative to 
the respective treatment group. Percentages will be rounded to one decimal place. The 
category "missing" will be displayed only if there are actually missing values. Percentages 
will be based on all patients in the respective patient set no matter whether they have non-
missing values or not. 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Only descriptive statistics are planned for this section of the report. Demographic 
parameters collected and to be presented include, but are not limited to, the following: 
• . . 
• . 
• 
Sex (Male, Female) 
Race and ethnicity (as defined in the eCRF)
Region
Age [years] 
Height [cm] 
Weight [kg] (continuous) 
Body mass index [kg/m2] ( defined as weight [kg]/(height [cm]/ 100)2)
•
Smoking history (Never-smoked, Former-smoker, Currently smokes)
•
Alcohol History (Never drink, Former-drinker, Currently drinker) 
•
COVID-19 Symptom 
•
SARS-CoV-2 Seropositive at baseline
•
WHO clinical progression scale at baseline
•
Clinical Frailty Scale
•
Blood type
•
Cardiac disease disease (Yes, No) 
•
Hypertension (Yes, No) 
•
Respiratory disease (Yes, no) 
•
Diabetes mellitus (Yes, No) 
•
Kidney disease (Yes, No) 
•
Coagulation parameters (Normal, Abnormal) 
•
Infection date to admission ( < 7 days,   7 days)


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•
Time to drug intake from hospitalization(< 24 hours,   24 hours)
•
Duration of symptoms before hospitalization
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Concomitant diseases will be summarised descriptively. The frequency [N (%)] of patients 
with different concomitant diseases (baseline conditions) will be presented. The 
concomitant medications taken at baseline and those taken while on treatment will be 
coded using the World Health Organization (WHO) Drug coding dictionary. These will 
then be summarized by standardized drug grouping and listed by patient with each 
medication taken. 
Concomitant non-Drug Therapies will also be summarized descriptively. 
7.3 
TREATMENT COMPLIANCE 
This section is not applicable because study medication is not dispensed directly to patients 
and instead is administered to hospitalized patients by a site staff member. Any missed 
doses are recorded in the eCRFs. 
7.4 
PRIMARY ENDPOINTS 
7.4.1 Primary Analysis 
The primary objective is to evaluate the difference in proportions of patients alive and free 
of mechanical ventilation at Day 29 with BI 7 64198 and placebo. The primary analysis of 
the primary efficacy endpoint will be performed on the full analysis set (FAS) following 
the treatment policy, i.e., patients who initiate other therapies during the treatment period 
or patients who terminate the study medication prematurely will be followed up for data 
collection until the time point of interest and all these data will be included in the analysis. 
A logistic regression model will be used including covariates of treatment, WHO clinical 
progression scale at baseline, age, creatinine at baseline, and duration of symptoms before 
hospitalization. The point estimate, standard error and confidence interval for the risk 
difference in proportions will be derived based on the estimates from the logistic 
regression model. The fitted logistic regression model will be used to predict the 
probability ofresponse for every subject in the study as if they had received treatment or 
placebo, and the average in the difference of response probabilities between treatment and 
placebo will be calculated. For primary analysis, nominal p-value for the risk difference 
will be provided. 


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With a data set of n subjects, define a binary response vector for n patients alive and free of 
mechanical ventilation at Day 29 as Y = (yi, y2, • • · ,  Yn) T, and covariate matrix X = 
[xi, x2 , · · · ,  xnF ., where x; indicates a covariate vector that consists of treatment, severity
grade at baseline, age, creatinine at baseline, and duration of symptoms before 
hospitalization for ith subject. A logistic regression model assumes log P(yi=ll i)
) = p r xi. 
1-P(yi=l Xi 
Define b as the maximum likelihood estimate of f3, and its estimated variance-covariance 
matrix is V. To estimate the proportions of responders in both treatment and placebo arms, 
and their difference: 
1. Create the new covariate matrix Xt from X by adjusting the column corresponding to 
treatment assignment such that all subjects are in the treatment group. Then calculate the 
vector of estimated probabilities of response to treatment, f t from X t and b, Pt = 
logit-1(Xtb). 
2. Similarly, assume each subject is assigned to placebo and repeat the step 1 to get Xc and 
Pc for placebo group.
I.·(P ·-P -) 
ε 
ε 
3. The estimated difference in proportions is d = 
1 ti 
ci, where Ptiand Pei are the ith 
n 
elements of Pt and Pc, respectively. Define At as a vector with elements Ati = Pti (1 - Pti)
and Aci = Pci(l - Pea · Then, the standard errors of these estimators are derived as 
follows: 
The confidence interval of the estimation is d ± Z1_  · SE(d). The details oflogistic
2 
regression analysis and SAS code are provided in Section 10 .1.1 and Ge, et al. (2011) f f i
In addition to the primary analysis, an analysis using composite strategy will be conducted 
to handle intercurrent events. The expected intercurrent events of interest in this trial are 
treatment discontinuation, death, and use of new therapies which are SoC for COVID-19 
including Remdexivir and Dexamethasone. This analysis strategy considers patients with 
intercurrent events as treatment failure. 
Sensitivity analyses will be conducted on the primary endpoint as follows: 
•
A logistic regression model including covariates of treatment, severity grade at 
baseline, age, creatinine at baseline, D-dimer at baseline, and duration of symptoms
before hospitalisation in FAS. 


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•
A logistic regression model including covariates of treatment, severity grade at 
baseline, age, creatinine at baseline, and time from first symptoms to start
medication in FAS. 
•
A logistic regression model including covariates of treatment, severity grade at 
baseline, age, creatinine at baseline, and time from screening of patient to first drug
in mouth in FAS. 
•
A logistic regression model including covariates of treatment, severity grade at 
baseline, age, creatinine at baseline, and time from hospitalization to first drug in 
FAS. 
• . A logistic regression model including covariates of treatment, severity grade at 
baseline, age, creatinine at baseline, and duration of symptoms before
hospitalization on PPS. This analysis will be performed only if number of patients 
with IPDs excluded from PPS is greater than 10% of total number of randomised 
patients. 
•
A Cochran-Mantel-Haenszel type weighted average of differences with weights by
severity grade at baseline on FAS. The details of Cochran-Mantel-Haenszel test and
SAS code are provided in Section 10. 1. 2. 
•
To deal with patients who stop treatment due to sponsor's request, a logistic
regression model including covariates of treatment, severity grade at baseline, age,
creatinine at baseline, and duration of symptoms before hospitalization by defining
a hypothetical estimand: treating these patients as non-responders (i.e. neither alive
nor free of mechanical ventilation).
•
A logistic regression model including covariates of treatment, severity grade at 
baseline, and age in FAS 
7.4.2 
Subgroup analysis 
Analyses for subgroups specified in Section 6.4 will be performed for the primary endpoint 
using the logistic regression model to evaluate treatment-by-subgroup interactions. 
7.5 
SECONDARY ENDPOINTS 
7.5.1 
Key secondary endpoints 
This section is not applicable as no key secondary endpoint has been specified in the 
protocol. 
7.5.2 
(Other) Secondary endpoints 
Secondary endpoints will be analyzed on the FAS using treatment policy estimand. 


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•
Analysis of patients alive and discharged free of oxygen at Day 29 will be conducted
using the same model as for the primary endpoint, to assess the difference in 
proportions of patients with BI 764198 and placebo.
•
Analysis of patients with occurrence of any component of composite: In-hospital
mortality or intensive care unit (ICU) admission or mechanical ventilation at Day 29, 
will be conducted using the same model used as the primary endpoint, to assess the 
difference in proportions of patients with BI 764198 and placebo.
•
Time to response, defined as clinical improvement of at least 2 points (from
randomisation) on the World Health Organization Clinical Progression Scale, discharge
from the hospital, or considered fit for discharge ( a score of 0, 1, 2, or 3 on the Clinical
Progression Scale), whichever comes first, by Day 29, will be analysed using the Cox 
proportional-hazards model adjusting for treatment, age, creatinine at baseline, and 
duration of symptoms before hospitalisation. Hazard ratio and Kaplan-Meier curves
with 95% confidence interval will be provided. Patients who do not respond will be 
censored at Day 29. Patients who prematurely discontinued from the treatment or lost
to follow-up will be censored at the time of their last observed assessment. Patients
who die prior to observing response will be censored at Day 29. 
•
The number of ventilator free days will be analysed using an AN COVA model
including treatment, age, creatinine at baseline, and duration of symptoms before
hospitalisation. WHO progression scale below 7 are defined as ventilator free. Hence, 
ventilator free days can be counted as number of days with WHO progression scale 
below 7 from the day ofrandomization to day 29. A sensitivity analysis excluding
patients who died during treatment period will be conducted.
•
Analysis of mortality at Day 15, 29, 60 and 90 will be conducted using the same model
as for the primary endpoint, to assess the difference in proportions of patients with BI 
764198 and placebo.


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7.7 
EXTENT OF EXPOSURE 
based on dose received for total study 
medication intake. Only descriptive statistics are planned for this section of the 
report. Summaries will be provided on FAS during treatment period. Total exposure 
(in days) is defined as date of last administration of study medication - date of first 
administration of study medication+ 1, ignoring the temporary interruptions, i.e. 
intermittent off-treatment periods were considered in the extent of exposure. 


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7.8 
SAFETY ANALYSIS 
All safety analyses will be performed on the FAS during on-treatment period. 
7 .8.1 
Adverse events 
Analyses of adverse events will be descriptive in nature. All analyses of AEs will be based 
on the number of patients with AEs and NOT on the number of AEs. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first drug intake t i l l -
after last drug intake will be 
assigned to the randomised treatment. All AEs occurring before first drug intake will be 
assigned to 'screening' and all AEs occurring after last drug i n t a k e -
will be 
assigned to 'follow-up' (for listings only). For details on the treatment definition, see 
Section 6.1. 
According to ICH E3 (10), in addition to Deaths and Serious Adverse Events, 'other 
significant' AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug ( e.g. discontinuation or dose 
reduced or interrupted). 
For further details on summarization of AE data, please refer to the guideline 'Handling 
and summarization of adverse event data for clinical trial reports and integrated summaries' 
ill: 
An overall summary of adverse events will be presented. 
The frequency of subjects with AEs will be summarised by treatment, primary system 
organ class and PT (mention MedDRA levels to be displayed in the tables). Separate tables 
will be provided for subjects with SAEs, AEs leading to treatment discontinuation, AEs of 
at least moderate severity and related AEs. with significant non-serious adverse events 
The system organ classes will be sorted by default alphabetically, PTs will be sorted by 
frequency (within SOC). Customized sorting orders may also be used based on trial needs, 
e.g. SOC sorted by frequency. 
The following are considered as protocol-specified AESI: 
Hepatic injury 
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
•
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) 2:3 fold ULN combined with an elevation of total bilirubin 2:2 
fold ULN measured in the same blood draw sample, or 
•
aminotransferase (ALT, and/or AST) elevations 2:10 fold ULN. 


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7.8.2 
Laboratory data 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards, 001-MCG-157: "Display and Analysis of Laboratory Data", current version, 
IDEA for CON. ill 
7 .8.3 
Vital signs 
Only descriptive statistics are planned for this section of the report. 
7.8.4 
ECG 
ECGs will be evaluated locally by eCRF. Summary statistics will be displayed. Additional 
summaries will be produced for patients who have abnormal ECG findings at baseline or 
during the study period: patients with confirmed QT prolongation of QTc interval to 
greater than 450 ms in males or 470 ms in females. 
7 .8.5 
Others 
Frequency of patients with extrapulmonary organ failure (based on reported AEs) will be 
summarized descriptively by treatment group and organ class: cardiovascular failure, CNS 
failure, renal failure, hepatic failure, and coagulation abnormalities. 


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8. 
TIMEPOINT OF RELEASE OF TREATMENT
INFORMATION
Once the last patient has completed their End-of-Treatment (EOT) visit and all 
corresponding data has been entered and cleaned to the level documented in the "Data 
Delivery Request" (DDR) form, the data will be declared ready to be unblinded via the 
"Data Ready to be Unblinded and/or Final Trial Closure Notification" (RUN) form. 
Snapshot will be at EOT or any time after once thresholds are met (including Day 29 data 
thresholds). Then the treatment information will be released for analysis. 
The data collection for the off-treatment residual effect period until the End-of-Study 
(EoS)/ Follow-Up visit will continue into the unblinded trial database. Once trial data 
collection has been completed and all data has been entered and cleaned as documented on 
the RUN form, a final data lock will be performed. 
After the release of treatment information, it is expected that only trial data related to the 
off-treatment residual effect period will be entered and changed. Therefore, after the 
timepoint of release of treatment information, all changes affecting trial data up to the End-
of-Treatment (EoT) visit will be documented and summarized in the CTR. 


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9. 
REFERENCES
1. 
CPMPIICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2. 
001-MCG-156: "Handling and summarization of adverse event data for clinical trial
reports and integrated summaries", current version; IDEA for CON. 
3. 
00 l-MCG-15 7: "Handling, Display and Analysis of Laboratory Data", current version;
IDEA for CON. 
4. 
Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-adjusted
difference in proportions from clinical trials using logistic regression and weighted risk
differences. Drug information journal: DIJ/Drug Information Association, 45(4), 481-493.
5. 
Greenland Sand Robin JM. Estimation of a common effect parameter from sparse
follow-up data. Biometrics 1985;41 :55-68 [R09-1299]


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companies 


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companies 
11.
HISTORY TABLE
Table 11: 1 History table 
Version 
Initial 
Date 
Author 
(DD-MMM-YY) 
08-APR-2021
Sections 
Brief description of change 
changed 
None 
This is the final TSAP 


APPROVAL/ SIGNATURE PAGE 
Document Number: c35421742 
Document Name: 8-01-tsap-core 
Boehringer 
 1!1111/ lngelheim 
Technical Version Number:1.0 
Title: BI 764 I 98 efficacy and safety in prevention/progression of ARDS 
Signatures (obtained electronically) 
Meaning of Signature 
Date Signed 
Approval-Project Statistician 
08 Apr 2021 07:50 CEST 
Author-Trial Medical Writer 
08 Apr 2021 I 0:06 CEST 
Approval-Clinical Trial Leader 
08 Apr 2021 17:36 CEST 
Approval-Team Member Medicine 
08 Apr 2021 18:44 CEST 


Boehringer Ingelheim 
Document Number: c35421742 
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(Continued) Signatures (obtained electronically) 
Meaning of Signature 
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Date Signed 
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