Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
This study is open to adults with mild to moderate symptoms of COVID-19 (coronavirus disease). The purpose of this study is to find out whether a medicine called BI 767551 helps people with COVID-19. BI 767551 is an antibody against the coronavirus.

The study has 2 parts.

Part 1 wants to find out the best dose of BI 767551 given as infusion into a vein. It also tests how BI 767551 is taken up by the body when taken via an inhaler. Participants are put into 4 groups by chance. Participants get BI 767551 or placebo once.

* 1 group gets a high dose of BI 767551 as an infusion into a vein
* 1 group gets a low dose of BI 767551 as an infusion into a vein
* 1 group gets BI 767551 via an inhaler
* 1 group gets placebo both as an infusion into a vein and via an inhaler

The placebo infusion and inhaler look like the BI 767551 infusion and inhaler but do not contain any medicine.

Doctors check how BI 767551 reduces the amount of coronavirus. Once the best dose of BI 767551 is found, part 2 of the study tests BI 767551 in a larger group of people. Also, in part 2, the participants get BI 767551 or placebo as an infusion into a vein once. In this part, doctors will check how many people need to be treated in a hospital or die. The results will be compared between the groups.

For each part, participants are in the study for about 13 weeks. During this time, they visit the study site about 8 times and get about 3 remote visits.

The doctors also regularly check participants' health and take note of any unwanted effects of BI 767551.

Detailed description:

Arms:
arm 1: Single dose of sterile normal saline (NaCl 0.9%) used as placebo for intravenous (i.v.) was administered as intravenous infusion over a period of 60 minutes plus a single inhaled of solvent for dilution of BI 767551 used as placebo for inhalation administered via inhalation through a mouthpiece (Aerogen® Ultra) using a mesh nebulizer (Aerogen® Solo) on Day 1, followed by a 90-day follow-up period. The inhalation procedure was to start approximately 25 min after the start of infusion. arm 2: None arm 3: None arm 4: Single dose of sterile normal saline (NaCl 0.9%) used as placebo for intravenous (i.v.) was administered as intravenous infusion over a period of 60 minutes plus a single inhaled of 250 milligrams (mg) of BI 767551 administered via inhalation through a mouthpiece (Aerogen® Ultra) using a mesh nebulizer (Aerogen® Solo) on Day 1, followed by a 90-day follow-up period. The inhalation procedure was to start approximately 25 min after the start of infusion. arm 5: None arm 6: None

Interventions: intervention 1: BI 767551 intravenous intervention 2: BI 767551 inhaled intervention 3: Placebo intravenous intervention 4: Placebo inhaled
Intervention descriptions: intervention 1: BI 767551 intravenous intervention 2: BI 767551 inhaled intervention 3: Placebo intravenous intervention 4: Placebo inhaled

Protocol document:
Prot_000.pdf: 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim (BI)
Original Protocol date
11 Feb 2021
Revision date
20 April 2021
BI trial number
1487-0001
Title of trial
A Phase II/III seamless, randomised, double-blind, placebo-controlled, 
parallel-group, group-sequential study to evaluate efficacy, safety and 
tolerability of BI 767551 for the treatment of symptomatic, non-
hospitalized adults with mild to moderate COVID-19.
Coordinating Investigator
Phone: 
; Fax: 
Trial site(s)
Multi-centre trial conducted in approximately 20 countries.
Clinical Phase
II/III
Trial rationale
This study will be conducted in SARS-CoV-2 positive symptomatic, 
non-hospitalized patients. The trial will be conducted in two parts.
Phase II part will assess viral load measures of SARS-CoV-2 RNA by 
nasopharyngeal (NP) swab. The Phase II part will confirm the 
neutralizing mode of action (MoA) of BI 767551 which in combination 
with safety data may support progression to the Phase III part. The 
Phase III part is designed to include the lowest efficacious and safe 
dose group from Phase II and will assess clinical outcomes.  
The patients will be followed for a 90 day observation period to assess 
any long-term outcomes from patients.
Trial objective(s)
To evaluate the concept of pharmacological activity of BI 767551 in 
non-hospitalized patients with mild to moderate COVID-19 symptoms 
and to identify an efficacious and safe dose regimen from Phase II part 
to take into the Phase III part.
To evaluate the efficacy, safety and tolerability of BI 767551 for the 
treatment of symptomatic, non-hospitalized adults with mild to 
moderate COVID-19.
Trial endpoints
Exploratory Phase II, as follows: 
o
Primary endpoint:
o
Time-weighted change from baseline in viral shedding in 
nasopharyngeal swabs by RT-qPCR over 8 days
o
Secondary endpoints:


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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o
Time-weighted change from baseline in viral shedding in 
nasopharyngeal (NP) swabs by RT-qPCR over 29 days
o
Loss of detection of SARS-CoV-2 RNA by NP swab at Days
4, 8, 15, 22 and 29 
Confirmatory Phase III, as follows:
o
Primary endpoint:
o
Hospitalization or death from any cause by Day 29
o
Secondary endpoints:
o
Time to death over 29 days
o
Hospitalization by Day 29
o
Hypoxia or hospitalization or death from any cause by Day 
29
o
Hypoxia by Day 29 
o
Time to clinical improvement over 29 days
o
Time to loss of detection of SARS-CoV-2 RNA by site 
collected nasopharyngeal (NP) swabs over 29 days
Trial design
Exploratory Phase II: 
Exploratory, randomised, double-blind, placebo controlled, double-
dummy, Phase II, parallel group design comparing different doses and
modes of administration (i.v and inhaled) of BI 767551 to placebo. At 
the start of the trial, patients will be randomised in a 2:2:2:1 ratio to 
receive a single dose of either Placebo i.v. + Placebo inhaled, BI 767551 
i.v. 10 mg/kg dose + Placebo inhaled, BI 767551 i.v. 40 mg/kg + 
Placebo inhaled, or Placebo i.v. + BI 767551 250 mg inhaled, 
respectively, followed by 90 days follow up. Following Clinical Trial 
Protocol (CTP) amendment 1, it is planned to include patients in an 
equal allocation ratio to each treatment arm. Therefore, patients will be 
randomised in a 1:1:1:2 ratio to receive a single dose of either Placebo 
i.v. + Placebo inhaled, BI 767551 i.v. 10 mg/kg dose + Placebo inhaled, 
BI 767551 i.v. 40 mg/kg + Placebo inhaled, or Placebo i.v. + BI 767551 
250 mg inhaled, respectively, once approximately 112 patients have 
been randomised using the initial randomisation ratio. When 
approximately 112 patients have been randomised, the randomisation 
scheme will be implemented in sites or countries with approval for CTP 
amendment 1. At the time of implementation of the revised scheme, 
sites or countries may be placed on hold for recruitment until approval 
of CTP amendment 1 is granted. BI will conduct unblinded interim 
analysis after patients have completed one week of follow-up. The 
results from this analysis will also be shared with a Data Monitoring 
Committee (DMC) for review of safety and efficacy data and to provide 
recommendation how to move forward with the trial. Data from patients 
included in the Phase II part of the trial will not be included in the 
confirmatory analyses.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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Confirmatory Phase III:
Confirmatory, randomised, double-blind, placebo-controlled, parallel 
group, Phase III comparing BI 767551 to placebo. Patients will be 
randomised in a 1:1 ratio to receive a single i.v. or inhaled dose of study 
treatment or placebo followed for 90 days of follow up. In addition, 
randomisation will be stratified by “high” versus “low” risk of 
progresson to COVID-19 to ensure equal distribution between treatment 
arms. The study will have a group-sequential design including two 
interim analyses that will be performed by the DMC. These analyses 
encompass futility and efficacy. Only the DMC will have access to 
unblinded data during this portion of the study.
Total number of patients 
randomised 
Phase II: approximately 200 patients to be randomised.
Phase III: approximately 1300 patients to be randomised.
Number of patients per
treatment group
Phase II approximately:

Placebo i.v. + Placebo inhaled: 50 patients

BI 767551 i.v. 10 mg/kg + Placebo inhaled: 50 patients

BI 767551 i.v. 40 mg/kg + Placebo inhaled: 50 patients

Placebo i.v. + BI 767551 inhaled: 50 patients
Phase III approximately:

BI 767551 i.v. 700 mg or 2800 mg: 650 patients
or

BI 76551 250 mg inhaled
and

Placebo: 650 patients
Diagnosis
COVID-19 detected by SARS-CoV-2 positive test confirmed by RT-
qPCR or antigen test.
Main inclusion and 
exclusion criteria
Eligibility criteria for Phases II and III are identical. Patients 
participating in Phase II are not eligible for Phase III.
Main criteria for inclusion:
1. Age ≥ 18 years old, males and females.
2. Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.
3. Documentation of laboratory-confirmed SARS-CoV-2 infection, 
as determined by a molecular test (antigen or nucleic acid) from 
any respiratory tract specimen (NP or nasal swab or saliva) 
collected no more than 72 hours prior to start of treatment.
4. Patients experienced mild to moderate COVID-19-related
symptoms or measured fever for no more than 5 days prior to 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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start of treatment where symptoms are defined by fever, feeling 
feverish, fatigue, cough, shortness of breath at rest or during 
activity, sore throat, body pain or muscle pain/ aches, chills, 
headache, nasal obstruction or congestion, loss of smell or taste, 
nausea, diarrhea, vomiting, or dysgeusia.
5. One or more of the following COVID-19-related 
signs/symptoms present on day of start of treatment: fever, 
feeling feverish, fatigue, cough, shortness of breath at rest or 
during activity, sore throat, body pain or muscle pain/ aches, 
chills, headache, nasal obstruction or congestion, loss of smell or 
taste, nausea, diarrhea, vomiting, or dysgeusia.
Main criteria for exclusion:
1. Severe or critical COVID-19 including at least one of:

Oxygen saturation (SpO2) ≤ 93% on room air or on their 
usual level of oxygen supplementation in case of chronic 
oxygen use

Ratio of arterial oxygen partial pressure (PaO2 in millimeters 
of mercury) to fractional inspired oxygen (FiO2) < 300 (in 
case arterial blood sample was taken)

Respiratory rate ≥ 30/min or heart rate ≥ 125/min

History of hospitalization for COVID-19

Current or imminent need of hospitalization or immediate 
medical attention. Does not include patients hospitalized for 
isolation only.
2. Receipt of intraveneous immunoglobulin (IVIG) within 12 
weeks prior to Visit 2.
3. Receipt of COVID-19 convalescent plasma or SARS-CoV-2 
monoclonal antibody treatment at any time prior to Visit 2.
4. Receipt of SARS-CoV-2 vaccine at any time prior to Visit 2.
5. Receipt of an investigational product for COVID-19 within 5 
half-lives prior to Visit 2.
6. Body weight of less than 40 kg.
Test product(s)
BI 767551
Dose
Phase II :
1. Single 10 mg/kg or 40 mg/kg i.v. infusion
2. Single 250 mg inhalation (nebulized)


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Phase III:
1. Single 700 mg or 2800 mg i.v. infusion or Single 250 mg 
inhalation (nebulized)
Mode of administration
Phase II:
Weight based i.v or fixed dose inhalation (nebulized)
Phase III:
Fixed dose i.v. or inhalation
Comparator product(s)
Placebo
Dose
Not applicable
Mode of administration
Phase II: Intravenous infusion (i.v.) / inhalation (nebulized)
Phase III: Intravenous infusion (i.v.) or inhalation (nebulized)
Duration of treatment
Single dose followed by 90 days follow-up
Statistical methods
Phase II – Exploratory:
All analyses will be exploratory. An analysis of covariance (ANCOVA) 
model with baseline viral load as covariate will be used to analyse the 
primary endpoint of the Phase II part.
Phase III – Confirmatory:
The cumulative proportion of patients who were hospitalized or who 
died over 29 days will be estimated for each randomised group using 
Kaplan-Meier methods to take account of losses to follow-up. The 
difference between randomised groups in the estimated log cumulative 
proportion will be calculated and the variance for this difference will be 
obtained using Greenwood’s formula. To account for the planned 
interim analyses, the local nominal alpha-level will follow an O`Brien 
and Fleming spending function to preserve the global alpha of 0.025 
(one-sided). One sided p-values will be derived from the z-test. Two 
unblinded interim analyses are planned once 33% and 67% of patients 
have been followed up over 29 days, respectively. The futility boundary 
is defined as a relative reduction of 5% at the first interim analysis and 
as a relative reduction of 10% at the second one. Efficacy boundaries are 
derived using O’Brien-Fleming like boundaries. The interim analyses in 
this phase of the trial will be performed by the DMC and only the DMC 
will get access to unblinded data. 
Safety will be assessed based on adverse events, laboratory parameters 
and vital signs. Only descriptive analyses are planned.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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FLOW CHART
Trial Periods
Screening 
Randomisation
Follow-up
Prematurely 
discontinued
(Before Day 29)
Prematurely 
discontinued
(After Day 29)
Visit
11
2
3
43
5
64
7
82
9
EOS
Visit Location: C=in clinic visit; 
R=remote visit2
C
C
R
C
C
R
C
C/R
C
C
C
C
Week
Wk 
1
Wk 
2
Wk 
3
Wk 
4
Wk
12
Days
0
1
3
4
8
11
15
22
29
91
Time window for visits
-2 to 
1
days
±1 day
±2 days
±4 days
+14
days
Informed consent 
X
Demographics
X
Review of in-/exclusion criteria5
X
X5
SARS-CoV-2 test6
X
Medical history5
X
X5
Smoking status
X
All AEs/SAEs/AESIs5,7
X
X5
X
X
X
X
X
X
X
X
X
X
Concomitant therapy5
X
X5
X
X
X
X
X
X
X
X
X
X
COVID-19 symptom screen
X
X5
11-point WHO Clinical 
Progression Scale (see Section 
5.1.2) 5,8
X
X5
X
X
X
X
X
X
X
X
X
Collect/update secondary 
contacts20
X
X
X
X
X
X
X
X
Vital signs9 (refer to Section 
5.2.2)
X
X
X
X
X
X
X
X
X
Physical Exam (refer to Section 
5.2.1) 5,10
X
X5
X21
X21
X
X
X
X
Weight
X
X
X
X
X
Height
X
Participant completed study diary
including temperature and 
oxygen saturation11
Days 1-29
Study diary reminder11
X
X
X
X
X
X
X
X
Staff review of patient diary12
X
X
X
X
X
X
X
Review by e.g. phone and 
retrieval of study diary
X
X
Staff-collected nasopharyngeal 
swab 13
X
X
X
X
X
X
X


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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FLOW CHART (continued)
Trial Periods
Screening 
Randomisation
Follow-up
Prematurely 
discontinued 
(Before Day 29)
Prematurely 
discontinued 
(After Day 29)
Visit
11
2
3
43
5
64
7
82
9
EOS
Visit Location: C=in clinic visit; 
R=remote visit2
C
C
R
C
C
R
C
C/R
C
C
C
C
Week
Wk 
1
Wk
2
Wk
3
Wk
4
Wk
12
Days
0
1
3
4
8
11
15
22
29
91
Time window for visits
-2 to 
11
days
±1 day
±2 days
±4 day
+14 
day
SARS-CoV-2 Antibody Serology
X
Haematology16
X
X
X
X
X
X
X
Chemistry16
X
X
X
X
X
X
X
Urinalysis16
X
X
X
X
X
X
X
Coagulation and Inflammation 
markers16
X
X
X
X
X
X
X
Pregnancy testing17
X17
X17
XU
, (S)
XU, 
(S)
XU, (S)
XU, 
(S)
XU, (S)
XU, (S)
IRT call 18
X
X
Prepare and administer trial drugs
X
Completion of patient 
participation19
X
X
Vital status data19
X
X
X
Wk = Week; EOS = End of Study; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2
1
Visit 1 and Visit 2 can be on the same day if required (see also footnote 5). Initiation of randomised 
treatment at Visit 2 can only begin if the patient meets the criteria for Initiation of Treatment. 
2
For any given day of an in clinic visit (except Visit 2), if the patient cannot return to the clinic, the visit may 
occur remotely as a home-based visit (defined as home visits by healthcare nurses or site staff), or by 
phone. Visit 2 must be completed in clinic. For visits occurring remotely, every effort should be made to 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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complete as home-based visit (by a home healthcare nurse or site staff).  Remote visits can be completed as 
a home-based visit or by phone. 
3
Visit 4 is a clinic visit for Phase II only. Remote visit for Phase III. 
4
Visit 6 must be completed at least 2 days after Visit 5.
5
The procedures do not need to be be repeated/performed when V1 and V2 are performed on the same day.
6
SARS-CoV-2 laboratory confirmation (antigen or nucleic acid) as a pre-requisite before or at screening 
(collection within 72 hrs of treatment). The test can be completed via local lab or rapid Point-of-Care
device. Result confirmation must be documented and filed in patient records.
7
After the individual patient’s end of the trial the investigator should report only any cancers of new 
histology and exacerbations of existing cancer, trial treatment related SAEs and trial treatment related 
AESIs of which the investigator may become aware of and only via the BI SAE form, please see Section 
5.2.6.2.2.
8
For remote visits, 11-point WHO Clinical Progression Scale (Section 5.1.2) must be collected by home 
healthcare nurse or site staff.
9
Vital signs measurement shall include BP measurement, body temperature, respiratory rate, pulse 
rate and resting peripheral oxygen saturation. At screening only respiratory rate, pulse rate and resting 
peripheral oxygen saturation should be taken to confirm eligibility. Confirmation of PaO2/FiO2 ratio <300 
only required in case arterial blood sample was previously taken. At Visit 2, measurements of vital signs 
should be taken pre-dose, at end of the infusion and 2 hours post study drug administration and precede 
blood sampling (see Section 5.2.2).
10
Complete Physical exam at Visit 1. Complete physical exam includes at a minimum general appearance, 
neck, lungs, cardiovascular system, abdomen, extremities, and skin. Symptom directed exam at all clinic 
visits after screening.
11
At Visit 2 Site staff will provide a thermometer and pulse oximeter to the participant as well as present and 
review the study diary.  Participants will complete the diary with site staff prior to administration of study 
drug. On subsequent days with a clinic or remote visit, patients will be reminded to record their 
temperature, oxygen saturation, and complete all entries every day (preferably the same time every day). 
Participants will be reminded to bring their diary with them to the next clinic visit. Clinic visit day entry 
may also be completed at the clinic.
12
At clinic visits and remote visits if completed by home healthcare nurse or site staff. If visit is completed by 
phone, patient will be reminded to complete diary entry for that day. Study staff will enter the participant’s
answers on the study diary into the electronic case report forms (eCRFs) following each visit.  In case of 
remote visits, every effort should be made to retrieve the study diary answers (or a copy of the answers if 
paper) for entry into the eCRFs, otherwise entery into the eCRF will be completed at the next clinic visit.
13
If V2 occurs on the same day as V1 and the sample collected for screening was NP or nasal, the V2 NP 
sample should preferably be taken from the other nostril. In this case care must be taken to ensure one (1) 
sample is taken at screening for eligibility and the second sample is taken as part of V2 procedures. On 
Day 1, NP 
 swabs should be collected prior to the intravenous and inhaled dose of investigational 
agent. For home-based visits, the swab will be collected by the home healthcare nurse or site staff. 
14
15
16  
Tests at Visit 2 and subsequent trial visits will be performed centrally. If Visit 1 and Visit 2 done on the 
same day, samples should be collected after eligibility has been confirmed. Blood samples will be collected 
prior to administration of study drug.
17
Women of childbearing potential only. Negative urine pregnancy test must be confirmed prior to study drug 
administration. Serum test required at Visit 2 together with blood sample collection. U-urine pregnancy test 
performed at all visits after Visit 2 as indicated in the Flow Chart. (S) - in case of a positive urine pregnancy 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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test, a serum pregnancy test will be done. In case of remote visits, clinical site may provide subjects with at-
home urine pregnancy test kits (may be sponsor-provided)
18
Phase II: weight needed in IRT at randomization for body-weight based dosing.
19
Should a patient prematurely discontinue before their scheduled EOS visit, every effort should be made to 
keep the patient in the trial and complete all of the remaining study visits if possible. At the very least, vital 
status and information on whether the patient has been hospitalized shall be collected at planned completion 
date of each individual patient, please see Section 3.3.4. Any locally approved way of obtaining vital status 
information is accepted.
20
Details can be entered in site source not CRF
21
Physical examination at Visit 5 and 7 performed only if clinic visit


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
PK/ADA/NAB BLOOD SAMPLING FLOW CHART......................................................11
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS AND DEFINITIONS...........................................................................18
1.
INTRODUCTION...............................................................................................21
1.1
MEDICAL BACKGROUND.............................................................................21
1.2
DRUG PROFILE................................................................................................23
1.2.1
Mode of action.....................................................................................................23
1.2.2
Predicted and observed pharmacokinetic characteristics...............................23
1.2.3
Drug interactions.................................................................................................25
1.2.4
Residual Effect Period ........................................................................................25
1.2.5
Data from non-clinical studies ...........................................................................25
1.2.6
Data from clinical studies...................................................................................28
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................30
1.4
BENEFIT - RISK ASSESSMENT.....................................................................31
1.4.1
Benefits.................................................................................................................31
1.4.2
Risks .....................................................................................................................31
1.4.3
Discussion.............................................................................................................35
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................36
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........36
2.1.1
Main objectives....................................................................................................36
2.1.2
Primary endpoint(s)............................................................................................37
2.1.3
Secondary endpoint(s) ........................................................................................37
2.1.3.1
Secondary endpoints in Phase II........................................................................37
2.1.3.2
Secondary endpoints in Phase III......................................................................37


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................41
3.1
OVERALL TRIAL DESIGN.............................................................................41
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................42
3.3
SELECTION OF TRIAL POPULATION .......................................................43
3.3.1
Main diagnosis for trial entry ............................................................................44
3.3.2
Inclusion criteria .................................................................................................44
3.3.3
Exclusion criteria ................................................................................................45
3.3.4
Discontinuation of patients from treatment or assessments ...........................46
3.3.4.1
Discontinuation of Trial Treatment ..................................................................47
3.3.4.2
Withdrawal of consent to trial participation....................................................47
3.3.4.3
Discontinuation of the trial by the sponsor.......................................................47
4.
TREATMENTS...................................................................................................49
4.1
INVESTIGATIONAL TREATMENTS ...........................................................49
4.1.1
Identity of the Investigational Medicinal Products..........................................49
4.1.1.1
Test Products for Phase II..................................................................................49
4.1.1.2
Test Products for Phase III ................................................................................50
4.1.2
Selection of doses in the trial and dose modifications......................................52
4.1.3
Method of assigning patients to treatment groups...........................................55
4.1.4
Drug assignment and administration of doses for each patient......................55
4.1.5 
Blinding and procedures for unblinding...........................................................56
4.1.5.1
Blinding................................................................................................................56
4.1.5.2
Unblinding and breaking the code ....................................................................57
4.1.6
Packaging, labelling, and re-supply...................................................................58


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4.1.7
Storage conditions...............................................................................................58
4.1.8
Drug accountability.............................................................................................58
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS ................................................................................................59
4.2.1
Other treatments and emergency procedures..................................................59
4.2.2
Restrictions ..........................................................................................................59
4.2.2.1
Restrictions regarding concomitant treatment ................................................59
4.2.2.2
Restrictions on diet and life-style......................................................................60
4.2.2.3 
Contraception requirements..............................................................................60
4.3
TREATMENT COMPLIANCE........................................................................61
5.
ASSESSMENTS..................................................................................................62
5.1
ASSESSMENT OF EFFICACY........................................................................62
5.1.1
SARS-COV-2 RNA Assessment.........................................................................62
5.1.2
Improvements on the WHO Clinical Progression Scale..................................62
5.2
ASSESSMENT OF SAFETY.............................................................................64
5.2.1
Physical examination ..........................................................................................64
5.2.2
Vital signs.............................................................................................................64
5.2.3 
Safety laboratory parameters ............................................................................64
5.2.4
Electrocardiogram ..............................................................................................67
5.2.5
Other safety parameters.....................................................................................67
5.2.6
Assessment of adverse events.............................................................................67
5.2.6.1
Definitions of AEs...............................................................................................67
5.2.6.1.1
Adverse event.......................................................................................................67
5.2.6.1.2
Serious adverse event..........................................................................................68
5.2.6.1.3
AEs considered “Always Serious”.....................................................................68
5.2.6.1.4
Adverse events of special interest ......................................................................68
5.2.6.1.5
Intensity (severity) of AEs..................................................................................69
5.2.6.1.6
Causal relationship of AEs.................................................................................70


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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5.2.6.2 
Adverse event collection and reporting.............................................................71
5.2.6.2.1
AE Collection.......................................................................................................71
5.2.6.2.2
AE reporting to the sponsor and timelines.......................................................71
5.2.6.2.3
Pregnancy ............................................................................................................72
5.3
DRUG CONCENTRATION MEASUREMENTS AND
PHARMACOKINETICS...................................................................................72
5.3.2
Methods of sample collection .............................................................................73
5.5
BIOBANKING ....................................................................................................75
5.6
OTHER ASSESSMENTS...................................................................................75
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................76
6.
INVESTIGATIONAL PLAN.............................................................................77
6.1
VISIT SCHEDULE.............................................................................................77
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................77
6.2.1
Screening and run-in period(s)..........................................................................78
6.2.2
Treatment Period(s)............................................................................................79
6.2.3
Follow-up period and trial completion..............................................................81
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE....................................................................................................84
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................84
7.2
PLANNED ANALYSES.....................................................................................84
7.2.1
General considerations .......................................................................................84


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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7.2.2
Handling of Intercurrent Events .......................................................................85
7.2.3
Primary objective analyses.................................................................................86
7.2.4
Secondary objective analyses.............................................................................89
7.2.6
Safety analyses.....................................................................................................92
7.2.8
Interim Analyses .................................................................................................93
7.3
HANDLING OF MISSING DATA ...................................................................93
7.3.1
Efficacy endpoints...............................................................................................93
7.3.2
Safety endpoints ..................................................................................................95
7.4
RANDOMISATION ...........................................................................................95
7.5
DETERMINATION OF SAMPLE SIZE .........................................................96
7.5.1
Determination of sample size for Phase II........................................................96
7.5.2
Determination of sample size for Phase III ......................................................97
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........99
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................99
8.2
DATA QUALITY ASSURANCE ....................................................................100
8.3
RECORDS.........................................................................................................100
8.3.1
Source documents .............................................................................................100
8.3.2
Direct access to source data and documents...................................................102
8.3.3
Storage period of records .................................................................................102
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................102
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......102
8.5.1
Collection, storage and future use of biological samples and 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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corresponding data ...........................................................................................102
8.6
TRIAL MILESTONES.....................................................................................103
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................103
9.
REFERENCES..................................................................................................105
9.1
PUBLISHED REFERENCES..........................................................................105
9.2
UNPUBLISHED REFERENCES....................................................................107
10.
APPENDICES...................................................................................................109
10.1
INSTRUCTIONS FOR THE USE OF THE AEROGEN SOLO 
NEBULISER......................................................................................................109
10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19 ..........................................................111
10.4
DIAGNOSIS OF ANAPHYLAXIS .................................................................112
10.5
BI 767551 AND THE EMERGING VARIANTS OF CONCERN...............113
11.
DESCRIPTION OF GLOBALB AMENDMENT(S).....................................117
11.1
GLOBAL AMENDMENT 1 ............................................................................117


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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ABBREVIATIONS AND DEFINITIONS
ADA
Anti Drug Antibody
ADE
Antibody-dependent enhancement
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CI
Confidence Interval
COVID-19
Coronavirus Disease 2019
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DAIDS
Division of AIDS
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
EC
Ethics Committee
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
ELF
Epithelial Lining Fluid


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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EoS
End of Study
ePRO
Electronic Patient Reported Outcome
EoT
End of Treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice
HA
Health Authority
i.v.
Intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INN
International Non-Proprietary Name
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IVIG
Intravenous immunoglobulin
LPLT
Last patient last treatment
LPLV
Last patient last visit
LPLV PE
Last Patient Last Visit Primary Endpoint
MedDRA
Medical Dictionary for Drug Regulatory Activities
MoA
Mode of action  
NIAID
National Institutes of Allergy and Infectious Diseases 
NP
Nasopharyngeal  
OP
Oropharyngeal
OPU
Operative Unit


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PD
Pharmacodynamics
PFU
Plaque forming units
PK
Pharmacokinetics
RA
Regulatory Authority
RBD
Receptor Binding Domain
REP
Residual effect period
RM
Risk Management
RT-qPCR
Quantitative Reverse Transcription Polymerase chain reaction
SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
VoC
Variant of Concern
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
After emerging at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) has rapidly spread across the globe. By January 2021, over 99 million confirmed cases 
of SARS-CoV-2 infection and more than 2.1 million coronavirus disease 2019 (COVID-19) 
associated deaths have been reported (WHO Coronavirus Disease Dashboard; 
https://covid19.who.int). The development of safe and effective options for treatment and 
prevention of SARS-CoV-2 infection is therefore of urgent concern for global public health.
SARS-CoV-2 is an enveloped positive-sense single-stranded ribonucleic acid RNA 
Betacoronavirus of the subgenus Sarbecovirus. It is related to SARS-CoV, the causative agent of 
the 2002/2003 SARS outbreak, and to coronaviruses circulating in bat populations. Although a 
definitive animal reservoir has not yet been identified, SARS-CoV-2 is likely of zoonotic 
origin[R20-4053].
Human-to-human transmission of SARS-CoV-2 occurs primarily through respiratory droplets 
and aerosols[R20-4052]. It is notable for the occurrence of superspreading events, in which a 
limited number of index cases results in the infection of a large number of contacts. Importantly, 
asymptomatic and presymptomatic individuals shedding the virus at high concentrations create a 
challenge to identify origins of transmission chains[R20-4051]. In addition to the respiratory 
route, transmission of SARS-CoV-2 by fomites has been suggested as plausible[R20-4050].
Following exposure, symptoms typically manifest after a median of 5-6 days, although this 
period can range from 1 to more than 14 days. In addition, a sizeable fraction of infected 
individuals appears not to develop clinically apparent signs. A majority of infections 
(approximately 80%) results in mild to moderately severe courses of disease that are 
characterized by symptoms of upper respiratory tract infections (e.g., cough, fever, rhinorrhea, 
coarse throat, or disturbances of smell or taste). More severe cases of COVID-19 primarily 
demonstrate signs of lower respiratory tract infection (e.g., dyspnea, pneumonia) and can result 
in respiratory failure with a need for mechanical ventilation or extracorporeal oxygenation of the 
blood. Beyond respiratory symptoms, an increasing number of additional manifestations have 
been associated with SARS-CoV-2 infection, including thromboembolic events, cardiac or 
systemic inflammation, and renal failure[P20-10977]. 
A number of investigational and approved drugs that were developed for the use in other 
indications are under evaluation for their potential use in the treatment of SARS-CoV-2 
infection. For example, remdesivir is a nucleoside analogue prodrug that acts as an inhibitor of 
viral RNA polymerase following intracellular biotransformation. Based on its demonstrated in 
vitro activity against human coronaviruses, including SARS-CoV-2, clinical investigation of 
remdesivir for SARS-CoV-2 infection was rapidly initiated. In hospitalized adults with COVID-
19, administration of remdesivir resulted in a significantly reduced time to recovery compared to 


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placebo[R20-3802]. Based on these observations, remdesivir has received full or conditional 
approval (e.g., by the FDA and EMA) for use in SARS-CoV-2 infected individuals requiring 
supplemental oxygen therapy. However, remdesivir requires a 5-to-10-day intravenous treatment 
course and its efficacy in prevention of SARS-CoV-2 infection has not been demonstrated yet. In 
addition to antiviral compounds, agents aimed at modulating immune-mediated organ injury are 
under investigation for their efficacy in COVID-19. Importantly, in hospitalized patients with 
COVID-19 requiring oxygen therapy, the anti-inflammatory corticosteroid dexamethasone has 
resulted in reduced 28-day mortality[R20-4049]. However, no effects in mortality were noted in 
individuals not receiving respiratory support [R20-4049].
As of November 21, 2020, two neutralizing antibody (nAb) products (bamlanivimab [
], 
casirivimab and imdevimab [
]) received EUA for treatment of mild-to-moderate 
COVID-19 in patients who are 12 years of age or older weighing at least 40 kg and who are at 
high risk for progressing to severe COVID-19 and/or hospitalization who are not yet hospitalized 
or on supplementary oxygen for COVID-19. This includes those who are 65 years or age or older 
or who have certain chronic medical conditions. The current EUA-issued monoclonal antibodies 
are administered as a single dose IV infusion.  Results from the interim analyses of these studies 
in outpatients showed that bamlanivimab (LY-CoV555) reduced the patients’ symptoms at 
earlier timepoints during treatment (Day 3) when compared to placebo with no difference 
between the three dose arms. In addition, the frequency of hospitalization was reduced for all 
treatment arms (1.6%) versus 6.3% in the placebo group.  The reduction in hospitalization was 
most promounced in the high-risk subgroups approved as part of the EUA (4.2% in LY-CoV555 
group compared to 14.2% in the placebo group) [R20-4045]
Similar effects were observed in REGN-COV2 study in ambulatory patients.  The interim 
analysis from 275 patients showed an enhanced clearance of the virus in patients who were 
seronegative or those with with high viral loads (>106 copies/ml) at baseline.  A numerical 
difference in the number of medically attended visits were also observed for all treatment arms 
(3%) when compared to placebo (6%). This relative reduction of 49% was increased to 59% 
when the subgroup of seronegative patients was analysed. [R21-0329]
These interim reports suggest that treatment with neutralizing antibodies against SARS-CoV-2 
can provide an effective antiviral therapy to enhance viral clearance and lead to improved 
clincial outcomes or prevention of hospitalization particularly in those patients at highest risk.  
These studies will complete the Phase III portions and final readouts should provide additional 
information on the benefits of this therapy. These nAbs are also under evaluation in a subset of 
hospitalized patients and in post-exposure prevention settings. 
As of the end of 2020, several SARS-CoV-2 variants began to emerge with unusually large 
numbers of mutations which may impact the transmission rates and effectiveness of therapies 
such as neutralizing antibodies and vaccines. Investigation are ongoing to understand the 
virologic, epidemiologic and clinical impact of these rapidly evolving variants of SARS-CoV-2.  
At the time of the finalization of the protocol, in vitro assessments of the impact of the most 
prevalent variants (B.1.1.7 (UK), B.1.351 and P.1 (Brazil)) on the effectiveness of BI 767551 


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was ongoing in the Sponsor’s laboratories and in collaboration with academic centers as well as 
with National Institutes of Health and National Institutes of Allergy and Infectious Diseases 
(NIAID).
SARS-CoV-2 infection of target cells occurs through the interaction of the receptor-binding 
domain (RBD) of the homotrimeric spike (S) protein on the viral surface with its host target cell 
receptor ACE2 [R20-3952, R20-3955]. Moreover, SARS-CoV-2-infected cells can be identified 
through the expression on the SARS-CoV-2 S protein on the cellular surface [R20-4048]. Thus, 
strategies that target the S protein are of potential interest both for the treatment and prevention 
of SARS-CoV-2 infection.
1.2
DRUG PROFILE
BI 767551 is a potent human SARS-CoV-2-neutralizing antibody that was identified from a 
blood sample of a COVID-19-convalescent patient obtained 35 days after diagnosis of infection
[R20-2985]. To isolate SARS-CoV-2-neutralizing antibodies from this and 11 additional 
patients, single memory B cells reactive to the SARS-CoV-2 spike protein were sorted using 
flow cytometry. Antibody heavy and light chain sequences were subsequently amplified from 
individually lysed cells using specific reverse transcription polymerase chain reaction (RT-
qPCR) and sequenced, facilitating the recombinant production of exact antibody replicates[R20-
4047]. Using this approach, the human monoclonal antibody HbnC3t1p1_F4 was identified and 
later modified by eliminating the heavy chain C-terminal lysine to reduce potential charge 
heterogeneity, resulting in antibody BI 767551. BI 767551  is a monoclonal antibody of the IgG1 
kappa isotype with low somatic hypermutation compared to its germline sequence (% germline 
nucleotide identity of 93.2% and 96.1% for the heavy chain and light chain variable genes, 
respectively) [R20-2985]. 
1.2.1
Mode of action
BI 767551 targets the receptor binding domain (RBD) of the SARS-CoV-2 spike protein with 
high affinity. When tested in vitro, BI 767551 demonstrates potent neutralizing activity both 
against authentic SARS-CoV-2 as well as SARS-CoV-2 spike-typed pseudoviruses[R20-2985, 
[R20-3347]. For example, infection of Vero E6 cells with the SARS-CoV-2 variant 
BavPat1/2020 was completely blocked in the presence of BI 767551 at concentrations as low as 
0.05 µg/ml as indicated by the absence of detectable cytopathic effects. Moreover, BI 767551 
demonstrated high activity against a panel of six SARS-CoV-2 pseudovirus variants with an 
average 50% inhibitory concentration (IC50) of 0.007 µg/ml in a neutralization assay using 
ACE2-expressing human 293T cells.
1.2.2
Predicted and observed pharmacokinetic characteristics
A two-compartment pharmacokinetic model was applied to characterize monoclonal antibody
(mAb) distribution and clearance, assuming that the systemic pharmacokinetic parameters in
the model are the same as that of a typical mAb [R15-2538]. Antibody concentrations in lung
interstitial and epithelial lining fluids after intravenous and after inhalative administration of




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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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For more detailed information, please refer to Investigator Brochure (IB)[c34274645-02].
1.2.3
Drug interactions
BI 767551 is a therapeutic protein and its clearance occurs mainly by protein catabolism. The
clearance of therapeutic antibodies does not involve CYP enzyme-mediated metabolism or
drug transporters but is mediated primarily by non-saturable elimination pathways such as
fluid-phase endocytosis, phagocytosis, and catabolism. Therefore, the potential of small
molecule drugs to affect the exposure of BI 767551 is considered to be limited. The virus
neutralizing activity of BI 767551 is mediated by the interaction with free virions and
preventing cellular infection. This mode of action is not anticipated to affect the PK profile of
co-administered medications, since BI 767551 is not expected to directly modulate
inflammatory cytokine expression, modulate the expression of CYP 450 enzymes or alter
human physiological processes that regulate small molecule drug metabolism.
1.2.4
Residual Effect Period
The Residual Effect Period (REP) of BI 767551 is 90 days. 
1.2.5
Data from non-clinical studies
To date, the following attributes of BI 767551 have been determined:








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Safety summary
Clinical data for BI 767551 is limited at this time, and the safety profile of BI 767551 has not 
been established. As described below, a limited number of healthy volunteers and SARS-CoV-2-
infected individuals have been administered BI 767551.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Details on all reported AEs as of April 01, 2021 are presented in the Investigator’s Brochure 
(c34274645-02). 
1.3
RATIONALE FOR PERFORMING THE TRIAL
This clinical trial is potentially a pivotal registration study for the i.v administration of the 
SARS-CoV-2- neutralizing human monoclonal antibody BI 767551 for the treatment of non-
hospitalized patients with COVID-19. It is conducted to clinically evaluate the efficacy, safety 
and tolerability of BI 767551 for the treatment of symptomatic, non-hospitalized adults with mild 
to moderate COVID-19. 
The preliminary results from the Phase II part will evaluate the concept of pharmacological 
activity of BI 767551 in non-hospitalized patients with mild to moderate COVID-19 symptoms. 
This part of the trial is designed to establish MoA for this compound.  From this Phase II part, 
the lowest efficacious and safe dose and regimen from Phase II will be taken into the Phase III 
part to assess clinical outcomes. 
The Phase III part will evaluate the efficacy, safety and tolerability of BI 767551 for the 
treatment of symptomatic, non-hospitalized adults with mild to moderate COVID-19. 
The safety and establishment of the concept of pharmacological activity may warrant the 
investigation in alternate disease severities and settings for infection. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Treatment with BI 767551 has the potential to provide benefit to patients with mild to moderate 
COVID-19 by reducing the risk of progressing to hospitalization or death, by preventing viral 
uptake and accelerating viral clearance. 
The inhaled route of administration may provide accelerated virus neutralization in the 
respiratory tract being the first to be exposed by the virus. 
First in man studies are currently being carried out in both healthy volunteers and SARS-CoV-2 
infected individuals and as data from that study becomes available, the data will be incorporated 
into the program and where necessary, this protocol will be adapted via  amendment(s).
1.4.2
Risks
In order to protect the patient’s safety during conduct of this trial, an independent DMC has been 
established for the review of clinical trial safety data.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 1.4.2:1 Overview of trial related risks 
Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product / BI 767551
Hypersensitivity 
reaction
As BI 767551 is a human 
monoclonal antibody, the 
anticipated adverse effect is a 
hypersensitivity reaction induced 
via intravenous and/or inhaled 
route of administrations. Typical 
compound-related signs and 
symptoms of hypersensitivity 
reactions of mild to severe 
grading could include pruritus, 
urticaria, fever, rigor/chills, 
diaphoresis, bronchospasm, 
cardiovascular collapse, 
anaphylaxis, and cytokine release 
syndrome.
In case of systemic hypersensitivity 
reactions including anaphylactic 
reaction emerging during or after 
administration of trial medication, the 
investigator should consider in 
accordance with the severity of the 
reaction and local standard of care to 
interrupt and treat the condition. 
Emergency medicines and ability to
handle such reactions must be 
available at the site. Systemic 
hypersensitivity reaction is defined as 
an adverse event of special interest 
(AESI). It is subject to close 
monitoring.
Irritation of 
Airways
Administration of inhaled BI 
767551 and excipients may result 
in irritation of the airways and 
pulmonary tissues that could 
manifest as cough, wheezing, 
bronchial narrowing, or 
bronchospam resulting in 
respiratory distress.
Inhalers and/or nebulizers for the 
application of bronchodilators will be 
available at the site of the trial drug 
administration.
Off-target 
toxicity
As BI 767551 was identified from 
a human memory B cell in a 
SARS-CoV-2-convalescent 
individual and based on the results 
of off-target profiling, the risk of 
off-target-mediated toxicity of BI 
767551 can be considered as low. 
Please refer to current IB 
(c34274645-02).
Trial patients will be carefully 
monitored for any unspecific 
toxicities.




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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 1.4.2:1 Overview of trial related risks (continued)
Possible or 
known risks of 
clinical 
relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Blunting of 
vaccine 
response
Administration of BI 767551 
may result in blunting of SARS-
CoV-2 vaccine responses should 
these vaccines become available. 
Monitoring of the immune response 
to vaccination or delayed or 
repeated vaccination may be 
required. Patients with previous 
SARS-CoV-2 vaccination are 
excluded. 
Drug-induced 
liver injury 
(DILI)
Rare but severe event, that must 
be monitored in all clinical 
studies, independent of 
intervention and indication, thus 
under constant surveillance by 
sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure patients´ 
safety.
Trial procedures
Blood sampling
As with all blood sampling, there 
is a risk of mild pain, local 
irritation, or bruising (a black or 
blue mark) at the puncture site. 
Furthermore, there is a small risk 
of lightheadedness and/or 
fainting. In rare cases, the 
puncture site can also become 
infected or nerves may be 
damaged, inducing long-lasting 
abnormal sensations 
(paresthesia), impaired sensation 
of touch and persistent pain.
These risks will be addressed by 
careful safety monitoring and risk 
mitigation measures such as
(a) compression;
(b) close clinical monitoring for 
AEs;
(c) selection of experienced sites 
and site staff;
(d) Safety recommendations 
provided in laboratory manual
NP and OP 
swabs 
Upper respiratory tract samples 
will be obtained by naso- and 
oropharyngeal swabs that may 
cause discomfort, tissue irritation 
or damage, or local bleeding.
Deeper swab biosamples will be 
obtained by trained trial staff.
Anterior nasal swabs have more 
limited risk. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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1.4.3
Discussion
BI 767551 is currently under evaluation in Phase I in healthy volunteers and ambulatory 
COVID-19 patients. It is not yet known whether its administration results in beneficial clinical 
effects.  In SARS-CoV-2-infected subjects, administration of BI 767551 may reduce the risk of 
progressing to severe disease and contribute to accelerated viral clearance. 
Several other SARS-CoV-2-neutralizing antibodies are under clinical development. Recently, 
two new therapies (Bamlanivimab by 
; Casirivimab in combination with Imdevimab by 
) have gained FDA-authorization for emergency use for the indication of mild-to-
moderate COVID-19 in adults and pediatric patients (12 years and older) with a positive 
COVID-19 test, who are at high risk for progressing to severe COVID-19 and/or hospitalization.
Antibody-dependent enhancement cannot be ruled out completely, but the risk is considered low 
that BI 767551 increases the risk of progression of COVID-19 based on preclinical studies.
Rather, by targeting the receptor-binding domain of the SARS-CoV-2 spike (S) protein with high 
affinity and by not blocking the ACE-2 receptor, BI 767551 neutralizes SARS-CoV-2, 
preventing infection and increasing clearance thereby reducing the risk of severe disease.
Hypersensitivity reactions are anticipated adverse effects. In addition, although no human 
antigen target is described for BI 767551, all trial subjects will be carefully monitored for any 
unspecific effects.  As described in this section, this and other theoretical risks associated with
BI 767551 will be monitored along with a mitigation plan.
The data will be evaluated between the first (Phase II) and second (Phase III) parts to ensure that 
the antibody can perform as expected regarding increase in viral clearance.  Only then will the 
study proceed to the larger Phase III portion. In addition, an Independent DMC will monitor 
subject’s safety and BI 767551 efficacy during the the trial. In case BI 767551 does not 
demonstrate a potential for efficacy (interim futility analysis), the study may also be 
recommended to be stopped by the DMC.
Taking into account current knowledge of nonclinical data and relevant anticipated effects,        
BI 767551 has currently a positive Benefit-Risk profile for the treatment of patients with mild to 
moderate COVID-19 symptoms.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This trial has two sequentially enrolling parts with different objectives.
The overall objective of this trial is to evaluate the concept of pharmacological activity of BI 
767551 in non-hospitalized patients with mild to moderate COVID-19 symptoms and to identify 
a potentially efficacious and safe dose regimen from Phase II part to take into the Phase III part.
The Phase II part of the trial will aim to prove the concept of pharmacological activity of 
different dose levels and routes of administration of BI 767551 in comparison to placebo and to 
identify efficacious and safe dose regimens in non-hospitalized patients with mild to moderate 
COVID-19 symptoms. The primary objective is to numerically compare the BI 767551 dose 
levels and routes of administration to placebo for the ratio of the time-weighted change from 
baseline in viral shedding over 8 days. The primary treatment comparison will be as treated, 
including all data prior to start of any other treatment with a similar mode of action that has 
proven efficacy (either preliminary via EUA by FDA or via full approval by the FDA or EMA).  
Secondary objectives of Phase II are to numerically compare the BI 767551 doses and routes of 
administration to placebo for virological outcomes.
The Phase II part of the trial will support the decision on whether to move to Phase III and which 
dose level and route of administration to take to the Phase III part of the study. The IV route of 
administration has been shown to be efficacious in development programs for other neutralizing 
antibodies however, the inhaled route of administration is a convenient, novel route of delivery 
and more directly addresses lung infection. If shown to be efficacious in Ph II, the protocol may
be amended to select the inhaled route of administration to be carried forward into Ph III. 
The Phase III part of the trial will aim to confirm efficacy, safety and tolerability of the dose 
regimen of BI 767551 selected from the Phase II part in comparison to placebo in non-
hospitalized patients with mild to moderate COVID-19 symptoms. The primary objective is to 
demonstrate superiority of the BI 767551 dose regimen for the difference in the proportion of 
patients hospitalized or death from any cause over 29 days. The primary treatment comparison 
will be performed on all randomised patients, including all data prior to start of any other 
treatment with a similar mode of action that has proven efficacy (either preliminary via EUA by 
FDA or via full approval by the FDA or EMA). 
Secondary objectives of Phase III are to numerically compare the BI 767551 dose regimen to 
placebo for virological and other clinical outcomes.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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2.1.2
Primary endpoint(s)
The primary endpoint in Phase II is the time-weighted change from baseline in viral shedding 
over 8 days in site collected nasopharyngeal (NP) swabs by RT-qPCR, defined as a change from 
baseline in log10 viral load. Refer to Section 7.2.3 for further details.
The primary endpoint in Phase III is hospitalization or death from any cause by Day 29.
2.1.3
Secondary endpoint(s)
2.1.3.1
Secondary endpoints in Phase II
The secondary endpoints in Phase II are:

Time-weighted change from baseline in viral shedding over 29 days in site collected NP 
swabs by RT-qPCR, defined as a change from baseline in log10 viral load.

Loss of detection of SARS-CoV-2 RNA by site collected NP swab at Day 4, 8, 15, 22 
and 29.   
2.1.3.2
Secondary endpoints in Phase III
The secondary endpoints in the Phase III are:

Time to death over 29 days

Hospitalization by Day 29

Hypoxia or hospitalization or death from any cause by Day 29

Hypoxia by Day 29

Time to clinical improvement over 29 days, defined as the time to either an improvement 
of two points on the 11-point WHO Clinical Progression Scale or a score of 0 on the 
Clinical Progression Scale, whichever comes first (see Section 5.1.2).

Time to loss of detection of SARS-CoV-2 RNA by site collected NP swabs over 29 days


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a Phase II/III seamless, randomised, double-blind, placebo controlled, parallel group, 
design study to evaluate efficacy, safety and tolerability of BI 767551 for the treatment of 
symptomatic, non-hospitalized adults with mild to moderate COVID-19.
The study comprises two parts in an operationally seamless design. The exploratory Phase II part
will assess viral load measures of SARS-CoV-2 RNA by NP swab to evaluate the neutralizing 
mode of action (MoA) of BI 767551 and provide data to select the dose level or dose regimen 
also considering safety and tolerability to take into the Phase III portion should there be adequate 
neutralizing ability. Phase II includes both inhaled and i.v. routes to explore neutralizing 
potential, safety and PK to provide a comparison against Placebo of doses and routes ahead of 
decision of dose and route for the Phase III portion. For more details please see Section 4.1.2.
The confirmatory Phase III part of the study will investigate clinical outcomes for events of 
hospitalization or death throughout a 29 day period and further assessment of safety and 
tolerability for one dose regimen vs placebo. The patients will be followed for a 90-day 
observation period to assess any long-term outcomes from patients.
In Phase III, randomisation will be stratified by “high” versus “low” risk of progression to 
COVID-19. This is to ensure equal distribution of patients in these two groups to each treatment 
group. There is no minimum number of “high” risk patients for this study. For the definition of 
“high” and “low” risk please refer to Section 7.4.
Patients will be enrolled (screened) in the trial once the appropriate informed consent has been 
obtained. At the start of the trial, patients who successfully complete screening and still meet the 
inclusion/exclusion will be randomised in Phase II in a 2:2:2:1 ratio to one of the four arms:

Single placebo i.v. infusion with placebo inhalation 

Single low dose 10 mg/kg of BI 767551 i.v. infusion with placebo inhalation

Single high dose 40 mg/kg of BI 767551 i.v. infusion with placebo inhalation 

Single placebo i.v. infusion with inhalation 250 mg of BI 767551
Following CTP amendment 1, it is planned to include patients in an equal allocation ratio to each 
treatment arm. Therefore, patients will be randomised in a 1:1:1:2 ratio to receive a single dose 
of either Placebo i.v. + Placebo inhaled, BI 767551 i.v. 10 mg/kg dose + Placebo inhaled, BI 
767551 i.v. 40 mg/kg + Placebo inhaled or Placebo i.v. + BI 767551 250 mg inhaled, 
respectively, once approximately 112 patients have been randomised using the initial 
randomisation ratio. When approximately 112 patients have been randomised, the randomisation 
scheme will be implemented in sites or countries with approval for CTP amendment 1. At the 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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time of implementation of the revised scheme, sites or countries may be placed on hold for 
recruitment until approval of CTP amendment 1 is granted.
Patients will receive one single dose of active treatment or placebo on day of randomisation (Day 
1). 
In Phase III, eligible patients will be randomised in a 1:1 ratio to receive active treatment as a 
fixed dose (either 700 mg i.v. or 2800 mg i.v. or 250 mg inhaled), or placebo.
Patients in both Phase II and Phase III parts will be followed for a 90-day observation period. 
The study schematic is shown in Figure 3.1:1.
Figure 3.1:1 Study Schematic
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This seamless, trial design, with separate exploratory Phase II and a confirmatory Phase III, will 
include pre-defined decision criteria for continuing BI 767551 dose and selecting the dose 
regimen from Phase II into Phase III (see Section 3.1), with the intent of ensuring that a positive 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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proof of concept of pharmacological activity will quickly be followed by the confirmation of 
clinical efficacy and safety of BI 767551. 
A parallel group, randomised, seamless, double-blind, placebo controlled, design trial was 
considered most appropriate to assess the efficacy and safety of BI 767551 in symptomatic, non-
hospitalized adults with mild to moderate COVID-19 symptoms. 
Phase II will aim to prove the concept of pharmacological activity and dose/exposure-response 
relationship, and thus to select the dose regimen for Phase III of this trial. Phase III will 
investigate the most efficacious, tolerable and safe dose regimen from the Phase II regimens, 
unless an unexpected safety or efficacy finding requires dose modification beyond the pre-
specified transition scenarios in Section 3.1.
A control placebo group is included in this study to reduce bias with regard to the treatment 
dependent effects and to preserve the integrity of the assessments of safety and efficacy. The 
control arm reduces the subjective bias in completion of symptom diaries by participants.
A DMC, which is independent of the sponsor 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. The DMC will also assess efficacy at two planned interim analyses (See Section 7.2.8). 
Futher details are provided in the DMC charter.
3.3
SELECTION OF TRIAL POPULATION
Approximately 200 patients are planned to be randomised in Phase II at approximately 30-40
study sites; each site is expected to randomise approximately 3 patients. In Phase III there are 
approximately 1300 patients planned to be randomised at approximately 60 sites and 
approximately 23 patients per site are planned to be randomised. 
The majority of sites in Phase II are located in 7 countries and may expand to other countries to 
focus on regions where the incidence of COVID-19 is high. Approximately 20 countries are 
planned for Phase III. Given the expected regional fluctuation in SARS-CoV-2 infection rates, it 
may become necessary to open new countries and sites and to potentially suspend existing sites, 
or countries.
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 be directed to stop screening additional 
patients for this trial. This applies to both parts of the study. Patients already in screening at this 
time will be allowed to continue to randomisation if eligible.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
If retrospectively it is found that a patient has been randomised in error (i.e., did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment a decision will be made 
whether continued trial participation is possible or not.
Patients will be selected for the trial according to pre-defined eligibility criteria and written 
informed consent has to be obtained prior to initiation of any trial related procedures.
Randomisation of patients shall happen no later than 3 days after informed consent and within 5
days of symptom onset.
3.3.1
Main diagnosis for trial entry
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements pertaining 
to the in- and exclusion criteria.
Eligibility criteria for Phase II and Phase III are the same. Patients participating in Phase II are 
not eligible for Phase III. The trial will include non-hospitalized patients with mild to moderate 
COVID-19.
The trial will also include patients with mild to moderate COVID-19 symptoms that are at high 
risk for progression of disease due to underlying cardiovascular or respiratory disease, diabetes, 
chronic kidney disease, or other comorbidities, and immunocompromised persons (e.g., HIV-
infected patients, organ transplant recipients, or patients receiving cancer chemotherapy) as long 
as they do not meet other exclusion criteria. See Section 7.4 for the definition of high risk 
patients.
3.3.2
Inclusion criteria
1. ≥ 18 years old, males and females.
2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3. Documentation of laboratory-confirmed SARS-CoV-2 infection, as determined by a 
molecular test (antigen or nucleic acid) from any respiratory tract specimen (NP or nasal 
swab or saliva) collected no more than 72 hours prior to start of treatment.
4. Patients experienced mild to moderate COVID-19-related symptoms or measured fever for 
no more than 5 days prior to start of treatment where symptoms are defined by fever, feeling 
feverish, fatigue, cough, shortness of breath at rest or during activity, sore throat, body pain 
or muscle pain/ aches, chills, headache, nasal obstruction or congestion, loss of smell or taste, 
nausea, diarrhea, vomiting, or dysgeusia.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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5. One or more of the following signs/symptoms present on day of start of treatment: fever, 
feeling feverish, fatigue, cough, shortness of breath at rest or during activity, sore throat, 
body pain or muscle pain/ aches, chills, headache, nasal obstruction or congestion, loss of 
smell or taste, nausea, diarrhea, vomiting, or dysgeusia.
6. Women of childbearing potential (WOCBP)1 and men able to father a child must be ready 
and able to 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. A list of 
contraception methods meeting these criteria is provided in Section 4.2.2.3.
3.3.3
Exclusion criteria
1. Body weight of less than 40 kg.
2. Severe or critical COVID-19 including at least one of:
o
Oxygen saturation (SpO2) ≤ 93 % on room air or on their usual level of oxygen 
supplementation in case of chronic oxygen use
o
Ratio of arterial oxygen partial pressure (PaO2 in millimeters of mercury) to 
fractional inspired oxygen (FiO2) < 300 (in case arterial blood sample was taken)
o
Respiratory rate ≥ 30/min or heart rate ≥ 125/min.  Measure should be obtained at rest 
by study staff within 24 hours of start of treatment.
o
History of hospitalization for COVID-19
o
Current or imminent need for hospitalization or immediate medical attention in the 
clinical opinion of the site investigator. Does not include patients hospitalized for 
isolation only.
3. Receipt of intraveneous immunoglobulin within 12 weeks prior to Visit 2 (see Section 
4.2.2.1).
4. Receipt of COVID-19 convalescent plasma treatment at any time prior to Visit 2 (see Section 
4.2.2.1).
5. Receipt of any SARS-CoV-2 monoclonal antibody treatment at any time prior to Visit 2 (see 
Section 4.2.2.1).
6. Receipt of SARS-CoV-2 vaccine at any time prior to Visit 2.
7. Receipt of an investigational product for COVID-19 within 5 half-lives prior to Visit 2.
8. Receipt of systemic steroids (e.g. prednisone, dexamethasone) within 4 weeks prior to Visit 2
unless used for chronic condition (see Section 4.2.2.1).
9. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
                                                          
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 post menopausal state is defined as post menopausal for at least one year. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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10. Any co-morbidity requiring surgery within 7 days prior to study entry, or that is considered 
life threatening in the opinion of investigator within 30 days prior to study entry.
11. Have any serious concomitant systemic disease, condition or disorder that, in the opinion of 
the investigator, should preclude participation in this study.
12. Patients not expected to comply with the protocol requirements or not expected to complete 
the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the 
investigator’s opinion, makes the patient an unreliable trial participant).
13. Currently enrolled in any other type of medical research judged not to be compatible with 
this study.
14. Known allergy/sensitivity or any hypersensitivity to any of the components used in the 
formulation of the interventions.
15. Previous enrolment in this trial. Patients participating in Phase II are not eligible for Phase 
III. Re-screening is allowed once, for repeat of RT-qPCR or antigen SARS-CoV-2 test, if 
required. The test method used for initial screening (RT-qPCR or antigen) should be used for 
re-screening. See Section 6.2.1.
16. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.3.4
Discontinuation 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.
Every effort should be made to keep the patients in the trial: if possible, to complete all 
procedures in clinic and/or remotely as indicated in the Flow Chart, or at least to collect 
important information on vital status and whether the patient has been hospitalized at the planned 
completion date.  In case of early discontinuation, site staff should make every effort to retrieve 
all trial materials (i.e study diary) from patient. 
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 Section 5.2.6.2).
As there is only one time drug administration, patients may be less motivated to adhere to the 
study visit schedule. Investigator and site staff should work to detect early signs of lost interest 
and strongly encourage the patients to continue to complete regularly scheduled study visits until 
the trial ends. Should that not be acceptable to the patient, the patient should complete the 
Prematurely Discontinued before Day 29 or the Prematurely Discontinued after Day 29 visit 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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(whichever is appropropriate). Vital status and whether the patient has been hospitalized should 
be collected at the planned completion date. 
If a patient experiences a worsening of COVID-19 during the course of the trial, he/she can 
receive treatment with other therapies at investigator discretion and responsibility and will be 
followed up as initially planned (refer to Section 4.2.1). If a treated patient receives a prohibited 
treatment during the trial, he/she will continue the trial as initially planned and the prohibited 
treatment should be recorded as concomitant medication.
3.3.4.1
Discontinuation of Trial Treatment
In case the infusion or inhalation of study drug is permanenty discontinued before the whole 
amount of prepared solution has been administered to the patient, drug administration will not be 
re-initiated. Every effort should be made to keep the patient in the trial and perform all study 
procedures. If not possible, the patient will undergo the procedures at the Prematurely 
Discontinued before Day 29 or the Prematurely Discontinued after Day 29 visit (whichever is 
appropriate) and follow-up as outlined in the Flow Chart and Section 6.2.3. A phone contact at 
the end of the planned observation period should occur to collect the most relevant information: 
vital status (please see Section 5.2.6.1.1), outcome events, adverse events, or last contact date in 
case of lost to follow-up. The reason for interrupting trial treatment must be documented in the 
patient files and CRF.
If new efficacy / safety information becomes available, BI 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.
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.
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.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
Further treatment and 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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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The study will include BI 767551 and placebo. The identity of the medicinal products is divided 
by phase of the study.
In Phase II the medication is dose by weight i.v or fixed dose inhalation (nebulized) with the 
following treatment arms: 

Placebo i.v. + Placebo inhaled

BI 767551 i.v. 10 mg/kg + Placebo inhaled

BI 767551 i.v. 40 mg/kg + Placebo inhaled

Placebo i.v. + BI 767551 250 mg inhaled
In Phase III, the medication will be administered via either i.v as a fixed dose or inhalation with 
the following potential treatment arms:

BI 767551 i.v. 700 mg or 2800 mg or 250 mg inhaled

Placebo
4.1.1
Identity of the Investigational Medicinal Products
4.1.1.1
Test Products for Phase II
Sterile normal saline (NaCL 0.9%) procured from a commercial source and approved for clinical 
application will be used as placebo for the intravenous infusion.
Table 4.1.1.1:1
BI 767551
Substance:
BI 767551
Pharmaceutical formulation:
Concentrate for solution for infusion/nebulizer solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
1000 mg/vial (50 mg/ml), 20 ml
Posology:
i.v. infusion or inhalation (as required per instructions)
Single i.v. infusion, 10 mg/kg or 40 mg/kg
Single i.v. inhalation, 250 mg
Mode of administration:
i.v. infusion
Inhalation


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 4.1.1.1:2 
Solvent for dilution
Substance:
Solvent for dilution of BI 767551
(used as placebo for inhalation)
Pharmaceutical formulation:
Solvent for dilution of BI 767551 concentrate for 
solution for infusion/nebulizer solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
n/a, 20 ml in glass vial
Posology:
To be used for i.v.infusion (calculated by body weight) 
or inhalation (as required per instructions)
Mode of administration:
i.v. infusion
inhalation
4.1.1.2
Test Products for Phase III
Table 4.1.1.2:1
BI 767551 (For infusion)
Substance:
BI 767551
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
1000 mg/vial (50 mg/ml), 20 mL in glass vial
Posology:
i.v. infusion (as required per instructions)
Single i.v. infusion 700 mg or 2800 mg
Mode of administration:
i.v. infusion 
Table 4.1.1.2:2 
BI 767551 (for inhalation)
Substance:
BI 767551 
Pharmaceutical formulation:
Concentrate for nebulizer solution 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
250 mg/vial (50 mg/ml), 5 mL in glass vial 
Posology:
Single inhalation 250 mg
Mode of administration:
Inhalation
Table 4.1.1.2:3
Placebo for BI 767551 (for infusion)
Substance:
Placebo for BI 767551
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
n/a, 20 ml in glass vial
Posology:
Single i.v. infusion equal to the volume of treatment 
for 700 mg or 2800 mg
Mode of administration:
i.v. infusion


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 4.1.1.2:4
Placebo for BI 767551 (for inhalation)
Substance:
Placebo for BI 767551
Pharmaceutical formulation:
Concentrate for nebulizer solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
n/a, 5 ml in glass vial
Posology:
Single inhalation equal volume for 250 mg
Mode of administration:
Inhalation
Table 4.1.1.2:5
Solvent for dilution
Substance:
Solvent for dilution of BI 767551 or for dilution of 
Placebo, if needed
Pharmaceutical formulation:
Solvent for dilution of BI 767551 concentrate for 
solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
n/a, 20 ml in glass vial
Posology:
To be used as diluent for i.v. infusion for BI 767551 or 
placebo up to final volume defined in instructions
Mode of administration:
i.v. infusion 
4.1.2
Selection of doses in the trial and dose modifications
A viral dynamic model, based on the influenza A model developed by Baccam et al. was used in 
combination with a pharmacokinetic model to predict the human efficacious dose [R20-3336]
(refer to n00282535 and Section 1.2.2 for further details). 
In the 1487-0001 study, patients will receive treatment no more than 5 days after symptom onset. 
For this later treatment start, which is considered a more realistic scenario in clinical practice, the 
viral dynamics model indicates that the maximum obtainable response in the model is smaller 
than with treatment onset at symptom onset. In addition, the maximum obtainable response is 
less sensitive to dose (i.e. no relevant difference between e.g. 40 mg/kg and 10 g/kg). Therefore, 






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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised to 
treatment groups according to a randomisation plan in a 2:2:2:1 ratio at Visit 2 (and in a 1:1:1:2
ratio after CTP amendment 1 has been approved, please refer to Section 7.4 for further details) in 
Phase II to either Placebo i.v. + Placebo inhaled, BI 767551 i.v. 10 mg/kg dose + Placebo
inhaled, BI 767551 i.v. 40 mg/kg + Placebo inhaled or Placebo i.v. + BI 767551 250 mg inhaled, 
respectively, and in a 1:1 ratio to BI 767551 i.v. or placebo in Phase III via Interactive Response 
Technology (IRT). The appropriate medication numbers will be assigned and documented by the 
unblinded pharmacist (Phase II part only). For Phase III, the pharmacist will be blinded to the 
treatment assignment.
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
BI 767551 is a human monoclonal antibody of the IgG1 kappa isotype (see Section 1.2). It is 
produced by Boehringer Ingelheim and provided to the study pharmacies as a stock solution at a 
concentration of 50 mg/ml in single-use vials containing a volume of 20 ml. Stock vials will be 
stored at 5±3°C. The Solvent for dilution of BI 767551 will also be provided in single-use vials 
containing a volume of 20 ml.
At Day 1, patients will be randomised to one of four treatment arms in Phase II or to one of the 
two treatment arms in Phase III by the IRT.
The pharmacist or his/her qualified delegate (unblinded for Phase II) will prepare the trial 
medication according to the medication handling instructions (as specified in the ISF). 
For Phase II, the unblinded pharmacist or his/her qualified delegate will prepare the medication 
as instructed to ensure that the treatment blinding is maintained throughout administration.
Inhalation
BI 767551 or placebo will be administered as a single inhalation through a mouthpiece 
(Aerogen® Ultra) using a mesh nebuliser (Aerogen® Solo) to generate an aerosol. The 
inhalation procedure will start approximately 25 minutes following start of infusion and will 
require approximately 15-20 minutes. Please see Appendix 10.1 for Instructions for use of the 
Aerogen® Solo nebuliser.
Infusion
BI 767551  or placebo for intravenous infusion will be administered as a single infusion using a 
peripherally inserted catheter, preferably into an upper extremity vein, over a period of 60 min 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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(+/- 10 minutes) using a 0.2 µm nylon in-line filter and polyurethane-based infusion system. 
Polypropylene-coated infusion bags containing the appropriate quantitify of diluted or undiluted 
BI 767551 or placebo will be provided by the local study pharmacy after preparation according 
to the handling instructions. At the end of the infusion, the infusion system will be flushed using 
at least 25 ml of sterile normal saline at the infusion flow rate. For Phase II, the dose of BI 
767551 or the amount of placebo will be body weight adjusted (weight to be entered in IRT). For 
Phase III the dose of BI 767551 or the amount of placebo will be fixed dose.
No specific rescue therapy for BI 767551 is available. In case of an acute infusion reaction, the 
infusion will be interrupted and not be re-initiated. For infusion reactions requiring medical 
intervention, rescue medication including, but not limited to, acetaminophen/paracetamol, 
antihistamines, glucocorticoids, and IV fluids must be available on-site. In case of bronchial 
hyperresponsiveness (e.g., bronchospasm), bronchodilators and antiinflammatroy medication 
may be provided by inhalation or intravenously as deemed clinically appropriate.
Phase II
The solvent for dilution of BI 767551 will be used a placebo for the inhaled application.
Sterile normal saline (NaCl 0.9%) procured from a commercial source and approved for clinical 
application will be used as placebo for the intravenous infusion.
Prior to the reconstitution, preparation and the administration, the vials should be checked by the 
unblinded pharmacist or his/her qualified delegate for any changes (e.g. color).
Phase II and Phase III
Handling and preparation of the medicinal product should be performed according to routine site 
procedures using aseptic techniques. Prior to the reconstitution, preparation and the 
administration, the vials should be checked for the absence of particles. 
The local Clinical Monitor or CRA should be contacted for questions or concerns regarding 
appearance of the solution. 
4.1.5 
Blinding and procedures for unblinding
4.1.5.1
Blinding
The access to the randomisation code will be kept restricted until its release for analysis.
For Phase II, patients, investigators, central reviewers, and everyone involved in trial conduct 
with exception of the pharmacist, or analysis or with any other interest in this double-blind trial 
will remain double-blind with regard to the randomised treatment assignments until a snapshot is 
taken after the last patient randomised completes Day 8 for the interim analysis.  This snapshot 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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will be used to determine the dose of BI 767551 to be used in the Phase III part. At the timepoint 
of the interim analysis for Phase II, the sponsor will be unblinded to the treatment allocation of 
patients in Phase II, but patients and investigators will remain double-blind until after the final 
database lock.
This study design includes an unblinded pharmacist who prepares the medication for the patient 
during the Phase II part. This unblinded function is needed due to a visible difference in 
packaging and the colouration of the BI 767551 versus placebo. The pharmacy/dispensing team 
will be unblinded to treatment group and will receive appropriate training in advance of starting 
the trial, to ensure they maintain compliance within the pharmacy department. Only unblinded
pharmacists will be involved in IMP preparation for Phase II and will not be involved in the 
assessment of patients.
For Phase III patients, investigators and everyone involved in trial conduct or analysis or with 
any other interest in this double-blind part of the trial will remain blinded with regard to the 
randomised treatment assignments until after the database lock after Last Patient Completed.
The access to the randomisation code for the Phase III part will be kept restricted until its release 
for analysis.
The randomisation codes will be provided to bioanalytics prior to last patient completed in Phase 
II and Phase III to allow for the exclusion from the analyses of pharmacokinetic (PK) samples 
taken from placebo patients. Bioanalytics will not disclose the randomisation code or the results 
of their measurements until the trial is officially unblinded to the sponsor.
The independent DMC will have access to the unblinded treatment codes in order to allow them 
to periodically assess the trial data to ensure the overall safety and integrity of the trial, as well as 
to conduct the pre-specified interim analyses during the Phase III part as detailed in Section 
7.2.8. For further details refer to Section 8.7 as well as the DMC charter.
Further details regarding the timepoint of unblinding the database for analysis are documented in 
the TSAP.
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 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 BI’s Pharmacovigilance group to access the 
randomisation code for individual patients during trial conduct. The access to the code will only 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 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. 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 or deligate 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 (if applicable).
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 by 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. 
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 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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provided 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 or appointed CRO, the investigator or designee must verify that all unused or partially 
used drug supplies have been returned by the clinical trial patient 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
Stable doses of concomitant therapies for chronic conditions, for which neither the condition nor 
the treatment are judged to exclude the patient from participation (see Section 3.3), are 
permissible. In case of adverse event in need of treatment, symptomatic therapy according to 
investigator judgement will be permitted.
Infusion reaction
In case of an acute infusion reaction, the infusion will be interrupted and not be re-initiated. For 
infusion reactions requiring medical intervention, rescue medication including, but not limited to, 
acetaminophen/paracetamol, antihistamines, glucocorticoids, and IV fluids must be available on 
site.
Inhalation reaction
In case of bronchial hyperresponsiveness (e.g., bronchospasm), bronchodilators and/or anti-
inflammatory medications may be provided by inhalation or intravenously as deemed clinically 
appropriate.
Rescue treatment
During the trial, if COVID-19 worsens, the patient can be treated with medications at the 
discretion of the investigator (refer to Restricted medication Table 4.2.2.1:1, footnote 2) as per 
local guidelines. Any additional investigational products related to COVID-19 could be given for 
COVID-19 disease worsening, after Day 2 at the discretion of the investigator but may require 
additional safety monitoring by the site.
All efforts should be made to inform the patient of the importance of completing the protocol 
specified visits (See Flow Chart) up to Visit 9. Patients refusing to complete the scheduled visits 
after the day of treatment should at least provide safety information by phone at the respective 
visits.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications listed in Table 4.2.2.1:1 must not have been taken before Visit 2 (V2) for the 
time periods as specified, and are not permitted throughout the study participation to Visit 9
(V9), Day 29.:


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 4.2.2.1:1
Restricted medications
Medication or class of medications
Restriction before 
randomisation (V2) 
Restriction from 
randomisation (V2) 
until V9 (Day 29)
Systemic steroids1,2
4 weeks prior to V2
Not allowed
Ivermectin1,2
Starting from V2
Not allowed
Remdesivir2
Starting from screening 
visit to V2
Not allowed
HIV protease inhibitors1
Starting from screening 
visit to V2
Not allowed
Intravenous immunoglobulin2
12 weeks prior to V2 
Not allowed
COVID-19 convalescent plasma treatment2
Any time prior to V2
Not allowed
Other SARS-CoV-2 monoclonal antibody2,3
Any time prior to V2
Not allowed
SARS-CoV-2 vaccine3
Any time prior to V2
Not allowed
Investigational products (including those for 
COVID-19)2
5 half-lives prior to V2
Not allowed
Hydroxychloroquine, Chloroquine, 
Methotrexate1,2
Starting from screening 
visit to V2
Not allowed
Systemic immunomodulating or 
immunosuppressive treatments1,2
4 weeks prior to V2
Not allowed
1Unless used for treatment of chronic or urgent, acute condition other than COVID-19. No restrictions on 
corticosteroids with only a topical effect (e.g. inhaled, dermal, otic or opthalic corticosteroids).
2In case of COVID-19 disease worsening, please refer to Section 4.2.1 for the details on use of treatment.
3Not recommended to be given until after Day 91 unless used with discretion as rescue therapy.
4.2.2.2
Restrictions on diet and life-style
Not Applicable
4.2.2.3 
Contraception requirements
Women of childbearing potential (for the definition of WOCBP, please refer to Section 3.3.2)
and men able to father a child 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 the trial, and for a period of at least 90 days after the study drug administration. 
A list of contraception methods meeting these criteria is also provided in the patient information. 
For female Patients:
Acceptable methods of birth control for this trial are:

Hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or post-menopausal for at 
least one year

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)


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
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)
-
Note that progestogen-only hormonal contraception where inihibition is ovulation is not   
     the primary mode of action is not considered as highly effective

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner (if partner is sole sexual partner and has received medical assessment 
of surgical success)

Abstinence. This is defined as being in line with the preferred and usual lifestyle of the 
patient. 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. 
For male Patients:
Acceptable methods of birth control for this trial are:

Barrier contraception (i.e., condom)

Vasectomised sexual partner with documented absence of sperm

Abstinence. This is defined as being in line with the preferred and usual lifestyle of the 
patient. 
In addition, men with pregnant partners should use barrier contraception (i.e., condom) during 
the pregnancy of the partner.
4.3
TREATMENT COMPLIANCE
Study medication will be administered in accordance with the protocol, under supervision of the 
investigating physician or a designee at the site. At the time of study medication administered, 
the date, time and route(s) will be entered into the eCRFs. 
The only reasons for deviations from the treatment schedule in the protocol would be due to the 
rare events of dosing mistakes or damaged treatment kits.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Efficacy in the exploratory Phase II part will be assessed via viral load measures of SARS-CoV-
2 RNA in NP swabs and OP swabs. The neutralizing MoA of BI 767551 is expected to reduce 
viral load in the treatment groups to a larger degree compared to placebo.
The confirmatory Phase III part will investigate clinical outcomes for events of hospitalization or 
death throughout a 28 day period. 
5.1.1
SARS-COV-2 RNA Assessment
SARS-CoV-2 RNA levels will be determined from frozen (-80°C) transport medium using a 
clinically validated quantitative reverse-transcriptase PCR assay (RT-qPCR) at the visits 
specified in the Flowchart. Results will be provided as Ct (Cycle threshold) values as well as 
quantitatively (copies/mL) based on a reference standard.
At the screening visit, a single NP, nasal swab or saliva is sufficient to document the absence or 
presence of SARS-CoV-2 infection by RT-qPCR or antigen test. This will be performed at the 
trial site’s local laboratory and/or Point-of-Care testing. Documentation of laboratory-confirmed 
SARS-CoV-2 infection, as determined by a molecular test from any respiratory tract specimen 
(NP, nasal swab or saliva) is also acceptable.
Starting on day of randomisation (Day 1), NP swabs and OP swabs will be collected at clinic 
visits and remotely (at patient’s home).  On in-person clinic visits and in-person remote visits, 
swabs will be collected by a home health care nurse or site staff. Anterior nasal swabs will be 
self-collected (or collected by home healthcare nurse or site staff) on days outlined in the 
Flowchart.
Baseline viral load measures taken and analyzed by the central lab will be used for the analysis.
5.1.2
Improvements on the WHO Clinical Progression Scale
The following 11-point WHO Clinical Progression Scale will be used for the assessment of 
Clinical improvement (Figure 5.1.2:1):


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Figure 5.1.2:1
WHO Clinical Progression Scale [R20-2002]


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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5.2
ASSESSMENT OF SAFETY
Safety will be assessed based on adverse events, serious adverse events (SAEs), laboratory 
parameters, physical examination, and vital signs. Observational period is 90 days. Only 
descriptive analyses are planned.
5.2.1
Physical examination
A complete physical examination will be performed at Screening (Visit 1). It includes at a 
minimum general appearance, neck, lungs, cardiovascular system, abdomen, extremities, and 
skin. Subsequent physical examinations after screening should be targeted to symptoms.
Height and body weight measurements as well as smoking status review will be performed at the 
time points specified in the Flowchart.  The results must be included in the source documents 
available at the site. 
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling. This includes systolic and diastolic blood pressure, body temperature, respiratory rate, 
pulse rate (electronically or by palpation count for 1 minute) and resting peripheral oxygen 
saturation. Measurements must be taken while patient is in a seated position after 5 minutes of 
rest. The results must be included in the source documents available at the site.
At screening to confirm eligibility only respiratory rate, pulse rate (electronically or by palpation 
count for 1 minute) and resting peripheral oxygen saturation should be taken. Confirmation of 
PaO2/FiO2 ratio <300 only required in case arterial blood sample was previously taken. 
At dosing visit (Day 1), vital signs will be assessed pre-dose, at the end of the infusion and 2h 
(+/- 5 min) after the infusion. 
The results must be included in the source documents available at the site.
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 Flowchart. Patients do not have to be fasted for the blood sampling for the 
safety laboratory. The maximum volume of blood needed per patient for all laboratory 
assessments is approximately 300 mL during the course of the trial.
For all scheduled visits, all analysis will be performed by a central laboratory. Local laboratories 
may be used for safety laboratory assessments in case of urgent need. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Instructions regarding sample collection, sample handling/ processing and sample shipping for 
all visits after screening are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. 
It is the responsibility of the investigator to evaluate the laboratory reports. 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.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.3:1 
Safety laboratory tests
Functional lab group
Test name 
Anti-SARS-CoV-21
RT-qPCR Anterior nasal swab
RT-qPCR Nasopharyngeal
RT-qPCR Oropharyngeal
Haematology
Blood typing (only at Baseline)
Complete blood count:
Red blood cell count (RBC)
Haematocrit (Hct)
Haemoglobin (Hb)
White Blood cell count including 
differential/Leukocytes
Platelet Count/ Thrombocytes
Coagulation and Inflammation
D-Dimer 
Fibrinogen
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
International Normalised Ration (INR)
C-Reactive Protein (CRP)
  Ferritin


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 5.2.3:1 
Safety laboratory tests (continued)
Functional lab group
Test name
Enzymes
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)  
Creatine kinase (CK)
Troponin, only if CK is elevated
Lactate dehydrogenase
Lipase
Type B natriuretic peptide (BNP), or NT-proBNP
Electolytes
Potassium
Sodium
Calcium
Chloride
Glucose
Substrates
Creatinine
Total Bilirubin,
Total protein
Albumin
Uric Acid
Urea
eGFR
SARS-CoV-2 Antibody Serology1
IgG, IgA, IgE3
Urine pregnancy test2
Human Serum Chorionic Gonadotropin in urine
Serum Pregnancy test2
Human Serum Chorionic Gonadotropin
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Leukocytes Esterase
Urine pH
Specific Gravity
Urobilinogen
Urine Bilirubin
Urine Blood
Urine sediment (microscopic examination if 
erythrocytes, leukocytes nitrite or protein are 
abnormal in urine)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sediment Crys., Unspecified
Urine Sediment RBC/Erythrocytes
Urine Sediment WBC/Leucocytes
1
Not for safety parameter but collected for central lab


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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2
Only for female patients of childbearing potential. Urine and serum pregnancy testing will be performed as 
indicated in the Flow Chart. In case of remote visits, clinical site may provide subjects with at-home urine 
pregnancy test kits (may be sponsor-provided)
3     
To be performed if a validated assay is available.
5.2.4
Electrocardiogram
Not applicable.
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, 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.
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use of 
the product within or outside the terms of the marketing authorisation or from occupational 
exposure. Conditions of use outside the marketing authorisation include off-label use, overdose, 
misuse, abuse and medication errors.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 hospitalization or prolongation of existing hospitalization
-
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 
hospitalization 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 eDC 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 5.2.6.1.2.
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 Section 5.2.6.1.2, 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 5.2.6.1.2.
The following are considered as AESIs:


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Inhalation related bronchospasm
Inhalation of the investigational medicinal product may result in airway irritation and/or 
hypersensitivity that can result in bronchospasm manifesting wheezing, prolonged expiration and 
respiratory distress.
Hypersensitivity/allergic reaction 
Any suspicion of severe infusion reaction and of any potential cases of anaphylaxis should be 
defined and assessed using the criteria discussed in the statement paper from Sampson HA 
(Appendix 10.4; R11-4890)
Infusion of biological products including monoclonal antibodies may be associated with the 
development of infusion related reactions that can occur during and/or within hours of the 
infusion. Symptoms of infusion related reactions may be related to immediate hypersensivity 
(allergic reaction, anaphylaxsis) or cytokine-release syndrome. Symptoms of cytokine release 
syndrome may include, but are not limited to, fever, tachypnea, headache, tachycardia, 
hypotension, all types of rashes including flushing, and/or hypoxia.
Potential Severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the 
following alterations of hepatic laboratory parameters: 

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 sample, or in samples drawn within 30 days of each other, or

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 adverse events should be classified and recorded in the CRF according 
to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known
as the DAIDS AE Grading Table; R21-0379)
For specific events that are not included in the DAIDS AE Grading Table, the generic scale 
(Table 5.2.6.1.5:1) is to be used:


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 5.2.6.1.5:1
Generic AE Grading Scale [R21-0379]
Grade 1
Events causing no or minimal interference with usual social and 
functional activities, and NOT raising a concern, and NOT requiring a 
medical intervention/therapy.
Grade 2
Events causing greater than minimal interference with usual social 
and functional activities; some assistance may be needed; no or 
minimal medical intervention/therapy required.
Grade 3
Events causing inability to perform usual social and functional 
activites; some assistance usually required; medical 
intervention/therapy required.
Grade 4
Events causing inability to perform basic self-care functions; medical 
or operative intervention indicated to prevent permanent impairment, 
persistent disability, or death.
Grade 5
Events resulting in death.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event and 
the BI investigational compund, 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 trial 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:


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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
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 of 
drug administration; an allergic reaction weeks after discontinuation of the trial 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.

There is an 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 individual patient’s end of trial (= the 
End of Study (EoS) visit): all AEs (serious and non-serious) and all 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 drug related SAEs and trial drug 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 5.2.6.1.2), but not on 
the CRF.
Vital Status Data Collection
Patients who discontinue the trial 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, discontinuation of 
trial treatment. From then on until the individual patient’s end of the trial the investigator must 
report any occurrence of cancer, report all deaths / fatal AEs regardless of relationship, and trial 
drug related SAEs and trial drug related AESIs the investigator becomes aware of as well as 
information on any AEs leading to hospitalization, whether related to trial drug or not. 
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 hours 
of becoming aware of the event, the country specific process will be specified in the ISF. The 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 the BI SAE form.
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.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Details on sample collection for BI 767551 characteristics, processing, handling, and shipment 
are provided in the Laboratory Manual.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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5.4
ASSESSMENT OF BIOMARKER(S)
Refer to Section 5.6.2 for other assessments.


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5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS




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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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6.
INVESTIGATIONAL PLAN
The trial consists of three periods, a screening period, single dose treatment and a follow-up 
period. 
In Phase II, randomised patients will receive a single dose of BI 767551 or placebo as infusion or 
inhalation. In Phase III, randomized patients will receive a single dose of BI 767551 or placebo
as infusion or inhalation.
All required procedures are described in the Flowchart and in Sections 6.2. 
After single treatment patients will be followed-up on Day 3,4,8,11,15,22, 29 and Day 91 / EOS 
visit.
6.1
VISIT SCHEDULE
No study procedures may be initiated prior to the patient or patient’s legally acceptable 
representative signing the informed consent.
All subjects are to adhere to the visit schedule as specified in the Flowchart. Each visit date (with 
its window) is to be counted from Day 1 (Visit 2 date = visit with first IMP administration).  If 
any visit has to be rescheduled, subsequent visits should be calculated again from Day 1. 
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 flowchart and the respective 
protocol sections. Additional details on procedures at selected visits are provided below.
At all applicable visits vital signs should be collected prior to blood sampling.
NP swabs will be obtained by inserting a swab in one nostril along the nasal septum to the 
nasopharynx until resistance is felt, reaching a depth that is proximately the length from the outer 
nostril opening to the ear. Once resistance is felt, the swab will be left in place for a few seconds 
to allow for absorption of secretions and is slowly removed while rotating. OP swabs will be 
obtained by swabbing the posterior pharynx and tonsillar areas. Care should be taken to avoid 
accidental swabbing of the gums, tongue, or teeth. SARS-CoV-2 RNA levels will be determined 
from frozen (-80°C) transport medium using a clinically validated quantitative reverse-
transcripase real-time PCR assay (RT-qPCR) assay. Results will be provided as Ct (Cycle 
threshold) values as well as quantitatively (copies/ml) based on a reference standard. These 
assays will be performed at central laboratory. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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On days without an in-person visit, the anterior swabs will be self-collected by the patient on 
their own same time every day, when completing the study diary and temperature measurement. 
Patients will turn in their self-collected (remote) swabs at their next in-person visit.
6.2.1
Screening and run-in period(s)
Screening Period
Once the patient has consented, the patient is considered to be enrolled in the trial. The patient 
should be recorded on the enrollment log and be registered in the IRT. Each patient will be 
assigned a unique patient number, via the IRT system and enrollment will be recorded in eCRF. 
For the schedule of assessments and procedures during the screening period refer to the 
Flowchart.
During the screening visit, demographics information will be collected. This includes: 

age on the day of informed consent (in years) 

Sex (male, female in order to describe the subject`s sex at birth), 

For women: of childbearing potential yes / no in order to characterize the patient 
population and as a basis for contraception requirements 

Ethnicity and race in order to sufficiently characterize the patient population, to support 
possible subgroup analyses if needed and to support the calculation of the kidney 
function via the CKD EPI formula unless not acceptable according to local regulations.
Study requirements, including the procedure for the follow-up of prematurely withdrawn patients 
must be fully explained to the patient and written informed consent obtained prior to initiating 
any study-related evaluation. The importance of staying in the trial until completion of all study 
requirements will be emphasized. No trial procedures should be done unless the patient has 
consented to taking part in the trial.
SARS-CoV-2 infection documentation is recorded on the eCRF. Positive RT-qPCR or antigen 
test will be obtained prior to randomisation. Documentation of laboratory-confirmed SARS-
CoV-2 infection as determined by molecular test from any respiratory tract specimen (NP, nasal 
swab or saliva) is also acceptable.
Patients will be asked about their first symptoms related to COVID-19 and their current 
symptoms. The time of symptom onset should be recorded.
Urine pregnancy testing should be done prior to administration of study drug for all women of 
childbearing potential.  Study drug should only be administered in case of a negative test result.
Medical History:
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 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 or his legal 
representative, documented in their medical records, would be acceptable. Medical history 
includes estimated date and time of first SARS-CoV-2 infection symptoms as well as symptom 
details.
Information on clinically significant previous and concomitant illnesses, or any clinically 
significant signs or symptoms that are present before informed consent, or pre-existing 
conditions identified through findings from assessments and examinations done during the 
screening visits will be recorded as medical history at screening. 
Patients who do not meet eligibility critera should be documented as a screen failure. The patient 
must be registered as a screen failure in IRT system. 
Re-screening
Re-screening of a previously screen failed patient will be permited once. Patients who have or 
RT-qPCR or antigen SARS-CoV-2 test within the screening window with a value outside the 
range specified by the inclusion criteria may have the test repeated once to determine eligibility. 
The RT-qPCR or antigen SARS-CoV-2 re-test performed must be the same test method used for 
initial screening and the result must be available within the screening window, prior to Visit 2 
(Day 1). All remaining eligibility criteria must also be met.  In case of re-screening patient will 
obtain new patient number per IRT.
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.
Baseline Conditions
Baseline conditions include a number of co-morbidities (e.g. respiratory, cardiovascular, 
metabolic, malignancy, endocrine, gastrointestinal, immunologic and renal).
In addition, as noted in Section 5.2.6.1. if any worsening of the underlying disease or of other 
pre-existing conditions or changes in vital signs, physical examination and laboratory test results, 
as judged clinically relevant by the investigator already exist prior to trial inclusion, they will be 
considered as baseline conditions and should be collected in the eCRF only.
6.2.2
Treatment Period(s)
The patient is randomised (Day 1; Visit 2) not later than 3 days after information consent upon 
confirmation of the eligibility criteria via IRT. Study medication dispensing and administration 
can occur on the same day (Day 1).
For the schedule of assessments and procedures during the treatment period refer to the 
Flowchart.




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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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are planned during the follow-up period, clinical site may provide subjects with at-home urine 
pregnancy test kits (may be sponsor-provided).
NP
swabs will be taken by study staff for SARS-CoV-2 testing prior to IMP 
administration.
On day of treatment, participants will complete the study diary with site staff prior to IMP 
administration. Participant’s answers will be recorded into the eCRFs. Participants will be asked 
to complete the diary at approximately the same time every day.
Participants will be given a thermometer and pulse oximeter to record their temperature and 
oxygen saturation each day in the diary.
Sites will capture information for a secondary contact that the site can contact if the participant 
cannot be reached (e.g. spouse, friend, neighbour). Contact information for secondary contacts 
will not be recorded in the eCRF
Concomitant medication review
Data concerning concomitant medications will be collected throughout the trial, as specified in 
the Flowchart.
Adverse event review is to be done at every visit, see Section 5.2.6 for more details.
6.2.3
Follow-up period and trial completion
Patients will be followed after treatment period up to Day 91. Follow-up period consists of 
8 visits:  Days 3,4,8,11,15,22,29 and Day 91 /EOS visit.
For the schedule of assessments and procedures during the follow-up period refer to the Flow 
chart. Sites will review with patient if there are any updates to the information provided for their 
secondary contact. Contact information will not be recorded in the eCRF
Participants will complete a study diary by recording their temperature, oxygen saturation and 
completing all questions every day up to protocol Day 29 (within the visit window). On days 
with a clinic or remote visit, patients will be reminded to complete all entries every day 
(preferably the same time every day) and to bring their diary with them to the next clinic visit. 
Clinic visit diary entry may also be completed at the clinic. In case of remote visits, every effort 
should be made to retrieve the study diary answers (or a copy of the answers), otherwise retrieve 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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the study diary from the participant at the next clinic visit. Guidance for reviewing and data entry 
of the participant’s answers will be provided in the ISF. 
NP 
swabs will be collected during in-patient visits as per Flowchart by site staff.
Symptom targeted physical examination will be performed up to Day 91. Weight will be 
collected at Days 29 and 91.
Vital signs measurements shall include blood pressure measurement, body temperature, 
respiratory rate, pulse rate and resting peripheral oxygen saturation. Measurements shall be 
performed before blood sampling at each clinic visit until Day 29. 
Blood samples for haematology and chemistry will be collected at timepoints indicated in the 
Flowchart. For women of childbearing potential urine pregnancy tests will be performed at 
timepoints indicated in the Flowchart. In case urine pregnancy test positivity, serum pregnancy 
test shall be performed as well. 
Blood samples (plasma and serum) for inflammatory and coagulation markers will be collected 
at time points indicated in the Flowchart.
Concomitant therapy information is to be collected at each visit, during on site visit or per 
telephone or e-mail during remote visits until Day 91 and at last visit in case patient discontinues 
the trial prematurely before completion Day 29.
AEs/SAEs collection shall be performed until Day 91 and at last visit in case patient discontinues 
the trial prematurely before completion Day 29.
If needed in the opinion of the investigator, after the EoS (End of Trial) visit additional visits 
may be scheduled for continued safety monitoring. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Abnormal assessments or lab values judged clinically relevant by the investigator will be 
monitored until they returned to a medically acceptable level. 
Vital status information is to be collected for each patient that completes the EOS visit. In case 
patient discontinues the trial prematurely before their scheduled EOS visit, vital status 
information and information whether the patient has been hospitalized shall be collected at 
planned completion date of each individual patient. Any locally approved means of vital status 
information collection is accepted. 
Early treatment discontinuation
In case the infusion or inhalation of study drug is permanenty discontinued before the whole 
amount of prepared solution has been administered to the patient, drug administration will not be 
re-initiated. Patients should be encouraged to follow all study procedures until their individual 
EOS visit. Given the patient’s agreement, the patient will undergo the procedures for early 
treatment discontinuation (see Section 3.3.4.1) and follow up as outlined in the Flowchart (and 
Section 6.2.3).
Trial completion:
Trial completion is defined as a patient having reached the EOS visit. EOS visit will be at Week 
12, Day 91. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE            
Phase II of the study is exploratory in nature. Phase III has a group-sequential design with two 
planned interim analyses. Further details about the interim analyses can be found in Section 
7.2.8. The methods to control the global overall significance level for the primary endpoint are 
described in Section 7.1. Sample size calculations and information on the O’Brien and Fleming 
local nominal alpha levels for the different interim analyses and the final analysis and the 
probabilities of stopping the trial at an interim analysis or at the final analysis are summarized in 
Table 7.5.2:1.
7.1
NULL AND ALTERNATIVE HYPOTHESES
In Phase II, no confirmatory testing is performed and hence no null and alternative hypotheses 
are defined. All p-values are to be understood as exploratory. A justification of the sample size is 
provided in Section 7.5.1.
In Phase III, the superiority of BI 767551 compared to placebo will be tested for the proportion 
of patients hospitalized or who died from any cause by Day 29. 
The null hypothesis is:
H0: The probability to get hospitalized or to die by Day 29 in the BI 767551 arm is equal to the 
probability to get hospitalized or to die by Day 29 in the placebo arm.
The alternative hypothesis is:
H1: The probability to get hospitalized or to die by Day 29 in the BI 767551 arm is smaller than 
the probability to get hospitalized or to died by Day 29 in the placebo arm.
The control of the global overall significance level of 2.5% (one-sided) is assured for the primary 
endpoint as follows: Adjustments accounting for the planned interim analyses are done using the 
Lan-DeMets spending function approach with an O’Brien and Fleming boundary. For the 
primary endpoint, statistical significance will be declared (either at one of the interim analyses or 
in the final analysis) if the analysis is significant at the local nominal one-sided alpha level. 
These O’Brien and Fleming local nominal one-sided alpha levels are given in Table 7.5.2:1 for 
each interim and the final analysis for the planned information fraction. The one-sided p-value is 
required for the primary endpoint due to the use of a group sequential design. 
7.2
PLANNED ANALYSES
7.2.1
General considerations
In Phase II, efficacy analyses will be based on all randomised patients that have been treated.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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In Phase III, efficacy analyses will follow the intention-to-treat principle and will include all 
randomised patients whether the patient is treated with the study medication or not. For the 
confirmatory analysis of the primary endpoint of Phase III of the study, only the data of the 
patients randomised in Phase III will be included.
Safety analyses will include all treated patients who are documented to have taken any dose of 
the study medication and will be reported separately for Phase II and Phase III patients, as well 
as integrated across both parts where possible.
In Phase II, all analyses will be based on the treatment group as treated. In Phase III, all analyses 
will be based on the treatment group as randomised by IRT.
Although there is no per protocol data set in the study, reasons for important protocol deviations 
will be specified in the TSAP. Patients with important protocol deviations will be identified at 
Review Planning Meetings and listed in the CTR.
7.2.2
Handling of Intercurrent Events
The expected intercurrent events of interest in this trial are:

Start of a product with a similar mode of action as trial medication that has proven 
efficacy (either preliminary via EUA by FDA or via full approval by the FDA or EMA)

Start of a restricted medication as defined in Table 4.2.2.1:1, except any product with a 
similar mode of action as trial medication that has proven efficacy (either preliminary via 
EUA by FDA or via full approval by the FDA or EMA)

Death
The strategies for handling intercurrent events in this trial are as follows:
Primary strategy: This is the effect of randomising a patient to a treatment, but excluding the 
effects of any other products with a similar mode of action as trial medication that have proven 
efficacy (either preliminary via EUA by FDA or via full approval by the FDA or EMA). Start of 
a restricted medication as defined in Table 4.2.2.1:1, except any product with a similar mode of 
action as trial medication that has proven efficacy (either preliminary via EUA by FDA or via 
full approval by the FDA or EMA) will be handled using the treatment policy approach as 
defined in ICH E9(R1). Death will be handled using the composite approach as defined in ICH 
E9(R1). The use of any other products with a similar mode of action as trial medication that have 
proven efficacy will be handled using the while-on-treatment approach as defined in ICH 
E9(R1), with the treatment period defined as the period from first administration of randomised 
medication to the end of the residual effect period or to the start of the intercurrent event, 
whichever occurs first.
Secondary strategy: This strategy is similar to the primary strategy, except for the intercurrent 
event “use of any other products with a similar mode of action as trial medication that have 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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proven efficacy (either preliminary via EUA by FDA or via full approval by the FDA or EMA)”, 
which will be handled using the composite approach as defined in ICH E9(R1).
Table 7.2.2:1 provides an overview of the handling of intercurrent events within the different 
strategies.
Table 7.2.2:1 Handling of intercurrent events as per ICH E9(R1) within the different strategies
Intercurrent Event
Strategy for handling of intercurrent events
Primary strategy
Secondary 
strategy
Start of a product with a similar mode 
of action as trial medication that has 
proven efficacy (either preliminary via 
EUA by FDA or via full approval by 
the FDA or EMA).
While-on-treatment
Composite
Start of a restricted medication as 
defined in Table 4.2.2.1:1, except any 
product with a similar mode of action 
as trial medication that has proven 
efficacy (either preliminary via EUA 
by FDA or via full approval by the 
FDA or EMA)
Treatment policy
Treatment policy
Death
Composite
Composite
Each analysis will reference the strategy for handling intercurrent events that it will be estimating. 
The estimand for each main analysis in this protocol is the combination of the relevant detailed 
clinical objective from Section 2.1 and this strategy.
The handling of intercurrent events that are not listed will be decided during blinded review and 
will be documented in the TSAP.
7.2.3
Primary objective analyses
Primary endpoint analyses in Phase II
The primary endpoint of Phase II is defined in Section 2.1.2. 
Viral load data will be log-transformed prior to analysis. Time-weighted average change in log10
viral load from baseline is defined as:
∑
{0.5 ∗( + ) ∗( −)}


( −)


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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
Where

 = baseline assessment at Day 1

 = last assessment at or prior to the threshold day (Day 8 for the primary endpoint)

 = change from baseline in log10 viral load at visit i (and where Ya=0)

 = time at the specified time point (the actual study day)
An analysis of covariance (ANCOVA) model with log10 baseline viral load and baseline serology 
status as covariates will be used. Adjusted means and 95% confidence intervals (CIs) will be 
provided by treatment group. The ratio of the mean time-weighted change from baseline in log10 
viral load will be used to quantify the treatment effect, comparing each active treatment arm to 
placebo as the reference. Intercurrent events will be handled using the Primary strategy as 
defined in Section 7.2.2.
Primary endpoint analyses in Phase III
The primary endpoint of Phase III is defined in Section 2.1.2.
The cumulative proportion of patients hospitalized or dying by Day 29 will be estimated for each 
randomised group using Kaplan-Meier (KM) methods to take account of losses to follow-up. It 
will be estimated overall and within each stratum. The analysis will be stratified by “high” versus 
“low” risk of progression to severe COVID-19 and baseline serology status.
For patients with known event of hospitalization or death:
Time to hospitalization or death [days] = earlier date of hospitalization or death – date of 
randomisation + 1.
For patients with no known event of hospitalization or death or where censoring rules apply:
Time to hospitalization or death [days] = date of censoring – date of randomisation + 1.
Missing data are handled by using survival analysis techniques. Intercurrent events will be 
handled using the Primary strategy as defined in Section 7.2.2. For further details on censoring 
rules of the primary analysis, refer to Table 7.3.1:1.
At each interim analysis and the final analysis, the two-sided asymptotic 95% repeated 
confidence interval for the difference in the KM hospitalization or death probability estimate by 
Day 29 will be found within each stratum. Repeated confidence intervals will be derived as 
described in (R20-3707).
Since the observations in the two treatment groups are independent, the variance of the Kaplan-
Meier probability difference is equal to the sum of the Kaplan Meier probabilities’ variances 
found by Greenwood's method.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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The difference in the Kaplan-Meier estimates by Day 29 overall will be calculated as the 
weighted average of the estimated Kaplan-Meier probability differences within each stratum. 
The weights will be defined as the "Mantel-Haenszel" weights, using the derivation as described 
in Greenland and Robins (R09-1299). The variance for the overall risk difference will be 
calculated accordingly. The two-sided asymptotic 95% repeated confidence interval for the 
Kaplan-Meier probability differences will be shown overall and within each stratum.
One sided p-values will be obtained from a z-test and will be compared with the O’Brien and 
Fleming local nominal alpha levels.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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7.2.4
Secondary objective analyses
No key secondary endpoints have been defined for this study.
Secondary endpoints are defined in Section 2.1.3.
Time-weighted change from baseline endpoints will be analysed as described in Section 7.2.3 for 
the Phase II primary endpoint.
Endpoints relating to the occurrence of a certain event by Day 29 (such as Hospitalization by 
Day 29, Hypoxia or hospitalization or death from any cause by Day 29, Hypoxia by Day 29) will 
be analysed as described in Section 7.2.3 for the Phase III primary endpoint.
For binary endpoints, comparisons between treatment groups will be performed using a logistic 
regression model adjusting for the binary covariate baseline serology status. For binary endpoints 
that are not based on viral load data, “high” versus “low” risk of progression to severe COVID-
19 will also be included in the model as a covariate. A likelihood-ratio test will be performed to 
evaluate the differences between treatments. Adjusted odds ratios together with 95% confidence 
intervals will be used to quantify the effect of treatment, comparing each active treatment arm to 
placebo as the reference. 
For time-to-event endpoints, a Cox proportional-hazards model will be used to derive the hazard 
ratio and 95 % confidence interval (CI) of the active treatment regimens versus placebo. The 
model will include baseline serology status as covariate. For endpoints that are not based on viral 
load data, “high” versus “low” risk of progression to severe COVID-19 will also be included in 
the model as a covariate. Breslow’s method for handling ties will be used. A log-rank test will be 
used to evaluate the effect of each active treatment arm compared to Placebo. Kaplan-Meier 
plots by treatment group will also be presented. The cumulative proportion of patients presenting 
an event will be estimated for each treatment group using Kaplan-Meier methods. For those 
endpoints where a sufficient number of events can be observed to calculate the median time-to-
event, the median and the corresponding 95% CI using Greenwood variance that is incorporated 
into the Brookmeyer and Crowley method (R09-6372) with a loglog transformation will be 
provided for each treatment group. 
Any p-values presented for the secondary endpoints will be considered nominal in nature and no 
adjustment for multiplicity will be made. Two-sided p-values will be provided.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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The strategy for handling of intercurrent events will be specified in the TSAP for secondary 
endpoints.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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7.2.6
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. All adverse events with 
an onset between start of treatment and end of the REP, a period of 90 days after the last dose of 
trial medication, will be assigned to the on-treatment period for evaluation.
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 (as graded according to DAIDS Table 5.2.6.1.5:1 [R21-0379]), 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.
7.2.7
Other Analyses
This section is not applicable.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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7.2.8
Interim Analyses
In Phase II, an unblinded interim analysis will take place after all patients have completed one 
week of follow-up. This interim analysis will be performed by the sponsor. The purpose of this 
exploratory interim analysis is to perform an evaluation of the pharmacological activity by 
looking at viral load data over time from all patients of this Phase II part. If the drug does not 
have the expected effect on viral load, no effect on clinical endpoints can be expected. In this 
case, the trial will be stopped after the exploratory Phase II part. Otherwise, the confirmatory 
Phase III part of the trial will be started. One active treatment arm will be kept in Phase III 
depending on data collected and evaluated in the Phase II part. Data from patients included in the 
Phase II part of the trial will not be used for any confirmatory analyses. 
In Phase III, two interim analyses are planned: a first interim analysis is planned after 
approximately 33% of patients have been followed up for 28 days. The second interim analysis is 
planned after approximately 67% of patients have been followed up for 28 days. Depending on 
the primary endpoint results based on the data available at the time of the interim analyses, the 
decision will be taken to either continue the trial or to stop the trial, either for efficacy or for 
futility. 
If the trial claims for early efficacy at the first interim analysis the recruitment will continue until 
a total of 650 patients are included in the Phase III part of the trial. At the point of claiming for 
early efficacy at the first interim analysis the placebo arm will stop recruitment. Both interim 
analyses in the Phase III will be performed by a DMC and only the DMC will get access to 
unblinded data. 
The DMC will also review data on a regular basis during Phase II and Phase III.
7.3
HANDLING OF MISSING DATA
7.3.1
Efficacy endpoints
For the analysis of the primary endpoint of Phase II and of other continuous endpoints, missing 
data will not be imputed. For continuous endpoints analysed using a MMRM, the mixed effect 
model will handle missing data based on a likelihood method under the "missing at random 
assumption".
For the analysis of the primary endpoint of the Phase III and of other time-to-event endpoints or 
endpoints assessing the occurrence of an event by a pre-defined timepoint, missing or incomplete 
data will not be imputed but will be handled using standard survival analysis techniques (i.e. 
censoring). For the primary analysis of the primary endpoint the censoring rules are outlined in 
Table 7.3.1:1.




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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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case. Further details will be provided in the TSAP.
For further endpoints, handling of missing data will be described in the TSAP.
7.3.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards. Other missing
safety data will not be imputed.
7.4
RANDOMISATION
Patients will be randomised in blocks to double-blind treatment. 
At the start of Phase II, patients will be randomised in a 2:2:2:1 ratio to either Placebo i.v. + 
Placebo inhaled, BI 767551 i.v. low dose + Placebo inhaled, BI 767551 i.v. high dose + Placebo 
inhaled, or Placebo i.v. + BI 767551 inhaled, respectively. Following CTP amendment 1, it is 
planned to include patients in an equal allocation ratio to each treatment arm (1:1:1:1 ratio). 
Therefore, patients will be randomised in a 1:1:1:2 ratio to receive a single dose of either Placebo 
i.v. + Placebo inhaled, BI 767551 i.v. 10 mg/kg dose + Placebo inhaled, BI 767551 i.v. 40 mg/kg 
+ Placebo inhaled, or Placebo i.v. + BI 767551 250 mg inhaled, respectively, once approximately 
112 patients have been randomised using the initial randomisation ratio. When approximately 
112 patients have been randomised, the randomisation scheme will be implemented in sites or 
countries with approval for CTP amendment 1. At the time of implementation of the revised 
scheme, sites or countries may be placed on hold for recruitment until approval of CTP 
amendment 1 is granted.
No stratification will be used.
In Phase III, approximately equal numbers of patients will be randomised to each treatment 
group. Randomisation will be stratified by “high” versus “low” risk of progression to severe 
COVID-19. High risk is defined as patients who meet at least one of the following criteria:

Have a BMI ≥35

Have chronic kidney disease

Have diabetes

Have immunosuppressive disease

Are currently receiving immunosuppressive treatment

Are ≥65 years of age

Are ≥55 years and <65 years of age AND have
o
cardiovascular disease, OR
o
hypertension, OR
o
chronic obstructive pulmonary disease/other chronic respiratory disease.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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There is no minimum number of “high” risk patients required for this study. 
BI will arrange for the randomisation and the 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 CTR. Access to the codes will be controlled and 
documented.
7.5
DETERMINATION OF SAMPLE SIZE
7.5.1
Determination of sample size for Phase II
To determine the sample size for the Phase II part of the trial, we simulated log10 scale viral load 
data over time per patient similar to the results published for other neutralizing antibodies (R20-
3600, R20-3601). The average reference slope is 1.25 (similar to R10933+R10987 8.0g IV in 106
in (R20-3600) and similar to LY-COV555+LY-CoV016 in (R20-3601)). An additional average 
slope of 0.85 for the treatment arm is assumed similar to the results published for other 
neutralizing antibodies (R20-3600, R20-3601).
Table 7.5.1:1 shows the likelihood of an AUC ratio above different thresholds calculated on 
1000 simulation runs with varying number of patients per treatment arm.
Table 7.5.1:1 Percentage of simulation runs with AUC ratio for one treatment group above 
thresholds (“true positives”/power).
AUC ratio
Number of 
patients per
treatment arm
>1.5
>1.45
>1.4
>1.35
>1.3
40
66%
74%
81%
87%
92%
50
69%
78%
85%
90%
94%
60
72%
81%
88%
93%
96%
Table 7.5.1:1 shows that a sample size of 50 patients per treatment arm gives a probability of 
85% that the AUC ratios are above 1.4. We consider this to be sufficiently large probability 
(>80%) to show a relevant difference in time weighted viral load between the treatment arms 
(measured by the AUC ratio). Furthermore, an evaluation of false positive signals showed that 
the probability for an AUC ratio >1.4 is 2% if there is no difference in the slope between the 
treatment arms.
Table 7.5.1:2 shows the likelihood of an AUC ratio above different thresholds for at least one out 
of three treatment groups (two i.v. and one inhaled) calculated on 1000 simulation runs with 
varying number of patients per treatment arm. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 7.5.1: 2 Percentage of simulation runs with AUC ratio for at least one out of three 
treatment groups above thresholds (“true positives”/power).
AUC ratio
Number of 
patients per
treatment arm
>1.5
>1.45
>1.4
>1.35
>1.3
40
76%
83%
88%
94%
97%
50
79%
87%
91%
95%
98%
60
82%
90%
94%
97%
99%
Table 7.5.1:2 shows that a sample size of 50 patients per treatment arm gives a probability of 
91% that the AUC ratios are above 1.4. This is a sufficiently large probability to show a relevant 
difference in time weighted viral load between the treatment arms (measured by the AUC ratio). 
Furthermore, an evaluation of false positive signals showed that the probability for an AUC ratio 
>1.4 is only 4% if there is no difference in the slope between the treatment arms.
7.5.2
Determination of sample size for Phase III
In  Phase III, with a sample size of 641 per treatment group, the study has 80% power to detect a 
relative reduction of 50% in the proportion of patients hospitalized or dying over 29 days 
between the study groups (BI 767551 vs. placebo), using the following assumptions:

There are limited data available on the treatment effect and variability for the primary 
endpoint. Based on recent publications, the proportion of patients who get hospitalized or 
die over 29 days in the placebo arm is assumed to be 7.5%.

Two interim analyses and one final analysis, with stopping guideline for efficacy of BI 
767551 versus placebo determined using the Lan-DeMets spending function approach 
with an O’Brien and Fleming boundary. 
Table 7.5.2:1 summarizes the details of such a design.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Table 7.5.2:1 Design details and sample size calculation for a group sequential design in 
Phase III
Assuming that only a low number of patients might be lost to follow up, it is planned to 
randomise approximatively 1300 patients in Phase III.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 or delegate 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 CTR.
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 investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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.  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 or alternative plan, in line with the guidance provided by ICH Q9 and ICH-GCP E6, for 
fully outsourced trials, 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).


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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.
The investigator must ensure that all patient identifiers (e.g. patient’s name, initials, address, 
phone number, social security number) have properly been removed or redacted from any copy 
of the patients’ source documents before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
Due to COVID-19 restrictions study conduct, including site monitoring and access to source 
documents, may need to be adjusted accordingly.  See Appendix 10.3 for further details.
For the eCRF, 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, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

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.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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8.3.2
Direct access to source data and documents
During the conduct of the study, it may not be possible for the investigator / institution to allow 
site trial-related monitoring, audits, IRB/IEC review or regular inspections due to COVID-19. 
However, once site visits are allowed again, the site will need to provide a direct access to the 
eCRF 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 eCRFs 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 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
Not Applicable


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 Study is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Completed”). 
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last patient 
in the whole trial is administered the 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. 
Last Patient Last Visit for Primary Endpoint (LPLVPE) 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. (please refer to Section 2.1.2 Primary Endpoints)
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).
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. 
Principal Investigators participating in the trial include those with a specialty in infectious 
disease, critical care, or pulmonary disease. 
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 results from the unblinded interim analysis for the Phase II will be shared with the DMC for 
review of safety and efficacy data and to provide recommendation how to move forward with the 
trial.The DMC will recommend to the sponsor whether to continue or stop the trial due to safety 
or ethical concerns. Two interim analyses will be performed by the DMC during Phase III. Thse 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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analyses encompass futulity and efficacy. Only the DMC will have access to unblinded data 
during this portion of the study. Measures will be put in place to ensure blinding of the project
and trial team and all other trial participants during the conduct of each Phase (see Section 4.1.5
for further details). The tasks and responsibilities of the DMC will be specified in a charter. The 
DMC will maintain written records of all its meetings.
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. 
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 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.
In the participating countries the trial will be performed by the respective local or regional BI-
organisation (Operative Unit, OPU) in accordance with applicable regulations and BI SOPs, or 
by a Contract Research Organisation (CRO) based on a contract. The CRO will perform project 
management, clinical field monitoring, medical monitoring, and reporting.
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.
A central laboratory service, a central images service, and an IRT vendor will be used in this 
trial. Details will be provided in the IRT Manual and Central Laboratory Manual, available in the 
ISF.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Branum A., et al. Second symposium on the definition and management of 
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Management of Anaphylaxis, Jul  2005. J Allergy Clin Immunol 2006; 117 (2); 
391-397.
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Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A guide to 
rational dosing of monoclonal antibodies. Clin Pharmacokinet 2012; 51(2); 
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rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients 
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Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic 
monoclonal antibodies. Clin Pharmacokinet 2010; 49(10); 633-659.
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Fryar CD, Gu Q, Ogden CL, Flegal KM. Anthropometric reference data for 
children and adults: United States, 2011-2014. Vital Health Stat (3) 2016 (39); 
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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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 June12, 2020, 
diuL 10.1016/S1473-3099(20)30483-7;2020.
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Longitudinal isolation of potent near-germline SARS-CoV-2 neutralizing 
antibodies from COVID-19 patients. Cell 2020; 182; 843-854.
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influenza A virus infection in humans. J Virol 2006; 80(15); 7590-7599.
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al. Randomized, double-blind, placebo-controlled, single-ascending-dose study 
of the penetration of a monoclonal antibody combination (ASN100) targeting 
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of an erythropoietin-Fc fusion protein by inhalation in humans through an 
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REGN-COV2 antibody cocktail program update (September 29, 2020).  
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8eb5-d52d87a99070 (access date: 4 November 2020); Regeneron; 2020.
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SARS-CoV-2 neutralizing antibody program update (October 7, 2020). Source: 
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(access date: 4 November 2020) ; Lilly; 2020.
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Jennison C, Turnbull BW. Repeated confidence intervals for group sequential 
clinical trials. Controlled Clin Trials 1984 ; 5(1): 33-45.
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Beigel, J.H, Tomashek KM, Dodd LE, Mehta AK, Zingman VS, Kalil AC, et 
al. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med
2020; 383(19): 1813-1826.
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Walls, A.C, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D., et al. 
Structure, Function and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. 
Cell 2020; 181, 281-292 e286.
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Hoffmann, M, Kleine-Weber H, Schroeder S, Krueger N, Herrler T, Erichsen 
S., et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is 
Blocked by a Clinically Proven Protease Inhibitor. Cell 2020; 181, 271-280 
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Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. 
Antibody-dependent enhancement of severe dengue disease in humans. Science 
2017; 358; 929-932.
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Hendrikx JJMA, Haanen JBAG, Voest EE, Schellens JHM, Huitema ADR, 
Beijnen JH. Fixed dosing of monoclonal antibodies in oncology. Oncologist 
2017; 22; 1212-1221.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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R20-4045
Chen, P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J.,et al. BLAZE 
Investigators. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients 
with Covid-19. NEJM 2021; 384(3): 229-237.
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Kreer, C, Doering M, Lehnen N, Ercanoglu MS, Gieselmann L, Luca D., et al. 
openPrimeR for multiplex amplification of highly diverse template. J Immunol 
Methods 2020; 480, 112752.
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Topalidou, I., Cattin-Ortola, J., Hummer, B., Asensio, C.S. & Ailion, M. 
EIPR1 controls dense-core vesicle cargo retention and EARP complex 
localization in insulin-secreting cells. Mol Biol Cell 2020; 31, 59-79.
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RECOVERY Collaborative Group, Dexamethasone in Hospitalized Patients 
with Covid-19 – Preliminary Report. New England Journal of Medicine, 
published on July 17, 2020, doi: 10.1056/NEJMoa2021436.
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van Doremalen, N, Bushmaker T, Morris DH, Hobrook MG, Gamble A, 
Williamson BN,.et al. Aerosol and Surface Stability of SARS-CoV-2 as 
Compared with SARS-CoV-1. N Engl J Med 2020; 382, 154-1567.
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He, X, Lau EHY, Wu P, Den X, Wang J, Hao X., et al. Temporal dynamics in 
viral shedding and transmissibility of COVID-19. Nat Med 2020; 26, 672-675.
R20-4052
Meyerowtiz, E.A., Richterman, A., Gandhi, R.T. Sax, P.E. Transmission of 
SARS-CoV-2: A Review of Viral, Host, and Environmental Factors. Ann 
Intern Med, 17 September 2020, doi: 10.7326/M20-5008.
R20-4053
Andersen, K.G., Rambaut, A., Lipkin, W.I., Homes, E.C. & Garry, R.F. The 
proximal origin of SARS-CoV-2. Naure Med 2020; 26, 450-452.
R21-0329
Weinreich, D.M., Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R., et al.  
Trial Investigators. REGN-CoV2, a Neutralizing Antibody Cocktail, in 
Outpatients with Covid-19. N Engl J Med 2021; 384;238-51.
R21-0350
DeMets DL, Lan KKG. Interim Analysis: The alpha spending function 
approach. Stat Med 1994; 13: 1341-1352.
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Pediatric Adverse Events. Version 2.1
R21-1072
SARS-CoV-2 variant classifications and definitions (last updated March 16, 
2021). https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-
surveiUance/vari ant-info.html (access date: 23 March 2021); Centers for 
Disease Control and Prevention; 2021.
9.2
UNPUBLISHED REFERENCES
c34274645-02
Investigator’s Brochure BI 767551 (also known as DZIF-10c, EX 14870).        
03 Mar 2021.
c35065398
1487-0004 (UKK-4288) Synoptic Interim Report. A Phase 1/2a Trial of the 
Intravenous Administration of the SARS-CoV-2-Neutralizing Monoclonal 
Antibody DZIF-10c in SARS-CoV-2-Infected and –Uninfected Individuals. 
From 08 December 2020 to 01 March 2021 (date of the interim data cut-off). 
Draft report available.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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c35147730
1487-0005 (UKK-4370) Synoptic Interim Report. A Phase 1/2a Trial of the 
Inhaled Administration of the SARS-CoV-2-Neutralizing Monoclonal 
Antibody DZIF-10c in SARS-CoV-2-Infected and –Uninfected Individuals. 
From 14 December 2020 to 15 March 2021 (date of the interim data cut off). 
Draft report available.
c35245352
BI 767551: Emerging Variant Analysis Plan. 15 Mar 2021.
n00281411
Assessment of the binding profile of EX 14870 using a human plasma 
membrane protein cell array. RP1278. 22 Oct 2020.
n00281725
BI 767551: A single dose intravenous toxicity study in the cynomolgus 
monkey with a 2-week observation period. Draft date: 06 Jan 2021.
n00281769
Toxicological review of proposed excipients for the EX 14870 inhalation 
formulation. 05 Nov 2020.
n00282187
BI 767551: Two-Week Repeat Dose Intravenous Toxicity and Toxicokinetics 
Study in the Rat. Draft report available.
n00282535
Nonclincal Document. Prediction of BI 767551 (DZIF-10C) Pharmacokinetics 
in Human. 08Feb2021.
n00282791
Neutralization of Authentic SARS-CoV-2 with DZIF-10c. NST-BI-001. 17 
Dec 2020.
n00282792
SARS-CoV-2 Pseudovirus Neutralization with DZIF-10c. NST-BI-002.          
17 Dec 2020.
n00282793
Evaluation of antibody-dependent enhancement of infection with DZIF-10c. 
NST-BI-003. 17 Dec 2020.
n00285313
Neutralization of Authentic SARS-CoV-2 with DZIF-10c. 18 Mar 2021.
q00281077
Investigational Medicinal Product Documentation. EX 14870 concentrate for 
solution for infusion/nebulizer solution 50 mg/mL. Trial 1487-0003. Version 
1.0.  Mar 2021.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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10.
APPENDICES
10.1
INSTRUCTIONS FOR THE USE OF THE AEROGEN SOLO NEBULISER
BI 767551 nebuliser solution (50gm/mL) is intended to be nebulized undiluted or diluted with 
co-supplied Solvent for dilution of BI 767551. The materials for administration of the study 
medication are: Aerogen® Solo nebuliser, Aerogen® Pro-X Controller, Aerogen® Ultra and 
Mouthpiece
The Aerogen® Solo nebuliser and Aerogen® Ultra are for single patient use only, not to be used 
on more than one patient to prevent cross infection. The Aerogen® Pro-X Controller is for re-use.
Refer to the Aerogen Solo System Instruction Manual document in the ISF for information on 
how to install the system and conduct the inhalation procedure.  The following steps are outlined 
in the Instruction Manual and should be performed:
1. Assemble the Aerogen® Solo system
**Always perform a functional test of the Aerogen® Solo before use as described in the 
    Functional Test section of the manual
2. Follow the instructions for Installation for use Off-Ventilator for Use with a Mouthpiece
3. Once the nebuliser is assembled for use, transfer content of the syringes1 to the nebuliser 
product chamber. 
The inhalation procedure will take approximately 15-20 minutes.
Following completion of the inhalation, the used Aerogen® Solo nebuliser and Aerogen® Ultra 
will be discarded as per local standard procedures. The Aerogen® Pro-X Controller should be 
cleaned after each use following the instructions outlined in the Instruction Manual.
1Refer to the BI 767551 nebulization Medication Handling Instructions in the ISF for complete 
instructions on storage, handling preparation and administration of the nebuliser solution. 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
c33563257-02                             Clinical Trial Protocol
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10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19
Due to restrictions during the COVID-19 pandemic, study conduct may need to be adjusted. 
In exceptional cases, when it is impossible to conduct the visits at the trial site, visits may be 
performed at the patient’s home or remotely (via telephone and/or internet based means of 
communication). The visits may also be performed as a combination of home and remote visits. 
Based on the benefit-risk assessment (see Section 1.4), the visit procedures may be adjusted for 
the purpose of particular visits, whereby critical safety measures will remain in place. All 
home/remote visits need to be discussed with and approved by the sponsor`s trial team. Local 
regulatory and legal requirements of the participating country need to be respected for all 
modifications.
Under these circumstances, the following modifications can be considered: 
Remote visit
If a patient is not able to come to the site for an outpatient visit, a remote visit (by phone) should 
be performed instead and all assessments that can be done by phone should be performed.
Assessments that can be performed during a remote visit are:
Collection of adverse events, concomitant therapy, vital signs, physical exam, 11-point 
WHO Clinical Progression Scale data collection, collection of NP swabs, and review of 
study diary. If home visits by trial staff members are possible, further assessments can be 
done. 
Safety lab, other laboratory tests
Blood analysis for safety laboratory can be done in a local laboratory outside the hospital. The 
results of the laboratory tests are to be reported and transferred to the investigator, who has to 
ensure medical review and proper documentation in the eCRF. 
Monitoring
Due to the nature of this trial and the risks associated with COVID-19, site monitoring visits as 
physical on-site interaction may not take place, the focus will be on centralized 
oversight/monitoring. 
Site initiation visit (SIV), Site monitoring visits (SMV) and Site close out visits (COV) will 
occur remotely unless the Trial Team requires a visit to be on site due to an identified risk where 
the required mitigation may need to be performed on-site.


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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10.4
DIAGNOSIS OF ANAPHYLAXIS
Clinical Criteria for diagnosing anaphylaxis [R11-4890]
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 
mm Hg +[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.






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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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11.
DESCRIPTION OF GLOBALB AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of Amendment
20 April 2021
EudractCT number
2020-005588-29
BI Trial number
1487-0001
BI Investigational Product
BI 767551 (formerly EX 14870 or DZIF-10c)
Title of Protocol
A Phase II/III seamless, randomised, double-
blind, placebo controlled, parallel-group, 
group-sequential study to evaluate efficacy, 
safety and tolerability of BI 767551 for the 
treatment of symptomatic, non-hospitalized 
adults with mild to moderate COVID-19.
Global Amendment due to urgent safety reasons
Global Amendment
  X
Section to be changed
Clinical Trial Protocol Synopsis
Trial Rationale
Description of Change
Revised wording for Phase III part to remove 
reference to i.v. dose
Rationale for change
Includes the possibility to add the inhalation 
arm in Phase III
Section to be changed
Clinical Trial Protocol Synopsis
Trial Design
Description of Change
Phase II: revised wording to increase number 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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of patients randomised in the inhalation arm
Phase III: Trial Design
included inhalation arm
Rationale for change
Phase II: Include more patients in the inhaled 
arm 
Phase III: Includes the possibility to add the 
inhalation arm in Phase III.
Section to be changed
Clinical Trial Protocol Synopsis
Total number of patients randomised
Description of Change
Increased number of patients to be randomized 
in Phase II from 140 to 200
Rationale for change
To include more patients in the inhaled arm.
Section to be changed
Clinical Trial Protocol Synopsis
Number of patients per treatment group
Description of Change
Phase II: Increased number of patients in each 
treatment arm for Phase II from 40:40:40:20 to 
50:50:50:50
Phase III: Added inhaled arm
Rationale for change
  Phase II: To include more patients in the 
inhaled arm as well as the placebo and i.v. 
arms so that an equal number of patients per 
arm is reached at the end of recruitment in 
phase II.
  Phase III: Includes the possibility to add the 
inhalation arm in Phase III


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Section to be changed
Clinical Trial Protocol Synopsis
Dose Phase III
Description of Change
Added Single 250 mg inhalation (nebulized) 
under Phase III
Rationale for change
Includes the possibility to add the inhalation 
arm in Phase III
Section to be changed 
Clinical Trial Protocol Synopsis
Mode of administration
Description of Change
Added inhalation under Phase III
Rationale for change
Includes the possibility to add the inhalation 
arm in Phase III
Section to be changed 
Flow Chart:
Collect/update secondary contacts
Description of Change
Foot note #20 added: Details can be entered in 
site source not CRF
Rationale for change
It is sufficient to have this information in the 
source data only
Section to be changed 
Flow Chart:
Physical Examination 


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Description of Change
Added foot note #21 for Visit 5 and 7
Rationale for change
Performed only if these visits are clinic visits
Section to be changed 
Flow Chart:
“Retrieval of study diary”
Description of Change
Changed to “Review by e.g. phone and 
retrieval of study diary”
Rationale for change
In case of home visit the patients will send 
dairy only after the visit to the site
Sections to be changed 
Flow chart: Prematurely discontinued 
(Before/After Day 29) and EOS
Description of Change
Added all missing assessments so that these 
visits are identical 
Rationale for change
EOS and Premature discontinued have identical 
procedures
Sections to be changed 
Flow chart: Randomisation IRT call 
Description of Change
Changed name of procedure from 
Randomisation (IRT call) to IRT call
Added ‘X’ at screening visit
Rationale for change
Procedure is required at screening visit as well 
as randomisation visit






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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Description of Change
-patients per arm increased from 40/40/40/20 
(total 140) to 50/50/50/50 (200)
randomisation ratio changed from
2:2:2:1 to 1:1:1:2
Revised to include possibility to carry the 
inhalation arm into Phase III.  Changes 
included details on revised study design
Updated study schematic to reflect change to 
randomisation ratio and possibility of 
continuing the inhaled arm into Phase III
Rationale for change
Phase II to include both inhaled and i.v. routes 
to explore neutralizing potential, safety 
 
 to provide a comparison versus Placebo of 
doses and routes ahead of decision of dose 
and route for the Phase III. Randomisation 
ratio in phase II modified to include more 
patients in the Placebo i.v. + BI 767551 250 
mg inhaled arm so that an equal number of 
patients per arm is reached at the end of 
recruitment in phase II.
Sections to be changed 
Section 3.2 Discussion of trial design, 
including the choice of control groups
Description of Change
Updated information for Phase III as follows:
-
removed iv
-
replaced dose level with dose regimen
Rationale for change
To allow the possibility of carrying the 
inhalation arm into Phase III
Sections to be changed 
Section 3.3 Selection of Trial Population


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Description of Change
Changed number of patients planned to be 
randomised from 140 to 200
Rationale for change
To include more patients in the inhaled arm
Sections to be changed 
     Section 3.3.2 Inclusion criteria #6 updated 
footnote 1
Description of Change
A post-menopausal state is defined as post-
menopausal for at least 1 year
Rationale for change
Alignment with updated Investigator’s 
Brochure
Sections to be changed
Section 4 Treatments
Description of Change
Update of administration of investigational 
medication either i.v or inhalation as well as 
the update of test product details for Phase III. 
For inhalation arm the planned concentration 
was added. Further, rationale and details on 
selection of doses and dose modification for 
Phase III. Data updated in accordance to the 
most current IB
Rationale for change
To have the possibility to add the inhalation 
arm in Phase III
Sections to be changed
Section 4.1.8 Drug Accountability
Description of Change
Delete the following text:  "Patients should be 
instructed to return unused investigational 
drug".


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BI Trial No.: 1487-0001                                                                                   20 Apr 2021   
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Rationale for change
Not applicable to this trial.
Sections to be changed 
Section 4.2.2.3 Contraception requirements
Description of Change
Acceptable methods of birth control: updated 
first bullet to state post-menpausal for at least 1 
year
Rationale for change
Alignment with updated Investigator’s 
Brochure 
Sections to be changed 
Section 5.2.3 Safety Laboratory Parameters
Description of Change
Increased maximum volume of blood needed 
per patient for all laboratory assessments from 
250 mL to 300 mL
Rationale for change
To reflect the increased blood volume due to 
additional blood sample collections at Visit 5 
and Prematurely discontinued (Before Day 
29) and Prematurely discontinued (After Day 
29)
Sections to be changed 
Section 6  Investigational Plan
Description of Change
Addition of inhalation route for Phase III
Rationale for change
Update based on modified study design to 
possibly include inhalation group in Phase III
Sections to be changed 
Section 6.2 Details of Trial Procedures at 
Selected Visits






 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33563257
2.0
clinical-trial-protocol-02
A Phase II/III seamless, randomised, double-blind, placebo-controlled,
parallel-group, group-sequential study to evaluate efficacy, safety and tolerability of
BI 767551 for the treatment of symptomatic, non-hospitalized adults with mild to
moderate COVID-19.
Approval-Clinical Trial Leader
20 Apr 2021 18:54 CEST
Approval-Therapeutic Area 
20 Apr 2021 18:59 CEST
Approval-Team Member Medicine
21 Apr 2021 02:14 CEST
Author-Trial Statistician
21 Apr 2021 06:27 CEST
Author-Trial Clinical
Pharmacokineticist
21 Apr 2021 16:02 CEST
Verification-Paper Signature
Completion
21 Apr 2021 17:42 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33563257
2.0

SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c35105623-01
BI Trial No.:
1487-0001
Title:
A Phase II/III seamless, randomised, double-blind, placebo-
controlled, parallel-group, group-sequential study to evaluate 
efficacy, safety and tolerability of BI 767551 for the treatment of 
symptomatic, non-hospitalized adults with mild to moderate 
COVID-19.
Including Protocol Amendment 1 [c33563257-02]
Investigational
Product(s):
BI 767551 (formerly EX 14870 or DZIF-10c)
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
19 OCT 2021 SIGNED
Version:
1
Page 1 of 25
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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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT........................................................................................8
5.2
SECONDARY ENDPOINTS ...............................................................................8
5.2.1
Key secondary endpoint(s) ...................................................................................8
5.2.2
Secondary endpoints .............................................................................................8
5.2.2.1
Time-weighted change from baseline in viral shedding over 29 days in site 
collected NP swabs by RT-qPCR............................................................................8
5.2.2.2
Loss of detection of SARS-CoV-2 RNA by site-collected NP swabs at Day 4, 
8, 15, 22 and 29 .......................................................................................................9
5.4.3
Liver function tests..............................................................................................11
5.4.4
Marked changes in vital signs ............................................................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................12
6.5
POOLING OF CENTRES..................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................13
7.
PLANNED ANALYSIS ......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........15
7.2
CONCOMITANT DISEASES AND MEDICATION......................................15
7.2.1
Baseline conditions and targeted risk factors...................................................15
7.2.2
Concomitant therapies........................................................................................15
7.3
TREATMENT COMPLIANCE ........................................................................16
7.4
PRIMARY ENDPOINT......................................................................................16
7.4.1
Primary analysis of the primary endpoint........................................................16


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7.5
SECONDARY ENDPOINT(S)...........................................................................16
7.5.1
Key secondary endpoint(s) .................................................................................16
7.5.2
(Other) Secondary endpoints .............................................................................16
7.5.2.1
Time-weighted change from baseline in viral shedding over 29 days in site 
collected NP swabs by RT-qPCR..........................................................................16
7.5.2.2
Loss of detection of SARS-CoV-2 RNA by site collected NP swab at Day 4, 8, 
15, 22 and 29 .........................................................................................................17
7.7
EXTENT OF EXPOSURE .................................................................................17
7.8
SAFETY ANALYSIS..........................................................................................17
7.8.1
Adverse Events ....................................................................................................17
7.8.2
Laboratory data...................................................................................................18
7.8.3
Vital signs.............................................................................................................18
7.8.4
ECG ......................................................................................................................18
7.8.5
Others ...................................................................................................................18
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............19
9. 
REFERENCES ....................................................................................................20
10.
ADDITIONAL SECTIONS................................................................................21
10.1
EXAMPLE CODE ..............................................................................................21
10.1.1
Time-weighted average change in viral load ....................................................21
10.2
DEFINITION OF HIGH RISK OF PROGRESSION TO SEVERE 
COVID-19 AS PER NIH TREATMENT GUIDELINE..................................23
11.
HISTORY TABLE..............................................................................................25


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LIST OF TABLES
Table 6.3: 1
Subject sets analysed ........................................................................................13
Table 6.7: 1
Time windowing rules for site collected viral load related data.......................14
Table 10.2: 1 Dictionary codes for risk factors based on comorbidities or concomitant 
medications – Risk factor definition as per NIH treatment guidelines.............24
Table 11: 1
History table .....................................................................................................25


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ADA
Anti-drug antibodies
COVID-19
Coronavirus disease 2019
nAb
Neutralizing antibody
LLOD
Lower limit of quantification
LOQ
Limit of detection
mL
Milliliter
NP
Nasopharyngeal
RNA
Ribonucleic acid
RT-qPCR
Quantitative reverse transcription polymerase chain reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SDG
Standardised drug grouping


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3.
INTRODUCTION
As per ICH E9 (1), 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.
This TSAP covers only Phase II of the study. As the study has been  terminated early by BI, 
only a restricted set of analyses are planned.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Following BI’s decision to terminate the development program for BI 767551 (anti-SARS-
CoV-2 neutralizing antibody (nAb) under investigation for SARS-CoV-2-infected patients), 
study 1487-0001 has been discontinued as of 25 June 2021, with only a few patients screened 
(7), and randomized (5). Considering this low number of patients randomized in the study, the 
following changes to the planned analysis will be implemented:

No model based statistical analysis will be performed. Descriptive statistics will be 
provided for primary and secondary endpoints. Further endpoints will not be analysed
but data will be listed.

No subgroup analyses will be performed.

Unless described otherwise in Section 6.6, missing data will not be imputed.

PK and ADA samples will not be analysed.


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5.
ENDPOINTS
In this section, more details are given regarding endpoints. Note that baseline value definitions
for all endpoints and analyses are provided in Section 6.7. 
Handling of missing data points is described in Section 6.6.
All analyses of viral load endpoints will be based on the N1 gene. The lower limit of 
quantification (LLOQ) of the assay is 3.348 Log10 copies/mL (2228 copies/mL). Viral load 
measurements below the LLOQ will be set to half this limit on the log10 scale (1.674 Log10 
copies/mL). Undetectable viral load measurements will be set to 0. Inconclusive results will not 
be imputed but will be set to missing.
5.1
PRIMARY ENDPOINT
The primary endpoint in Phase II is the time-weighted change from baseline in viral shedding 
over 8 days in site-collected nasopharyngeal (NP) swabs by Quantitative Reverse Transcription 
Polymerase chain reaction (RT-qPCR), defined as a change from baseline in log10 viral load. 
Time-weighted average change in log10 viral load from baseline is defined as:
∑
{0.5 ∗( + ) ∗( −)}


( −)

Where

 = baseline assessment at Day 1

 = last assessment at or prior to the threshold day (Day 8 for the primary endpoint)

 = change from baseline in log10 viral load at visit i (and where Ya=0)

 = time at the specified time point (the actual study day)
The normalisation by the denominator assures comparability of the values if tb is different 
between patients.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint(s)
This section is not applicable, as no key secondary endpoints have been specified in the 
protocol.
5.2.2
Secondary endpoints
5.2.2.1
Time-weighted change from baseline in viral shedding over 29 days in site 
collected NP swabs by RT-qPCR
Time-weighted change from baseline in viral shedding over 29 days in site-collected NP 
swabs by RT-qPCR is defined as a change from baseline in log10 viral load. Time-weighted 
average change in log10 viral load from baseline is defined as described in Section 5.1, but 
using all measurements through Day 29 (b=Day29).


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5.2.2.2
Loss of detection of SARS-CoV-2 RNA by site-collected NP swabs at Day 4, 8, 
15, 22 and 29
Loss of detection of SARS-CoV-2 RNA will be evaluated by site-collected NP swabs at Day 
4, 8, 15, 22 and 29. Detection of SARS-CoV-2 RNA will be considered as lost at a specific 
timepoint if the quantitative viral load assessment at this timepoint is below the LOD. Refer to 
Section 6.7 for the definition of time windows for the different assessment times.


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5.4.3
Liver function tests
A listing of all liver function tests will be provided for all subjects who meet one of the 
following criteria at any time:

ALT and/or AST ≥3xULN and elevation of total bilirubin ≥2xULN measured in the 
same blood sample, or in later samples drawn within 30 days after the ALT and/or 
AST increase

ALT and/or AST ≥10xULN
5.4.4
Marked changes in vital signs
A marked increase is defined as: 

Systolic Blood Pressure >150 mmHg and increase ≥ 25 mmHg above baseline

Diastolic Blood Pressure >90 mmHg and increase ≥ 10 mmHg above baseline

Pulse Rate >100 bpm and increase ≥ 10 bpm above baseline
A marked decrease is defined as: 

Systolic Blood Pressure <100 mmHg and decrease >10 mmHg below baseline

Diastolic Blood Pressure <60 mmHg and decrease >10 mmHg below baseline

Pulse Rate <60 bpm and decrease >10 bpm below baseline


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For the definition of treatment administered during the trial, see Section 4 of CTP.
Note: the last day of each of the periods is excluded from the respective period. It defines the 
first day of the subsequent period.

Screening: From informed consent to randomisation

Post-randomisation (optional[a]): From randomisation to trial drug intake in 
treatment period

Treatment period: From date and time of trial drug intake to date of trial drug intake 
plus one day

Residual effect period: From the date of trial drug intake plus one day to 90 days 
plus one day after trial drug intake

Post-study[a]: From 90 days plus one day after trial drug intake
[a]
This period is optional insofar as it does not necessarily exist for all subjects.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. 
No per protocol set analysis will be performed for this study. The proportion of subjects with 
iPDs will be presented for completeness purposes and to demonstrate the adherence to the CTP.
6.3
SUBJECT SETS ANALYSED

Screened set (SCS): 
This subject set includes all subjects having signed informed consent

Randomised set (RS):
This subject set includes all randomised subjects, whether treated or not. This would 
correspond to the intention-to-treat set (ITT).

Treated set (TS):
This subject set includes all subjects who received any amount of study drug.

Modified Intention-To-Treat set (mITT):
This subject set includes all randomised subjects that received any amount of study 
drug and who have at least a measurable baseline value (above LLOQ) and a second 
measurement in the first week (up to 7 days after drug intake) of SARS-CoV-2 RNA 
by site collected NP swab.


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Please see Table 6.3: 1 for a general overview which patient set will be used for which type of 
analyses.
Table 6.3: 1
Subject sets analysed
Subject set
Type of analysis
SCS
RS
TS
mITT
Primary endpoint
X
Secondary endpoints 
X
X
Safety data, ADA & treatment exposure
X
Demographic/baseline characteristics
X
Disposition
X
X
Note that the number of subjects with available data for an endpoint may differ. For details, 
see Section 6.6 “Handling of missing data”.
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
In general, missing data will not be imputed. Missing or incomplete AE dates will be imputed 
according to BI standards (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, the last assessment / measurement observed prior to start of trial medication 
will be assigned to baseline. Note that for some trial procedures (e.g., body weight, vital signs, 
laboratory tests) this may be the value measured on the same day trial medication was started. 
In these cases it will be assumed that the measurements were taken prior to the intake of any 
study medication (if the measurement time was not captured). If no further data available, this 
can also be the last screening assessment. For viral load related data it is paramount that the 
sample is taken prior to drug administration, and for these procedures time of sampling will be 
taken into consideration and compared to the time of drug intake.
Visit windowing will be performed as described in Table 6.7: 1, in order to assign data to the 
relevant study visit based on the actual day of the assessment. For some endpoints, data will be 
analysed using the re-calculated visits in the statistical tables. However, in the listings, all visits 
performed will be displayed (even if outside time-window), along with the re-calculated visit.


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Table 6.7: 1
Time windowing rules for site collected viral load related data
Time window of actual day [1]
Allocated to
Start 
(Sn) 
day
End (included) 
(En) day
Length 
of 
the 
time-
window 
[days]
Visit 
number 
(n)
Visit name
Planned day 
of the visit 
(Vn)
-4
-2
3
1
Screening
-2
-1
-1
1
2
Baseline
-1
3
5
3
4
Day 4
4
7
9
3
5
Day 8
8
10
17
8
7
Day 15
15
18
24
7
8
Day 22
22
25
33
9
9
Day 29
29
34
105
72
EOS
Day 91
91
[1] First trial drug intake date is taken into account as a reference to calculate time windows
If after windowing of visits at baseline, two or more values fall within the same baseline 
interval, then the last value prior to first drug intake will be taken into account. If after 
windowing of post-baseline visits, two visits fall in the same interval, then the measurement 
closest to the planned visit will be taken into account. In case two measurements are equidistant 
from the planned visit, then the last one will be picked.


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7.
PLANNED ANALYSIS
For End-Of-Text tables, the set of summary statistics is: N / Mean / SD / Min / Q1 / Median / 
Q3 / Max. In descriptive statistics tables, mean, sd and median will be rounded to one additional 
digit than the raw data
Tabulations of frequencies for categorical data will include all categories depicted in the eCRF 
and will display the number of observations in a category as well as the percentage (%) relative 
to the respective treatment group (unless otherwise specified, all subjects in the respective 
subject set whether they have non-missing values or not). Percentages will be rounded to one 
decimal place. The category missing will be displayed only if there are actually missing values.
In Phase II, all analyses will be based on the treatment group as treated. If not specified 
otherwise, all analyses will be based on all randomised patients that have been treated.
Only descriptive analyses or listings will be provided due to the low patient numbers.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases and medication will be listed. No summary tables are planned.
7.2.1
Baseline conditions and targeted risk factors
The baseline conditions will be included as coded items using the current Medical Dictionary 
for Regulatory Activities (MedDRA) version in use at BI at the time of database lock. They 
will be listed by MedDRA system organ class (SOC) and Preferred Term. No summary tables 
are planned.
Targeted risk factors for progression to severe COVID-19 infection as collected on the 
corresponding eCRF page will be listed.
7.2.2
Concomitant therapies
The following categories of concomitant therapies have been created:

Previous therapies
o
Defined as treatments with an end date before trial drug intake. 

Baseline therapies
o
Defined as treatments with a start date before trial drug intake and taken after or 
on the day of the trial drug intake.


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
On-treatment concomitant therapies
o
Defined as treatments with a start date after or on the day of trial drug intake and 
before or on the last day of the residual effect period (for details, please see 
Section 6.1).

Post-study therapies
o
Defined as treatments with a start date after the end of the residual effect period 
(for details, please see Section 6.1).
Concomitant therapies will be listed. No summary tables are planned.
7.3
TREATMENT COMPLIANCE
This section is not applicable as no analyses on treatment compliance are planned.
7.4
PRIMARY ENDPOINT
The primary endpoint in Phase II is the time-weighted change from baseline in viral shedding 
over 8 days in site collected NP swabs by RT-qPCR. Please refer to Section 7.1, 7.2.2 and 7.2.3
of the CTP for additional information on the underlying hypotheses and assessment strategy.
7.4.1
Primary analysis of the primary endpoint
Only descriptive analyses will be performed.
Evaluation will be performed on the mITT set and will take into account all data up to and 
including Day 8.
Missing values will not be imputed and since a linear trajectory on the log scale is expected.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoints
7.5.2.1
Time-weighted change from baseline in viral shedding over 29 days in site 
collected NP swabs by RT-qPCR
Only descriptive analyses will be performed.


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Evaluation will be performed on all patients included in the randomised set that received any 
amount of study drug and who have at least a measurable baseline value (above LLOQ) of 
SARS-CoV-2 RNA by site collected NP swab and a second measurement after baseline.
All SARS-CoV-2 RNA measurements by site collected NP swab up to and including Day 29 
will be used in the analysis.
Viral load will be plotted individually for each patient over time.
7.5.2.2
Loss of detection of SARS-CoV-2 RNA by site collected NP swab at Day 4, 8, 
15, 22 and 29
The number and proportion of patients with loss of detection of SARS-CoV-2 RNA by site 
collected NP swab will be calculated on Day 4, 8, 15, 22 and 29. Please refer to Section 6.7 for 
the definition of time-windowing rules. 
Evaluation will be performed on all patients included in the randomised set that received any 
amount of study drug and, who have at least a measurable baseline value (above LLOQ) of 
SARS-CoV-2 RNA by site collected NP swab and a second measurement after baseline.
7.7
EXTENT OF EXPOSURE
Exposure data will be listed for all patients treated.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse Events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects 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 adverse events occurring after drug intake until the end of the residual effect period (+90 
days thereafter) will be assigned to the treatment. All adverse events occurring before drug 
intake will be assigned either to ‘screening’ or ‘post-randomisation’ (for listings only). All 
adverse events occurring after drug intake +90 days will be assigned to ‘post-study’ (for listings 
only). For details on the treatment definition, see Section 6.1.
All AEs that occur at any time during trial participation after drug administration, including 
all AEs occurring between drug intake (included) and up to the end of the residual effect 
period analyses will  be included in the analysis.
An overall summary of adverse events will be presented. 


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The frequency of subjects with any adverse events will be summarised by treatment group, 
primary system organ class and preferred term. The system organ classes will be sorted 
according to the standard sort order specified by EMA, preferred terms will be sorted by
decreasing frequency in the BI 767551 arm (within SOC).
In addition, infusion related reactions and inhalation related reactions will be listed based on 
the data reported on the dedicated eCRF pages.
7.8.2
Laboratory data
Laboratory data will be listed. No summary tables are planned.
The analyses of laboratory data will be based on BI standards. It will be based on SI units. All 
analyses will be performed on the treated set. E-dish plots will be provided for ALT and AST. 
7.8.3
Vital signs
Vital signs will be listed. No summary tables are planned.
7.8.4
ECG
Not applicable.
7.8.5
Others
To support the clinical trials disclosure process special safety displays may be necessary, e.g. 
the number of non-serious adverse events. All required outputs (including the following 
information) will be included in Appendix 16.1.13.1 of the CTR:

Number of subjects included by country

Number of subjects inside (member states) and outside the EU (third countries)

Frequency of serious drug-related AEs by treatment, primary system organ class and 
preferred term.

Frequency of serious AEs

Frequency of non-serious AEs with incidence >5% in any treatment arm


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
In phase II, it was planned to release the treatment information for interim analysis to the 
sponsor. Following the decision to terminate the study early, the database was unblinded on 7th
July 2021, while patients were still followed in the study.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version KMED.


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10.
ADDITIONAL SECTIONS
10.1
EXAMPLE CODE
The provided sample code will have to be modified to suit the needs of the corresponding 
analysis.
10.1.1
Time-weighted average change in viral load
##################################################
%MACRO auc (idvar =, dsname =, timevar =, yvar =, resultds =);
      %LOCAL lastid;
      %* All data mapulations are to be made outside of the macro;
      %* Sort dataset -> 1st data point is the starting point;
      PROC SORT DATA = &dsname OUT = _tmp;
            BY &idvar &timevar;
      RUN;
      %* Get last idvar;      
      DATA _null_;
            y = COMPBL ("&idvar");
            y1 = COMPRESS (y);
            n = LENGTH (y) - LENGTH (y1);
            CALL SYMPUT ('lastid', COMPRESS (PUT (n+1, 5.)));
      RUN;
      %PUT lastid = &lastid;
      %LET lastvar = %SCAN (&idvar, &lastid, %STR ( ));
      DATA _tmp1;
            SET _tmp;
            RETAIN _ltime _lyvar _difftime _mintime;
            BY &idvar;
            IF FIRST.&lastvar THEN DO;
                  _ltime = &timevar;
                  _lyvar = &yvar;
                  _difftime = .;
                  _mintime = &timevar;
            END;
            IF NOT FIRST.&lastvar THEN DO;
                  auccomp = 0.5 * (&yvar + _lyvar) * (&timevar - _ltime);


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                  diff = (&yvar - _lyvar);
                  difft = (&timevar - _ltime);
                  _ltime = &timevar;
                  _lyvar = &yvar;
                  IF last.&lastvar THEN _difftime = &timevar - _mintime;
                  OUTPUT;
            END;
      RUN;
      PROC SUMMARY DATA = _tmp1;
            BY &idvar;
            VAR auccomp;
            OUTPUT OUT = &resultds._pre SUM = auc;
      RUN;
      DATA &resultds;
            MERGE &resultds._pre _tmp1 (WHERE = (_difftime NE .) KEEP = &idvar 
_difftime);
            BY &idvar;
            auc = auc / _difftime;
      RUN;
%MEND;
%auc (idvar = subject swab_type gene, dsname = rawdata3, timevar = day, yvar = log_cp_ml_d, 
resultds = auc_result);


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10.2
DEFINITION OF HIGH RISK OF PROGRESSION TO SEVERE COVID-
19 AS PER NIH TREATMENT GUIDELINE
According to the NIH COVID-19 Treatment Guidelines, version dated April 8, 2021, high risk 
of progression to severe COVID-19 is defined as patients who meet at least one of the following 
criteria:
o
Have a BMI ≥35
o
Have chronic kidney disease
o
Have diabetes
o
Have immunosuppressive disease
o
Are currently receiving immunosuppressive treatment
o
Are ≥65 years of age
o
Are ≥55 years and <65 years of age AND have

cardiovascular disease, OR

hypertension, OR

chronic obstructive pulmonary disease/other chronic respiratory 
disease.


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Table 10.2: 1 Dictionary codes for risk factors based on comorbidities or concomitant 
medications – Risk factor definition as per NIH treatment guidelines
Risk factor
Dictionary (level)
Code (label)
Chronic kidney disease
MedDRA (PT)
10064848 (Chronic kidney 
disease)
Diabetes type 1 and type 2
MedDRA (PT)
10067584 (Type 1 diabetes 
mellitus)
10067585 (Type 2 diabetes 
mellitus)
Immunosuppressive disease
MedDRA (PT)
10061598 
(Immunodeficiency)
10080575 (Solid organ 
transplant)
Cardiovascular disease
MedDRA (PT)
10007649 (Cardiovascular 
disorder)
Hypertension
MedDRA (PT)
10020772 (Hypertension)
Chronic obstructive 
pulmonary disease
MedDRA (PT)
10009033 (Chronic 
obstructive pulmonary 
disease)
Other chronic respiratory 
disease
MedDRA (PT)
10038683 (Respiratory 
disorder)
10011762 (Cystic fibrosis)
10037383 (Pulmonary 
fibrosis)
10003553 (Asthma)
From baseline conditions 
page:
10022611 (Interstitial lung 
disease)
10037400 (Pulmonary 
hypertension)
Immunosuppressive 
treatment
WHODrug (SDG)
0000000186
(Immunosuppressant drugs)
For prednisone, doses below 
20mg will not be considered 
as risk factor.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
19-10-2021
None
This is the final TSAP