Clinical trial NCT04402060
Conditions: COVID Covid-19 Coronavirus Coronavirus Infection Severe Acute Respiratory Syndrome Severe Acute Respiratory Syndrome Coronavirus 2 Sars-CoV2 Ards Acute Respiratory Distress Syndrome
Sponsor: Apellis Pharmaceuticals, Inc.
Start date: 2020-05-28; Completion date: 2021-02-13
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and effectiveness of APL-9 in adults with mild to moderate ARDS (acute respiratory distress syndrome) caused by COVID-19 who are hospitalized and require supplemental oxygen therapy with or without mechanical ventilation.

It is thought that COVID-19 activates the complement system, part of the immune system that responds to infection or tissue damage, and increases inflammation in the lungs. APL-9 has been designed to inhibit or block activation of part of the complement pathway, and potentially reduce inflammation in the lungs.

Part 1 of the study is open-label to evaluate safety; all participants will receive APL-9 plus standard of care. Part 2 of the study is double-blind, randomized; participants will receive either APL-9 or the vehicle-control plus standard of care.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: APL-9 intervention 2: Vehicle Control
Intervention descriptions: intervention 1: Complement (C3) Inhibitor intervention 2: Normal saline of equal volume to active arm

Protocol documents:
Prot_000.pdf: 
1.
TITLE PAGE
APL-9 
PROTOCOL APL9-COV-201, AMENDMENT 3 
A RANDOMIZED, DOUBLE-BLIND, 
VEHICLE-CONTROLLED, MULTICENTER, 
PARALLEL-GROUP STUDY OF APL-9 IN MILD TO 
MODERATE ACUTE RESPIRATORY DISTRESS 
SYNDROME DUE TO COVID-19 
US IND No.: 148361
Phase: 1/2  
Date: 09 November 2020  
 
 
 
Confidentiality Statement
This document is confidential. It contains proprietary information of Apellis Pharmaceuticals, 
Inc. Any viewing or disclosure of such information that is not authorized in writing by Apellis 
Pharmaceuticals, Inc, is strictly prohibited. Such information may be used solely for the purpose 
of reviewing or performing this study. 
 
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APL-9 
APL9-COV-201 Protocol Amendment 3
09 November 2020


APL-9 
APL9-COV-201 Protocol Amendment 3 
09 November 2020 
INVESTIGATOR’S AGREEMENT
I have received and read the investigator’s brochure for APL-9. I have read 
Protocol APL9-COV-201 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
Printed Name of Investigator 
Signature of Investigator 
Date
 
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APL-9 
APL9-COV-201 Protocol Amendment 3 
09 November 2020 
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 3 (09 November 2020) 
Updates to the protocol implemented in this amendment are provided in the table below. 
Additions to the protocol are marked in underline; deletions are marked by strikethrough. 
Description of change 
Section(s) affected by 
change 
Nonsubstantial changes that did not impact content of the document have been 
made for clarity. 
Entire document 
Protocol Amendment Summary of Changes: Moved Amendment 2 Summary of 
Changes to Appendix 3, Amendment History 
Protocol Amendment 
Summary of Changes,
Appendix 3 
Synopsis
Part 1 (Open-Label Period): 
The DMC will recommend to the sponsor whether: 
 
the maximum allowed treatment duration in Part 2 can be extended 
(The DMC can extend the treatment duration beyond Day 7 up to and 
including Day 21; extended treatment will be allowed only in subjects 
who still have mild or moderate ARDS at Day 7 with at least a 
20-mm Hg increase in PaO2 from baseline.) refer to Part 2 
[Randomized Double-Blind Period].) 
Synopsis, Section 7.1
Update regarding Part 2 treatment period: 
*Subjects may continue treatment for up to 21 days (only in subjects who still 
require respiratory support at Day 7 with at least a 20-mm Hg increase in PaO2 
from baseline) per DMC recommendation and PI discretion (treatment may be 
modified at any point during Part 2) 
*Subjects are eligible to continue treatment for up to and including 21 days if 
they still require respiratory support at Day 7 with an improved PaO2/FiO2 ratio 
of at least 20 mm Hg from baseline if ABG test results are available for 
comparison. If ABG test results are not available, an improvement in FiO2 of at 
least 4% in nonventilated subjects (eg, those on nasal cannula) and 10% in 
mechanically ventilated subjects is needed. FiO2 should be weaned following the 
site’s protocol to keep oxygen saturation at 89% or above. Treatment beyond 
Day 7 and up to and including any DMC-approved extension will be at the 
discretion of the investigator per DMC recommendation and PI discretion 
(treatment may be modified at any point during Part 2). 
Figure 2 
Update regarding arterial blood gas test result availability: … extended treatment 
will be allowed only in subjects who still require respiratory support (oxygen 
supplementation or mechanical ventilation) at Day 7 with at least a 20 mm Hg 
increase in PaO2 from baseline a PaO2/FiO2 ratio improved by at least 20 mm Hg 
from baseline if arterial blood gas (ABG) test results are available for 
comparison. If ABG test results are not available, an improvement in FiO2 of at 
Synopsis, Section 7.1, 
Table 1 (footnote a), 
Section 9.1.1, 
Section 10.1
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least 4% in nonventilated subjects (eg, those on nasal cannula) and 10% in 
mechanically ventilated subjects is needed. FiO2 should be weaned following the 
site’s protocol to keep oxygen saturation at 89% or above.  
Add the following exploratory objective: 
 
 
Section 6.1.3 
Deleted the following secondary endpoints: 
 
Observed values and changes from baseline in markers of 
complement activation (C3, C3a, C4, C4a, Bb, C5a, TCC, and 
alternative complement pathway hemolytic activity [AH50]), 
coagulopathy (reticulocyte count, schistocytes, lactate 
dehydrogenase, D-dimer, ferritin, haptoglobin, fibrinogen,
 
 and 
inflammatory cytokines (C-reactive protein, tumor necrosis 
factor 
-
-6).  
Synopsis, Section 6.2.2
Added the following exploratory endpoints: 
 
 
Section 6.2.3 
Updated inclusion criterion 3:  
a. 
The arterial blood gas (ABG) test is used to determine the PaO2/FiO2 
ratio. An ABG test should be performed for every subject, but if an 
ABG test result cannot be obtained, the peripheral oxygen saturation 
(SpO2) can be measured and the SpO2/FiO2 ratio can be used. 
b. If the SpO2/FiO2 ratio is used for inclusion in the study, it must be >89. 
See Appendix 1 for more details. 
Synopsis, Section 8.1 
Updated exclusion criterion 4:  
Current participation in an interventional a clinical study with an investigational 
drug or biologic. NOTE: Participation in studies with the following therapies is 
NOT excluded:
a. 
Therapies approved (indicated) for COVID-19 by the applicable health 
authority 
b. Therapies with emergency use authorization for COVID-19 by the 
US Food and Drug Administration or equivalent authorization by the 
applicable health authority 
c. 
Therapies approved (indicated) by the applicable health authority and 
used for COVID-19 as part of standard care 
Synopsis, Section 8.2 
Updated and clarified dosing time frame: 
 
Dosing must occur on Day 1, on the same day as randomization. 
 
In Part 2, subjects will receive treatment up to and including the 
DMC-approved treatment duration, discontinuation of respiratory 
Synopsis, Table 1 
(footnote a), Section 7.1, 
Figure 2, Section 9.1.1, 
Section 11 
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support (oxygen supplementation or mechanical ventilation), or hospital 
discharge (whichever occurs earlier latest). 
 
Through Part 2, the DMC may review efficacy and safety data and 
recommend changes to the study conduct on an ongoing basis, but it 
will be required to review efficacy and safety data after the 10th and 
30th subjects reach the DMC-approved treatment duration, 
discontinuation of respiratory support, or hospital discharge (whichever 
occurs earlier latest). 
 
Subjects who reach the end of the approved treatment duration, 
discontinuation of respiratory support, or hospital discharge (whichever 
occurs earlier latest) … 
Clarified end of treatment period: 
Subjects who reach the end of the approved treatment duration, discontinuation 
of respiratory support, or hospital discharge (whichever occurs earlier) must be 
assessed as indicated in the EOT visit column (for example, a subject who 
reaches the end of the approved treatment and achieves discontinuation of 
respiratory support for example, a subject who achieves discontinuation of 
respiratory support on Day 6 should be evaluated with a radiograph or CT scan 
even though it is not indicated as a Day 6 assessment). 
Table 1 (footnote a) 
Updated schedule of assessments footnote b: Those subjects who are fully 
eligible can have baseline and screening assessments on the same day or may 
qualify for baseline assessments if they have met enrollment requirements within 
the previous 7 days as baseline, which is defined as the day of initial study drug 
treatment. 
Table 1 
Updated schedule of assessments footnote c: Any FDA–approved test may be 
used for confirmation of SARS-CoV-2. Confirmation of SARS-CoV-2 infection
may be completed more than 7 days before baseline. Presence of SARS-CoV-2 
viral RNA or viral antigen may be detected in respiratory specimens (collected 
using nasopharyngeal or oropharyngeal swabs) with a qualitative nucleic acid 
amplification test (such as reverse transcriptase polymerase chain reaction), viral 
antigen test, or other diagnostic method that is authorized, cleared, or approved 
by the US Food and Drug Administration or equivalent authority) for 
SARS-CoV-2 viral detection. Note: Serology-based antibody tests do not detect 
presence of virus and therefore are not considered diagnostic for active infection 
and cannot be used for study eligibility screening or for subsequent 
SARS-CoV-2 assessments.
Table 1 
Updated schedule of assessments footnote j: Refer to the procedure for handling 
infusion-related reactions in Section 9.1.1. 
Table 1 
Updated schedule of assessments footnote k: If confirmation of active 
SARS-CoV-2 infection has occurred within 7 days of screening, the viral RNA 
Table 1 
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or viral antigen test at screening/baseline is not mandatory. Confirmation of 
SARS-CoV-2 infection for screening may be completed more than 7 days before 
baseline. 
Updated schedule of assessments EOT column to include discharge day and 
clarified timing of PK/PD samples at the end-of-treatment visit and discharge 
day visit: 
Schedule of assessments EOT column and footnote a: EOT and discharge daya,n 
Schedule of assessments footnote m: A PK/PD assessment will be done on the 
last day of treatment. If EOT and discharge day visit are on different days, a 
PK/PD sample will be collected on the discharge day visit as an unscheduled 
visit.  
Schedule of assessments EOT and discharge day column and footnote n: If EOT 
and discharge day visit are on different days, perform EOT assessments on the 
last day of treatment and repeat on the day of discharge as an unscheduled visit. 
Perform/record vital signs, ECG, concomitant medications/procedures, infusion 
site reactions, and AEs daily up to and including day of discharge. After EOT, 
record as unscheduled visits. 
Section 11.5: Blood will then be collected once daily between 1-2 hours after the 
first dose on Days 3, 5, 7, 11 (if treatment is ongoing), and 15 (if treatment is 
ongoing) and at the end-of-treatment visit. (if the patient is discharged on a day 
not indicated for a clinical laboratory test sample). If the subject is discharged 
after the end-of-treatment visit, another sample will be collected on the day of 
discharge. 
Section 11.6: These blood samples will be collected at the same time as the 
pharmacokinetic samples described in Section 11.5. Blood will be collected 
3 times on Day 1: (1) once prior to administration of the APL-9 bolus, (2) once 
as soon as possible following the bolus (within 5-10 minutes) prior to the 
continuous infusion, and (3) once at 2 hours after the beginning of the 
continuous infusion. If the subject discharges on a day not indicated for a clinical 
laboratory test sample, blood will be collected between 1-2 hours after first dose 
of the end-of-treatment (EOT) visit. 
Table 1, Section 11.5, 
Section 11.6 
Updated schedule of assessments row: Vital signs/SpO2 saturation 
Table 1 
Updated schedule of assessments row:  
PK (APL-9)/PD (complement, coagulation, and inflammation)m 
Table 1 
Clarification of screening timeline for SARS-CoV-2 infection: 
Confirmation of SARS-CoV-2 infection may be completed more than 7 days 
before baseline. All other inclusion and exclusion criteria must be met within 
–7 days of baseline.  
Section 8.4 
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Clarified study drug administration: 
Dosing of subjects receiving APL-9 either as open-label treatment or by random, 
blinded assignment . . . will be initiated with an IV infusion of 180 mg APL-9 in 
50 mL of saline over a 10-minute period, followed within 1 hour by continuous 
infusion of 180 mg APL-9 in 250 mL saline at the rate of 15 mg/h 
(approximately 21 mL/h) until the end of study drug administration as follows:at 
Day 7 (or approved treatment extension), discontinuation of respiratory support 
(oxygen supplementation or mechanical ventilation), or hospital discharge, 
whichever occurs earlier. (This results in the infusion of two 250-mL bags, each 
containing 180 mg of APL-9 every 24 hours.) 
 
Part 1: at Day 7 or until or resolution of ARDS (PaO2/FiO2 ratio 
>300 mm Hg), whichever occurs earlier
 
Part 2: at Day 7 or up to and including the approved treatment duration, 
discontinuation of respiratory support (supplemental oxygen or 
mechanical ventilation), or hospital discharge, whichever occurs latest 
This results in the infusion of two 250-mL bags, each containing 180 mg of 
APL-9, every 24 hours. 
Section 9.1.1 
Clarified study drug administration: 
Treatment with study drug (APL-9 IV or matching vehicle IV infusion) will 
terminate either on Day 7 or at hospital discharge (whichever occurs earlier).as 
follows: 
 
Part 1: at Day 7 or until or resolution of ARDS (PaO2/FiO2 ratio 
>300 mm Hg), whichever occurs earlier
 
Part 2: at Day 7 or up to and including the approved treatment duration, 
discontinuation of respiratory support (supplemental oxygen or 
mechanical ventilation), or hospital discharge, whichever occurs latest 
In Part 2, the The DMC may decide … 
Section 10.1 
Clarified time points for data collection: 
See the schedule of assessments (SoA) for data to be collected at the time of 
discontinuation of study treatment, discharge, and safety follow-up and for any 
further evaluations to be completed. 
Section 10.1 
Updated “Lost to Follow-up”:  
A subject will be considered lost to follow-up for failure to complete the study 
end-of-treatment assessments and are unable to be contacted by the study site 
through the 30-day follow-up period. safety follow-up assessment 30 days after 
the last dose of study drug (up to Study Day 51 with a +7-day window). 
The following actions must be taken if a subject fails to complete the required 
study end-of-treatment assessments safety follow-up assessment 30 days after 
the last dose of study drug (up to Study Day 51 with a +7-day window): 
Section 10.3 
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Update study end-of-treatment assessments: 
 
The study end-of-treatment assessments are to be conducted on the 
day of hospital discharge. The study end-of-treatment assessments 
are to be conducted at the end of treatment or on the day of hospital 
discharge, whichever occurs later.  
Section 11 
Updated Sequential Organ Failure Assessment score variables: 
 
PaO2/FiO2 ratio (mm Hg) or SpO2/FiO2 ratio—collected and entered 
into the database locally … 
g
SOFA score variables (PaO2/FiO2 ratio or SpO2/FiO2 ratio,  
Section 11.1.1, Table 1
(footnote g) 
Clarified adverse event recording time frame: 
Adverse events and SAEs will be collected from the signing of the consent form 
until the safety follow-up assessment, or 30 days after the last dose of study 
treatment, up to Study Day 51 (+7). up to and including the safety follow-up 
assessment 30 days after the last dose of study drug (up to Study Day 51 with a 
+7-day window). 
Section 11.2.5 
Clarified treatment-emergent adverse event time frame: 
As described in Section 11.2, TEAEs are defined as those AEs that develop or 
worsen after the first dose of study medication until study end-of-treatment or 
the early termination follow-up visit. up to and including the safety follow-up 
assessment 30 days after the last dose of study drug (up to Study Day 51 with a 
+7-day window). 
Section 12.4 
 
 
Table 2 
Calculation of PaO2/FiO2 ratio:
For the purpose of calculating PaO2/FiO2 ratio… 
3.  If radial artery needle puncture attempt is unsuccessful then attempt radial 
artery needle puncture in contralateral upper extremity unless 
contraindicated for any reason. If ABG sampling remains unsuccessful for 
any reason, then SpO2 (peripheral oxygen saturation) will be measured and 
the SpO2/FiO2 value will be derived, and the corresponding PaO2/FiO2 ratio 
will be used to determine the SOFA respiratory score according to Table 6.  
4.  If radial artery puncture unsuccessful or contraindicated, then obtain ABG 
by placing arterial line, or puncture of femoral artery, or puncture of brachial 
artery, by qualified provider.  
5. In the event that ABG sampling remains unsuccessful for any reason, then 
SpO2/FiO2 value will be derived, and the corresponding of PaO2/FiO2 ratio 
will be used to determine the SOFA respiratory score according to Table 6. 
Appendix 1
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2.
SYNOPSIS
Name of Sponsor/Company: 
Apellis Pharmaceuticals, Inc 
Name of Investigational Product, Dosage, and Mode of Administration: 
APL-9, 30 mg/mL in 6-mL vials for intravenous (IV) infusion in isotonic saline 
Name of Reference Product or Comparator, Dosage, and Mode of Administration: 
Reference treatment is IV infusion of isotonic saline as vehicle control. 
Name of Active Ingredient: 
APL-9 
Protocol Number: APL9-COV-201 
Phase: 1/2 
Title of Study:  
A Randomized, Double-Blind, Vehicle-Controlled, Multicenter, Parallel-Group Study of APL-9 in Mild to 
Moderate Acute Respiratory Distress Syndrome Due to COVID-19 
Objectives:  
Primary: 
 
To evaluate the safety of APL-9 compared with that of vehicle control (as add-on therapy to 
standard of care [SOC]) in subjects with coronavirus disease 2019 (COVID-19) who have 
respiratory failure, including mild to moderate acute respiratory distress syndrome (ARDS) 
Secondary: 
To evaluate the effect of APL-9 on: 
 
Hospital length of stay 
 
Overall survival 
 
Change in Sequential Organ Failure Assessment (SOFA) score 
 
Time on mechanical ventilation  
 
Time on oxygen therapy 
Assessment of pharmacokinetics and pharmacodynamics
Endpoints: 
Primary: 
 
Cumulative incidence of treatment-emergent serious adverse events and treatment-emergent 
adverse events 
Secondary: 
 
Hospital length of stay (measured in days) 
 
Any-cause mortality (measured from beginning of treatment until the safety follow-up assessment 
30 days after last study treatment [up to and including Study Day 51 with a +7-day window]) 
 
SOFA score 
 
Total duration of mechanical ventilation (measured in days)  
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Total duration of oxygen therapy (by continuously worn mask or nasal cannula, measured in days) 
APL-9 PK parameters
 
Observed values and changes from baseline in markers of complement activation (C3, C3a, C4, 
C4a, Bb, C5a, terminal complement complex, and alternative complement pathway hemolytic 
activity), coagulopathy (reticulocyte count, presence of schistocytes, lactate dehydrogenase, 
D-dimer, ferritin, haptoglobin, fibrinogen), and inflammatory cytokines (C-reactive protein [CRP], 
tumor necrosis factor  
, IL-1 , and IL-6) 
Overall Study Design: 
This is a randomized, double-blind, vehicle-controlled, multicenter, parallel-group Phase 1/2 study (with an 
initial open-label period) evaluating the safety and efficacy of APL-9 versus those of vehicle as an add-on 
therapy to SOC in subjects with respiratory failure due to COVID-19 infection.  
The study will be conducted in 2 parts: 
Part 1 (Open-Label Period): 
Initially, a cohort of 6 subjects will receive open-label treatment with APL-9 as add-on therapy to SOC from 
Day 1 through Day 7 or resolution of ARDS (PaO2 [partial pressure of oxygen]/FiO2 [fraction of inspired 
oxygen] ratio >300 mm Hg), whichever occurs earlier.  
An independent data monitoring committee (DMC) will review the clinical data available for all 6 subjects once 
the last subject in Part 1 reaches Day 7 or is discharged following the resolution of ARDS (PaO2/FiO2 ratio 
>300 mm Hg). The DMC will recommend to the sponsor whether: 
 
the study can proceed to Part 2, and  
 
the maximum allowed treatment duration in Part 2 can be extended (The DMC can extend the 
treatment duration beyond Day 7 up to and including Day 21; refer to Part 2 [Randomized Double-
Blind Period].)  
Follow-up safety assessments for each subject will be collected 30 days following the last dose of APL-9 (with 
a +7-day window). These assessments will be conducted via inpatient assessment (for subjects still hospitalized) 
or by telephone call (for subjects discharged).  
Part 2 (Randomized Double-Blind Period): 
Part 2 of the study will be initiated only upon recommendation from the DMC. Required criteria for initiation of 
Part 2 will include (1) no fatal/life-threatening SAEs thought possibly related to APL-9 by the DMC, and (2) no 
more than 1 subject requiring premature treatment discontinuation by the investigator due to AEs or abnormal 
laboratory tests. All subjects will receive SOC independent of their randomization. Approximately 60 subjects 
will be randomly assigned in a 1:1 ratio to blinded treatment with either APL-9 or saline vehicle. Subjects will 
receive treatment with APL-9 or vehicle from Day 1 through Day 7 (or up to and including the approved 
treatment duration), discontinuation of respiratory support (supplemental oxygen or mechanical ventilation), or 
hospital discharge, whichever occurs latest.  
Subjects may receive treatment beyond Day 7 if the DMC approves an extended treatment duration following 
the review of data from Part 1 or during the conduct of Part 2. The DMC may approve any extended treatment 
duration up to and including Day 21; extended treatment will be allowed only in subjects who still require 
respiratory support (oxygen supplementation or mechanical ventilation) at Day 7 with a PaO2/FiO2 ratio 
improved by at least 20 mm Hg from baseline if arterial blood gas (ABG) test results are available for 
comparison. If ABG results are not available, an improvement in FiO2 of at least 4% in nonventilated subjects 
(eg, those on nasal cannula) and 10% in mechanically ventilated subjects is needed. FiO2 should be weaned 
following the site’s protocol to keep oxygen saturation at 89% or above. Treatment beyond Day 7 and up to and 
including any DMC-approved extension will be at the discretion of the investigator.  
For each subject, follow-up safety assessments will be collected 30 days after the subject’s last dose of study 
treatment (up to and including Study Day 51 with a +7-day window). Assessments between study drug 
discontinuation and the safety follow-up assessment may be conducted at the investigator’s discretion. These 
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assessments will be conducted via inpatient assessment (for subjects still hospitalized) or by telephone call (for 
subjects discharged). 
The DMC will perform safety and efficacy data reviews on an ongoing basis during Part 2. Two reviews will be 
required in Part 2:  
 
After the 10th subject reaches the approved treatment duration, discontinuation of respiratory 
support (oxygen supplementation or mechanical ventilation), or hospital discharge, whichever 
occurs latest 
 
After the 30th subject reaches the approved treatment duration, discontinuation of respiratory 
support (oxygen supplementation or mechanical ventilation), or hospital discharge, whichever 
occurs latest 
If the DMC approves an extended treatment period following Part 1 or at any time through the conduct of 
Part 2, the DMC’s safety and efficacy data review will be initiated when the 10th and 30th subjects reach the 
approved extended treatment duration, discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge, whichever occurs latest. For example, if, following Part 1, the 
DMC approves treatment up to and including Day 14 in Part 2, the DMC will be required to review safety and 
efficacy after the first 10 subjects reach Day 14 of treatment, discontinuation of respiratory support (oxygen 
supplementation or mechanical ventilation), or hospital discharge, whichever occurs latest. Enrollment will not 
be suspended during the DMC reviews. 
If a subject is treated up to and including the maximum allowed treatment duration and must discontinue 
treatment, treatment may not be reinitiated even if the DMC subsequently approves a longer treatment duration. 
Number of Subjects (Planned):  
 
Part 1: 6 
 
Part 2: 60 
In Part 1, an initial cohort of 6 subjects will receive open-label APL-9 treatment for up to and including 7 days 
to assess safety. In Part 2, approximately 60 subjects will be randomly assigned 1:1 to APL-9 or vehicle in order 
to ensure that there are approximately 58 evaluable subjects. 
Diagnosis and Main Criteria for Inclusion and Exclusion:  
Inclusion Criteria: 
1. At least 18 years of age at time of informed consent. 
2. Diagnosis of active SARS-CoV-2 infection. Presence of SARS-CoV-2 viral RNA or viral antigen may be 
detected in respiratory specimens (collected using nasopharyngeal or oropharyngeal swabs) with a 
qualitative nucleic acid amplification test (such as reverse transcriptase polymerase chain reaction) or viral 
antigen test or other diagnostic method that is authorized, cleared, or approved by the US Food and Drug 
Administration (or equivalent local authority) for SARS-CoV-2 viral detection. Note: Serology-based 
antibody tests do not detect presence of virus, and therefore are not considered diagnostic for active 
infection and cannot be used for study eligibility screening or for subsequent SARS-CoV-2 assessments.  
3. Have respiratory failure requiring oxygen supplementation or have either invasive or noninvasive 
mechanical ventilation with PaO2/FiO2 ratio >100 mm Hg. Respiratory failure cannot be fully explained by 
cardiac failure or fluid overload. 
a. 
The arterial blood gas (ABG) test is used to determine the PaO2/FiO2 ratio. An ABG test 
should be performed for every subject, but if an ABG test result cannot be obtained, the 
peripheral oxygen saturation (SpO2) can be measured and the SpO2/FiO2 ratio can be used. 
b. If the SpO2/FiO2 ratio is used for inclusion into the study, it must be >89.  
4. Written informed consent for study participation must be provided by the subject (or legally authorized 
representative) prior to any study-related procedures. 
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5.
Subject (or legally authorized representative) is willing and able to comply with study procedures and 
assessments, including imaging assessments and venous blood sample(s) per protocol. 
6. Each female subject of childbearing potential must have a negative serum pregnancy test at screening and 
must agree to use protocol-defined methods of contraception from screening through at least 90 days after 
receiving the last dose of APL-9. 
7. Male subjects must agree to use protocol-defined methods of contraception and agree to refrain from 
donating semen from screening through a minimum of 90 days after receiving the last dose of APL-9. 
Exclusion Criteria: 
1. Female subjects being pregnant or breastfeeding 
2. Active bacterial, fungal, or parasitic infection 
3. History of neuromuscular degenerative disease (eg, amyotrophic lateral sclerosis, Duchenne muscular 
dystrophy, or multiple sclerosis) 
4. Current participation in a clinical study with an investigational drug or biologic. NOTE: Participation in 
studies with the following therapies is NOT excluded: 
a. 
Therapies approved (indicated) for COVID-19 by the applicable health authority 
b. Therapies with emergency use authorization for COVID-19 by the US Food and Drug 
Administration or equivalent authorization by the applicable health authority 
c. 
Therapies approved (indicated) by the applicable health authority and used for COVID-19 as 
part of standard care 
5. Treatment with immune checkpoint inhibitors, or other immunomodulators within 3 months prior to study 
enrollment (however, treatment with convalescent plasma, steroids, IL-6 inhibitors, and antiviral agents is 
NOT excluded) 
6. Subjects who have, at screening, been on mechanical ventilation for >7 days 
7. Evidence of kidney AND liver failure at screening (estimated glomerular filtration rate 
<45 mL/min/1.73 m2 and alanine aminotransferase level >5× the upper limit of normal, as assessed by the 
local laboratory) 
8. Subjects with a hereditary complement deficiency  
Study Drug Treatments: 
Part 1: 
Subjects shall receive the institutional SOC to treat their conditions at the discretion of the investigator, 
including (but not limited to) supplemental oxygen, mechanical ventilation, fluid management, and required 
medication as provided by the hospital and allowed by the protocol. 
All subjects will receive prophylactic broad-spectrum antibiotic therapy from baseline until discontinuation of 
APL-9. Treatment with antibiotics may be adjusted according to culture results and at the discretion of the 
investigator. 
Dosing with open-label APL-9 will be initiated on Day 1 with an IV infusion of 180 mg APL-9 in 50 mL saline 
over a 10-minute period, followed within 1 hour by continuous infusion of 180 mg APL-9 in 250 mL saline at 
the rate of 15 mg/h (approximately 21 mL/h) until Day 7 or resolution of ARDS, whichever occurs earlier. (This 
results in the infusion of two 250-mL bags, each containing 180 mg of APL-9 every 24 hours.) 
Part 2: 
Subjects shall receive the institutional SOC to treat their conditions at the discretion of the investigator, 
including (but not limited to) supplemental oxygen, mechanical ventilation, fluid management, and required 
medication as provided by the hospital and allowed by the protocol. 
All subjects will receive prophylactic broad-spectrum antibiotic therapy from baseline until discontinuation of 
study drug treatment. Treatment with antibiotics may be adjusted according to culture results and at the 
discretion of the investigator. 
At Day 1 subjects will be randomized in a 1:1 ratio to APL-9 for infusion or matched vehicle control. 
Study drug (APL-9 for infusion or matched vehicle control) will be prepared by an unblinded pharmacist at the 
study site and transferred to blinded site personnel for administration to subjects. One vial of APL-9 (180 mg in 
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6 mL buffer) will be diluted in a 50-mL saline bag for infusion to initiate the study or in a 250-mL saline bag for 
the maintenance therapy. Vehicle control will be 50-mL and 250-mL saline bags that are identical in appearance 
but do not contain APL-9.  
The blinded site personnel will initiate therapy with study drug received from the pharmacists on Day 1 with an 
IV infusion of the 50-mL bag over a 10-minute period, followed within 1 hour by continuous infusion of the 
250-mL bag at the rate of approximately 21 mL/h until the end of study drug administration on Day 7 (or longer 
if DMC allowed), discontinuation of respiratory support, or hospital discharge, whichever occurs latest. This 
results in the infusion of two 250-mL bags every 24 hours. 
Statistical Methods:  
All efficacy and safety analyses will be summarized by treatment group. 
Continuous variables will be summarized using descriptive statistics (eg, median and mean); for categorical 
variables, the frequency and percentage in each category will be displayed. Time-to-event data (such as time to 
hospital discharge and time to mechanical ventilation discontinuation) will be summarized with Kaplan-Meier 
estimates accounting for censored observations (and analyzed using the Cox proportional hazard model if 
appropriate). 
Treatment-emergent adverse events will be summarized by System Organ Class and Preferred Term, according 
to the Medical Dictionary for Regulatory Activities. The number of subjects reporting each adverse event 
Preferred Term will be tabulated for all treatment-emergent adverse events and for those considered by the 
investigator as being possibly related to study treatment. The number of subjects reporting serious adverse 
events will also be tabulated. 
Independent DMC: 
The DMC and its chair will be appointed by the sponsor and will operate according to a charter. The DMC will 
review safety data and will recommend to the sponsor whether the study may proceed beyond the open-label 
safety period (Part 1) and whether to continue, terminate, or modify the study during Part 2. Required criteria 
for initiation of Part 2 will include (1) no fatal/life-threatening serious adverse events thought possibly related to 
APL-9 by the DMC and (2) no more than 1 subject requiring premature treatment discontinuation by the 
investigator due to adverse events or abnormal laboratory tests. Specifically, the DMC may recommend to the 
sponsor that the duration of treatment with APL-9/vehicle be extended beyond Day 7 during Part 2. The DMC 
will perform safety and efficacy data reviews on an ongoing basis during Part 2. Two reviews will be required 
in Part 2: 
1. After the 10th subject reaches the approved treatment duration, discontinuation of respiratory support 
(oxygen supplementation or mechanical ventilation), or hospital discharge, whichever occurs latest  
2. After the 30th subject reaches the approved treatment duration, discontinuation of respiratory support 
(oxygen supplementation or mechanical ventilation), or hospital discharge, whichever occurs latest  
If the DMC approves an extended treatment period following Part 1 or at any time through the conduct of 
Part 2, the DMC’s safety and efficacy data review will be initiated when the 10th and 30th subjects reach the 
approved extended treatment duration, discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge, whichever occurs latest. Enrollment will not be suspended during 
the DMC reviews. 
Treatment duration in Part 2 may be maximally extended up to and including Day 21; extended treatment will 
be allowed only in subjects who still require respiratory support (oxygen supplementation or mechanical 
ventilation) at Day 7 with a PaO2/FiO2 ratio improved by at least 20 mm Hg from baseline if an ABG test result 
is available for comparison. If an ABG test result is not available, an improvement in FiO2 of at least 4% in 
nonventilated subjects (eg, those on nasal cannula) and 10% in mechanically ventilated subjects is needed. FiO2
should be weaned following the site’s protocol to keep oxygen saturation at 89% or above. Treatment beyond 
Day 7 and up to and including any DMC-approved extension will be at the discretion of the investigator.  
Through the conduct of the study the DMC can recommend any changes to the protocol, including study 
termination for safety or futility reasons. 
 
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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1.
TITLE PAGE ................................................................................................................1
APPROVAL SIGNATURE .............................................................................................................2
INVESTIGATOR’S AGREEMENT...............................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES..........................................................4
2.
SYNOPSIS .................................................................................................................10
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20
5.
INTRODUCTION ......................................................................................................22
5.1. 
Study Rationale ...........................................................................................................22
5.2. 
Complement and APL-9 Background ........................................................................23
5.3. 
Benefit-Risk Assessment ............................................................................................23
6.
OBJECTIVES AND ENDPOINTS ............................................................................25
6.1. 
Objectives ...................................................................................................................25
6.1.1.
Primary Objective ...........................................................................................25
6.1.2.
Secondary Objectives .....................................................................................25
6.1.3.
Exploratory Objectives ...................................................................................25
6.2. 
Endpoints ....................................................................................................................25
6.2.1.
Primary Objective Endpoint ...........................................................................25
6.2.2.
Secondary Objective Endpoints ......................................................................26
6.2.3.
Exploratory Objective Endpoints ...................................................................26
7.
STUDY DESIGN .......................................................................................................27
7.1. 
Overall Study Design ..................................................................................................27
7.2. 
Scientific Rationale for Study Design ........................................................................28
7.3. 
Justification for Dose ..................................................................................................29
7.4. 
End of Study Definition ..............................................................................................29
7.5. 
Study Design and Schedule of Assessments ..............................................................30
8.
STUDY POPULATION .............................................................................................35
8.1. 
Subject Inclusion Criteria (Part 1 and Part 2) .............................................................35
8.2. 
Subject Exclusion Criteria (Part 1 and Part 2) ............................................................35
8.3. 
Lifestyle Considerations .............................................................................................36
8.4. 
Screening Failures ......................................................................................................36
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9.
TREATMENT OF SUBJECTS ..................................................................................37
9.1. 
Study Interventions .....................................................................................................37
9.1.1.
Study Drug Administration .............................................................................37
9.1.2.
Empiric Antibiotic Treatment for Possible Infection .....................................39
9.2. 
Preparation, Handling, Storage, and Accountability ..................................................39
9.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................40
9.3.1.
Randomization ................................................................................................40
9.3.2.
Blinding (Part 2 Only) ....................................................................................40
9.4. 
Treatment Compliance ................................................................................................40
9.5. 
Concomitant Medications ...........................................................................................40
9.5.1.
Restricted and Prohibited Medications ...........................................................41
9.6. 
Intervention After the End of the Study .....................................................................41
10.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................42
10.1. 
Discontinuation of Study Intervention ........................................................................42
10.2. 
Subject Discontinuation/Withdrawal From the Study ................................................43
10.3. 
Lost to Follow-up .......................................................................................................43
11.
STUDY ASSESSMENTS AND PROCEDURES ......................................................44
11.1. 
Safety and Efficacy Assessments ...............................................................................44
11.1.1.
SOFA Score ....................................................................................................45
11.1.2.
Computed Tomographic Scans/Radiographs: Pulmonary 
Consolidation ..................................................................................................45
11.1.3.
Demographic/Medical History .......................................................................45
11.1.4.
Assessment of Kidney and Liver Failure ........................................................45
11.1.5.
Vital Signs ......................................................................................................46
11.1.6.
Weight and Height ..........................................................................................46
11.1.7.
Infusion Site/Pump Safety Assessment ..........................................................46
11.1.8.
Clinical Laboratory Tests ...............................................................................46
11.1.8.1.
Pregnancy Screening ................................................................................48
11.2. 
Adverse Events ...........................................................................................................48
11.2.1.
Definition of AEs ............................................................................................48
11.2.2.
Serious Adverse Events ..................................................................................48
11.2.3.
Unexpected Adverse Events ...........................................................................49
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11.2.4.
Evaluation of AEs ...........................................................................................49
11.2.5.
Recording AEs ................................................................................................50
11.2.6.
Reporting AEs ................................................................................................50
11.2.7.
Pregnancy .......................................................................................................50
11.2.8.
Acceptable Methods of Contraception ...........................................................51
11.3. 
Drug Abuse, Misuse, Overdose, and Medication Error ..............................................51
11.4. 
SARS-CoV-2 Viral RNA/Viral Antigen Assessment ................................................52
11.5. 
Pharmacokinetics ........................................................................................................52
11.6. 
Pharmacodynamics .....................................................................................................52
11.7. 
Genetics ......................................................................................................................53
11.8. 
Immunogenicity Assessments ....................................................................................53
12.
STATISTICS ..............................................................................................................54
12.1. 
Determination of Sample Size ....................................................................................54
12.2. 
Analysis Set ................................................................................................................54
12.2.1.
Screened Set ....................................................................................................54
12.2.2.
Safety Set ........................................................................................................54
12.2.3.
Intent-to-Treat Set ...........................................................................................54
12.2.4.
Full Analysis Set .............................................................................................54
12.2.5.
Per-Protocol Set ..............................................................................................54
12.2.6.
Pharmacokinetic Set .......................................................................................55
12.2.7.
Pharmacodynamic Set ....................................................................................55
12.2.8.
Data Review for Analysis Set .........................................................................55
12.3. 
Efficacy Analysis ........................................................................................................55
12.3.1.
Analysis of Primary Efficacy Endpoint ..........................................................55
12.3.2.
Analysis of Secondary Efficacy Endpoints ....................................................55
12.3.3.
Analysis of Time-to-Event Data .....................................................................55
12.3.4.
Analysis of Exploratory Endpoints .................................................................56
12.4. 
Safety Analysis ...........................................................................................................56
12.5. 
Other Analyses ............................................................................................................56
12.6. 
Interim Analyses .........................................................................................................57
12.7. 
Independent Data Monitoring Committee ..................................................................57
13.
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................58
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13.1.2. 
Informed Consent Process ..........................................................................................58
13.1.3.
Data Protection ...........................................................................................................59
13.1.4.
Site Qualification and Study Monitoring ....................................................................59
13.1.5. 
Data Quality Assurance ..............................................................................................60
13.1.6. 
Source Documents ......................................................................................................61
13.1.7. 
Study and Site Start and Closure ................................................................................61
13.1.8.
Publication Policy .......................................................................................................62
14.
LIST OF REFERENCES ............................................................................................63
15.
APPENDICES ............................................................................................................65
Appendix 1.
Sequential Organ Failure Assessment (SOFA) ......................................................66
Appendix 2.
Glasgow Coma Scale ..............................................................................................69
Appendix 3.
Amendment History ...............................................................................................71
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LIST OF TABLES
Table 1: 
Schedule of Assessments ............................................................................................32
Table 2:
Clinical Laboratory Tests ...........................................................................................47
Table 3:  
Definitions of Adverse Event Relatedness .................................................................49
Table 4:  
Severity of Events .......................................................................................................49
Table 5:
Sequential Organ Failure Assessment (SOFA) Scoring .............................................67
Table 6: 
Derivation of SpO2/FiO2 Values Corresponding to PaO2/FiO2 Ratios in the 
Combined Anesthesia and ARMA Databasea ............................................................68
LIST OF FIGURES 
Figure 1:  Study Schema—Part 1 ................................................................................................30
Figure 2: 
Study Schema—Part 2 ................................................................................................31
 
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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation/specialist term 
Definition 
AE 
adverse event 
AH50
alternative complement pathway hemolytic activity 
ARDS 
acute respiratory distress syndrome 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRP 
C-reactive protein 
DMC 
data monitoring committee  
eCRF 
electronic case report form 
FiO2 
fraction of inspired oxygen
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use  
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
PaO2 
partial pressure of oxygen 
PD 
pharmacodynamic 
PEEP 
positive end-expiratory pressure 
PK 
pharmacokinetic 
RT-PCR 
reverse transcriptase polymerase chain reaction  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-1 
severe acute respiratory syndrome coronavirus 1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoA 
schedule of assessments 
SOC 
standard of care 
SOFA 
Sequential Organ Failure Assessment 
SpO2
peripheral oxygen saturation 
TCC 
terminal complement complex 
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Abbreviation/specialist term
Definition
TEAE
treatment-emergent adverse event
 
tumor necrosis factor  
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5.
INTRODUCTION
The rapid spread of coronavirus disease 2019 (COVID-19), the disease caused by the emerging 
coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an 
increasing threat to human health globally. Patients with COVID-19 are at risk of progressing to 
severe complications including acute respiratory distress syndrome (ARDS), pneumonia, 
pulmonary edema, and organ failure (Chen et al. 2020). These pathologies are driven by massive 
local and systemic inflammatory events and can be linked intrinsically to overactivation of the 
complement system (Robbins et al. 1987).  
5.1.
Study Rationale
Complement overactivation can damage host tissue in numerous pathologies. In the 1970s, the 
chemoattractant C5a (a product of complement activation) was shown to facilitate 
neutrophil-mediated damage to the pulmonary endothelium (Craddock et al. 1977). In the 1980s, 
investigations showed that C5a concentration in plasma is a prognostic marker for ARDS 
(Hammerschmidt et al. 1980). Subsequently, multiple studies have correlated ARDS severity and 
progression with complement activation by various products, eg, C1rC1s-C1 inhibitor 
(Langlois and Gawryl 1988) and C3d/C3 ratio (Duchateau et al. 1984), further substantiating the 
temporal association between complement activation and ARDS. 
Complement has been implicated in many viral respiratory infections, including respiratory 
syncytial virus (Bera et al. 2011) and influenza A subtypes H5N1 (Ng et al. 2006; 
Sun et al. 2013) and H7N9 (Sun et al. 2015). More recently, patients with ARDS secondary to 
SARS-CoV-2 infection have exhibited significant deposits of the terminal complement complex 
(TCC) C5b-9 in lung and skin specimens (Magro et al. 2020).  
Therefore, complement has been postulated as a rational therapeutic target in severe COVID-19 
(Campbell and Kahwash 2020). This strategy is supported by preclinical models of other 
coronaviruses that have caused notable outbreaks. When infected with a mouse-adapted form of 
severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; the virus that caused the 2003 
severe acute respiratory syndrome outbreak), transgenic mice deficient in C3 (C3–/– knockout 
mice) had viral titers similar to but reduced lung injury and pulmonary inflammation compared 
with wild-type mice (Gralinski et al. 2018). In a murine model of Middle East respiratory 
syndrome coronavirus (MERS-CoV) infection (which caused a 2012 outbreak), C5aR blockade 
reduced lung and spleen damage (Jiang et al. 2018). APL-9 is an investigational drug for 
intravenous (IV) infusion containing 2 cyclic pentadecapeptides covalently attached at the end of 
a 10-kDa linear poly(ethylene glycol) chain that bind and inhibit C3 and C3b complement 
components and therefore block complement activation. 
The proposed Phase 1/2 study includes an open-label safety period (Part 1), followed by a 
randomized, double-blind, vehicle-controlled period (Part 2). Part 2 of this study will assess the 
safety and efficacy of APL-9 in subjects treated with study intervention (APL-9 in addition to 
standard of care [SOC]) compared with those in a control group (subjects treated with vehicle in 
addition to SOC). 
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5.2.
Complement and APL-9 Background
Complement proteins exist in systemic circulation at high concentrations and can undergo rapid 
activation in response to infection or tissue damage, triggering local and systemic inflammation. 
The complement system is composed of 3 activation pathways: classical, lectin, and alternative. 
Initiation of each pathway generates proteolytic enzyme complexes (C3 or C5 convertases) that 
cleave peptide bonds in the C3 and C5 proteins. The C3 protein is central to the activation of all 
3 pathways of the complement cascade. Proteolytic cleavage of C3 releases the anaphylatoxin 
C3a and activates C3b, which with the factor B fragment Bb forms C3bBb, an enzyme complex 
(C3 convertase) with the ability to cleave C3. The C4 protein plays a role in both the classical 
and lectin pathways of complement activation. Following activation of these pathways, 
proteolytic enzyme complexes cleave a peptide bond in C4, releasing the anaphylatoxin C4a and 
activating C4b, which assembles with C2b to form a different C3 convertase, C2bC4b. 
Downstream of C3 activation, the cleavage of the C5 protein results in the production of the 
anaphylatoxin C5a and C5b, leading to the formation of the surface-bound membrane attack 
complex (C5b-9) or its soluble form, the TCC. 
APL-9 contains 2 cyclic pentadecapeptides covalently attached at the ends of a 10-kDa linear 
poly(ethylene glycol) chain. The cyclic peptides bind and inhibit C3 and its C3b fragment and 
are responsible for the bioactivity of APL-9. The compound is a potent inhibitor of all 
3 complement activation pathways and blocks the formation of most associated effector 
functions, including formation of the membrane attack complex. 
In a Phase 1, double-blind, randomized, placebo-controlled, single ascending dose study in 
healthy volunteers (Study APL9-101), 24 subjects were treated with a single dose of IV APL-9 
and 10 subjects were treated with matching placebo. The results of this study confirmed the 
potent inhibition of complement and established the pharmacokinetic (PK) profile; no significant 
safety findings were observed. 
APL-9 is manufactured under current Good Manufacturing Practices as outlined in the US Code 
of Federal Regulations (21 CFR §210, 211) and the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH Q7).  
More detailed descriptions of the chemistry, pharmacology, efficacy, and safety of APL-9 can be 
found in the APL-9 Investigator’s Brochure. 
5.3. 
Benefit-Risk Assessment 
This is an interventional study in COVID-19 subjects with respiratory failure, including mild to 
moderate ARDS, a life-threatening complication of SARS-CoV-2 infection. Based on the known 
pathological role of complement overactivation in ARDS, C3 inhibition by APL-9 may improve 
pulmonary function in subjects with COVID-19. If efficacious, APL-9 may also reduce 
COVID-19-associated morbidity and mortality and shorten the length of stay in intensive care 
and respiratory units, which may be in critical shortage during outbreaks. 
Nonclinical studies of SARS-CoV-1 have indicated that complement inhibition had beneficial 
effects to reduce lung inflammation, and a healthy volunteer clinical study of IV APL-9, a C3 
inhibitor, demonstrated acceptable PK and safety profiles. Subjects participating in this study 
will also receive SOC therapy independent from randomization. 
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The risks include local adverse effects from IV dosing, adverse effects that are currently 
unknown, additional infections secondary to COVID-19, possible increased risk of bacterial 
infection due to complement inhibition, and possible lack of efficacy. All subjects who are to 
receive study drug treatment will also receive a broad-spectrum antibiotic (see Section 9.5) to 
counter the theoretical concern of increased risk of bacterial infection due to complement 
inhibition. As a further subject safety mechanism, the study will initially enroll and treat 
6 subjects in an open-label fashion with APL-9 (Part 1). A data monitoring committee (DMC) 
will review the clinical data collected in Part 1 before Part 2 of the study will be initiated. 
Required criteria for initiation of Part 2 will include (1) no fatal/life-threatening serious adverse 
events (SAEs) thought possibly related to APL-9 by the DMC, and (2) no more than 1 subject 
requiring premature treatment discontinuation by the investigator due to adverse events (AEs) or 
abnormal laboratory tests. After Part 2 is initiated, the DMC will perform further reviews of 
clinical data after the 10th and 30th subjects have reached the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or mechanical ventilation), or 
hospital discharge, whichever occurs latest.  
 
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6.
OBJECTIVES AND ENDPOINTS
6.1. 
Objectives 
6.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety of APL-9 compared with that of 
vehicle control (as add-on therapy to SOC) in subjects with COVID-19 who have respiratory 
failure, including mild to moderate ARDS. 
6.1.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate the effect of APL-9 on: 
 Hospital length of stay 
 Overall survival 
 Change in Sequential Organ Failure Assessment (SOFA) score 
 Time on mechanical ventilation 
 Time on oxygen therapy 
 APL-9 PK  
 APL-9 pharmacodynamics (PD; the effect of APL-9 on complement, coagulation, and 
inflammation biomarkers) 
6.1.3. 
Exploratory Objectives 
The exploratory objectives of this study are to evaluate: 
 The effect of APL-9 on presence of active SARS-CoV-2 infection  
The effect of APL-9 on new oxygen use during the study (reinitiation 24 hours or 
more after cessation of prior oxygen therapy) 
The effect of APL-9 on new mechanical ventilation use (reinitiation 24 hours or more 
after cessation of prior mechanical ventilation) 
6.2. 
Endpoints 
6.2.1. 
Primary Objective Endpoint
 Cumulative incidence of treatment-emergent SAEs and treatment-emergent adverse 
events (TEAEs) 
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6.2.2. 
Secondary Objective Endpoints 
 Hospital length of stay (measured in days) 
 Any-cause mortality (measured from beginning of treatment until the safety 
follow-up assessment 30 days after last study treatment [up to and including Study 
Day 51 with a +7-day window]) 
 SOFA score 
 Total duration of mechanical intervention (measured in days) 
 Total duration of oxygen therapy (by continuously worn mask or nasal cannula, 
measured in days) 
 APL-9 PK parameters 
 Observed values and changes from baseline in markers of complement activation (C3, 
C3a, C4, C4a, Bb, C5a, TCC, and alternative complement pathway hemolytic activity 
[AH50]), coagulopathy (reticulocyte count, schistocytes, lactate dehydrogenase, 
D-dimer, ferritin, haptoglobin, and fibrinogen), and inflammatory cytokines 
(C-reactive protein [CRP], tumor necrosis factor
[TNF
, IL-1
and IL-6).  
6.2.3. 
Exploratory Objective Endpoints 
 Incidence, duration, and extent of new supplemental oxygen use (reinitiation 24 hours 
or more after cessation of prior supplemental oxygen therapy) 
Incidence, duration, and extent of new mechanical ventilation use (reinitiation 
24 hours or more after cessation of prior mechanical ventilation) 
 
Presence of active SARS-CoV-2 infection at the end-of-treatment visit. Presence of 
SARS-CoV-2 viral RNA or viral antigen may be detected in respiratory specimens 
(collected using nasopharyngeal or oropharyngeal swabs) with a qualitative nucleic 
acid amplification test (such as reverse transcriptase polymerase chain reaction 
[RT-PCR]), viral antigen test, or other diagnostic method that is authorized, cleared, 
or approved by the US Food and Drug Administration (or equivalent local authority) 
for SARS-CoV-2 viral detection. Serology-based antibody tests do not detect the 
presence of virus and therefore are not considered diagnostic and cannot be used for 
study eligibility screening or for subsequent SARS-CoV-2 assessments.
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7.
STUDY DESIGN
7.1. 
Overall Study Design 
This Phase 1/2 trial includes an initial open-label period (Part 1) before proceeding to a 
randomized, double-blind, vehicle-controlled, parallel-group period (Part 2). Part 1 of the study 
is designed to evaluate the safety of open-label APL-9 with SOC in a small number of subjects 
who have respiratory failure (including mild to moderate ARDS) due to COVID-19 and who 
require respiratory support (supplemental oxygen or mechanical ventilation). A DMC will 
analyze the data for Part 1 and decide whether Part 2 of the study will be initiated. Required 
criteria for initiation of Part 2 will include (1) no fatal/life-threatening SAEs thought possibly 
related to APL-9 by the DMC, and (2) no more than 1 subject requiring premature treatment 
discontinuation by the investigator due to AEs or abnormal laboratory tests. Part 2 of the study is 
designed to evaluate the safety and efficacy of APL-9 with SOC compared with those of vehicle 
with SOC in a larger number of subjects who have respiratory failure (including mild to 
moderate ARDS) due to COVID-19 and who require respiratory support (supplemental oxygen 
or mechanical ventilation).  
Subjects will participate only in either Part 1 or Part 2 of the study (ie, subjects who participate 
in Part 1 of the study will not participate in Part 2). 
Further details on the study design for each part of the study are provided below. 
Part 1 (Open-Label Period):
Initially, a cohort of 6 subjects will receive open-label treatment with APL-9 as add-on therapy 
to SOC (CDC 2020) from Day 1 through Day 7 or resolution of ARDS (PaO2 [partial pressure of 
oxygen]/FiO2 [fraction of inspired oxygen] ratio >300 mm Hg), whichever occurs earlier. 
Resolution of ARDS in this study is defined according to the Berlin definition as PaO2/FiO2 ratio 
>300 mm Hg (ARDS Definition Task Force 2012). 
An independent DMC will review the clinical data available for all 6 subjects once the last 
subject in Part 1 reaches Day 7 or is discharged following the resolution of ARDS (PaO2/FiO2 
ratio >300 mm Hg). The DMC will recommend to the sponsor whether: 
 the study can proceed to Part 2, and  
 the maximum allowed treatment duration in Part 2 can be extended (The DMC can 
extend the treatment duration beyond Day 7 up to and including Day 21; refer to 
Part 2 [Randomized Double-Blind Period]). 
Follow-up safety assessments for each subject will be collected 30 days following the last dose 
of APL-9 (with a +7-day window). These assessments will be conducted via inpatient assessment 
(for subjects still hospitalized) or by telephone call (for subjects discharged).  
Part 2 (Randomized Double-Blind Period): 
Part 2 of the study will be initiated only upon recommendation from the DMC. Required criteria 
for initiation of Part 2 will include (1) no fatal/life-threatening SAEs thought possibly related to 
APL-9 by the DMC, and (2) no more than 1 subject requiring premature treatment 
discontinuation by the investigator due to AEs or abnormal laboratory tests. All subjects will 
receive SOC independent of their randomization. Approximately 60 subjects will be randomly 
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assigned in a 1:1 ratio to blinded treatment with either APL-9 or saline vehicle. Subjects will 
receive treatment with APL-9 or vehicle from Day 1 through Day 7, discontinuation of 
respiratory support (supplemental oxygen or mechanical ventilation), or hospital discharge, 
whichever occurs latest.  
Subjects may receive treatment beyond Day 7 if the DMC approves an extended treatment 
duration following the review of data from Part 1 or during the conduct of Part 2. The DMC may 
approve any extended treatment duration up to and including Day 21; extended treatment will be 
allowed only in subjects who still require respiratory support (oxygen supplementation or 
mechanical ventilation) at Day 7 with an improved PaO2/FiO2 ratio of at least 20 mm Hg from 
baseline if arterial blood gas (ABG) test results are available for comparison. If ABG test results 
are not available, an improvement in FiO2 of at least 4% in nonventilated patients (eg, those on 
nasal cannula) and 10% in mechanically ventilated patients is needed. FiO2 should be weaned 
following the site’s protocol to keep oxygen saturation at 89% or above. Treatment beyond 
Day 7 and through any DMC-approved extension will be at the discretion of the investigator. 
Treatment beyond Day 7 and up to and including any DMC-approved extension will be at the 
discretion of the investigator.  
Follow-up safety assessments for each subject will be collected 30 days following the last dose 
of study treatment (up to and including Study Day 51 with a +7-day window). Safety 
assessments may be performed any time during the 30-day follow-up period at the investigator’s 
discretion but are required 30 days after the last dose of study drug (up to and including Study 
Day 51 with a +7-day window). These assessments will be conducted via inpatient assessment 
(for subjects still hospitalized) or by telephone call (for subjects discharged). 
The DMC will perform safety and efficacy data reviews on an ongoing basis during Part 2. 
Two reviews will be required in Part 2: 
1. After the 10th subject reaches the approved treatment duration, discontinuation of 
respiratory support (oxygen supplementation or mechanical ventilation), or hospital 
discharge, whichever occurs latest 
2. After the 30th subject reaches the approved treatment duration, discontinuation of 
respiratory support (oxygen supplementation or mechanical ventilation), or hospital 
discharge, whichever occurs latest 
If the DMC approves an extended treatment period following Part 1 or at any time through the 
conduct of Part 2, the DMC’s safety and efficacy data reviews will be initiated when the 10th 
and 30th subjects reach the approved extended treatment duration, discontinuation of respiratory 
support (oxygen supplementation or mechanical ventilation), or hospital discharge, whichever 
occurs latest. For example, if, following Part 1, the DMC approves treatment up to and including 
Day 14 in Part 2, the DMC will be required to review safety and efficacy after the first 
10 subjects reach Day 14 of treatment, discontinuation of respiratory support (oxygen 
supplementation or mechanical ventilation), or hospital discharge, whichever occurs latest. 
Enrollment will not be suspended during the DMC reviews. 
7.2. 
Scientific Rationale for Study Design 
This study is designed to evaluate the safety of APL-9 in subjects with respiratory failure due to 
COVID-19, the disease caused by SARS-CoV-2 infection. Secondary objectives include 
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assessments of efficacy of APL-9 (evaluating survival, length of hospital admission, and lung 
function), APL-9 PK results, and the effect of APL-9 on complement activation biomarkers.  
This study is being executed during a worldwide outbreak of COVID-19 that has resulted in 
capacity issues at many medical facilities. Additionally, the highly contagious nature of 
COVID-19 (compounded by a shortage of personal protective equipment) has caused concerns 
about the safety of health care providers caring for these seriously sick patients. Consequently, 
this study is designed to minimize any additional burden on clinical sites, including minimizing 
the number of assessments and interventions that the study will require in addition to SOC, while 
still ensuring the safety of subjects. 
The first portion of this 2-part study will entail initial DMC review and confirmation of product 
safety in 6 subjects under open-label treatment conditions. The second part will be a double-
blind, vehicle-controlled comparison of safety and efficacy. The investigational product (APL-9 
in saline vehicle for infusion) and reference product (vehicle control) will be prepared by 
unblinded pharmacists and will be indistinguishable to blinded study personnel to limit bias in 
study assessments. Either APL-9 or vehicle control will be administered as add-on therapy to 
SOC. Most interventions and assessments may be accomplished in conjunction with SOC, 
without requiring additional hospital visits or resources. 
Subjects with active bacterial, fungal, or parasitic infection are excluded, and enrolled and 
treated subjects will also receive treatment with a broad-spectrum antibiotic to prevent the 
theoretical risk of bacterial infections due to complement inhibition. A DMC will conduct 
periodic reviews of safety and efficacy data to ensure the safety of study subjects and to advise 
the sponsor on futility. 
7.3. 
Justification for Dose 
A single bolus infusion of 180 mg of APL-9 followed by continuous infusion of 360 mg/day will 
be tested in this study. This will result in an initial dose of 540 mg of APL-9 in the first 24 hours 
of dosing (followed by 360 mg/day on all subsequent days). This dose and higher doses were 
well tolerated in a previous study in healthy volunteers and demonstrated comparable PK and 
complement inhibition to that in prior cynomolgus monkey studies. More detailed information 
can be found in the APL-9 Investigator’s Brochure. 
The purpose of this dosing scheme is to achieve rapid complement inhibition by APL-9 upon 
initiation of treatment, followed by a regimen selected to keep the complement system 
consistently suppressed for the duration of study drug administration. Discontinuation of dosing 
is expected to restore normal complement activity within 24 hours.  
7.4. 
End of Study Definition 
A subject is considered to have completed the study if all obtainable study assessments, 
including those at the day of discharge from the hospital and during follow-up, have been 
collected. 
The end of the study is defined as the date of the safety follow-up assessment 30 days after the 
last dose of study drug (up to and including Study Day 51 with a +7-day window) for the last 
subject in the study. 
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7.5.
Study Design and Schedule of Assessments
Figure 1:  
Study Schema—Part 1
Subjects admitted, consented, screened, enrolled 
 
 
Open-label treatment with APL-9 + SOC
(N = 6)
 
 
Treatment for 7 days 
(or to resolution of ARDS)
 
 
Safety follow-up 
(30 days after last study treatment [with a +7-day window]) 
If subject is still hospitalized: inpatient follow-up 
If subject is discharged: phone follow-up 
 
 
DMC safety review 
 
 
DMC recommendations:
(1) Initiate Part 2 of study (yes/no) 
(2) Determine whether, for Part 2 duration of study, treatment can be extended beyond 
Day 7 (up to and including Day 21; treatment may be extended only for subjects who still 
require respiratory support (oxygen supplementation or mechanical ventilation) at Day 7 
with at least a 20-mm Hg increase in PaO2 from baseline). 
Required criteria for initiation of Part 2 will include (1) no fatal/life-threatening SAEs 
thought possibly related to APL-9 by the DMC and (2) no more than 1 subject requiring 
premature treatment discontinuation by the investigator due to AEs or abnormal laboratory
tests. 
Abbreviations: ARDS = acute respiratory distress syndrome; AEs = adverse events; DMC = data monitoring 
committee; PaO2 = partial pressure of oxygen; SAEs = serious adverse events; SOC = standard of care. 
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Figure 2: 
Study Schema—Part 2 
DMC recommendation to initiate Part 2 of study 
Subjects admitted, consented, screened, enrolled
Randomization 1:1 
(N = 60) 
Note: Two DMC reviews will occur: (1) after first 10 subjects reach the approved treatment 
duration, discontinuation of respiratory support, or hospital discharge, whichever occurs latest; and
(2) after the first 30 subjects reach the approved treatment duration, discontinuation of respiratory 
support, or hospital discharge, whichever occurs latest. The DMC may recommend changes to the 
protocol, including treatment extension up to and including 21 days for eligible subjects. 
Enrollment will not be suspended during DMC reviews.
 
 
APL-9 + SOC 
(n  30) 
 
Vehicle + SOC 
(n  30)
 
 
Treatment for 7 days*
*Subjects are eligible to continue treatment for up to and including 21 days if they still require 
respiratory support at Day 7 with an improved PaO2/FiO2 ratio of at least 20 mm Hg from baseline 
if ABG test results are available for comparison. If ABG test results are not available, an 
improvement in FiO2 of at least 4% in nonventilated subjects (eg, those on nasal cannula) and 10% 
in mechanically ventilated subjects is needed. FiO2 should be weaned following the site's protocol 
to keep oxygen saturation at 89% or above. Treatment beyond Day 7 and up to and including any 
DMC-approved extension will be at the discretion of the investigator per DMC recommendation 
and PI discretion (treatment may be modified at any point during Part 2). 
 
 
Safety follow-up 
(30 days after last study treatment [with a +7-day window]) 
If subject is still hospitalized: inpatient follow-up 
If subject is discharged: phone follow-up 
(Safety assessments may be performed at any time during the 30-day follow-up period at PI’s 
discretion but are required 30 days after last dose of study drug [up to and including Study Day 51 
with a +7-day window]) 
Abbreviations: ABG = arterial blood gas; DMC = data monitoring committee; FiO2 = fraction of inspired oxygen; 
PaO2 = partial pressure of oxygen; PI = primary investigator; SOC = standard of care. 
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Table 1: 
Schedule of Assessments 
 
Study Day(s)a 
Part 1 and Part 2a 
Part 2 only a
Part 1 and Part 2a
List of activities/assessments 
Screening/baseline 
–7 to 1b 
2 
3 4 5 
6 
7 
8-10 
11 12-14 15 16-21 
EOT and 
discharge 
daya,n 
Safety follow-
up assessmenta 
Up to and 
including 
Study  
Day 51 (+7)
Informed consentb
X
Inclusion/exclusionb 
X
SARS-CoV-2 confirmationc
X
Medical historyl
X
Demographics
X
eGFR/ALT
X
Serum pregnancy test
X
Height/body weight/BMId
X
Randomization (Part 2 only)
X
Study drug administrationa
X
X
X X X
X
X
X
X
X
X
X
X
Discharge card dispensatione
X
SAFETY ASSESSMENTS
Vital signs f
X
X
X X X
X
X
X
X
X
X
X
X
ECGf
X
X
X X X
X
X
X
X
X
X
X
X
SOFA scoreg
X
X
X
X
X
X
X
Clinical laboratory testsh
X
X
X
X
X
X
X
Viral RNA or viral antigen assessmentk
X
X
X
X
Radiograph/CT scan (pulmonary consolidation)
X
X
X
Concomitant medications and proceduresi
X
X
X X X
X
X
X
X
X
X
X
X
X
Infusion site reactionsj
X
X
X X X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X X X
X
X
X
X
X
X
X
X
X
PHARMACODYNAMIC AND PHARMACOKINETIC ASSESSMENTS
PK (APL-9)/PD (complement, coagulation, and 
inflammation) 
X 
X 
X 
X 
X 
X 
X m
Abbreviations: ABG = arterial blood gas; AE = adverse event; ALT = alanine aminotransferase; ARDS = acute respiratory distress syndrome; BMI = body mass 
index; CT = computed tomographic; DMC = data monitoring committee; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOT = end-
of-treatment visit; FiO2 = fraction of inspired oxygen; GCS = Glasgow Coma Scale; ICU = intensive care unit; PaO2 = partial pressure of oxygen; 
PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
SOFA = Sequential Organ Failure Assessment; SpO2 = peripheral oxygen saturation. 
 
 
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a Dosing must occur on Day 1, on the same day as randomization. The duration of subject participation in this trial may be variable. In Part 1, subjects may 
receive open-label treatment through Day 7 or resolution of ARDS (whichever occurs earlier). A DMC will review safety data from Part 1 and determine 
whether Part 2 can be initiated and whether Part 2 treatment can be extended beyond Day 7. Required criteria for initiation of Part 2 will include (1) no 
fatal/life-threatening SAEs thought possibly related to APL-9 by the DMC, and (2) no more than 1 subject requiring premature treatment discontinuation by 
the investigator due to AEs or abnormal laboratory tests. In Part 2, dosing may be extended only in subjects who still require respiratory support (oxygen 
supplementation or mechanical ventilation) at Day 7 with an improved PaO2/FiO2 ratio of at least 20 mm Hg from baseline if ABG test results are available for 
comparison. If ABG test results are not available, an improvement of FiO2 of at least 4% in nonventilated subjects (eg, those on nasal cannula) and 10% in 
mechanically ventilated subjects is needed. FiO2 should be weaned following the site’s protocol to keep oxygen saturation at 89% or above. Treatment beyond 
Day 7 and through any DMC-approved extension will be at the discretion of the investigator. In Part 2, subjects will receive treatment up to and including the 
DMC-approved treatment duration, discontinuation of respiratory support (oxygen supplementation or mechanical ventilation), or hospital discharge 
(whichever occurs latest). Through Part 2, the DMC may review efficacy and safety data and recommend changes to the study conduct on an ongoing basis, 
but it will be required to review efficacy and safety data after the 10th and 30th subjects reach the DMC-approved treatment duration, discontinuation of 
respiratory support, or hospital discharge (whichever occurs latest). Enrollment will not be suspended during the DMC reviews. Subjects who reach the end of 
the approved treatment duration, discontinuation of respiratory support, or hospital discharge (whichever occurs latest) must be assessed as indicated in the 
EOT and discharge day column (for example, a subject who reaches the end of the approved treatment and achieves discontinuation of respiratory support on 
Day 6 should be evaluated with a radiograph or CT scan even though it is not indicated as a Day 6 assessment). All subjects will be followed up at the safety 
follow-up assessment 30 days after last study treatment (up to and including Study Day 51 with a +7-day window), either in person (for subjects still 
hospitalized) or by phone (for subjects who have been discharged). 
b Fully eligible subjects can have screening assessments on the same day as baseline, which is defined as the day of initial study drug treatment. 
c Confirmation of SARS-CoV-2 infection may be completed more than 7 days before baseline. Presence of SARS-CoV-2 viral RNA or viral antigen may be 
detected in respiratory specimens (collected using nasopharyngeal or oropharyngeal swabs) with a qualitative nucleic acid amplification test (such as reverse 
transcriptase polymerase chain reaction), viral antigen test, or other diagnostic method that is authorized, cleared, or approved by the US Food and Drug 
Administration or equivalent authority for SARS-CoV-2 viral detection. Note: Serology-based antibody tests do not detect presence of virus and therefore are 
not considered diagnostic for active infection and cannot be used for study eligibility screening or for subsequent SARS-CoV-2 assessments. 
d Height/weight can be by subject assertion. 
e Discharged subjects who are followed up by phone will be provided with emergency study cards that include a list of symptoms associated with infections. The 
study card also guides subjects with instructions to contact their study physicians or seek emergency medical care if they experience any of the listed 
symptoms. 
f For continuous variables, the worst observed daily value will be recorded. Vital signs and ECG must be collected between the administration of the loading 
dose of study treatment and the initiation of the maintenance dose. 
g SOFA score variables (PaO2/FiO2 ratio or SpO2/FiO2 ratio, platelets, bilirubin, hypotension/vasopressor use, GCS score, creatinine) are detailed in 
Section 11.1.1 and Appendix 1. 
h A list of laboratory assessments is provided in Section 11.1.8. Blood will be collected 3 times on Day 1: (1) once prior to administration of the APL-9 bolus, 
(2) once as soon as possible following the bolus (within 5-10 minutes) prior to the continuous infusion, and (3) once at 2 hours after the beginning of the 
continuous infusion. Following that, assessments should be collected within the time frame of each calendar day. The use of silica reagents in coagulation 
panels should be avoided in subjects treated with APL-9. 
i The concomitant procedures include recording the day that the subject was admitted to the ICU (or ICU-type environment), use of ventilatory support, use of 
oxygen therapy, date of ICU discharge, date of hospital discharge, and survival. The time and date of any changes to concomitant medications and procedures 
are to be recorded at the days indicated in the schedule of assessments. In case of early hospital discharge, the data is collected via phone interviews. 
 
 
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j Infusion-related reactions that occur during the administration of the 50-mL loading dose should be treated as follows: For mild infusion-related reactions: The 
50-mL bag infusion time should be increased from 10 min to 20-40 min and the reaction should be monitored. Treatment with diphenhydramine may be 
required. The infusion time of the 250-mL bag should not be increased. For severe or persistent mild infusion-related reactions (instances in which the subject’s 
symptoms do not respond to the increased infusion time), treatment should be discontinued, and the institution’s emergency hypersensitivity protocol should be 
employed. Refer to the procedure for handling infusion-related reactions in Section 9.1.1. 
k Confirmation of SARS-CoV-2 infection for screening may be completed more than 7 days before baseline.
l Vaccination history should be attempted to be collected as a component of medical history.
m A PK/PD assessment will be done on the last day of treatment. If EOT and discharge day visit are on different days, a PK/PD sample will be collected on the 
discharge day as an unscheduled visit.  
n If EOT and day of discharge visit are on different days, perform EOT assessments on the last day of treatment and repeat on the day of discharge as an 
unscheduled visit. Perform/record vital signs, ECG, concomitant medications/procedures, infusion site reactions, and AEs daily up to and including day of 
discharge. After EOT, record as unscheduled visits. 
 
 
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8.
STUDY POPULATION
8.1. 
Subject Inclusion Criteria (Part 1 and Part 2) 
A subject must meet all the following criteria for enrollment: 
1. At least 18 years of age at time of informed consent.  
2. Diagnosis of active SARS-CoV-2 infection. Presence of SARS-CoV-2 viral RNA or viral 
antigen may be detected in respiratory specimens (collected using nasopharyngeal or 
oropharyngeal swabs) with a qualitative nucleic acid amplification test (such as RT-PCR) 
or viral antigen test or other diagnostic method that is authorized, cleared, or approved by 
the US Food and Drug Administration (or equivalent local authority) for SARS-CoV-2 
viral detection. Note: Serology-based antibody tests do not detect presence of virus, and 
therefore are not considered diagnostic for active infection and cannot be used for study 
eligibility screening or for subsequent SARS-CoV-2 assessments. 
3. Have respiratory failure requiring oxygen supplementation or have either invasive or 
noninvasive mechanical ventilation with PaO2/FiO2 ratio >100 mm Hg. Respiratory 
failure cannot be fully explained by cardiac failure or fluid overload. 
a. The ABG test result is used to determine the PaO2/FiO2 ratio. An ABG test should be 
performed for every subject, but if an ABG result cannot be obtained, the peripheral 
oxygen saturation (SpO2) can be measured and the SpO2/FiO2 ratio can be used.  
b. If the SpO2/FiO2 ratio is used for inclusion in the study, it must be >89. See 
Appendix 1 for more details. 
4. Written informed consent for study participation must be provided by the subject (or 
legally authorized representative) prior to any study-related procedures. 
5. Subject (or legally authorized representative) is willing and able to comply with study 
procedures and assessments, including imaging assessments and venous blood sample(s) 
per protocol. 
6. Each female subject of childbearing potential must have a negative serum pregnancy test 
at screening and must agree to use protocol-defined methods of contraception from 
screening through at least 90 days after receiving the last dose of APL-9. 
7. Male subjects must agree to use protocol-defined methods of contraception and agree to 
refrain from donating semen from screening through at least 90 days after receiving the 
last dose of APL-9. 
Acceptable methods of contraception are described in Section 11.2.8. Contraceptive use by men 
or women should be consistent with local regulations regarding the methods of contraception for 
those participating in clinical studies. 
8.2. 
Subject Exclusion Criteria (Part 1 and Part 2) 
Subjects are excluded from the study if any of the following criteria apply: 
1. Female subjects being pregnant or breastfeeding 
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2. Active bacterial, fungal, or parasitic infection
3. History of neuromuscular degenerative disease (eg, amyotrophic lateral sclerosis, 
Duchenne muscular dystrophy, or multiple sclerosis) 
4. Current participation in a clinical study with an investigational drug or biologic. NOTE: 
Participation in studies with the following therapies is NOT excluded: 
a. Therapies approved (indicated) for COVID-19 by the applicable health authority 
b. Therapies with emergency use authorization for COVID-19 by the US Food and Drug 
Administration or equivalent authorization by the applicable health authority 
c. Therapies approved (indicated) by the applicable health authority and used for 
COVID-19 as part of standard care 
5. Treatment with immune checkpoint inhibitors or other immunomodulators within 
3 months prior to study enrollment (however, treatment with convalescent plasma, 
steroids, IL-6 inhibitors, and antiviral agents is NOT excluded) 
6. Subjects who have, at screening, been on mechanical ventilation for >7 days 
7. Evidence of kidney failure AND liver failure at screening (estimated glomerular filtration 
rate <45 mL/min/1.73 m2 and alanine aminotransferase level >5× the upper limit of 
normal, as assessed by the local laboratory) 
8. Subjects with a hereditary complement deficiency 
8.3. 
Lifestyle Considerations 
Because of the nature of the study, no lifestyle considerations are applicable. 
8.4. 
Screening Failures 
Sites may initiate screening procedures prior to a subject’s diagnosis of respiratory failure or 
ARDS. Confirmation of SARS-CoV-2 infection may be completed more than 7 days before 
baseline. All other inclusion and exclusion criteria must be met within –7 days of baseline. 
Screening failure is defined as the situation of a subject who consents to participate in the clinical 
study but does not receive study treatment. A minimal set of screening failure information is 
required to ensure transparent reporting of screening failures to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screening failure details, eligibility 
criteria, and any SAEs. 
Subjects may be rescreened with approval from the sponsor. 
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9.
TREATMENT OF SUBJECTS
9.1. 
Study Interventions 
All subjects participating in this study independent of randomization shall receive the 
institutional SOC at the discretion of the investigator, to treat their conditions including (but not 
limited to) supplemental oxygen, mechanical ventilation, fluid management, and required 
medication as provided by the hospital and allowed by the protocol. 
APL-9 is supplied in 6-mL glass vials. Changes to sponsor-supplied packaging prior to dosing 
may not occur without full agreement, in advance, by Apellis Pharmaceuticals, Inc. 
Labels containing study information and pack identification are applied to the investigational 
product containers. 
All investigational product is labeled with a minimum of the following: protocol number, dosage 
form (including product name and quantity in pack), route of administration, directions for use, 
storage conditions, batch number and/or packaging reference, the statements “For clinical trial 
use only” and/or “CAUTION: New Drug—Limited by Federal (or US) Law to Investigational 
Use,” and name and address of the sponsor. 
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy national, local, or institutional requirements but must not do any of the following: 
contradict the clinical study label, obscure the clinical study label, or identify the study subject 
by name. 
Additional labels may not be added without the prior full agreement of Apellis Pharmaceuticals, 
Inc. 
9.1.1. 
Study Drug Administration 
APL-9 is provided in sterile vials, each containing 180 mg of APL-9 in 6 mL buffer (30 mg/mL). 
Study drug infusion bags are prepared by an unblinded pharmacist at the study site by dilution of 
the study drug in isotonic saline for infusion and transferred to site personnel for administration 
to subjects according to their assigned randomization numbers. Two types of infusion bags 
containing APL-9 will be prepared: 
 50-mL bag containing 1 vial of APL-9 (ie, 180 mg of APL-9 in 50 mL) 
 250-mL bag containing 1 vial of APL-9 (ie, 180 mg of APL-9 in 250 mL) 
Dosing of subjects receiving APL-9 either as open-label treatment or by random, blinded 
assignment must occur on Day 1, on the same day as randomization, and will be initiated with an 
IV infusion of 180 mg APL-9 in 50 mL of saline over a 10-minute period, followed within 
1 hour by continuous infusion of 180 mg APL-9 in 250 mL saline at the rate of 15 mg/h 
(approximately 21 mL/h) until the end of study drug administration as follows: 
 Part 1: at Day 7 or until or resolution of ARDS (PaO2/FiO2 ratio >300 mm Hg), 
whichever occurs earlier 
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 Part 2: at Day 7 or up to and including the approved treatment duration, 
discontinuation of respiratory support (supplemental oxygen or mechanical 
ventilation), or hospital discharge, whichever occurs latest 
This results in the infusion of two 250-mL bags, each containing 180 mg of APL-9, every 
24 hours. 
Dosing of subjects randomly assigned to vehicle control must occur on Day 1, on the same day 
as randomization, and will be initiated with an IV infusion of 50 mL of saline over a 10-minute 
period followed immediately (and up to and including within 1 hour) by continuous infusion of 
approximately 21 mL of saline per hour until the end of study drug administration at Day 7 (or 
approved treatment extension), discontinuation of respiratory support (oxygen supplementation 
or mechanical ventilation), or hospital discharge, whichever occurs latest. This results in the 
infusion of 2 bags of 250 mL saline every 24 hours.  
Research nurses or other appropriately qualified personnel will administer the IV infusions. 
The pharmacists and investigator can change the size of the infusion bags in the event that 
50-mL and 250-mL isotonic saline bags are in short supply if: 
 the infusion rates of a 180-mg loading dose of APL-9 in the initial 10 minutes and 
15 mg/h thereafter to subjects receiving APL-9 are maintained and  
 vehicle-only bags of identical size and appearance are given to the vehicle control 
group.  
In the event that isotonic saline for infusion is not available, the pharmacists must contact Apellis 
Pharmaceuticals, Inc, to select an alternative vehicle. 
The treatments are intended to continue to either Day 7 or until the subject no longer requires 
respiratory support (oxygen supplementation or mechanical ventilation) or is discharged from the 
hospital (whichever occurs later), except upon allowance by the DMC and by investigator 
discretion to administer treatment up to and including Day 21 (Part 2 only; extended treatment 
will be allowed only in subjects who still require respiratory support at Day 7 with an improved 
PaO2/FiO2 ratio of at least 20 mm Hg from baseline if ABG test results are available for 
comparison. If ABG test results are not available, an improvement in FiO2 of at least 4% in 
nonventilated patients (eg, those on nasal cannula) and 10% in mechanically ventilated patients 
is needed. FiO2 should be weaned following the site’s protocol to keep oxygen saturation at 89% 
or above. Treatment beyond Day 7 and up to and including any DMC-approved extension will be 
at the discretion of the investigator. If treatment is interrupted for any reason for more than 
24 hours, treatment may not be resumed. 
A relapse of respiratory failure or ARDS due to COVID-19 must be reported as an AE. Under no 
circumstances can study drug be administered beyond the DMC-approved treatment window, 
and treatment may not be reinitiated if it is discontinued. 
The SOC to be used at each study site will be determined by the investigator. A recent guideline 
for the treatment of critically ill patients with COVID-19 has been published and should be 
considered (CDC 2020).  
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Infusion-related reactions that occur during the administration of the 50- mL loading dose should 
be treated as follows:  
For mild infusion-related reactions: The 50 mL bag infusion time should be increased 
from 10 min to 20-40 min and the reaction should be monitored. Treatment with 
diphenhydramine may be required. The infusion time of the 250-mL bag should not 
be increased. 
 For severe or persistent mild infusion-related reactions (instances in which the 
subject’s symptoms do not respond to the increased infusion time): treatment should 
be discontinued, and the institution’s emergency hypersensitivity protocol should be 
employed. 
9.1.2. 
Empiric Antibiotic Treatment for Possible Infection 
Body temperature, vital signs, relevant blood parameters, and bacterial cultures will be 
monitored regularly throughout the study to assess for signs of secondary bacterial infections. All 
enrolled subjects will receive a broad-spectrum antibiotic during the treatment period to cover 
possible additional serious bacterial infections (see Section 9.5 for details). Subjects who are 
discharged prior to the allowable treatment duration will have follow-up conducted by phone and 
will be provided with emergency study cards that include a list of symptoms associated with 
infections. The study card also guides subjects with instructions to contact their study physician 
or seek emergency medical care in the event they experience any of the listed symptoms. 
9.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigational product should be stored frozen at a nominal temperature of –20 °C. 
Temperature monitoring is required at the investigator site (or documented storage 
location) to ensure that the investigational product is maintained within a defined and 
maintained temperature range.
2. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported 
and resolved before use of the study intervention. 
3. Only subjects enrolled in the study and assigned to active treatment may receive study 
drug and only authorized site staff may supply or administer study drug. All study drug 
must be stored in a secure, environmentally controlled, and monitored area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized 
site staff. 
4. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). Where allowed, the investigator 
may choose to delegate drug accountability responsibilities to a pharmacist or other 
appropriate individual.
5. Apellis Pharmaceuticals, Inc, or the clinical study sites may supply infusion sets and 
saline bags as required. Refer to the pharmacy manual for further details.
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6. All unused and used study drug vials should be retained at the study site until they are 
inventoried by the study monitor. All used, unused, or expired study drug vials will be 
returned to Apellis Pharmaceuticals, Inc, or its designee for destruction, and destruction 
will be documented, or if authorized, disposed of at the study site per the site’s standard 
operating procedures and documented. Please refer to the pharmacy manual for further 
guidance and information. 
7.  Please refer to the pharmacy manual for further guidance and information. 
9.3. 
Measures to Minimize Bias: Randomization and Blinding 
9.3.1. 
Randomization 
The first 6 subjects enrolled will be assigned to open-label APL-9 treatment. For the remaining 
60 subjects, approximately 30 subjects will be enrolled in each treatment arm for a total of 
approximately 60 subjects. Subjects will be randomly assigned (1:1) to receive either APL-9 in 
addition to SOC or vehicle control plus SOC. Randomization will be stratified by need of 
mechanical ventilation (yes vs no) and age (younger than 65 years vs at least 65 years). 
9.3.2. 
Blinding (Part 2 Only) 
All subjects or their legally assigned representatives, investigators, and all study personnel 
involved in the conduct of the study, including data management and biostatistics, will be 
blinded to treatment assignment. Study drug infusion bags are prepared by dilution of the study 
drug in isotonic saline for infusion by an unblinded pharmacist at the study site and transferred to 
site personnel for administration to subjects according to their assigned randomization number. 
Unblinded tables, figures, and listings will be provided to the DMC for review. An unblinded, 
independent biostatistician will be assigned to prepare the randomization schedule and unblinded 
tables, figures, and listings for the DMC. The unblinded statistician will not otherwise participate 
in study procedures. 
Unblinding is discouraged but will be permitted in a medical emergency that requires immediate 
knowledge of the subject’s assigned treatment. All subjects should be treated as though they are 
receiving APL-9. Emergency unblinding will be acceptable only if it affects the medical 
management of the subject. 
9.4. 
Treatment Compliance 
Subjects will receive study drug directly from the investigator or designee, under medical 
supervision. The date, time, and duration of each dose administered will be recorded in the 
source documents and in the electronic case report form (eCRF). If treatment is interrupted for 
any reason for greater than 24 hours, treatment may not be resumed.  
9.5. 
Concomitant Medications 
Any medications administered (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements), and all procedures performed within 4 weeks of screening will be 
recorded as prior medications and procedures. Oral history is acceptable from the subject or 
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caregiver. Medications administered and procedures performed from the time of informed 
consent through the end-of-treatment visit must be recorded as concomitant, along with: 
Reason for use
Dates of administration including start and end dates
Dosage information including dose and frequency 
All enrolled subjects will receive a broad-spectrum antibiotic during the treatment period to 
provide coverage for Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus 
influenzae unless contraindicated because of hypersensitivity or allergy. Treatment with 
antibiotics may be adjusted according to culture results and at the discretion of the investigator.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
9.5.1. 
Restricted and Prohibited Medications 
The use of any approved or investigational anticomplement therapy other than APL-9 is 
prohibited within 5 half-lives of that product prior to screening. Use of corticosteroids is 
permitted. Treatment with immune checkpoint inhibitors or other immunomodulators is 
prohibited during the study (however, treatment with steroids, IL-6 inhibitors, and antiviral
agents is NOT excluded). 
9.6. 
Intervention After the End of the Study 
There is no intervention following the end of the study. Any additional care provided to subjects 
after they complete or discontinue the study will be provided by the subjects’ personal physicians 
according to what is normally expected for their conditions. 
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10.
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
10.1. 
Discontinuation of Study Intervention 
Treatment with study drug (APL-9 IV or matching vehicle IV infusion) will terminate as 
follows: 
 Part 1: at Day 7 or until or resolution of ARDS (PaO2/FiO2 ratio >300 mm Hg), 
whichever occurs earlier 
 Part 2: at Day 7 or up to and including the approved treatment duration, discontinuation 
of respiratory support (supplemental oxygen or mechanical ventilation), or hospital 
discharge, whichever occurs latest 
In Part 2, the DMC may decide to allow treatment with study drug beyond Day 7. If allowed by 
the DMC, study drug infusions can be extended at the discretion of the investigator beyond 
Day 7 up to and including Day 21. In Part 2, dosing may be extended only in subjects who still 
require respiratory support (oxygen supplementation or mechanical ventilation) at Day 7 with a 
PaO2/FiO2 ratio improved by at least 20 mm Hg from baseline if ABG test results are available 
for comparison. If ABG test results are not available, an improvement of FiO2 of at least 4% in 
nonventilated patients (eg, those on nasal cannula) and 10% in mechanically ventilated patients 
is needed. FiO2 should be weaned following the site’s protocol to keep oxygen saturation at 89% 
or above. Treatment beyond Day 7 and up to and including any DMC-approved extension will be 
at the discretion of the investigator. However, study drug administration must end at the DMC-
allowed maximal time point or upon the subject’s discharge from the hospital. The time of 
transfer and termination of study drug treatment must be recorded in the subject’s medical 
records and eCRF. If treatment is interrupted for any reason for greater than 24 hours, treatment 
may not be resumed. 
In rare instances, it may be necessary for a subject to permanently discontinue study treatment 
(definitive discontinuation). The date of and reason for treatment discontinuation must be 
determined by the investigator and recorded in the subject’s medical record and on the 
appropriate eCRF. If it is determined that there was more than one reason for the discontinuation, 
each reason should be documented in the source document and the most clinically relevant 
reason, as determined by the investigator, should be entered on the eCRF (see also Section 10.2). 
Any subject who discontinues treatment early or is withdrawn from the study early because of a 
TEAE, whether serious or nonserious, will be followed up until the TEAE resolves (returns to 
normal or baseline values) or stabilizes or until it is judged by the investigator to no longer be 
clinically significant. 
If study treatment is definitively discontinued, the subject will remain in the study to be 
evaluated for safety. See the schedule of assessments (SoA) for data to be collected at the time of 
discontinuation of study treatment, discharge, and safety follow-up and for any further 
evaluations to be completed. 
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10.2.
Subject Discontinuation/Withdrawal From the Study
 A subject may withdraw from the study at any time at his/her own request (or at the 
request of his/her legal representative) or at the discretion of the investigator for 
safety, behavioral, compliance, or administrative reasons.  
 At the time of discontinuing from the study, if possible, an end-of-treatment visit 
should be conducted, as shown in the SoA. See the SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations to be 
completed. The subject will be permanently discontinued both from the study 
intervention and from the study at that time. 
 If the subject withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 Subjects who withdraw from the study may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
10.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up for failure to complete the safety follow-up 
assessment 30 days after the last dose of study drug (up to Study Day 51 with a +7-day window). 
The following actions must be taken if a subject fails to complete the required safety follow-up 
assessment 30 days after the last dose of study drug (up to Study Day 51 with a +7-day window): 
 The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of final study assessments, and 
ascertain whether the subject wishes to and/or should continue in the study. 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
 Subjects who continue to be unreachable will be considered to have withdrawn from 
the study. 
Closure of specific sites or of the study as a whole are described in Section 13.1.7. 
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11.
STUDY ASSESSMENTS AND PROCEDURES
 Day 1 is defined as the day upon which study treatment is first administered. 
The last predose assessments will be considered as baseline assessments. 
Study procedures and their timings are summarized in the SoA (Table 1). Protocol 
waivers or exemptions are not allowed. 
Significant safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine whether the subject should continue or 
discontinue study participation. 
 Adherence to the study design requirements, including those specified in the SoA 
(Table 1), is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 Procedures conducted as part of the subject’s routine clinical management and 
obtained before signing of the informed consent form (ICF) may be utilized for 
screening or baseline purposes provided that the procedures met the protocol-
specified criteria and were performed within the time frame defined in the SoA 
(Table 1). 
 The study end-of-treatment assessments are to be conducted at the end of treatment or 
on the day of hospital discharge, whichever occurs later. The posttreatment follow-up 
assessment, conducted 30 days after the last dose of study drug (with a +7-day 
window), may be conducted either in the hospital or by telephone so that subjects do 
not have to be exposed to the hospital environment after hospital discharge.  
 Discharged subjects will be provided with emergency study cards that include a list of 
symptoms associated with infections. The study card also guides subjects with 
instructions to contact their study physicians or seek emergency medical care in the 
event they experience any of the listed symptoms. 
11.1. 
Safety and Efficacy Assessments 
The safety and efficacy of APL-9 treatment will be assessed by objective endpoints and 
compared between treatment groups. These endpoints relate to AEs, overall hospitalization, use 
of mechanical ventilation and oxygen, assessments of organ failure, and overall survival. The 
SoA (Table 1) provides details of the scheduling of these assessments. 
Assessments to be performed during the study are described below and in the SoA (Table 1). 
Every effort should be made to ensure that the protocol-required assessments are completed as 
described. 
If deemed necessary, additional safety measurements will be performed at the discretion of the 
investigator.
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11.1.1. 
SOFA Score 
Organ failure status will be assessed using the SOFA score, which assesses 6 organ systems: 
respiration, coagulation, liver, cardiovascular, central nervous system, and renal (Ferreira et al. 
2001). A subject will be defined as being free of organ failure when the SOFA score is zero. The 
score will be assessed at baseline on Day 1 and as listed in the SoA based on worst daily values. 
The SOFA score variables to be assessed are: 
 PaO2/FiO2 ratio (mm Hg) or SpO2/FiO2 ratio—collected and entered into the database 
locally (see calculation instructions in Appendix 1) 
 Platelets × 103/µL—based on data provided by the local laboratory  
Bilirubin (µmol/L or mg/dL)—based on data provided by the local laboratory  
Hypotension/use of vasopressors—collected and entered into the database locally
Glasgow Coma Scale score—collected and entered into the database locally (see
Appendix 2) 
Creatinine (µmol/L or mg/dL)—based on data provided by the local laboratory
See Appendix 1 for additional information on calculating the SOFA score. 
11.1.2. 
Computed Tomographic Scans/Radiographs: Pulmonary Consolidation 
Pulmonary consolidation is defined as presence or absence of alveolar opacity observed in chest 
computed tomographic scans or radiographs in each of the 4 lung quadrants (left upper, left 
lower, right upper, and right lower), as determined by the investigator. 
11.1.3. 
Demographic/Medical History 
Relevant medical history will be recorded at screening. Investigators should document the 
occurrence, signs, and symptoms of the subject’s preexisting conditions, including all prior 
significant illnesses, up to and including 1 year before screening. Additional preexisting 
conditions present at the time when informed consent is given up to the time of first dosing are to 
be regarded as concomitant. Medical history will include alcohol consumption and smoking 
history, if applicable. Vaccination history should be attempted to be collected as a component of 
medical history. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 11.2.5. 
Additionally, demographic data will be collected for all subjects, as allowed per applicable 
regulations. 
11.1.4. 
Assessment of Kidney and Liver Failure 
Evidence of kidney and liver failure will be assessed at screening using the following 
parameters: 
 Estimated glomerular filtration rate <45 mL/min/1.73 m2 AND
 Alanine aminotransferase more than 5 times the upper limit of normal
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11.1.5. 
Vital Signs 
Vital signs (body temperature, respiration rate, heart rate, and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the SoA (Table 1). All vital 
signs will be measured after the subject has been resting in a sitting/prone position for at least 
5 minutes, except when they are supine or semireclined because of study procedures and/or AEs, 
or if deemed necessary by the investigator. Blood pressure measurements are to be taken in the 
same arm for the duration of the study. 
Vital signs measurements will be repeated if clinically significant or if machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be repeated 
at the investigator’s discretion. Any confirmed, clinically significant changes in vital signs 
measurements must be recorded as AEs. 
11.1.6. 
Weight and Height 
Body weight and height will be noted at screening and can be as estimated by the subject. 
11.1.7. 
Infusion Site/Pump Safety Assessment 
Study drug will be administered by trained and qualified site staff. All clinically significant 
findings related to injection/infusion procedures will be recorded as AEs. 
11.1.8. 
Clinical Laboratory Tests 
Laboratory test samples (Table 2) are to be obtained at designated visits as detailed in the SoA 
(Table 1). Blood will be collected 3 times on Day 1: (1) once prior to administration of the 
APL-9 bolus, (2) once as soon as possible following the bolus (within 5-10 minutes) prior to the 
continuous infusion, and (3) once at 2 hours after the beginning of the continuous infusion. 
Following that, assessments should be collected within the time frame of each calendar day. 
Blood samples will be analyzed at one or more central (or local) laboratory facilities, as defined 
in the laboratory manual. All laboratory reports must be reviewed, signed, and dated by the 
investigator. A legible copy of all reports must be filed with both the subject’s eCRF and medical 
record (source document) for that visit. Any laboratory test result considered by the investigator 
to be clinically significant should be considered an AE (clinically significant AEs include those 
that at minimum require an intervention). Clinically significant abnormal values occurring during 
the study will be followed up until repeat test results return to normal, stabilize, or are no longer 
clinically significant. 
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate laboratory reference manual prior to study initiation. 
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Table 2: 
Clinical Laboratory Tests
PARAMETERS ANALYZED AT THE LOCAL LABORATORY 
Blood/serum/plasma samples 
Hematology
ABG
Hb 
Hematocrit 
Platelet count 
RBC count 
Reticulocyte count 
Schistocytes 
WBC count with differential 
 
Coagulation panela
D-dimer 
Fibrinogen 
INR 
PT 
Serum chemistry
Albumin 
ALT 
ALP 
AST 
Bicarbonate 
Bilirubin (total, direct, and indirect) 
BUN 
C-reactive protein (CRP) 
C3 and C4 
Calcium 
Chloride 
Creatinine 
Creatine kinase  
Cystatin C 
eGFR 
Ferritin
Glucose 
Haptoglobin
HDL
Iron 
LDH 
LDL 
Phosphorus 
Potassium 
Pregnancy 
Sodium 
Total cholesterol 
Total protein 
Triglycerides 
Troponin 
Uric acid 
Urine samples 
Urinalysis  
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopic examination of urine sediment, including for presence of 
RBCs, WBCs, and casts, will be performed on all abnormal urinalyses 
 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Respiratory swab
Viral RNA or viral antigen assessment
SARS-CoV-2 
PARAMETERS ANALYZED AT CENTRAL/SPECIALTY LABORATORIES 
Plasma samples 
Complement biomarkers 
Bb, C3a, C4a, C5a, TCC
 
Inflammation biomarkers
 
IL-
 
IL-6 
 
 
 
 
Serum samples 
PK concentrations 
AH50 
Abbreviations: ABG = arterial blood gas; ACR = albumin-to-creatinine ratio; AH50 = alternative complement pathway 
hemolytic activity; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
 
 AST = aspartate aminotransferase; BCR = B-2 microglobulin:creatinine ratio; BUN = blood urea nitrogen; 
eGFR = estimated glomerular filtration rate; Hb = hemoglobin; HDL = high-density lipoprotein; INR = international 
normalized ratio; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; PK = pharmacokinetics; PT = prothrombin 
time; RBC = red blood cell; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TCC = terminal complement 
complex; TNF  = tumor necrosis factor ; WBC = white blood cell. 
a The use of silica reagents in coagulation panels should be avoided in subjects treated with APL-9. 
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11.1.8.1. Pregnancy Screening 
For women of childbearing potential, a serum pregnancy test will be performed at screening. 
Subjects with a positive test result will be excluded or discontinued from the study.  
11.2. 
Adverse Events 
11.2.1. 
Definition of AEs
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered drug related. An AE can, therefore, be any unfavorable and unintended 
sign, including a clinically significant abnormal laboratory finding, symptom, or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the investigational product. 
Adverse events can be spontaneously reported by the subject and/or in response to an open 
question from the study personnel or revealed by observation and will be recorded during the 
study at the investigational site. All identified AEs must be recorded and described on the 
appropriate AE or SAE page of the eCRF.  
Fluctuating or nonsignificant changes in laboratory values do not necessarily qualify for AE 
reporting. If these changes in laboratory values are assessed as clinically significant and/or lead 
to discontinuation of administration of investigational product, these should be reported as an 
AE. If these laboratory values are linked to a diagnosis, only the diagnosis should be reported as 
AE. 
11.2.2. 
Serious Adverse Events 
An SAE is any AE or suspected adverse reaction that, in the view of either the investigator or 
sponsor, results in any of the following outcomes: death; life threatening; inpatient 
hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity 
or substantial disruption of the ability to conduct normal life functions; or a congenital 
anomaly/birth defect. 
Important medical events that may not result in death, be life threatening*, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the subject and may require medical/surgical intervention to prevent one of the 
outcomes listed in the above definition. 
Examples of important medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or the development of drug dependency or drug abuse. 
*Life threatening is defined as an AE or suspected adverse reaction, which, in the view of either
the investigator or sponsor, places the subject at immediate risk of death as it occurred. It does
not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
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11.2.3. 
Unexpected Adverse Events 
An AE is considered “unexpected” if it is not listed in the Reference Safety Information section
of the investigator’s brochure in effect at that time of event onset. 
11.2.4. 
Evaluation of AEs 
All AEs that occur during this study will be recorded; however, only TEAEs will be analyzed 
and reported in the study report. The investigator or their medically qualified designee will 
review each event and assess its relationship to study drug treatment (not related, unlikely to be 
related, possibly related, or definitely related). The date and time of onset, time relationship to 
study drug dosing, duration, and outcome (recovered/resolved, recovered/resolved with sequelae, 
recovering/resolving, not recovered/not resolved, or fatal) of each event will be noted. 
Table 3 should be considered when evaluating the relationship of AEs/SAEs to study treatment. 
Table 3:  
Definitions of Adverse Event Relatedness 
Classification 
Definition 
Definitely 
related 
Strong evidence of a causal relationship; the influence of other factors is unlikely 
Possibly related 
Some evidence of a causal relationship, but other factors may have caused or 
contributed to the event (eg, another illness or concomitant treatment) 
Unlikely to be 
related 
A causal relationship is not a reasonable possibility, but it cannot be completely 
ruled out with the available evidence 
Not related 
No evidence of a causal relationship 
If the AE/SAE is determined to be possibly or definitely related to the study drug, the event will 
be considered to be related to the study drug for the purposes of expedited regulatory reporting.
Table 4 presents the definitions that should be considered when evaluating the severity of AEs 
and SAEs.  
Table 4:  
Severity of Events
Severity  
Definition/description 
Mild 
Event results in mild or transient discomfort, not requiring intervention or 
treatment; does not limit or interfere with daily activities (eg, insomnia, mild 
headache). 
Moderate 
Event is sufficiently discomforting so as to limit or interfere with daily activities; 
may require interventional treatment (eg, febrile illness requiring oral 
medication). 
Severe 
Event results in significant symptoms that prevent normal daily activities; may 
require hospitalization or invasive intervention (eg, anemia resulting in blood 
transfusion). 
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11.2.5. 
Recording AEs 
Adverse events and SAEs will be collected from the signing of the consent form up to and 
including the safety follow-up assessment 30 days after the last dose of study drug (up to Study 
Day 51 with a +7-day window). 
Any events that occur prior to dosing will be categorized as pretreatment events; events 
occurring after dosing will be recorded as TEAEs (start date of dosing and, therefore, 
categorization of the event will be dependent on randomization assignment). 
For each AE, the investigator will evaluate and report the onset date (and time if applicable), 
resolution date (and time if applicable), intensity, causality, action taken, serious outcome, and 
whether or not it caused the subject to discontinue the study. 
If possible, the outcome of any AE that caused permanent discontinuation or was present at the 
end of the study should be reported, particularly if the AE was considered by the investigator to 
be related to the investigational product. Subjects experiencing AEs that cause interruption or 
discontinuation of investigational product, or those experiencing AEs that are present at the 
safety follow-up assessment (30 days after the last dose of APL-9), up to and including Study 
Day 51 (+7) should receive follow-up as appropriate. 
All SAEs must be reported to the sponsor/Apellis Safety via eCRF immediately and within 
24 hours of becoming aware of the event, whether or not the event is deemed treatment-related. 
If the electronic data capture system is not operational (or for paper-based study[ies]), the site 
must complete the paper SAE form and email to 
, also within 24 hours of 
becoming aware of the event. The reported information submitted as a paper SAE must be 
entered into the electronic data capture system once it becomes operational. 
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA). If known, the diagnosis of the underlying illness or disorder should be 
recorded, rather than its individual symptoms. 
11.2.6. 
Reporting AEs 
The sponsor has the responsibility to inform concerned health authorities, ethics committees, and 
investigators about suspected unexpected serious adverse reactions in line with Good Clinical 
Practice (GCP) guidance and applicable regulatory requirements. 
If required, specific SAEs should be reported to the concerned ethic committees in compliance 
with local requirements. 
11.2.7. 
Pregnancy 
Although pregnancy is not an AE, all pregnancies and suspected pregnancies (including a 
positive pregnancy test regardless of age or disease state) occurring with a female subject or the 
female partner of a male subject must be followed to conclusion to determine their outcome and 
are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Apellis 
Safety within 24 hours of the investigator’s awareness using the paper Pregnancy Report Form. 
The Pregnancy Report Form shall be signed and dated by the investigator and submitted via 
email to 
. 
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The investigator must follow the subject until completion of the pregnancy and must report the 
outcome of the pregnancy (eg, delivery, termination, etc) and neonatal status up to and including 
12 months post delivery. An abnormal outcome is defined as any pregnancy that results in the 
birth of a child with persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions (formerly referred to as disabilities), congenital anomalies, or birth 
defects. In the event of an abnormal outcome, an SAE Report Form will be required. 
11.2.8. 
Acceptable Methods of Contraception
Approved methods of contraception include: 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
oral, intravaginal, or transdermal
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, or implantable 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the trial subject who is a woman of childbearing potential and that the 
vasectomized partner has received medical assessment of surgical success) 
 Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with study treatments) 
 Male condom with or without spermicide (for male study subjects with female 
partners of childbearing potential only)
Not all methods of contraception may be available in all of the countries in which this study is 
being conducted. 
Note: Sexual abstinence is accepted only when it is the preferred and usual lifestyle of the 
subject. 
Subjects must agree to use an approved method of contraception during the study and for 90 days 
after their last dose of study drug. Male subjects will be counseled to avoid donating semen 
during the time between the first screening and the final end-of-treatment visit and for 90 days 
after the last dose of study drug. 
11.3. 
Drug Abuse, Misuse, Overdose, and Medication Error 
Occurrences of events of drug abuse, drug misuse, drug overdose, and medication error must be 
reported to Apellis Safety. 
Abuse of a medicinal product: Persistent or sporadic, intentional excessive use of medicinal 
products, which is accompanied by harmful physical or psychological effects. 
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Misuse: Intentional and inappropriate use of a medicinal product not in accordance with the 
prescribed or authorized dose, route of administration, and/or the indication(s) or not within the 
legal status of its supply. 
Overdose: Administration of a quantity of study drug given per administration or per day, which 
is above the assigned dose. 
Medication Error: An error made in prescribing, dispensing, administration and/or use of the 
study drug. Medication errors are reportable to the sponsor as defined below: 
 The dispensing, administration, and/or use of the unassigned study drug. 
 The administration and/or use of an expired study drug. 
All AEs or SAEs associated with drug abuse, drug misuse, drug overdose, or medication error 
must be reported as appropriate.  
11.4. 
SARS-CoV-2 Viral RNA/Viral Antigen Assessment 
Presence of SARS-CoV-2 viral RNA or viral antigen will be detected in respiratory specimens 
(collected using nasopharyngeal or oropharyngeal swabs) with a qualitative nucleic acid 
amplification test (such as RT-PCR) or viral antigen test or other diagnostic method that is
authorized, cleared, or approved by the US Food and Drug Administration (or equivalent local 
authority) for SARS-CoV-2 viral detection. Serology-based antibody tests do not detect the 
presence of virus and therefore are not considered diagnostic for active infection and cannot be 
used for study eligibility screening or for subsequent SARS-CoV-2 assessments. 
11.5. 
Pharmacokinetics 
The exposure of subjects to APL-9 will be evaluated in serum from blood collected in a serum 
separator tube. Two serum aliquots of at least 0.5 mL will be stored at –70 °C and shipped on dry 
ice. Blood will be collected 3 times on Day 1: (1) once prior to administration of the APL-9 
bolus, (2) once as soon as possible following the bolus (within 5-10 minutes) prior to the 
continuous infusion, and (3) once at 2 hours after the beginning of the continuous infusion. 
Blood will then be collected once daily between 1-2 hours after the first dose on Days 3, 5, 7, 11 
(if treatment is ongoing), and 15 (if treatment is ongoing) and at the end-of-treatment visit. If the 
subject is discharged after the end-of-treatment visit, another sample will be collected on the day 
of discharge. 
11.6. 
Pharmacodynamics 
The pharmacodynamic parameters evaluated in this study related to complement activation are 
levels of C3, C3a, Bb, C4, C4a, C5, and TCC) and AH50. The pharmacodynamic parameters 
evaluated in this study related to coagulopathy are reticulocyte count, presence of schistocytes, 
levels of D-dimer, ferritin, lactate dehydrogenase, haptoglobin, fibrinogen,
 
 The pharmacodynamic parameters 
evaluated in this study related to inflammation are levels of C-reactive protein (CRP), tumor 
necrosis factor  (TNF
, IL-1  and IL-6. The complement activation markers and 
inflammatory cytokines will be analyzed in plasma from blood collected in K2 EDTA 
(dipotassium ethylenediaminetetraacetic acid) tubes with the exception of C-reactive protein, 
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which is measured from serum. The AH50 hemolytic assay will be measured in serum from 
blood collected in red plain top (no gel) tubes. The coagulopathy markers will be analyzed in 
plasma collected in sodium citrate tubes or serum. These blood samples will be collected at the 
same time as the samples described in Section 11.5.  
11.7. 
Genetics 
Genetic markers related to the complement system as well as the susceptibility to SARS-CoV-2 
infection may be evaluated in this study as an optional post hoc analysis contingent upon initial 
study results.
11.8.
Immunogenicity Assessments
Presence or absence of IgG/IgM against SARS-CoV-2 may be evaluated in this study on 
available samples as an optional post hoc analysis contingent upon initial study results.  
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12.
STATISTICS
A formal statistical analysis plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentations and analyses will be provided in the SAP. 
Additional statistical analyses other than those described in this section may be performed if 
deemed appropriate and included in the SAP. Any deviations from the final SAP or from what is 
outlined in the protocol will be discussed in the final study report.  
12.1. 
Determination of Sample Size 
In Part 1 of the study, a cohort of 6 subjects will receive open-label APL-9 (as add-on therapy to 
SOC), and safety data will be evaluated to determine initiation of Part 2. No formal sample size 
calculation was performed.  
In Part 2 of the study, with approximately 30 subjects treated in each treatment group, there is a 
greater than 95% chance of an SAE being reported if the true incidence is 10% or higher. 
Similarly, there is a 26%, 71%, or 89% chance of an SAE being reported if the true incidence is 
1%, 4%, or 7%, respectively. 
12.2. 
Analysis Set 
12.2.1. 
Screened Set 
The screened set will include all subjects who provide written informed consent. This set will be 
used only for the purpose of describing subject disposition. 
12.2.2. 
Safety Set
The safety set will include all subjects who received at least 1 dose of study treatment. This set 
will be used for safety analyses. Subjects will be analyzed according to the treatment they 
received.
12.2.3. 
Intent-to-Treat Set 
The intent-to-treat set will include all randomized subjects. Subjects will be analyzed according 
to their assigned treatment, regardless of the treatment actually received. This set will be used for 
supportive efficacy analyses. 
12.2.4. 
Full Analysis Set 
The full analysis set (FAS) set will include all subjects who receive at least one dose of study 
treatment. The analyses using the FAS will be based upon the actual treatment allocated. The 
FAS will be used for all efficacy analyses. 
12.2.5. 
Per-Protocol Set 
The per-protocol set will include all subjects in the FAS who have not violated any inclusion or 
exclusion criteria and/or deviated from the protocol in a way that could influence their efficacy 
assessment. Decisions concerning the exclusion of subjects from the per-protocol analysis set 
will be made and documented prior to database lock. Randomized subjects will be required to 
receive their randomized treatment to be included in the set so that analyses using this set will, 
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by default, be based upon the actual treatment allocated. This set will be used for supportive 
efficacy analyses. 
12.2.6. 
Pharmacokinetic Set 
The pharmacokinetic (PK) set is defined as all subjects in the safety set and for whom at least 
1 PK sample is evaluable. 
12.2.7. 
Pharmacodynamic Set
The pharmacodynamic (PD) set is defined as all subjects in the safety set with at least 1 PD 
evaluation. 
12.2.8. 
Data Review for Analysis Set 
After all data have been verified, coded, and entered into the database, a review will be 
performed. The purpose of this review will be to define the analysis populations. The review will 
also check the quality of the data, identifying outliers, and make decisions on how to deal with 
any data issues (eg, missing values, withdrawals, protocol deviations). After the preanalysis 
review, resolution of all issues, and documentation of all decisions, the database will be locked. 
12.3. 
Efficacy Analysis 
All efficacy analyses will be summarized by treatment group. 
Unless otherwise specified, baseline for all efficacy analyses is defined as the last measurements 
recorded prior to taking the first dose of study drug. 
All CIs will be presented with 2-sided 90% and/or 95% CI. All statistical tests will be 2-sided 
hypothesis tests performed at the 10% level of significance. 
12.3.1. 
Analysis of Primary Efficacy Endpoint 
Not applicable. 
12.3.2.
Analysis of Secondary Efficacy Endpoints 
Continuous variables will be summarized using descriptive statistics (eg, median and mean); for 
categorical variables, the frequency and percentage in each category will be displayed. Time-to-
event data (such as time to hospital discharge and time to mechanical ventilation discontinuation) 
will be summarized using Kaplan-Meier estimates accounting for censored observations (and 
analyzed using the Cox proportional hazard model if appropriate). 
12.3.3. 
Analysis of Time-to-Event Data 
The following time-to-event endpoints will be assessed by using the Kaplan-Meier method. 
Overall survival
Hospital length of stay
 Duration of mechanical ventilation and/or oxygen therapy 
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Time-to-event curves between the 2 treatment groups will be compared by using a log-rank test 
along with the corresponding hazard ratio. Event rates (eg, mortality through the safety 
follow-up assessment) will be estimated along with the corresponding 2-sided 95% CI (or 
2-sided 90% CI if appropriate). 
12.3.4. 
Analysis of Exploratory Endpoints 
Analyses of exploratory endpoints will follow the methods described in Section 12.3.2 
considering the type of variables (ie, continuous, categorical, or time-to-event). 
12.4. 
Safety Analysis 
All safety analyses will be summarized for the safety set.
Adverse events will be coded using MedDRA. All AEs, including TEAEs, will be summarized 
by System Organ Class, Preferred Term, and treatment group for number of subjects and 
proportion reporting the event. A similar summary will be produced for SAEs, AEs leading to 
termination, severe AEs, and AEs related to the investigational product. The intensity of AEs and 
the relationship to investigational product will be summarized for each System Organ Class and 
Preferred Term by treatment group.  
Withdrawals because of AEs will be summarized for each body system and Preferred Term by 
treatment group. 
As described in Section 11.2, TEAEs are defined as those AEs that develop or worsen after the 
first dose of study medication up to and including the safety follow-up assessment 30 days after 
the last dose of study drug (up to Study Day 51 with a +7-day window). 
AE summaries will be presented across all subjects. All AEs will be listed by subject, along with 
information regarding onset, duration, relationship, and severity to investigational product, action 
taken with investigational product, treatment of event, and outcome.  
All laboratory assessments will be summarized by treatment group using appropriate descriptive 
statistics. 
Changes from baseline in clinical laboratory tests will be summarized, using descriptive 
statistics, by visit and nominal time after dosing, and by treatment group. Baseline will be taken 
as the last predose assessment. Out-of-range values will be flagged in data listings. 
Changes from baseline in vital signs will be summarized, using descriptive statistics, by 
treatment, visit, and nominal time after dosing. Baseline will be taken as the last predose 
assessment. 
Values of potential clinical significance will be flagged in listings and summarized by treatment. 
12.5. 
Other Analyses 
Demographics, baseline characteristics, concomitant medication, medical history, and study 
medication exposure will be summarized by treatment group. 
World Health Organization and MedDRA coding dictionaries will be used for the concomitant 
medications and medical histories, respectively.  
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12.6.
Interim Analyses 
Not applicable. 
12.7.
Independent Data Monitoring Committee
Data monitoring committee reviews on safety endpoints will be conducted after the 6 subjects in 
Part 1 reach Day 7. In Part 2, two reviews will be required: 
1. After the 10th subject reaches the approved treatment duration, discontinuation of 
respiratory support (oxygen supplementation or mechanical ventilation), or hospital 
discharge, whichever occurs latest
2. After the 30th subject reaches the approved treatment duration, discontinuation of 
respiratory support (oxygen supplementation or mechanical ventilation), or hospital 
discharge, whichever occurs latest 
These data reviews will be performed by an independent statistician external to the sponsor, and 
the results will be provided to the DMC by the independent statistician. The sponsor will remain 
blinded throughout these processes and will be unblinded if the study stops early or at the time of 
the final analysis. Enrollment will not be suspended during the DMC reviews. 
The DMC for this study will be appointed by the sponsor in accordance with its standard 
procedures. The DMC chair will also be appointed by the sponsor, and the DMC will operate 
according to an approved charter. 
Initially, the DMC will review the safety data obtained from open-label APL-9 treatment of the 
first 6 subjects. The DMC will review cumulative safety/tolerability data (eg, physical 
examinations, vital sign measurements, clinical laboratory tests, and AEs). Additional data may 
be reviewed that are related to efficacy, but the DMC will only be reviewing data for risk-benefit 
purposes. The DMC will have the responsibility to conduct a thorough safety assessment at 
regular predefined intervals during the treatment period of the study. 
Data monitoring committee meetings will be held according to the schedule in the DMC charter. 
An ad hoc DMC data review may be recommended by the DMC or requested by Apellis 
Pharmaceuticals, Inc, at any time during the study. 
The remit, roles, and responsibilities of the DMC will be specified in a separate DMC charter.
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13.
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
13.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following 
items: 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
Applicable ICH Good Clinical Practice Guidelines 
Applicable laws and regulations 
The Apellis Pharmaceuticals, Inc, policy on bioethics 
 The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. The 
investigator must provide a copy of the IRB/IEC approval to Apellis Pharmaceuticals, 
Inc, before enrollment of any subject into the study. 
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects.  
 The investigator will be responsible for the following: 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/IEC, European 
regulations for clinical trials (if applicable), and all other applicable local 
regulations 
13.1.2. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative, including full and adequate oral 
and written information about the nature, purpose, and possible risks and benefits of 
the study, and answer all questions regarding the study. Subjects should have the 
opportunity to consider the information provided before providing their consent. 
 Subjects must be informed that their participation is voluntary and that they are free 
to discontinue from the study at any time. Subjects or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
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requirements of 21 CFR §50, local regulations, ICH GCP guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF.
 Subjects must be reconsented to the most current version of the ICF(s) during their 
participation in the study.  
 A copy of the ICF(s) must be provided to the subject or the subject’s legally 
authorized representative.  
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research, including testing for genetic markers related to the 
complement system as well as the susceptibility to SARS-CoV-2 infection. The investigator or 
authorized designee will explain to each subject the objectives of the exploratory research. 
Subjects will be told that they are free to refuse to participate and may withdraw their consent at 
any time and for any reason during the storage period. A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for exploratory 
research. Subjects who decline to participate in this optional research will not provide this 
separate signature. 
13.1.3. 
Data Protection 
 Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
 The subjects must be informed that their personal study-related data will be used by 
the sponsor in accordance with local data protection laws. The level of disclosure 
must also be explained to the subject, who will be required to give consent for their 
data to be used as described in the informed consent. 
 The subjects must be informed that their medical records may be examined by 
clinical quality assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
13.1.4.
Site Qualification and Study Monitoring
Before an investigational site can enter a subject into the study, a representative of Apellis 
Pharmaceuticals, Inc, will contact the investigational study site to: 
 Determine the adequacy of the facilities
 Discuss with the investigator(s) and other personnel their responsibilities regarding 
protocol adherence, and the responsibilities of Apellis Pharmaceuticals, Inc, or its 
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representatives. This will be documented in a clinical study agreement between 
Apellis Pharmaceuticals, Inc, and the investigator.
During the study, a monitor from Apellis Pharmaceuticals, Inc, or representative will have 
regular contacts with the investigational site, for the following: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms (CRFs), and that investigational product 
accountability checks are being performed 
 Perform source data verification as described in Section 13.1.5 
 Record and report any protocol deviations not previously sent to Apellis 
Pharmaceuticals, Inc 
 Confirm that all AEs and SAEs have been properly documented on CRFs and 
confirm that any SAEs have been forwarded to Apellis Pharmaceuticals, Inc, and 
those SAEs that met criteria for reporting have been forwarded to the IRB 
The investigator must allow the monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, subject charts and study source documents, and other records relative to 
study conduct. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
13.1.5. 
Data Quality Assurance 
 All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 
 The investigator must maintain accurate documentation (source data; see 
Section 13.1.6) that supports the information entered in the CRF. 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The investigator should contact Apellis Pharmaceuticals, Inc, immediately if 
contacted by a regulatory agency about an inspection. 
 Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the monitoring plan. 
The sponsor or designee is responsible for the data management of this study 
including quality checks of the data.  
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 The sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol, and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for a period of 2 years after the last 
marketing application approval, or if not approved, for 2 years following the 
discontinuance of the test article for investigation, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the 
sponsor.  
13.1.6. 
Source Documents 
 Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s 
site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 Definition of what constitutes source data can be found in the SAP. 
13.1.7. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects at the first site. 
The sponsor designee reserves the right to close any study site or terminate the study at any time, 
for any reason, at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected, and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or ICH GCP guidelines 
 Inadequate recruitment of subjects by the investigator 
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 Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up 
13.1.8. 
Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission to allow the sponsor to protect proprietary information and 
to provide comments. 
 The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Both the use of data and the publication policy will be detailed within the clinical study 
agreement. Intellectual property rights (and related matters) generated by the investigator and 
others performing the clinical study will be subject to the terms of a clinical study agreement that 
will be agreed between the institution and Apellis Pharmaceuticals, Inc, or its designee. With 
respect to such rights, Apellis Pharmaceuticals, Inc, or its designee will solely own all rights and 
interests in any materials, data, and intellectual property rights developed by investigators and 
others performing the clinical study described in this protocol, subject to the terms of any such 
agreement. In order to facilitate such ownership, investigators will be required to assign all such 
inventions, either to their institution or directly to Apellis Pharmaceuticals, Inc, or its designee, 
as will be set forth in the clinical study agreement. 
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14.
LIST OF REFERENCES
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress 
syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. doi: 10.1001/jama.2012.5669 
Bera MM, Lu B, Martin TR, et al. Th17 cytokines are critical for respiratory syncytial virus-
associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. 
J Immunol. 2011;187(8):4245-4255. doi: 10.4049/jimmunol.1101789 
Campbell CM, Kahwash R. Will Complement Inhibition be the New Target in Treating 
COVID-19 Related Systemic Thrombosis? Circulation. 2020. doi: 
10.1161/CIRCULATIONAHA.1120.047419 
Centers for Disease Control and Prevention (CDC). Interim Clinical Guidance for Management 
of Patients with Confirmed Coronavirus Disease (COVID-19). Published 2020. Updated 
3 April 2020. Accessed 20 April 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
guidance-management-patients.html  
Chen N, Zhou M, Dong X, Qu J, Gong F, et al. Epidemiological and clinical characteristics of 99 
cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 
395: 507-13. doi: 10.1016/S0140-6736(20)30211-7 
Craddock PR, Fehr J, Brigham KL, Kronenberg RS, Jacob HS. Complement and leukocyte-
mediated pulmonary dysfunction in hemodialysis. N Engl J Med. 1977;296(14):769-774. doi: 
10.1056/NEJM197704072961401 
Duchateau J, Haas M, Schreyen H, et al. Complement activation in patients at risk of developing 
the adult respiratory distress syndrome. Am Rev Respir Dis. 1984;130(6):1058-1064. doi:
10.1164/arrd.1984.130.6.1058 
Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to 
predict outcome in critically ill patients. JAMA. 2001;286(14):1754-1758. doi: 
10.1001/jama.286.14.1754 
Gralinski LE, Sheahan TP, Morrison TE, et al. Complement Activation Contributes to Severe 
Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio. 2018;9(5). doi: 
10.1128/mBio.01753-18 
Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS. Association of 
complement activation and elevated plasma-C5a with adult respiratory distress syndrome. 
Pathophysiological relevance and possible prognostic value. Lancet. 1980;1(8175):947-949. doi: 
10.1016/s0140-6736(80)91403-8 
Jiang Y, Zhao G, Song N, et al. Blockade of the C5a-C5aR axis alleviates lung damage in 
hDPP4-transgenic mice infected with MERS-CoV. Emerg Microbes Infect. 2018;7(1):77. doi: 
10.1038/s41426-018-0063-8 
Langlois PF, Gawryl MS. Complement activation occurs through both classical and alternative 
pathways prior to onset and resolution of adult respiratory distress syndrome. Clin Immunol 
Immunopathol. 1988;47(2):152-163. doi: 10.1016/0090-1229(88)90068-2 
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Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and 
thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 
2020. doi: 10.1016/j.trsl.2020.04.007 
Ng WF, To KF, Lam WW, Ng TK, Lee KC. The comparative pathology of severe acute 
respiratory syndrome and avian influenza A subtype H5N1—a review. Hum Pathol. 
2006;37(4):381-390. doi: 10.1016/j.humpath.2006.01.015 
Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of Spo2/Fio2 
ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure 
Assessment score. Crit Care Med. 2009;37(4):1317-1321. doi: 10.1097/CCM.0b013e31819cefa9 
Robbins RA, Russ WD, Rasmussen JK, Clayton MM. Activation of the complement system in 
the adult respiratory distress syndrome. Am Rev Respir Dis. 1987;135(3):651-658. 
doi:10.1164/arrd.1987.135.3.651 
Sun S, Zhao G, Liu C, et al. Inhibition of complement activation alleviates acute lung injury 
induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir Cell Mol Biol. 
2013;49(2):221-230. doi:10.1165/rcmb.2012-0428OC. 
Sun S, Zhao G, Liu C, et al. Treatment with anti-C5a antibody improves the outcome of H7N9 
virus infection in African green monkeys. Clin Infect Dis. 2015; 60(4):586-95. doi: 
10.1093/cid/ciu887 
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15.
APPENDICES
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APPENDIX 1.
SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) 
Organ failure status will be assessed using the SOFA score, which assesses 6 organ systems: 
respiration, coagulation, liver, cardiovascular, central nervous system, and renal (Ferreira et al.
2001). A subject will be defined as being free of organ failure when the SOFA score is zero. The 
score will be assessed at baseline on Day 1 and as listed in the SoA (Table 1) based on worst 
daily values. The SOFA score variables to be assessed are: 
 PaO2 (partial pressure of oxygen)/FiO2 (fraction of inspired oxygen) ratio (mm Hg)—
collected and entered into the database locally (see calculation instructions below) 
 Platelets × 103/mm3—based on data provided by the central laboratory
Bilirubin (µmol/L or mg/dL)—based on data provided by central laboratory
Hypotension/use of vasopressors—collected and entered into the database locally
 Glasgow Coma Scale score—collected and entered into the database locally (see 
Appendix 2) 
 Creatinine (µmol/L or mg/dL)—based on data provided by the central laboratory 
Table 5 details the SOFA scoring requirements. 
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Table 5: 
Sequential Organ Failure Assessment (SOFA) Scoring
Variables 
0 
1 
2 
3 
4 
Respiration  
PaO2/FiO2, mm Hg
>400
a 
a
Coagulation 
Platelets × 103/µL 
>150 
 
 
 
 
Liver  
Bilirubin, mg/dLb 
<1.2 
1.2 -1.9 
2.0 -5.9 
6.0 -11.9 
>12.0 
Cardiovascular  
Hypotension
No 
hypo-
tension 
MAP 
<70 mm Hg 
Dopamine 
dobutamine 
(any dose)c
Dopamine >5, 
epinephrine 
, or 
norepinephrine 
c 
Dopamine >15, 
epinephrine 
>0.1, or 
norepinephrine 
>0.1c 
Central nervous system  
Glasgow Coma Scale scored,e 
15 
13 -14 
10 -12 
6 -9 
<6 
Renal 
Creatinine, mg/dL 
or urine output (mL/d)f 
<1.2 
1.2 to 1.9 
2.0 to 3.4 
3.5 to 4.9 or 
<500 
>5.0 or <200 
Abbreviations: FiO2 = fraction of inspired oxygen; MAP = mean arterial pressure; PaO2 = partial pressure of 
oxygen. 
a Values are with respiratory support. 
b To convert bilirubin from mg/dL to µmol/L, multiply by 17.1. 
c Adrenergic agents administered for at least 1 hour (doses are given in µg/kg/min). 
d For subjects who are intubated, the verbal response is scored as: 
5 – Seems able to talk  
3 – Questionable ability to talk 
1 – Generally unresponsive 
e For subjects who are sedated, use an estimated score for Glasgow Coma Scale (the assumption is 15, if no other 
factors than sedation affect Glasgow Coma Scale score). 
f To convert creatinine from mg/dL to µmol/L, multiply by 88.4. 
Source: Ferreira et al. 2001. 
Calculation of PaO2/FiO2 ratio: 
For the purpose of calculating PaO2/FiO2 ratio, an arterial blood gas test (ABG) will be obtained 
from: 
1. An arterial line if already present 
2. A radial artery needle puncture unless contraindicated
3. If ABG sampling remains unsuccessful for any reason, then SpO2 (peripheral oxygen 
saturation) will be measured and the SpO2/FiO2 value will be derived, and the PaO2/FiO2
ratio will be used to determine the SOFA respiratory score according to Table 6.  
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Table 6: 
Derivation of SpO2/FiO2 Values Corresponding to PaO2/FiO2 Ratios in the 
Combined Anesthesia and ARMA Databasea 
SOFA respiratory score 
PaO2/FiO2 
SpO2/FiO2 
1 
<400 
<512 
2 
<300 
<357 
3 
<200 
<214 
4 
<100 
<89 
Abbreviations: ARMA = Acute Respiratory Management of ARDS; FiO2= fraction of inspired oxygen; 
PaO2 = partial pressure of oxygen; SOFA = Sequential Organ Failure Assessment; SpO2 = peripheral oxygen 
saturation. 
a Data derived from 4728 matched SpO2/FiO2 and PaO2/FiO2 measurements from the combined anesthesia and 
ARMA database. 
Source: Pandharipande et al. 2009. 
 
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APPENDIX 2.
GLASGOW COMA SCALE
Glasgow Coma Scale 
Eye Opening Response 
 Spontaneous—open with blinking at baseline 4 points
To verbal stimuli, command, speech 3 points
To pain only (not applied to face) 2 points
 No response 1 point 
Verbal Response 
 Oriented 5 points
Confused conversation, but able to answer questions 4 points
Inappropriate words 3 points
Incomprehensible speech 2 points
 No response 1 point 
Motor Response 
 Obeys commands for movement 6 points 
 Purposeful movement to painful stimulus 5 points 
 Withdraws in response to pain 4 points 
 Flexion in response to pain (decorticate posturing) 3 points 
 Extension response in response to pain (decerebrate posturing) 2 points 
 No response 1 point 
References
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974; 81-84. 
Teasdale G, Jennett B. Assessment and prognosis of coma after head injury. Acta Neurochir.
1976; 34:45-55. 
Categorization: 
Coma: No eye opening, no ability to follow commands, no word verbalizations (3-8) 
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Head Injury Classification:
Severe Head Injury—GCS score of 8 or less
Moderate Head Injury—GCS score of 9 to 12 
Mild Head Injury—GCS score of 13 to 15 
(Adapted from: Advanced Trauma Life Support: Course for Physicians, American College of 
Surgeons, 1993.) 
Disclaimer: 
Based on motor responsiveness, verbal performance, and eye opening to appropriate stimuli, the 
Glascow Coma Scale was designed and should be used to assess the depth and duration of coma 
and impaired consciousness. This scale helps to gauge the impact of a wide variety of conditions 
such as acute brain damage due to traumatic and/or vascular injuries or infections, metabolic 
disorders (eg, hepatic or renal failure, hypoglycemia, diabetic ketosis), etc. 
Education is necessary to the proper application of this scale (Teasdale G, Kril-Jones R, van der 
Sande J. Observer variability in assessing impaired consciousness and coma. J Neurol Neurosurg 
Psychiatry. 1978; 41:603-610. Rowley G, Fielding K. Reliability and accuracy of the Glasgow 
Coma Scale with experienced and inexperienced users. Lancet. 1991; 337:535-538). The 
predictive value of the GCS, even when applied early, is limited (Waxman K, Sundine MJ, 
Young RF. Is early prediction of outcome in severe head injury possible? Arch Surg. 1991; 
126:1237-1242). 
Despite these and other limitations (Eisenberg HM. Outcome after head injury: Part I: general 
Considerations, in Becker DP, Povlishock JR (eds): Central Nervous System Trauma Status 
Report, 1985. Washington, DC: U.S. Government Printing Office, 1988:271-280), health care 
practitioners continue to use this practical scale widely. 
Source: Adapted from Glascow Coma Scale, Womack Army Medical Center, Fort Bragg, NC. 
 
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APPENDIX 3. Amendment History 
AMENDMENT 1: SUMMARY OF CHANGES FROM THE PREVIOUS VERSION 
Updates to the protocol implemented in this amendment are provided in the table below. Additions to the 
protocol are marked in underline; deletions are marked by strikethrough. 
Protocol Versions 
 
Summary of Change(s) Since Last Version of Approved Protocol
Amendment 1
Amendment Date
07 May 2020  
Global
Description of Change
Section(s) Affected by Change 
Nonsubstantial editorial and technical changes that did not impact content of the 
document have been made for grammar, clarity, and document usability.
Entire document
Inclusion criteria 6 and 7 were added to the Synopsis. These criteria were 
previously included in the body of the protocol: 
6. Each female subject of childbearing potential must have a negative serum 
pregnancy test at screening and must agree to use protocol-defined methods 
of contraception from screening through at least 90 days after receiving the 
last dose of APL 9. 
7. Male subjects must agree to use protocol-defined methods of contraception 
and agree to refrain from donating semen from screening through at least 
90 days after receiving the last dose of APL-9. 
Synopsis 
Clarified that required criteria for initiation of Part 2 will include 1) No fatal/life-
threatening SAEs thought possibly related to APL-9 by the DMC, and 2) no more 
than 1 patient requiring premature treatment discontinuation by the investigator 
due to AEs or abnormal lab tests.
Synopsis 
Section 5.3  
Section 7.1  
Section 7.5 
Analysis of PK and PD parameters were elevated from exploratory objectives and 
exploratory endpoints to secondary objectives and secondary endpoints. 
PK and PD set definitions added to Section 12. 
Synopsis 
Section 6.1.2 
Section 6.1.3  
Section 6.2.2 
Section 6.2.3  
Section 7.2  
Section 12.2.6 (new section 
added) 
Section 12.2.7 (new section 
added) 
The any-cause mortality secondary endpoint was modified for clarity, as follows: 
 
Any-cause mortality (measured from beginning of treatment until the Day-30 
follow-up assessment) 
Synopsis 
Section 6.2.2  
Section 12.3.3  
Clarified that in Part 2 dosing will remain 7 days and may be extended only in 
patients who still have mild or moderate ARDS at Day 7 with at least a 20 mm Hg 
increase in PaO2 from baseline. 
Synopsis 
Section 7.1  
Section 7.5  
Section 9.1.1  
Section 10.1  
The safety follow-up duration was updated from a 7-day follow-up (-2/+7 days) to 
a 30-day follow-up (+ 7 days). 
Synopsis 
Section 7.1  
Section 7.4  
Section 7.5, Table 1  
Section 11
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Section 11.2.1
Exclusion criteria 2 was modified to exclude any active bacterial, fungal, or 
parasitic infection as follows: 
2. Active bacterial, fungal, or parasitic infection neisserial sepsis infection. 
Treatment with interleukin 6 inhibitors and hydroxychloroquine removed from 
exclusion criteria 5 as these treatments may be considered standard of care. 
 5. Treatment with interleukin 6 inhibitors, hydroxychloroquine, 
immune checkpoint inhibitors, or other immunomodulators within 3 
months prior to study enrollment (however, treatment with steroids, 
interleukin-6 inhibitors and antiviral agents is NOT excluded) 
Exclusion criteria 6 was modified to clarify that: 
6. Treatment with convalescent plasma for COVID-19 within 3 months 
of baseline 
Exclusion criteria 8 was modified as follows: 
8. Evidence of kidney and liver failure at screening (estimated 
glomerular filtration rate <45 mL/min/1.73 m2 and alanine 
aminotransferase level >5× >10x the upper limit of normal, as assessed 
by the local laboratory) 
Exclusion criteria 9 was added to exclude: 
9. Subjects with a hereditary complement deficiency 
Synopsis 
Section 7.2  
Section 8.2  
Section 9.5.1  
Clarified that a subject is considered to have completed the study if all obtainable 
study assessments, including those at the day of discharge from the hospital and 
during follow-up, have been collected. 
The end of the study was redefined as the date of the Day 30 follow-up 
assessment for the last subject in the study. 
Section 7.4 
Footnote “a” was modified to reflect the updates to the study design. Footnote “g” 
was added to indicate where the SOFA score variables are detailed in the protocol. 
Footnote “h” was modified to indicate where laboratory assessments are detailed 
in the protocol and to note that the use of silica reagents in coagulation panels 
should be avoided in subjects treated with APL 9 (this was previously included in 
the body of the original protocol). The previous footnote “g” detailing 
concomitant procedures is now footnote “i” due to the addition/modification of 
the previous footnotes. Footnote “j” was added to detail how infusion-relation 
reactions should be treated. Footnote “k” added to clarify that if confirmation of 
SARS-CoV-2 has occurred within 7 days of screening, the viral RNA at 
screening/baseline is not mandatory. Footnote “l” was modified to note that 
vaccination history should be attempted to be collected as a component of medical 
history. 
Section 7.5, Table 1  
  
Adverse Event collection added to the Schedule of Assessments 
ECGs added to the Schedule of Assessments 
Section 7.5, Table 1  
Section 7.5, Table 1 
For clarity, the “exit visit” has been re-labeled as the “end-of-treatment visit.”
Subjects must receive all assessments indicated in the “end-of-treatment visit” on 
the last day they receive treatment, regardless of which study day that occurs on. 
Section 7.5, Table 1  
Section 9.5 
Section 10.2  
Section 10.3  
Section 11  
Section 11.2.3  
Section 11.2.6  
Section 11.5  
Section 11.6  
Section 12.4  
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Inclusion Criteria 3 was updated to allow for inclusion of patients that are not 
mechanically ventilated as follows: 
3. Have: 
a. 
Respiratory failure requiring oxygen supplementation or 
either invasive or non-invasive mechanical ventilation with 
PaO2/FiO2 ratio >100 mm Hg
mm Hg with end positive 
airway pressure (EPAP) or positive end-expiratory pressure (PEEP) 
b. Worsening of respiratory symptoms in the past week. 
c. 
Bilateral opacities present on a chest radiograph or computed 
tomographic scan. These opacities must not be fully explained by 
pleural effusions, lobar collapse, lung collapse, or pulmonary 
nodules.
d. Respiratory failure cannot be fully explained by cardiac failure or 
fluid overload. 
3. Diagnosis of mild to moderate ARDS requiring mechanical ventilation 
according to the Berlin definition: 
a. 
Worsening of respiratory symptoms in the past week. 
b. Bilateral opacities present on a chest radiograph or computed 
tomographic scan. These opacities must not be fully explained 
by pleural effusions, lobar collapse, lung collapse, or pulmonary 
nodules. 
c. 
Respiratory failure cannot be fully explained by cardiac failure 
or fluid overload. 
d. Mild or moderate ARDS with PaO2/FiO2 ratio is >100 mm Hg 
 mm Hg on ventilator settings that include positive end-
expiratory pressure (PEEP) or continuous positive airway 
cm H2O. 
Synopsis
Section 8.1  
Instructions for treatment of infusion-related reactions were implemented in the 
protocol: 
Infusion-related reactions that occur during the administration of the 50 mL 
loading dose should be treated as follows:  
 
For mild infusion-related reactions: The 50 mL bag infusion time should 
be increased from 10 mins to 20-40 mins and the reaction should be 
monitored. Treatment with diphenhydramine may be required. The 
infusion time of the 250 mL bag should not be increased. 
 
For severe or persistent mild infusion-related reactions (instances in 
which the subject’s symptoms do not respond to the increased infusion 
time): treatment should be discontinued and the institution’s emergency 
hypersensitivity protocol should be employed. 
Section 9.1.1  
Section 7.5, Table 1  
The following edit was made for clarity: 
Subjects who are discharged prior to the allowable treatment duration 
study exit date will have follow-up conducted by phone and will be 
provided with emergency study cards that include a list of symptoms 
associated with infections. 
Section 9.1.2  
Clarified that:
Randomization will be stratified by need of mechanical ventilation (yes 
vs no) severity of ARDS (mild vs moderate) and age (younger than 
65 years vs at least 65 years). 
Section 9.3.1  
Reference to specific antibiotics was removed as these are covered by the “broad-
spectrum” antibiotic requirement.  
All enrolled subjects will receive a broad-spectrum antibiotic during the 
treatment period to provide coverage for Neisseria meningitidis, 
Section 9.5 
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Streptococcus pneumoniae, and Haemophilus influenzae unless 
contraindicated because of hypersensitivity or allergy. In that event, 
carbapenem, vancomycin, or aztreonam are the recommended alternates. 
Subjects with infection and cultures resistant to the prophylactic 
antibiotic should be switched to culture-specific antibiotic therapy. 
Treatment with antibiotics may be adjusted according to culture results 
and at the discretion of the investigator. 
Treatment with interleukin 6 inhibitors and hydroxychloroquine removed from the 
list of prohibited medications. 
Section 9.5.1
Noted that the SOFA score assessments will be conducted locally.
Section 11.1.1  
It was noted that: 
Vaccination history should be attempted to be collected as a component of 
medical history. 
Section 11.1.3  
Section 7.5, Table 1  
Liver failure criteria modified as follows: 
 
Alanine aminotransferase more than 5 10 times the upper limit of normal 
Section 11.1.4  
Reference to the following laboratory assessments being conducted locally was 
removed as noted below. These assessments were already included in the 
summary of labs (Table 2), and the laboratory manual will provide details of 
where laboratory values should be assessed. 
Local laboratory: eGFR, pregnancy, arterial blood gas test
Section 11.1.8  
An error was corrected to clarify that: 
Clinically significant changes in laboratory values, blood pressure, and pulse 
rate need not must be reported as AEs. 
Section 11.2.3  
AMENDMENT 2: SUMMARY OF CHANGES FROM THE PREVIOUS VERSION 
 
Updates to the protocol implemented in this amendment are provided in the table below. Additions to the 
protocol are marked in underline; deletions are marked by strikethrough. 
Amendment 2 
Amendment Date 
17 August 2020  
Global 
Description of Change
Section(s) Affected by 
Change 
Nonsubstantial changes that did not impact content of the document have been 
made for clarity. 
Entire document 
Updated primary objective to reflect the study population, which was revised in 
Protocol Amendment 1 (07 May 2020) per FDA request to include patients with 
respiratory failure requiring nonmechanical respiratory support, in addition to 
patients with ARDS (respiratory failure requiring noninvasive or invasive 
mechanical ventilation). The primary objective was not updated accordingly in 
Amendment 1, so it is now updated as follows: 
 
To evaluate the safety of APL-9 compared with that of vehicle control (as 
add-on therapy to standard of care [SOC]) in subjects with coronavirus 
disease 2019 (COVID-19) who have respiratory failure, including mild to 
moderate acute respiratory distress syndrome (ARDS) 
Synopsis 
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Updated secondary endpoints
 
Any-cause mortality (measured from beginning of treatment until the 
safety follow-up assessment 30 days after last study treatment (up to Study 
Day 51 with a +7-day window) Day 30 follow-up assessment) 
 
Observed values and changes from baseline in markers of complement 
activation (C3, C3a, C4, C4a, Bb, C5a, TCC, and alternative complement 
pathway hemolytic activity) thrombotic microangiopathy, coagulopathy 
(reticulocyte count, presence of schistocytes, lactate dehydrogenase, 
D-dimer, ferritin, haptoglobin, fibrinogen, von
 
 and inflammatory cytokines 
(C-reactive protein, tumor necrosis factor , IL-
-6) 
Updated overall study design 
This is a randomized, double-blind, vehicle-controlled, multicenter, parallel-group 
Phase 1/2 study (with an initial open-label period) evaluating the safety and efficacy 
of APL-9 versus those of vehicle as an add-on therapy to SOC in subjects with mild 
to moderate ARDS respiratory failure due to COVID-19 infection.  
Revised Part 2 (Randomized Double-Blind Period) 
Subjects will receive treatment with APL-9 or vehicle from Day 1 through Day 7 
(or approved treatment duration), or resolution of ARDS (PaO2/FiO2 ratio 
>300 mm Hg) discontinuation of respiratory support (supplemental oxygen or 
mechanical ventilation), or hospital discharge, whichever occurs earlier.  
The DMC may approve any extended treatment duration through Day 21 (extended 
treatment will be allowed only in subjects who still require respiratory support 
(oxygen supplementation or mechanical ventilation) at Day 7have mild or moderate 
ARDS with at least a 20-mm Hg increase in PaO2 from baseline). Treatment beyond 
Day 7 and through any DMC-approved extension will be at the discretion of the 
investigator.  
For each subject, follow-up safety assessments will be collected 30 days after the 
subject’s last dose of study treatment (up to Study Day 51 with a +7-day window). 
Assessments between study drug discontinuation and the safety follow-up 
assessment may be conducted at the investigator’s discretion. These assessments 
will be conducted via inpatient assessment (for patients still hospitalized) or by 
telephone call (for patients discharged). 
The DMC will perform safety and efficacy data reviews on an ongoing basis during 
Part 2. Two reviews will be required: after the 10th subject enrolled in Part 2 
reaches Day 7 (or is discharged following the resolution of ARDS) and after the 
30th subject enrolled in Part 2 reaches Day 7 (or is discharged following the 
resolution of ARDS) Two reviews will be required in Part 2:  
1. After the 10th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge; and 
2. After the 30th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge.  
If the DMC approves an extended treatment period following Part 1 or at any time 
through the conduct of Part 2, the DMC’s safety and efficacy data review will be 
initiated when the 10th and 30th subjects reach the approved extended treatment 
duration, discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation)(or achieve resolution of ARDS), or hospital discharge. For 
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example, if, following Part 1, the DMC approves treatment through Day 14 in 
Part 2, the DMC will be required to review safety and efficacy after the first 
10 patients reach Day 14 of treatment, discontinuation of respiratory support 
(oxygen supplementation or mechanical ventilation), or hospital discharge (or 
achieve resolution of ARDS). Enrollment will not be suspended during the DMC 
reviews. 
Revised Study Drug Treatments – Part 2 
The blinded site personnel will initiate therapy with study drug received from the 
pharmacists on Day 1 with an IV infusion of the 50-mL bag over a 10-minute 
period, followed within 1 hour by continuous infusion of the 250-mL bag at the rate 
of approximately 21 mL/h until the end of study drug administration on Day 7 (or 
longer if DMC allowed), or resolution of ARDS discontinuation of respiratory 
support, or hospital discharge. (This results in the infusion of two 250-mL bags 
every 24 hours.) 
Revised Independent DMC 
The DMC will perform safety and efficacy data reviews on an ongoing basis during 
Part 2. Two reviews will be required: after the 10th subject enrolled in Part 2 
reaches Day 7 (or is discharged following the resolution of ARDS), and after the 
30th subject enrolled in Part 2 reaches Day 7 (or is discharged following the 
resolution of ARDS). Two reviews will be required in Part 2: 
1. After the 10th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge  
2. After the 30th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge. 
If the DMC approves an extended treatment period following Part 1 or at any time 
through the conduct of Part 2, the DMC’s safety and efficacy data review will be 
initiated when the 10th and 30th subjects reach the approved extended treatment 
duration (or achieve resolution of ARDS), discontinuation of respiratory support 
(oxygen supplementation or mechanical ventilation), or hospital discharge. 
Enrollment will not be suspended during the DMC reviews. 
Treatment duration in Part 2 may be maximally extended through Day 21; extended 
treatment will be allowed only in subjects who still have mild or moderate 
ARDSrequire respiratory support (oxygen supplementation or mechanical 
ventilation) at Day 7 with at least a 20-mm Hg increase in PaO2 from baseline. 
Revised Section 5.3, Benefit-Risk Assessment 
This is an interventional study in COVID-19 subjects with respiratory failure, 
including mild to moderate ARDS, a life-threatening complication of SARS-CoV-2 
infection. 
WhenAfter Part 2 is initiated, the DMC will perform further reviews of clinical data 
whenafter the 10th and 30th subjects have reached the approved treatment duration, 
discontinued respiratory support (oxygen supplementation or mechanical 
ventilation), or been discharged from the hospital.  
Section 5.3 
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Revised Section 6.1.1, Primary Objective
The primary objective of this study is to evaluate the safety of APL-9 compared 
with that of vehicle control (as add-on therapy to SOC) in subjects with COVID-19 
who have respiratory failure, including mild to moderate ARDS. 
Section 6.1.1
Revised Section 6.1.2, Secondary Objective  
 
APL-9 pharmacodynamics (PD; the effect of APL-9 on the complement, 
coagulation, and inflammation panel biomarkers)  
Section 6.1.2 
Deleted pharmacokinetics and pharmacodynamics from exploratory objectives  
APL-9 PK 
 
APL-9 pharmacodynamics (PD; the effect of APL-9 on the complement 
panel)  
Section 6.1.3 
Revised Secondary Objective Endpoints 
 
Any-cause mortality (measured from beginning of treatment until the 
safety follow-up assessment 30 days after last study treatment (up to Study 
Day 51 with a +7-day window) Day 30 follow-up assessment) 
 
Observed values and changes from baseline in markers of complement 
activation (C3, C3a, C4, C4a, Bb, C5a, TCC, and alternative complement 
pathway hemolytic activity [AH50]), thrombotic microangiopathy 
coagulopathy (reticulocyte count, schistocytes, lactate dehydrogenase, 
D-dimer, ferritin, haptoglobin, fibrinogen,
 
 and inflammatory cytokines 
(C-
-
-6). 
Section 6.2.2 
Revised exploratory endpoints 
 
Presence of active SARS-CoV-2 infection assessed by qualitative reverse 
transcriptase polymerase chain reaction (RT-PCR), for SARS-CoV-2 on 
Day 28  
 
APL-9 PK parameters 
 
Observed values and changes from baseline in markers of complement 
activation (C3, C3a, C4, C4a, Bb, TCC, and AH50)  
 
Presence of active SARS-CoV-2 infection at the end-of-treatment visit. 
Presence of SARS-CoV-2 viral RNA or viral antigen may be detected in 
respiratory specimens (collected using nasopharyngeal or oropharyngeal 
swabs) with a qualitative nucleic acid amplification test (such as reverse 
transcriptase polymerase chain reaction [RT-PCR]), viral antigen test, or 
other diagnostic method that is authorized, cleared, or approved by the US 
Food and Drug Administration (or equivalent local authority) for 
SARS-CoV-2 viral detection. Serology-based antibody tests do not detect 
the presence of virus and therefore are not considered diagnostic and cannot 
be used for study eligibility screening or for subsequent SARS-CoV-2 
assessments. 
Section 6.2.3 
Revised Section 7.1 Overall Study Design to specify subjects who have respiratory 
failure and require respiratory support (supplemental oxygen or mechanical vent) 
Section 7.1 
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Part 1 of the study is designed to evaluate the safety of open-label APL-9 with SOC 
in a small number of subjects who have respiratory failure (including mild to 
moderate ARDS) due to COVID-19 and who require respiratory support 
(supplemental oxygen or mechanical ventilation).  
Part 2 of the study is designed to evaluate the safety and efficacy of APL-9 with 
SOC compared with those of vehicle with SOC in a larger number of subjects who 
have respiratory failure (including mild to moderate ARDS) due to COVID-19 and 
who require respiratory support (supplemental oxygen or mechanical ventilation).  
Part 2 (Randomized Double-Blind Period): 
Subjects will receive treatment with APL-9 or vehicle from Day 1 through Day 7, or 
resolution of ARDS (PaO2/FiO2 ratio >300 mm Hg) discontinuation of respiratory 
support (supplemental oxygen or mechanical ventilation), or hospital discharge, 
whichever occurs earlier. Resolution of ARDS in this study is defined according to 
the Berlin definition as PaO2/FiO2 ratio >300 mm Hg (ARDS Definition Task Force 
2012). 
The DMC may approve any extended treatment duration through Day 21; extended 
treatment will be allowed only in subjects who still require respiratory support 
(oxygen supplementation or mechanical ventilation) have mild or moderate ARDS 
at Day 7 with at least a 20-mm Hg increase in PaO2 from baseline. 
Follow-up safety assessments for each subject will be collected 30 days following 
the last dose of APL-9study treatment (up to Study Day 51 with a +7-day window). 
Safety assessments may be performed any time during the 30-day follow-up period 
at the investigator’s discretion but are required 30 days after the last dose of study 
drug (up to Study Day 51 with +7-day window).  
The DMC will perform safety and efficacy data reviews on an ongoing basis during 
Part 2. Two reviews will be required: after the 10th subject enrolled in Part 2 
reaches Day 7 (or is discharged following the resolution of ARDS) and after the 
30th subject enrolled in Part 2 reaches Day 7 (or is discharged following the 
resolution of ARDS). Two reviews will be required in Part 2: 
1. After the 10th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge 
2. After the 30th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge 
If the DMC approves an extended treatment period following Part 1 or at any time 
through the conduct of Part 2, the DMC’s safety and efficacy data reviews will be 
initiated when the 10th and 30th subjects reach the approved extended treatment 
duration, discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation)(or achieve resolution of ARDS), or hospital discharge. For 
example, if, following Part 1, the DMC approves treatment through Day 14 in 
Part 2, the DMC will be required to review safety and efficacy after the first 
10 patients reach Day 14 of treatment, discontinuation of respiratory support 
(oxygen supplementation or mechanical ventilation), or hospital discharge (or 
achieve resolution of ARDS). Enrollment will not be suspended during the DMC 
reviews. 
Revised scientific rationale 
This study is designed to evaluate the safety of APL-9 in subjects with respiratory 
failure mild to moderate ARDS due to confirmed COVID-19, the disease caused by 
SARS-CoV-2 infection. Secondary objectives include assessments of efficacy of 
Section 7.2 
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APL-9 (evaluating survival, length of hospital admission, and lung function), APL-9 
PK results, and the effect of APL-9 on the complement panel activation biomarkers.  
Revised end of study definition 
The end of the study is defined as the date of the safety follow-up assessment 
30 days after the last dose of study drug (up to Study Day 51 with +7-day window) 
Day 30 follow-up assessment for the last subject in the study. 
Section 7.4 
Revised Figure 1 Study Schema, DMC recommendation 2 
treatment may be extended only for subjects who still require respiratory support 
(oxygen supplementation or mechanical ventilation) have mild or moderate ARDS
at Day 7 with at least a 20-mm Hg increase in PaO2 from baseline). 
Revised Figure 2: Randomization 1:1 
Note: Two DMC reviews will occur: (1) after first 10 subjects reach the approved 
treatment duration, discontinuation of respiratory support, or hospital discharge; (or 
resolution of ARDS) and (2) after the first 30 subjects reach the approved treatment 
duration, discontinuation of respiratory support, or hospital discharge. (or resolution 
of ARDS) and The DMC may recommend changes to the protocol, including 
treatment extension up to 21 days for eligible subjects.  
Revised Figure 2: Treatment for 7 days 
Subjects may continue treatment for up to 21 days (only in subjects who still have 
mild or moderate ARDS require respiratory support at Day 7 with at least a 
20-mm Hg increase in PaO2 from baseline) per DMC recommendation and PI 
discretion (treatment may be modified at any point during Part 2) 
Revised Figure 2: Safety follow-up 
(Safety assessments may be performed at any time during the 30-day follow-up at 
PI’s discretion but are required 30 days after last dose of study drug [up to Study 
Day 51 with +7-day window]) 
Revised column heading for Schedule of Activities, Part 1, and Part 2 
Safety30-day follow-up assessmentperioda
Up to Study Day 51 (+7) 
Revised footnote a of Schedule of Activities, Table 1 
a. 
In Part 2, dosing may be extended only in subjects who still require respiratory 
support (oxygen supplementation or mechanical ventilation) have mild or 
moderate ARDS at Day 7 with at least a 20-mm Hg increase in PaO2 from 
baseline. In Part 2, subjects will receive treatment through the DMC-approved 
treatment duration, discontinuation of respiratory support (oxygen 
supplementation or mechanical ventilation), or hospital discharge or resolution 
of ARDS (whichever occurs earlier). Through Part 2, the DMC may review 
efficacy and safety data and recommend changes to the study conduct on an 
ongoing basis, but it will be required to review efficacy and safety data after the 
10th and 30th subjects reach the DMC-approved treatment duration, 
discontinuation of respiratory support, or hospital discharge, or resolution of 
ARDS (whichever occurs earlier). Enrollment will not be suspended during the 
DMC reviews. Subjects who achieve resolution of ARDS or reach the end of 
the approved treatment duration, discontinuation of respiratory support, or 
hospital discharge (whichever occurs earlier) must be assessed as indicated in 
the EOT visit column (for example, a subject who achieves resolution of ARDS 
discontinuation of respiratory support on Day 6 should be evaluated with a 
Section 7.5 
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radiograph or computed tomographic scan even though it is not indicated as a 
Day 6 assessment). All subjects will be followed up 30 days after last study 
treatment (with a +7-day window), either in person (for subjects still 
hospitalized) or by phone (for subjects who have been discharged). All subjects 
will be followed up 30 days at the safety follow-up assessment 30 days after 
last study treatment (up to Study Day 51 with a +7-day window), either in 
person (for subjects still hospitalized) or by phone (for subjects who have been 
discharged).  
Revised footnote f of Schedule of Activities, Table 1 
Vital signs and ECG must be collected between the administration of the loading 
dose of study treatment and the initiation of the maintenance dose. 
Revised footnote h of Schedule of Activities, Table 1 
A list of laboratory assessments is provided in Section 11.1.8. Day 1 assessments 
should be collected within 1-2 hours of loading infusion. Blood will be collected 
3 times on Day 1: (1) once prior to administration of the APL-9 bolus, (2) once as 
soon as possible following the bolus (within 5-10 minutes) prior to the continuous 
infusion, and (3) once at 2 hours after the beginning of the continuous infusion.  
Revised footnote k of Schedule of Activities, Table 1 
If confirmation of SARS-CoV-2 has occurred within 7 days of screening, the viral 
RNA or viral antigen test at screening/baseline is not mandatory. 
Revised subject inclusion criterion 2 
2. Diagnosis of active SARS-CoV-2 infection. Presence of SARS-CoV-2 
viral RNA or viral antigen may be detected in respiratory specimens 
(collected using nasopharyngeal or oropharyngeal swabs) with a qualitative 
nucleic acid amplification test (such as RT-PCR) or viral antigen test or 
other diagnostic method that is authorized, cleared, or approved by the US 
Food and Drug Administration (or equivalent local authority) for 
SARS-CoV-2 viral detection. Note: Serology-based antibody tests do not 
detect presence of virus, and therefore are not considered diagnostic for 
active infection and cannot be used for study eligibility screening or for 
subsequent SARS-CoV-2 assessments. 
2. Confirmed SARS-CoV-2 infection as determined by any method that is 
authorized, cleared, or approved by the US FDA (or equivalent local 
authority). Subjects may have previous confirmation of SARS-CoV-2 
(within 7 days of screening) or may be assessed for SARS-CoV-2 at 
screening. 
Revised subject inclusion criterion 3 
3. Have: 
a. 
Respiratory failure requiring oxygen supplementation or either 
invasive or non-invasive mechanical ventilation with PaO2/FiO2 
ratio >100 mm 
 mm Hg with end positive airway 
pressure (EPAP) or positive end-expiratory pressure (PEEP) 
b. Worsening of respiratory symptoms in the past week. 
c. 
Bilateral opacities present on a chest radiograph or computed 
tomographic scan. These opacities must not be fully explained by 
pleural effusions, lobar collapse, lung collapse, or pulmonary 
nodules. 
d. Respiratory failure cannot be fully explained by cardiac failure or 
fluid overload. 
Synopsis, Section 8.1 
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3. Have respiratory failure requiring oxygen supplementation or either invasive 
or noninvasive mechanical ventilation with PaO2/FiO2 ratio >100 mm Hg. 
Respiratory failure cannot be fully explained by cardiac failure or fluid 
overload. 
Revised subject exclusion criterion 3 and criterion 5; deleted criterion 6 and 
renumbered subsequent exclusion criteria accordingly 
3.
History of neuromuscular degenerative disease such as (eg, amyotrophic 
lateral sclerosis, Duchenne muscular dystrophy, or multiple sclerosis)
5. Treatment with immune checkpoint inhibitors or other immunomodulators 
within 3 months prior to study enrollment (however, treatment with 
convalescent plasma, steroids, IL-6 inhibitors, and antiviral agents is NOT 
excluded) 
6. Treatment with convalescent plasma for COVID-19 within 3 months of 
baseline
Synopsis, Section 8.2 
Revised Screening Failures
Sites may initiate screening procedures prior to a subject’s diagnosis of respiratory 
failure or ARDS. 
Section 8.4
Revised study drug administration 
Dosing of subjects receiving APL-9 either as open-label treatment or by random, 
blinded assignment will be initiated with an IV infusion of 180 mg APL-9 in 50 mL 
of saline over a 10-minute period, followed within 1 hour by continuous infusion of 
180 mg APL-9 in 250 mL saline at the rate of 15 mg/h (approximately 21 mL/h) 
until the end of study drug administration at Day 7 (or approved treatment 
extension), discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge, whichever occurs earlier.or 
resolution of ARDS. 
Dosing of subjects randomly assigned to vehicle control will be initiated with an IV 
infusion of 50 mL of saline over a 10-minute period followed immediately (and up 
to within 1 hour) by continuous infusion of approximately 21 mL of saline per hour 
until the end of study drug administration at Day 7 (or approved treatment 
extension), discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge, whichever occurs earlier.or 
resolution of ARDS. 
The treatments are intended to continue to either Day 7 or until thesubject’s ARDS 
is resolved (PaO2/FiO2 ratio >300 mm Hg) subject no longer requires respiratory 
support (oxygen supplementation or mechanical ventilation) or is discharged from 
the hospital (whichever occurs earlier), except upon allowance by the DMC and by 
investigator discretion to administer treatment up to Day 21 (Part 2 only; extended 
treatment will be allowed only in subjects who still have mild or moderate ARDS 
require respiratory support at Day 7 with at least a 20-mm Hg increase in PaO2 from 
baseline). If treatment is interrupted for any reason for more than 24 hours, 
treatment may not be resumed. 
A relapse of respiratory failure or ARDS due to COVID-19 must be reported as an 
adverse event. Under no circumstances can study drug be administered beyond the 
DMC-approved treatment window, and treatment may not be reinitiated if it is 
discontinued. 
Section 9.1.1 
Revised Discontinuation of Study Intervention 
Section 10.1 
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In Part 2 dosing may be extended only in subjects who still require respiratory 
support (oxygen supplementation or mechanical ventilation) at Day 7 have mild or 
moderate ARDS at day 7 with at least a 20-mm Hg increase in PaO2 from baseline.
Revised end-of-treatment assessments
 
The study end-of-treatment assessments are to be conducted on the 
day of hospital discharge. The 30-day (+7) posttreatment follow-up 
assessment, conducted 30 days after the last dose of study drug (with a 
+7-day window), may be conducted either in the hospital or by 
telephone so that subjects do not have to be exposed to the hospital 
environment after hospital discharge.  
Section 11
Revised wording for Day 1 Assessments 
Laboratory test samples (Table 2) are to be obtained at designated visits as detailed 
in the SoA (Table 1). Day 1 assessments should be collected within 5 hours of 
loading infusion Blood will be collected 3 times on Day 1: (1) once prior to 
administration of the APL-9 bolus, (2) once as soon as possible following the bolus 
(within 5-10 minutes) prior to the continuous infusion, and (3) once at 2 hours after 
the beginning of the continuous infusion.  
Revised Table 2, Clinical Laboratory Tests 
Additional laboratory tests were added to Table 2, which was reformatted to clearly 
indicate which tests would be performed at local and central/specialty laboratories. 
Section 11.1.8 
Updated definition of adverse events 
11.2.1 Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in 
humans whether or not it is considered drug related. An AE can, therefore, be any 
unfavorable and unintended sign, including a clinically significant abnormal 
laboratory finding, symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related causally to the 
investigational product (FDA Guidance for Industry). Any abnormal finding that is 
deemed not clinically significant is not an AE. 
Adverse events can be spontaneously reported by the subject and/or in response to 
an open question from the study personnel or revealed by observation and will be 
recorded during the study at the investigational site. All identified AEs must be 
recorded and described on the appropriate AE or SAE page of the eCRF.  
Fluctuating or nonsignificant changes in laboratory values do not necessarily qualify 
for AE reporting. If these changes in laboratory values are assessed as clinically 
significant and/or lead to discontinuation of administration of investigational 
product, these should be reported as an AE. If these laboratory values are linked to a 
diagnosis, only the diagnosis should be reported as an AE.Any medical condition 
that is present at the time when the subject is screened should be recorded on the 
medical history eCRF and not reported as an AE. However, if that condition 
deteriorates or severity changes at any time during the study, it should be recorded 
as an AE. 
Any AEs that occur prior to dosing on study Day 1 will be categorized as 
pretreatment events. Treatment-emergent adverse events will be defined as those 
AEs that occur or worsen in severity after initial dosing and during the 30-day (+7) 
posttreatment follow-up.  
Section 11.2.1 
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A suspected adverse reaction (ADR) is any AE for which there is a reasonable 
possibility that the investigational product caused the AE. Reasonable possibility 
means that there is evidence to suggest a causal relationship between the 
investigational product and the AE. 
Updated serious adverse events and moved to Section 11.2.2 
11.2.1.1 11.2.2 Serious Adverse Event 
If any AEs are serious, special reporting procedures will be followed, as described 
in Section 11.2.4.
An SAE is any AE occurring during any study period (ie, baseline, treatment, 
washout, or follow-up), and at any dose of the investigational product, comparator, 
or vehicle, that, in the view of either the investigator or Apellis Pharmaceuticals, 
Inc, fulfills one or more of the following criteria: 
 
Results in death 
 
Is immediately life threatening 
 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Results in a congenital abnormality or birth defect 
An SAE is any AE or suspected adverse reaction that, in the view of either the 
investigator or sponsor, results in any of the following outcomes: death; life-
threatening; inpatient hospitalization or prolongation of existing hospitalization; a 
persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening*, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment they may jeopardize the subject and may require medical/surgical 
intervention to prevent one of the outcomes listed in the above definition. 
Examples of important medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization; or the development of 
drug dependency or drug abuse. 
*Life-threatening is defined as an AE or suspected adverse reaction, which, in the 
view of either the investigator or sponsor, places the subject at immediate risk of 
death as it occurred. It does not include an AE or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death. 
Unexpected Adverse Event 
An AE is considered “unexpected” if it is not listed in the Reference Safety 
Information section of the investigator’s brochure in effect at that time of event 
onset.Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, according to appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of such medical events may include infections that require antibiotic 
treatment, allergic bronchospasm requiring intensive treatment in an emergency 
Section 11.2.2 
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room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
A life-threatening AE is defined as an AE or suspected ADR that, in the view of 
either the investigator or Apellis Pharmaceuticals, Inc, places the subject at 
immediate risk of death. It does not include an AE or suspected ADR that, had it 
occurred in a more severe form, might have caused death. 
An unexpected AE is defined as an AE or suspected ADR that is not listed in the 
investigator’s brochure, is not listed at the specificity or severity that has been 
observed, or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current protocol, as amended. 
Moved evaluation of adverse events to Section 11.2.3 
11.2.2 11.2.3 Evaluation of Adverse Events 
Section 11.2.3 
Updated recording of adverse events and moved to Section 11.2.4 
11.2.3 11.2.4 Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open 
question from the study personnel or revealed by observation will be recorded 
during the study at the investigational site. Clinically significant changes in 
laboratory values, blood pressure, and pulse rate must be reported as AEs. However, 
abnormal values that constitute SAEs or lead to discontinuation of administration of 
study drug must be reported and recorded as AEs. Information about AEs and SAEs 
will be collected from the signing of the ICF until the study end-of-treatment visit. 
The AE term should be reported in standard medical terminology when possible. 
For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, and serious outcome (if 
applicable) and whether or not the subject discontinued treatment as a result of the 
event. 
It is important to distinguish between serious and severe AEs. Severity is a measure 
of intensity, as summarized in Table 4, whereas seriousness is defined by the criteria 
under Section 11.2.2. An AE of severe intensity may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the Apellis 
Pharmaceuticals, Inc, pregnancy form. As described in Section 11.2.5, pregnancy in 
itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication 
Adverse events and SAEs will be collected from the signing of the consent form 
until the safety follow-up assessment, or 30 days after the last dose of study 
treatment, up to Study Day 51 (+7). 
Any events that occur prior to dosing will be categorized as pretreatment events; 
events occurring after dosing will be recorded as TEAEs (start date of dosing and, 
therefore, categorization of the event will be dependent on randomization 
assignment). 
For each AE, the investigator will evaluate and report the onset date (and time if 
applicable), resolution date (and time if applicable), intensity, causality, action 
taken, serious outcome, and whether or not it caused the subject to discontinue the 
study. 
If possible, the outcome of any AE that caused permanent discontinuation or was 
present at the end of the study should be reported, particularly if the AE was 
considered by the investigator to be related to the investigational product. Subjects 
experiencing AEs that cause interruption or discontinuation of investigational 
Section 11.2.4 
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product, or those experiencing AEs that are present at the safety follow-up 
assessment (30 days after the last dose of APL-9), up to study Day 51 (+7) should 
receive follow-up as appropriate.
All SAEs must be reported to the sponsor/Apellis Safety via eCRF immediately and 
within 24 hours of becoming aware of the event, whether or not the event is deemed 
treatment-related. If the electronic data capture (EDC) system is not operational (or 
for paper-based study[ies]), the site must complete the paper SAE form and email to 
, also within 24 hours of becoming aware of the event. The 
reported information submitted as a paper SAE must be entered into the EDC 
system once it becomes operational. 
Adverse events will be coded in accordance with the Medical Dictionary for 
Regulatory Activities (MedDRA). If known, the diagnosis of the underlying illness 
or disorder should be recorded, rather than its individual symptoms.
Updated reporting of adverse events and moved to Section 11.2.5
11.2.4 11.2.5 Reporting Adverse Events 
All SAEs and pregnancies must be reported to Apellis Pharmaceuticals, Inc, via 
eCRF immediately, whether or not the event is deemed treatment-related. If the 
electronic data capturing system is not operational, the site must complete the 
appropriate paper SAE form and email it to the number/address listed on the SAE 
form immediately on becoming aware of the event. The reported information 
submitted as a paper SAE must be entered into the electronic data capturing system 
once it becomes operational.  
The collection of clinical information will begin after the subject’s written consent 
to participate in the study has been obtained. Adverse events will be collected after 
signing the ICF through completion of the last study visit. Any events that occur 
prior to dosing will be categorized as pretreatment events; events occurring after 
dosing will be recorded as TEAEs (the start date of dosing and therefore the 
categorization of the event will be dependent on randomization assignment). 
Adverse events may be either spontaneously reported or elicited during questioning 
and examination of a subject. 
All identified AEs, including clinically significant laboratory findings, must be 
recorded and described on the appropriate AE page of the eCRF. If known, the 
diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. Adverse events will be coded in accordance with the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Subjects experiencing AEs that cause interruption or discontinuation of study drug 
or experiencing AEs that are present at the exit visit should receive follow-up as 
appropriate. SAEs should be followed up until resolution. If possible, the outcome 
of any AE that caused permanent discontinuation or was present at the end of the 
study should be reported, particularly if the AE was considered by the investigator 
to be related to the study drug 
The sponsor has the responsibility to inform concerned health authorities, ethics 
committees, and investigators about suspected unexpected serious adverse reactions 
in line with GCP guidance and applicable regulatory requirements. 
If required, specific SAEs should be reported to the concerned ethics committees in 
compliance with local requirements.  
Apellis Pharmaceuticals, Inc, and/or its designee are responsible for reporting SAEs 
to all applicable regulatory agencies and the central ethics committees within the 
required timelines. 
Section 11.2.5
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Investigators are responsible for submitting required safety information to their 
local institutional review board (IRB) or independent ethics committee (IEC) as per 
local regulations. This information includes but is not limited to any safety alert 
letters received from Apellis Pharmaceuticals, Inc, and any SAEs occurring at their 
investigative sites. 
Revised Pregnancy section and moved to Section 11.2.6 
11.2.5 11.2.6 Pregnancy 
Should a pregnancy occur, it must be reported and recorded on the Apellis 
Pharmaceuticals, Inc, pregnancy form. Although pregnancy is not considered an AE 
unless there is a suspicion that an investigational product may have interfered with 
the effectiveness of a contraceptive medication, the outcome of a pregnancy may be 
an SAE if there is a spontaneous abortion, congenital anomaly, or other adverse 
fetal outcome.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) must be followed up and documented even 
if the subject was discontinued from the study. 
All reports of congenital abnormalities, birth defects, or other adverse fetal 
outcomes are SAEs. Spontaneous miscarriages should also be reported and handled 
as SAEs. Elective abortions without complications should not be handled as AEs. 
All SAEs are to be reported to Apellis Pharmaceuticals, Inc, on the SAE form.  
If a female subject/partner of a male subject becomes pregnant during the study, the 
investigator should report the pregnancy to the safety monitor within 1 calendar day 
of being notified. The subject or partner should be followed by the investigator until 
completion of the pregnancy. At the completion of the pregnancy, the investigator 
will document and report the outcome. If the outcome of the pregnancy meets the 
criteria for classification as an SAE (ie, postpartum complication, stillbirth, neonatal 
death, spontaneous abortion, or congenital anomaly) the investigator should follow 
the procedures described in Section for reporting Although pregnancy is not an AE, 
all pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) occurring with a female subject or the female 
partner of a male subject must be followed to conclusion to determine their outcome 
and are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Apellis Safety within 24 hours of the investigator’s awareness using the paper 
Pregnancy Report Form. The Pregnancy Report Form shall be signed and dated by 
the investigator and submitted via email to 
. 
The investigator must follow the subject until completion of the pregnancy and must 
report the outcome of the pregnancy (eg, delivery, termination, etc) and neonatal 
status up to 12 months post delivery. An abnormal outcome is defined as any 
pregnancy that results in the birth of a child with persistent or significant incapacity 
or substantial disruption of the ability to conduct normal life functions (formerly 
referred to as disabilities), congenital anomalies, or birth defects. In the event of an 
abnormal outcome, an SAE Report Form will be required. 
Section 11.2.6 
Updated Section 11.3, Overdose 
11.3 Drug Abuse, Misuse, Overdose, and Medication Error 
Occurrences of events of drug abuse, drug misuse, drug overdose, and medication 
error must be reported to Apellis Safety. 
Section 11.3 
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Abuse of a medicinal product: Persistent or sporadic, intentional excessive use of 
medicinal products, which is accompanied by harmful physical or psychological 
effects.
Misuse: Intentional and inappropriate use of a medicinal product not in accordance 
with the prescribed or authorized dose, route of administration and/or the 
indication(s) or not within the legal status of its supply. 
Overdose: Administration of a quantity of study drug given per administration or 
per day, which is above the assigned dose. 
Medication Error: An error made in prescribing, dispensing, administration and/or 
use of the study drug. Medication errors are reportable to the sponsor as defined 
below: 
 
The dispensing, administration, and/or use of the unassigned study drug. 
The administration and/or use of an expired study drug.
All AEs or SAEs associated with drug abuse, drug misuse, drug overdose, or 
medication error must be reported as appropriate.To date, neither nonclinical nor 
clinical studies of APL-9 have identified safety risks specifically associated with an 
APL-9 overdose. In case of suspected overdose please contact the sponsor 
immediately. 
Revised section heading 11.4 and updated text 
11.4 Viral RNA/Viral Antigen Assessment 
Presence of SARS-CoV-2 viral RNA or viral antigen will be detected in respiratory 
specimens (collected using nasopharyngeal or oropharyngeal swabs) with a 
qualitative nucleic acid amplification test (such as RT-PCR) or viral antigen test or 
other diagnostic method that is authorized, cleared, or approved by the US Food and 
Drug Administration (or equivalent local authority) for SARS-CoV-2 viral 
detection. Serology-based antibody tests do not detect the presence of virus and 
therefore are not considered diagnostic for active infection and cannot be used for 
study eligibility screening or for subsequent SARS-CoV-2 assessments. 
Section 11.4 
Revised Section 11.5, Pharmacokinetics 
The exposure of subjects to APL-9 will be evaluated in serum from blood collected 
in a serum separator tube. Two serum aliquots of at least 0.5 mL will be stored at  
–70 °C and shipped on dry ice. Blood will be collected on Day 1, once prior to 
administration of the APL-9 bolus, once as soon as possible following the bolus 
(5-10 minutes), and before the continuous infusion commences. Blood will also be 
collected at 2 hours after the initial bolus administration.Blood will be collected 
3 times on Day 1: (1) once prior to administration of the APL-9 bolus, (2) once as 
soon as possible following the bolus (within 5-10 minutes) prior to the continuous 
infusion, and (3) once at 2 hours after the beginning of the continuous infusion. 
Blood will then be collected once daily between 1-2 hours after the first dose, on 
Days 3, 5, 7, 11 (if treatment is ongoing), and 15 (if treatment is ongoing) and at the 
end-of-treatment visit (if the patient is discharged on a day not indicated for a 
clinical laboratory testPK sample). 
Section 11.5 
Revised Section 11.6, Pharmacodynamics 
The pharmacodynamic parameters evaluated in this studyare related to complement 
activation markers (are levels of C3, C3a, Bb, C4, C4a, C5a, and TCC) and a 
hemolytic assay measuring the function of the alternative complement pathway 
(AH50). The pharmacodynamic parameters evaluated in this study related to 
Section 11.6 
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thrombotic microangiopathy coagulopathy are reticulocyte count, presence of 
schistocytes, levels of D-dimer, ferritin, lactate dehydrogenase, haptoglobin, 
fibrinogen, 
. The pharmacodynamic parameters evaluated in this study related to 
inflammation are levels of C-
-
IL-6. The complement activation markers and inflammatory cytokines will be 
analyzed in plasma from blood collected in K2 EDTA (dipotassium 
ethylenediaminetetraacetic acid) tubes with the exception of C-reactive protein, 
which is measured from serum. The AH50 hemolytic assay will be measured in 
serum from blood collected in red plain top (no gel) tubes. The thrombotic 
microangiopathy coagulopathy markers will be analyzed in plasma collected in 
sodium citrate tubes or serum. These blood samples will be collected at the same 
time as the pharmacokinetic samples described in Section 11.5. Blood will be 
collected on the first day, once prior to administration of the APL-9 bolus, once as 
soon as possible following the bolus (5 to 10 minutes), and before the continuous 
infusion commences. Blood will also be collected at 2 hours after the initial bolus 
administration. Blood will be collected then once daily, between 1-2 hours after first 
dose on Days 3, 5, 7, 11 (if treatment is ongoing), 15 (if treatment is ongoing), and 
the end-of-treatment visit (if the patient discharges on a day not indicated for a 
PK/PD sample). Blood will be collected 3 times on Day 1: (1) once prior to 
administration of the APL-9 bolus, (2) once as soon as possible following the bolus 
(within 5-10 minutes) prior to the continuous infusion, and (3) once at 2 hours after 
the beginning of the continuous infusion. If the patient discharges on a day not 
indicated for a clinical laboratory test sample, blood will be collected between 
1-2 hours after first dose of the end-of-treatment (EOT) visit. 
Revised Section 12.3.3 Analysis of Time-to-Event Data 
Event rates (eg, mortality through the safety Day 30 follow-up assessment) will be 
estimated along with the corresponding 2-sided 95% CI (or 2-sided 90% CI if 
appropriate). 
Section 12.3.3 
Updated schedule of reviews by the independent data monitoring committee for 
Part 2: 
In Part 2, DMC review will occur after first 10 subjects reach the approved 
treatment duration (or resolution of ARDS) and after the first 30 subjects reach the 
approved treatment duration (or resolution of ARDS). two reviews will be required: 
1.
After the 10th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge  
2. After the 30th subject reaches the approved treatment duration, 
discontinuation of respiratory support (oxygen supplementation or 
mechanical ventilation), or hospital discharge 
Section 12.7 
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SAP_001.pdf: 
A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  1  of 3 2                                        C o nfi de ntial  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
 
A R a n d o mize d, D o u ble -Bli n d, Ve hicle -C o ntr olle d, M ultice nter, P ar allel -
Gr o u p St u d y of A P L -9 i n Mil d t o M o der ate Ac ute Res pir at or y Distress 
S y n dr o me D ue t o C O VI D -1 9   
 
 
I N D N u m ber:  
1 4 8 3 6 1  
Pr ot oc ol N u m ber:  
A P L 9 -C O V -2 0 1  
Pr ot oc ol  V ersi o n a n d D ate :          
A me n d me nt 3  (0 9  N O V  2 0 2 0)  
A me n d me nt 2 ( 1 7 A U G 2 0 2 0)  
A me n d me nt 1 ( 0 7 M A Y 2 0 2 0)  
Ori gi nal ( 2 3 A P RI L 2 0 2 0)  
 
 
 
P h ase : 
P hase  I / II 
S p o ns or : 
A pellis P har mace uticals, I n c  
A n al ysis Pl a n  Versi o n:  
2 . 0 
A n al ysis Pl a n  D ate:  
1 1 M A Y 2 0 2 1  
 
 
N otice of C o nfi de nti al a n d Pr o priet a r y I nf or m ati o n:  
T his d oc u me nt is c o nfi de ntial. It c o ntai ns pr o priet ar y i nf or mati o n of A pellis P har mace utical, I nc. 
A n y vie wi n g or discl os ure of s uc h i nf or m ati o n t hat is n ot a ut h orize d i n writi n g b y A pellis 
P har m ace utical, I nc is strictl y pr o hi bite d. S uc h i nf or mati o n ma y b e use d s olel y f or t he p ur p os e of 
re vie wi n g or perf or mi n g t his st u d y. 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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R E VI SI O N HI S T O R Y  
Versi o n  
Iss u e Date 
S u m mar y of C ha n ges  
1. 0  
3 0 O C T 2 0 2 0  
Ne w D oc u m e nt  
2. 0  
1 1 M A Y 2 0 2 1  
1, U p date d t he si g nat ories.  
2, U p date d  la n g ua ges f or clarit y p er pr ot oc ol 
a me n d me nt 3. 
 
 
 
 
4 , Clarifie d f ull a nal ysis set defi niti o n  i n secti o n 
4. 4 . 
5, Re m o ve d per  pr ot oc ol set . 
6 , 
A d de d stratifie d 
L o g-ra n k test a n d 
C o x 
re gressi o n met h o d f or a nal ysis of ti me-t o-e ve nt 
e n d p oi nts  i n secti o n 6. 2. 1. 
 
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
C CI


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  3  of 3 2                                        C o nfi de ntial  
SI G N A T U R E P A G E  
 
B y si g ni n g t his d oc u m e nt, I ac k n o wle d ge t hat I h a ve rea d t he d oc u me nt a n d a p pr o ve of t he pla n ne d 
statistical a nal ys es descri be d herei n. I a gree t h at t he pla n ne d statistical a n al yses are a p pr o priat e f or 
t his st u d y, are i n acc or da nce wit h t he st u d y o bjecti ves, a n d are c o nsiste nt wit h t he statistical 
met h o d ol o g y descri be d i n t he  st u d y, a n d all a p plica ble re g ulat or y g ui da nce a n d g ui deli nes.  
 
 
 
Pre p are d b y:  
 
 
Date  
 
 
 
 
 
 
Re vie we d a n d A p pr o ve d b y:  
 
 
A pellis P har mace uticals, I n c  
 
Date  
 
 
 
 
Re vie we d a n d A p pr o ve d b y:  
 
  
A pellis P har mace uticals, I n c  
 
Date  
 
 
Re vie we d a n d A p pr o ve d b y:  
 
  
A pellis P har mace uticals, I n c  
 
Date  
 
 
  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
1 1 - M a y - 2 0 2 1  |  1 6 : 3 8  E D T
1 1 - M a y - 2 0 2 1  |  1 3 : 2 1  P D T
1 1 - M a y - 2 0 2 1  |  1 6 : 5 4  E D T
1 1 - M a y - 2 0 2 1  |  1 6 : 2 1  E D T
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  4  of 3 2                                        C o nfi de ntial  
T A B L E O F C O N T E N T S  
S T A TI S TI C A L A N A L Y SI S  P L A N  .................................................................................1  
R E VI SI O N HI S T O R Y  ......................................................................................................2  
SI G N A T U R E P A G E  ..........................................................................................................3  
T A B L E O F C O N T E N T S  ..................................................................................................4  
LI S T O F T A B L E S I N C L U D E D I N T H E T E X T  ............................................................7  
A B B R E VI A TI O N S  ............................................................................................................8  
1.  
I N T R O D U C TI O N................................................................................................1 0  
2.  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  ......................................................1 1  
2. 1  
O bjecti ves  ..........................................................................................................1 1  
2. 1. 1  Pri mar y O bj ecti ve  ......................................................................................1 1  
2. 1. 2  Sec o n dar y O bj ecti ves .................................................................................1 1  
2. 1. 3  E x pl orat or y O bjecti ves  ..............................................................................1 1  
2. 2  
E n d p oi nts  ..........................................................................................................1 1  
2. 2. 1  Pri mar y O bj ecti ve E n d p oi nt  ......................................................................1 1  
2. 2. 2  Sec o n dar y O bj ecti ve E n d p oi nts  .................................................................1 1  
2. 2. 3  E x pl orat or y O bjecti ve E n d p oi nts  ...............................................................1 2  
3.  
S T U D Y D E SI G N  ..................................................................................................1 3  
3. 1  
O ver vie w of St u d y D esi g n  ................................................................................1 3  
3. 2  
Sa m ple Siz e a n d P o wer C o nsi derati o ns  ............................................................1 5  
3. 3  
Ra n d o mizati o n ( Part 2 O nl y)  ............................................................................1 5  
3. 4  
Bli n di n g ( Part 2 O nl y)  .......................................................................................1 5  
4.  
S T A TI S TI C A L A N A L Y SI S S E T S  .....................................................................1 6  
4. 1  
Scree ne d Set  ......................................................................................................1 6  
4. 2  
Safet y Set  ..........................................................................................................1 6  
4. 3  
I nte nt-t o-Tre at Set  .............................................................................................1 6  
4. 4  
F ull A nal ysis Set  ...............................................................................................1 6  
4. 5  
P har mac o ki netic Set  ..........................................................................................1 6  
4. 6  
P har mac o d y na mic Set  .......................................................................................1 6  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  5  of 3 2                                        C o nfi de ntial  
5.  
S T U D Y S U B J E C T S  .............................................................................................1 7  
5. 1  
S u bjects Dis p ositi o n  ..........................................................................................1 7  
5. 2  
De m o gra p hics a n d Baseli ne C haract eristics  .....................................................1 7  
5. 3  
Me dical Hist or y  .................................................................................................1 8  
5. 4  
Pri or a n d C o nc o mita nt Me dicati o ns ..................................................................1 8  
5. 5  
Pri or a n d C o nc o mita nt Pr oce d ures  ...................................................................1 8  
5. 6  
E x p os ure t o St u d y Dr u g  ....................................................................................1 8  
5. 7  
Meas ure me nts of T reat me nt C o m plia nce .........................................................1 9  
5. 8  
Pr ot oc ol De viati o ns  ...........................................................................................1 9  
6.  
E F FI C A C Y A N A L Y SI S  ......................................................................................2 0  
6. 1  
A nal ysis of Pri mar y Effi cac y E n d p oi nt  ............................................................2 0  
6. 2  
A nal ysis of Sec o n dar y Efficac y E n d p oi nts  .......................................................2 0  
6. 2. 1  Ti me -t o-e ve nt e n d p oi nts  ............................................................................2 0  
6. 2. 2  Se q ue ntial Or ga n Fail ure Assess me nt ( S O F A) sc ore  ................................2 1  
6. 3  
A nal ysis of E x pl orat or y E n d p oi nts  ...................................................................2 2  
6. 3. 1  Prese nce of acti ve S A R S -C o V -2 i nfecti o n o n at t h e e n d -of -treat me nt visit2 2  
6. 3. 2  I n ci de nce, d urati o n, a n d e xte nt of ne w o x y ge n t hera p y use (re-i nitiati o n 2 4 
h o u rs or m ore after cessati o n of pri or o x y ge n t hera p y) .............................2 2  
6. 3. 3  I n ci de nce, d urati o n, a n d e xte nt of ne w mec h a nical ve ntilati o n use (re-i nitiati o n 
2 4 h o urs or m ore after cessati o n of pri or mec ha ni cal  ve ntilati o n)  ............2 2  
6. 3. 4  
 
......................................................................................................2 3  
7.  
S A F E T Y A N A L Y SI S ...........................................................................................2 3  
7. 1  
A d verse E v e nts ..................................................................................................2 3  
7. 2  
Cli nical La b orat or y D ata  ...................................................................................2 5  
7. 3  
Vital Si g ns  .........................................................................................................2 5  
7. 4  
Electr ocar di o gra m ( E C G)  .................................................................................2 5  
8.  
P H A R M A C O KI N E TI C A N A L Y SI S  .................................................................2 6  
8. 1  
Dr u g  C o nce ntr ati o n  ...........................................................................................2 6  
8. 2  
Ha n dli n g B L Q Val ues  .......................................................................................2 6  
9.  
P H A R M A C O D Y N A MI C A N A L Y SI S ...............................................................2 7  
9. 1  
P har mac o d y na mic D ata  ....................................................................................2 7  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
C CI


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1 0.  
I N T E RI M A N A L Y SI S ........................................................................................2 7  
1 1.  
I N D E P E N D E N T D A T A M O NI T O RI N G C O M MI T T E E ...............................2 7  
1 2.  
D A T A H A N D LI N G C O N V E N TI O N S  ..............................................................2 7  
1 2. 1  
Ge neral Data Re p orti n g C o n ve nti o ns  ...............................................................2 7  
1 2. 2  
Defi niti o n of St u d y Da ys  ..................................................................................2 8  
1 2. 3  
Defi niti o n of Bas eli ne  .......................................................................................2 8  
1 2. 4  
Defi niti o n of Visit Wi n d o ws  .............................................................................2 8  
1 2. 5  
Re peate d or U nsc he d ule d Assess me nts  ............................................................2 9  
1 2. 6  
Ha n dli n g of Missi n g, U n use d, a n d S p uri o us Data  ............................................2 9  
1 2. 6. 1  Missi n g Date of I n v esti gati o nal Pr o d uct ....................................................2 9  
1 2. 6. 2  Missi n g or Partial Dates f or Me dicati o ns  ..................................................2 9  
1 2. 6. 3  Missi n g or Partial Dates f or Pr oce d ures  ....................................................3 0  
1 2. 6. 4  Missi n g or Partial Dates f or A d verse E ve nts  .............................................3 0  
1 2. 6. 5  Missi n g Se verit y Assess me nt f or A d verse E ve nts .....................................3 1  
1 2. 6. 6  Missi n g Relati o ns hi p t o I n vesti gati o nal Pr o d uct f or A d verse E ve nts  .......3 1  
1 2. 6. 7  Detecta bl e Li mits of Cli nical La b orat or y Varia bles  ..................................3 2  
1 3.  
A N A L Y SI S S O F T W A R E  ...................................................................................3 2  
1 4.  
C H A N G E S T O A N A L Y S E S  ...............................................................................3 2  
1 4. 1  
C ha n ges t o A n al yses S pecifie d i n t h e pr ot oc ol  .................................................3 2  
1 4. 2  
C ha n ges fr o m A nal ys es S pecifie d i n t he Pre vi o us Versi o n of t he S A P  ...........3 2  
1 5.  
R E F E R E N C E S  .....................................................................................................3 2  
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  7  of 3 2                                        C o nfi de ntial  
LI S T O F T A B L E S I N C L U D E D I N T H E T E X T  
T A B L E 1: S E Q U E N TI A L O R G A N F AI L U R E  A S S E S S M E N T ( S O F A) S C O RI N G  ........................... 2 1  
T A B L E 2 : C RI TI E R A F O R P O T E NTI A L L Y C LI NI C A L L Y SI G NI FI C A N T VI T A L SI G N S  ......... 2 5  
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
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A B B R E VI A TI O N S  
A b bre vi ati o n  
Ter m  
A E  
A d verse E v e nt  
A H 5 0  
C o m ple me nt A lter nati ve P at h wa y A ssa y 
A T C  
A nat o mical T hera pe ut ic C he mical  
A R D S  
Ac ute Res pirat or y Distress S y n dr o me  
B L Q  
B el o w t he L i mit of Q ua ntificati o n  
B MI  
B o d y Mass I n d e x  
CI  
C o nfi de nce I nter val  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R O  
C o ntract Researc h Or ga nizati o n  
C T M S  
Cli nical Trial Ma na ge me nt S yst e m  
C V  
C oef ficie nt of V ariati o n 
D M C  
Data M o nit ori n g C o m mittee  
E C G  
Electr ocar di o gra m  
eC R F  
Electr o nic Case Re p ort F or m  
F A S  
F ull A nal ysis Set  
I C F 
I nf or me d C o nse nt F or m 
I T T 
I nte nt-t o-Treat  
K M  
Ka pla n -Mei er  
L L O Q  
L o w er L i mit of Q ua ntificati o n  
Me d D R A  
Me dical Dicti o n ar y for R e g ul at or y Acti vities  
P D  
P har mac o d y na mic(s)  
P K  
P har mac o ki netic(s)  
P T  
Preferre d Ter m  
S A E  
Seri o us A d verse E v e nt  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  9  of 3 2                                        C o nfi de ntial  
A b bre vi ati o n  
Ter m  
S A P  
Statistical A nal ysis Pla n  
S A R S -C o V -2  
Se vere A c ute Res pirat or y S y n dr o me C or o na vir us 2  
 
S D  
Sta n dar d de viati o n  
S O A  
Sc he d ule of Assess me nt s 
S O C  
S yste m Or ga n Class  
S O F A  
Se q ue ntial Or ga n Fail ure Assess me nt  
T E A E   
Treat me nt -E mer ge nt A d verse E ve nt  
T C C  
Ter mi nal C o m ple me nt C o m ple x  
W H O  
W orl d Healt h Or ga nizati o n  
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  1 0  of 3 2                                        C o nfi de ntial  
1.  
I N T R O D U C TI O N  
T his statistical a nal ysis pla n ( S A P) descri bes detaile d  statistical met h o ds t o be use d f or data 
ha n dli n g pr oce d ures,  a n al ysis a n d data pres e ntati o n f or A pellis st u d y pr ot oc ol A P L 9 -C O V -2 0 1 : A 
Ra n d o mize d, D o u ble -Bli n d, Ve hicle -C o ntr olle d, M ultice nter, Parallel -Gr o u p St u d y of A P L -9 i n 
Mil d  t o M o derate Ac ute Res pi rat or y Distress S y n dr o me D ue t o C O VI D-1 9 . 
T his d oc u me nt has b ee n pre pare d acc or di n g t o st u d y pr ot oc ol versi o n 1. 0, A me n d me nt 3 . 0 date d 
0 9 N o ve m ber  2 0 2 0 a n d e C R F versi o n 6 . 0 date d 2 5  N o v e mber 2 0 2 0 . T he a n al yses s pecifie d i n t his 
d oc u me nt s u perse d e t he a nal ysis pla n descri b e d i n t he st u d y pr ot oc ol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  1 1  of 3 2                                        C o nfi de ntial  
2.  
S T U D Y  O B J E C TI V E S A N D E N D P O I N T S 
2. 1  
O bjecti ves  
2. 1. 1  Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he safet y of A P L -9 c o m pare d wit h t hat of ve hicl e 
c o ntr ol (as a d d -o n t hera p y t o sta n dar d of care) i n s u bjects wit h c or o na vir us disease 2 0 1 9 ( C O VI D -
1 9) w h o ha v e res pir at or y fail ure, i ncl u di n g mil d t o m o derate ac ute res pirat or y distress s y n dr o me 
(A R D S ). 
2. 1. 2  Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t his st u d y are  to e v al u ate t he effect of A P L -9 o n:  
•  H os pital le n gt h of sta y  
•  O verall s ur vi val  
•  C ha n ge i n Se q u e ntial Or ga n Fail ure Assess me nt ( S O F A) sc ore  
•  Ti me o n mec ha nic al ve ntilati o n  
•  Ti me o n o x y ge n t hera p y  (i. e., ti me o n mec ha ni cal ve ntilati o n or  s u p ple me ntal o x y ge n 
thera p y)  
•  A P L -9 p h ar mac o ki netics ( P K )  
•  A P L 9 p h ar mac o d y n a mics ( P D; t he effect of A P L 9 o n c o m ple me nt,  a n d i nfla m mati o n 
bi o mar kers)  
2. 1. 3  E x pl or at or y O bjecti ves  
T he e x pl orat or y o bj ecti v es of t his st u d y are t o e val uate:  
•  T he effect of A P L -9 o n prese nce of acti ve S A R S -C o V -2 i nfecti o n  
•  T he effect of A P L -9 o n ne w o x y ge n t hera p y us e d uri n g t he st u d y (re -i nitiati o n 2 4 h o urs or 
m ore after cess ati o n of pri or o x y ge n t hera p y)  
•  T he effect of A P L 9 o n ne w mec ha nical v e ntilati o n use (re -i nitiati o n 2 4 h o urs or m ore aft er 
cessati o n of pri or me c ha nical ve ntilati o n)  
•  
 
2. 2  
E n d p oi nt s 
2. 2. 1  Pri m ar y O bjecti ve  E n d p oi nt  
•  C u m ulati ve i nci de nce of treat me nt -e mer ge nt seri o us a d verse e ve nts ( S A Es) a n d treat me nt -
e mer ge nt a d v erse e ve nts  ( T E A Es) 
2. 2. 2  Sec o n d ar y O bjecti ve  E n d p oi nt s 
•  H os pital le n gt h of sta y ( meas ure d i n da ys)  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
C CI


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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A pellis P har mace uticals, I n c                      Pa ge  1 2  of 3 2                                        C o nfi de ntial  
•  A n y -ca us e m ortalit y ( meas ure d fr o m be gi n ni n g of treat me nt u ntil t he safet y f oll o w-u p 
assess me nt 3 0 da ys aft er last st u d y treat me nt [u p t o a n d i ncl u di n g St u d y Da y 5 1 wit h a 
+ 7 -da y wi n d o w ]) 
•  S O F A sc ore  
•  T otal d urati o n of mec h a nical ve ntilati o n ( meas ure d i n da ys)  
•  T otal d urati o n of o x y ge n t hera p y ( o n mec ha nical v e ntilati o n or s u p ple me ntal o x y ge n ) 
•  A P L -9 P K para met ers  
•  O bser ve d v al ues a n d c ha n ges fr o m baseli ne i n mar kers of c o m ple me nt acti v ati o n ( C 3, C 3a, 
C 4, C 4a, B b, C 5 a, T C C, a n d alter nati ve c o m ple m e nt pat h wa y he m ol yti c acti vit y [ A H 5 0]), 
c oa g ul o pat h y (retic ul oc yte c o u nt, sc hist oc yt es, lactate de h y dr o ge n ase, D -di mer, ferriti n, 
ha pt o gl o bi n, fi bri n o ge n, ), a n d i nfla m mat or y c yt o ki nes ( C-reacti ve pr otei n, t u m or necr osis 
fact or α, I L-1 β, a n d I L -6)  
2. 2. 3  E x pl or at or y O bjecti ve E n d p oi nts  
•  Prese nce of acti ve S A R S -C o V -2 i nfecti o n at t he e n d -of -treat me nt visit. Prese nce of S A R S-
C o V -2 viral R N A or viral a nti ge n ma y be detect e d i n res pirat or y s peci me ns (c ollecte d 
usi n g nas o p har y n geal or or o p har y n geal s wa bs) 
wit h a q ualitati ve n ucleic aci d 
a m plificati o n test (s uc h as re verse tra ns cri ptase p ol y merase c h ai n reacti o n [ R T -P C R]), 
viral a nti ge n test, or ot her dia g n ostic met h o d t hat is a ut h orize d, cleare d, or a p pr o ve d b y t he 
U S F o o d a n d Dr u g A d mi nistrati o n ( or e q ui val e nt l ocal a ut h orit y) f or S A R S -C o V -2 viral 
detecti o n. Ser ol o g y -base d a nti b o d y tests d o n ot detect t he  prese n ce of vir us a n d t heref ore 
are n ot c o nsi dere d dia g n o stic a n d ca n n ot be use d f or st u d y eli gi bilit y scree ni n g or f or 
s u bse q ue nt S A R S-C o V -2 assess me nts.  
•  I n ci de nce, d urati o n, a n d e xte nt of ne w o x y ge n t hera p y us e (re -i nitiati o n 2 4 h o urs or m ore 
after cessati o n of pri or o x y ge n t h era p y)  
•  I n ci de nce, d urati o n, a n d e xte nt of ne w mec ha nical ve ntilati o n use (re-i nitiati o n 2 4 h o urs or 
m ore after cess ati o n of pri or mec ha nical ve ntilati o n)  
•  
 
 
 
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
C CI


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3.  
S T U D Y D E SI G N  
3. 1  
O ver vie w of St u d y Desi g n  
T his is a ra n d o mize d, d o u ble -bli n d, ve hicle -c o ntr olle d, m ultice nter, parallel -gr o u p P has e 1/ 2 st u d y 
( wit h a n i nitial o pe n-la bel peri o d) e val u ati n g t he safet y a n d efficac y of A P L-9 vers us t h ose of 
ve hicle as a n a d d -o n t hera p y t o sta n dar d of care i n s u bjects w h o ha ve res pirat or y fail ure (i ncl u di n g 
mil d t o m o derate A R D S ) d ue t o C O VI D -1 9 i nf ecti o n.  
T he st u d y will be c o n d ucte d i n 2 parts:  
P art  1 ( O pe n -L a bel Peri o d):  
I nitiall y, a c o h ort of 6 s u bjects will recei ve o pe n-l a bel treat me nt wit h A P L-9  as a d d -o n t hera p y t o 
sta n dar d of care fr o m 
Da y 1 t hr o u g h 
Da y  7 or res ol uti o n of 
A R D S ( Pa O2 / Fi O2  rati o 
> 3 0 0  m m  H g), w hic he ver occ urs earlier. Res ol uti o n of A R D S i n t his st u d y is defi ne d acc or di n g  
t o t he Berli n defi niti o n as Pa O 2/ Fi O 2 rati o > 3 0 0 m m H g ( A R D S Defi niti o n Tas k F orce 2 0 1 2).  
A n i n de pe n de nt data m o nit ori n g c o m mittee ( D M C) will re vie w t he cli nical data a vaila ble f or all 
6  s u bjects o nce t he last s u bject i n Part 1 reac hes Da y  7 or is disc har ge d f oll o wi n g t he res ol uti o n 
of A R D S ( Pa O 2 / Fi O2  rati o > 3 0 0 m m  H g). T h e D M C will rec o m me n d t o t he s p o ns or w het her:  
•  t he st u d y ca n pr ocee d t o Part 2, a n d  
•  t he ma xi m u m all o we d treat me nt d urati o n i n Part 2 ca n be e xte n de d. ( T h e D M C ca n e xte n d 
t he treat me nt d urati o n be y o n d Da y 7 u p t o a n d i ncl u di n g Da y  2 1; refer t o Part 2 
[ Ra n d o mize d D o u ble-Bli n d Peri o d]).   
F oll o w -u p safet y assess me nts f or eac h s u bject will be c ollecte d 3 0 da ys f oll o wi n g t he last d ose of 
A P L -9 ( wit h a + 7 -da y wi n d o w). T hese assess me nts will be c o n d ucte d vi a i n patie nt assess me nt 
(f or patie nts still h os pitaliz e d) or b y tel e p h o ne call (f or patie nts disc har ge d). 
P art  2 ( R a n d o mize d D o u ble -Bli n d Peri o d):  
Part  2 of t he st u d y will o nl y be i nitiate d u p o n rec o m me n dati o n fr o m t he D M C. Re q uire d criteria 
f or i nitiati o n of Part 2 will i ncl u de 1) N o fatal/lif e-t hreate ni n g S A Es t h o u g ht p ossi bl y relate d t o 
A P L -9 b y t he D M C, a n d 2) n o m ore t ha n 1 s u bject re q uiri n g pre mat ure treat me nt disc o nti n uati o n 
b y t he i n vesti gat or d u e t o A Es or a b n or mal la b t ests.  All s u bjects will recei ve sta n dar d of care 
i n de pe n de nt of t heir ra n d o mizati o n. A p pr o xi matel y 6 0 s u bjects will be ra n d o ml y assi g ne d at a 1: 1 
rati o t o bli n de d treat me nt wit h either A P L -9 or sali ne ve hicle . S u bjects will recei v e treat me nt wit h 
A P L -9 or ve hicle fr o m D a y  1 t hr o u g h Da y  7, disc o nti n uati o n of res pirat or y s u p p ort (s u p ple me ntal 
o x y ge n or mec h a nical ve ntilati o n), or h os pital disc har ge, w hic he v er occ urs latest.  
S u b jects ma y recei ve tr eat me nt be y o n d Da y 7 if t h e D M C a p pr o ves a n e xte n de d treat me nt d urati o n 
f oll o wi n g t he re vie w of data fr o m Part 1 or d uri n g t he c o n d uct of Part  2. T he D M C ma y a p pr o ve 
a n y e xte n de d treat me nt d urati o n u p t o a n d i ncl u di n g Da y  2 1; e x te n de d treat me nt will be all o we d 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


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o nl y i n s u bjects w h o still re q uire res pir at or y s u p p ort ( o x y ge n s u p ple me ntati o n or mec ha nical 
ve ntilati o n) at Da y  7 wit h a n i m pr o ve d Pa O 2/ Fi O 2 rati o of at least a 2 0 m m  H g fr o m bas eli ne if 
arterial bl o o d gas ( A B G) test res ults are a vaila bl e f or c o m paris o n. If A B G test res ults are n ot 
a vaila ble, a n i m pr o ve me nt i n Fi O 2 of at least 4 % i n n o n ve ntilate d p atie nts (e g, t h ose o n nasal 
ca n n ula) a n d 1 0 % i n mec ha nicall y ve ntilate d p atie nts is nee de d. Fi O 2 s h o ul d be wea ne d f oll o wi n g 
t he site’s pr ot o c ol t o kee p o x y ge n s at urati o n at 8 9 % or a b o ve. Treat me nt b e y o n d Da y 7 a n d u p t o 
a n d i ncl u di n g a n y D M C -a p pr o ve d e xte nsi o n will be at t he discreti o n of t he i n vesti gat or.  
F oll o w -u p safet y assess me nts f or eac h s u bject will be c ollecte d 3 0 da ys f oll o wi n g t he last d ose of 
st u d y tr eat me nt ( u p t o a n d i ncl u di n g St u d y Da y  5 1 wit h a + 7 -d a y wi n d o w). Safet y ass ess me nts 
ma y b e perf or me d a n y ti me d uri n g t h e 3 0 -da y f oll o w -u p peri o d at t he i n vesti gat or’s discreti o n b ut 
are re q uire d 3 0  d a ys after t he last d ose of st u d y dr u g ( u p t o a n d i ncl u di n g St u d y Da y  5 1 wit h + 7 da y 
wi n d o w). T hes e ass ess me nts will be c o n d u cte d via i n patie nt assess me nt (f or s u bjects still 
h os pitaliz e d) or b y tele p h o ne call (f or s u bjects disc har ge d).  
T he  D M C will perf or m s afet y a n d efficac y d ata re vie ws o n a n o n g oi n g basis d uri n g Part  2. 
T w o  re vie ws will be re q uire d i n Part 2:  
1.  After t he 1 0t h s u bject reac hes t he a p pr o ve d treat me nt d urati o n, disc o nti n uati o n of 
res pirat or y s u p p ort ( o x y g e n s u p ple me ntati o n or m ec ha nical ve ntilati o n), or h os pital 
disc har ge , w hi c he ver occ urs latest 
2.  After t he 3 0t h s u bject reac hes t he a p pr o ve d treat me nt d urati o n, disc o nti n uati o n of 
res pirat or y s u p p ort ( o x y g e n s u p ple me ntati o n or m ec ha nical ve ntilati o n), or h os pital 
disc har ge , w hi c he ver occ urs latest 
If t he D M C a p pr o ves a n e xte n de d treat me nt p eri o d f oll o wi n g Part 1 or at a n y ti me t hr o u g h t he 
c o n d uct of Part  2, t he D M C’s safet y a n d efficac y data re vie ws will be i nitiate d w he n t he 1 0t h a n d 
3 0t h s u bjects reac h t h e a p pr o ve d e xte n de d treat me nt d urati o n, disc o nti n uati o n of res pirat or y 
s u p p ort ( o x y ge n s u p ple me ntati o n or mec h a nical ve ntilati o n), or h os pital disc har ge , w hic he v er 
occ urs l atest . F or e x a m ple, if, f oll o wi n g Part 1, t h e D M C a p pr o ves treat m e nt t hr o u g h Da y  1 4 i n 
Part  2, t he D M C will be re q uire d t o re vie w safet y a n d efficac y aft er t he first 1 0 patie nts reac h 
Da y  1 4 of treat me nt, disc o nti n uati o n of res pirat or y s u p p ort ( o x y ge n s u p ple me ntati o n or 
mec ha nic al ve ntilati o n), or h os pital disc har ge , w hic he ver occ urs latest. E nr oll me nt will n ot be 
s us pe n de d d uri n g t he D M C re vie ws. 
If a s u bject is tr eate d u p t o t he ma xi m u m all o we d treat me nt d urati o n a n d m ust disc o nti n ue 
treat me nt, treat me nt ma y n ot b e rei nitiate d e v e n if t he D M C s u bs e q ue ntl y a p pr o ves a l o n ger 
treat me nt d urati o n. 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


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3. 2  
S a m ple Size  a n d P o w er C o nsi der ati o ns  
In Part  1 of t he st u d y, a c o h ort of 6  s u bjects will recei ve o pe n-la bel A P L-9 (as a d d -o n t hera p y t o 
sta n dar d of care), a n d s afet y data will be e v al uat e d t o deter mi ne i nitiati o n of Part 2. N o f or mal 
sa m ple siz e calc ulati o n was perf or me d.  
I n Part 2 of t he st u d y, wit h a p pr o xi matel y 3 0  s u bjects treat e d i n eac h tr eat me nt gr o u p ( A P L-9 pl us 
sta n dar d of care vs Ve hi cle C o ntr ol pl us sta n dar d of care), t here is a great er t ha n 9 5 % c ha nce of 
a n S A E bei n g re p orte d if t he tr ue i nci de nce is 1 0 % or hi g her. Si milarl y, t here is a 2 6 %, 7 1 %, or 
8 9 % c ha nce of a n S A E b ei n g re p orte d if t h e tr ue i nci de nce is 1 %, 4 %, or 7 %, res pecti vel y.  
3. 3  
R a n d o miz ati o n ( P art 2 O nl y) 
In P art 2, a p pr o xi matel y 6 0  s u bjects will be ra n d o ml y assi g ne d t o recei ve eit her A P L-9 pl us  
sta n dar d of care or v e hi cle c o ntr ol pl us sta n dar d of care at 1: 1 rati o . Ra n d o mizati o n will be 
stratifie d b y nee d of mec ha nical ve ntilati o n ( yes vs n o) a n d a ge ( y o u n ger t ha n 6 5 years vs at least 
6 5  years).  
3. 4  
Bli n di n g ( P art 2 O nl y)  
All s u bjects or t heir le gall y assi g ne d re prese nt ati ves,  i n vesti gat ors, a n d all st u d y pers o n nel 
i n v ol ve d i n t he c o n d u ct of t he st u d y, i ncl u di n g dat a ma na ge me nt a n d bi ostatistics, will be bli n de d 
t o treat me nt assi g n me nt. St u d y dr u g i nf usi o n ba gs are pre p are d b y dil uti o n of t he st u d y dr u g i n 
is ot o nic sali ne f or inf usi o n b y a n u n bli n de d p h ar macist at t he st u d y site a n d tra nsferre d t o site 
pers o n nel f or a d mi nistrati o n t o s u bjects acc or di n g t o t heir assi g ne d ra n d o mi zati o n n u m ber.  
U n bli n de d ta bles, fi g ures, a n d listi n gs will be pr o vi de d t o t he D M C f or re vie w. A n  u n bli n de d, 
i n de pe n de nt bi ostatisticia n will be assi g ne d t o pre pare t h e ra n d o mizati o n sc he d ule a n d u n bli n de d 
ta bles, fi g ures, a n d listi n gs f or t h e D M C. T he u n bli n de d statisticia n will n ot ot her wise partici pate 
i n st u d y pr oce d ures. 
U n bli n di n g is disc o ura ge d b ut w ill be per mitte d i n a me dical e mer ge nc y t hat re q uires i m me diate 
k n o wle d ge of t he s u bject’s assi g ne d treat me nt. All s u bjects s h o ul d be treate d as t h o u g h t he y are 
recei vi n g A P L-9. E mer ge n c y u n bli n di n g will be acce pta ble o nl y if it affects t he me dical 
ma na ge m e nt of t he s u bj ect.   
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


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4.  
S T A TI S TI C A L A N A L Y SI S  S E T S  
4. 1  
Scree ne d Set  
T he scree ne d set will i ncl u de all s u bjects w h o pr o vi de writte n i nf or me d c o nse nt. T his set will be 
use d o nl y f or t he p ur p os e of descri bi n g s u bject dis p ositi o n.  
4. 2  
S afet y Set    
T he safet y set will i ncl u de all s u bjects w h o recei ve d at least 1 d ose of st u d y tr eat me nt. T his s et 
will be use d f or safet y a n al yses. S u bje cts will be a nal yze d acc or di n g t o t he act ual treat me nt t he y 
recei v e d. 
4. 3  
I nte nt-t o-Tre at  Set    
T he i nte nt -t o-treat (I T T) set will i ncl u de all ra n d o mize d s u bjects. S u bjects will be a nal yz e d 
acc or di n g t o t heir assi g n e d treat me nt, re gar dless of t he act ual tr eat me nt recei ve d. T his s et will be 
use d f or s u p p orti ve effic ac y a n al ys es.  
4. 4  
F ull A n al ysis  Set    
T he f ull a nal ysis set ( F A S) set will i ncl u de all ra n d o mize d s u bjects w h o recei ve at least o ne d ose 
of st u d y treat me nt. T he a nal yses usi n g t he F A S will be base d u p o n t he act u al treat me nt all ocate d. 
T he F A S will be use d f or all effic ac y a n al ys es.  
4. 5  
P h ar m a c o ki netic Set   
T he p har mac o ki n etic ( P K) set is defi ne d as all s u bjects i n t he safet y set a n d f or w h o m at least 1 
P K sa m ple is e val ua ble.  
4. 6  
P h ar m a c o d y n a mi c Set  
T he p har m ac o d y na mic ( P D) set is defi n e d as all s u bjects i n t he safet y set wit h at least 1 P D 
e val uati o n . 
 
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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5.  
S T U D Y S U B J E C T S  
U nless ot her wise s pecifi e d, s t u d y s u bjects will be s u m marize d f or eac h part. St u d y s u bjects will 
be a nal yz e d b y  treat me nt gr o u p i n Part 2. 
U nless ot her wise state d, listi n g will be pr o vi de d f or safet y set f or Part 1 a n d f or I T T set f or Part 2. 
5. 1  
S u bjects  Dis p ositi o n  
T he f oll o wi n g dis p ositi o n cate g ories will be ta b ulate d  f or scree ne d set: 
•  N u m ber of s u bjects  wit h i nf o r me d c o nse nt f or m si g ne d 
•  N u m ber of s u bjects  wit h scree n fail ure  
•  N u m ber of s u bjects  ra n d o mize d ( Part 2 O nl y) 
•  N u m ber a n d p erce nta ge of s u bjects w h o recei ve d  at least o ne d ose of st u d y treat me nt  
•  N u m ber a n d p erce nta ge of s u bjects wit h ≥ 1 p ost -d ose P K assess me nt  
•  N u m ber a n d p erce nta ge of s u bjects wit h ≥ 1 p ost -d ose P D assess me nt  
•  N u m ber a n d p erce nta ge of s u bjects w h o c o m plete d  t he st u d y treat me nt 
•  N u m ber a n d perce nta ge of s u bjects w h o disc o nti n ue d st u d y treat me nt a n d pri ma r y reas o ns 
of st u d y tr eat me nt disc o nti n uati o n  
•  N u m ber a n d p erce nta ge of s u bjects w h o c o m plete d  t he st u d y 
•  N u m ber a n d perce nta ge of s u bjects w h o dis c o nti n ue d fr o m  st u d y a n d pri mar y reas o ns of 
st u d y disc o nti n uati o n 
Perce nta ge will be calc ul ate d base d o n n u m ber  of s u bjects i n safet y set. A s e parat e listi n g will be 
pr o vi de d f or scree n fail ures al o n g wit h t he reas o ns.  
5. 2  
De m o gr a p hic s a n d B aseli ne C h ar acteristics  
De m o gra p hics a n d baseli ne c haracteristics  will be s u m marize d f or  safet y set  i ncl u di n g: 
•  A ge at scree ni n g ( years)  
If n ot c ollecte d, t he n it will be calc ulate d as ( year of i nf or me d c o nse nt f or m si g ne d - birt h 
year)  
•  A ge i n cate g ories (< 6 5 years a n d ≥ 6 5 years)  
•  Se x , C hil d beari n g P ote ntial, Race , Et h nicit y  
•  Baseli ne W ei g ht ( k g) , Hei g ht (c m) , B o d y Mass I n de x ( B MI, k g / m2) 
•  Ra n d o mizati o n Stratificati o n Fact ors  ( Part 2 O nl y) 
•  Baseli ne us e of me c ha nic al ve ntilati o n , Baseli ne use of s u p ple me ntal o x y ge n 
•  Baseli ne Res pir at or y Rat e , O x y ge n Sat urati o ns , Te m perat ure, Bl o o d Press ur e ( S yst olic a n d 
Diast olic), Heart Rate  
•  Baseli ne Le v el of C o nsci o us ness  
•  Baseli ne Se q u e ntial Or ga n Fail ure Assess me nt ( S O F A) s c ore  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
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5. 3  
Me dic al Hist or y  
Me dical hist or y will be c o de d usi n g M e dical Di cti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
Versi o n 2 3. 0 . T he fre q u e nc y c o u nt a n d perce nta ge of patie nts e x perie nci n g a n y m e dical c o n diti o ns 
will be ta b ulate d b y s yst e m or ga n class ( S O C) a n d preferre d ter m ( P T).  If a preferre d ter m or 
s yste m or ga n class were re p orte d m or e t ha n o nce f or a patie nt, t he p atie nt w o ul d o nl y be c o u nt e d 
o nce i n t he i nci de n ce f or t hat preferr e d t er m or s yste m or ga n class.  
5. 4  
Pri o r a n d C o nc o mit a nt Me dic ati o n s  
Pri or a n d c o nc o mita nt m e dicati o ns will be c o d e d usi n g W orl d Healt h Or ga nizati o n ( W H O) Dr u g 
Dicti o nar y Marc h 2 0 2 0 v ersi o n.   
Pri or me dicati o ns are defi ne d as a n y me dicati o ns, ot her t ha n st u d y  dr u g, wit h a st o p date bef ore 
t he first d ose of st u d y dr u g.  
C o nc o mita nt me dicati o ns are me dicati o ns, ot her t ha n st u d y dr u g, bei n g ta ke n o n or after t he first 
d ose of st u d y dr u g a n d u p t o t he e n d of st u d y. Me dicati o ns t hat starte d bef ore t he first d ose of 
st u d y dr u g a n d w ere o n g oi n g o n t he date of t he first d ose of st u d y dr u g  will be c o nsi dere d  as  
c o nc o mita nt me dicati o ns.  Pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d b y A nat o mical 
T hera p e utic C he mical ( A T C ) classificati o n s yst e m le vel 2 (t hera pe utic m ai n gr o u p) a n d preferre d 
na me, usi n g t he n u m bers a n d perce nta ges of patie nts w h o recei ve d t he me di cati o ns. A s u bject w h o 
ta kes m ore t ha n o n e me dicati o n will be c o u nte d o nl y o nce if t hese me dicati o ns bel o n g t o t he sa m e 
e xte n de d A T C classificati o n.  
5. 5  
Pri o r a n d C o nc o mit a nt Pr o ce d ures  
Pri or a n d c o n c o mita nt pr oce d ure s will be c o d e d usi n g W orl d Healt h Or ga nizati o n ( W H O) Dr u g 
Dicti o nar y Marc h 2 0 2 0 v ersi o n.   
Pri or pr oce d ures are d efi ne d as a n y pr oce d ures wit h a st o p date bef ore t he first d ose of st u d y dr u g. 
C o nc o m ita nt pr oce d ures are pr oce d ures perf or m e d o n or aft er t he first d ose of st u d y dr u g a n d u p 
t o t he e n d of st u d y. Pr oce d ures t hat starte d b ef ore t he first d ose of st u d y dr u g a n d were still o n g oi n g 
o n t he date of t he first d ose of st u d y dr u g will be c o nsi dere d  as c o nc o mita nt pr oce d ures.  
Pri or a n d c o nc o mita nt pr oce d ures  will be s u m marize d b y t he pr oce d ures perf or me d, usi n g t he 
n u m bers a n d perce nta ges of patie nts w h o recei ve d t he pr oce d ures .  
5. 6  
E x p os ure t o St u d y Dr u g  
T he f oll o wi n g p ara m eters will be calc ulate d a n d prese nte d f or safet y set:  
•  D urati o n of treat me nt ( da ys) defi n e d as ( t he start date of last i nf usi o n –  t he start date of 
first inf usi o n date + 1)  
•  N u m ber of i nf usi o ns recei ve d ( 1 i nf usi o n, 2 i nf usi o ns, etc.) 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  1 9  of 3 2                                        C o nfi de ntial  
•  N u m ber of i nf usi o ns c o m plete d  
•  N u m ber of i nf usi o ns i nterr u pte d 
•  N u m ber a n d p erce nta ge of patie nts wit h a n y d ose i nterr u pti o n  
•  N u m ber a n d p erce nta ge of s u bjects wit h i nf usi o n relate d reacti o n  
Details of st u d y tr eat me nt e x p os ure will be liste d f or safet y set.  
5. 7  
Me as ure me nts of Tre at me nt C o m pli a nce  
C o m plia nce  ( %) = total d ose a d mi nistere d ( m g) / t otal d ose prescri be d ( m g) x  1 0 0   
T otal d ose a d mi nistere d ( m g) is defi ne d as t he s u m of t he act ual d oses ( m g) a d mi nistere d. T otal 
d ose prescri be d ( m g) is d efi ne d as t he s u m of t h e d oses ( m g) pres cri be d.  If t he i n vesti gat or i nstr ucts 
t he st u d y staff t o i nterr u pt st u d y me dicati o n f or a ti me i nter val, e. g. d ue t o a n a d verse e v e nt, t he n 
t his peri o d will n ot be i ncl u de d i n t he de n o mi nat or f or t he c o m plia nce calc ulati o n. 
Dr u g c o m plia nce will b e s u m marize d f or t he safet y p o p ulati o n b y n u m ber a n d perce nta ge of 
s u bjects i n i ncre me nts of 1 0 % (e. g., ≥ 7 0 % - < 8 0 %, ≥ 8 0 % - < 9 0 % a n d ≥ 9 0 - ≤1 0 0 %).  
T reat me nt c o m plia nce will be liste d f or safet y set.  
5. 8  
Pr ot oc ol D e vi ati o ns  
All pr ot oc ol de viati o ns will be re vie we d a n d d oc u me nte d bef ore d ata bas e l oc k. Pr ot oc ol de viati o ns 
are rec or de d i nt o Cli nical Trial Ma na ge me nt S yste m ( C T M S). Pr ot oc ol de viati o ns ca n be d etecte d 
b y ( b ut n ot li mite d t o) t he s u bject, i n vesti gati o nal site pers o n nel, site 
ma na ge me nt, data 
ma na ge me nt, safet y/ p h ar mac o vi gila nce, 
m e dical 
m o nit ori n g, 
bi ostatistics, a u dit ors, a n d 
re g ulat ors. T he y m a y als o be i de ntifie d t hr o u g h pr o gra m ma ble c h ec ks of t h e data.  
Ke y pr ot oc ol de viati o ns i ncl u de a n y vi olati o ns of i ncl usi o n a n d e x cl usi o n criteria. T his i ncl u des 
u n k n o w n vi olati o ns at e nr ol me nt a n d o n -st u d y vi olati o ns, s uc h as ta ki n g a pr o hi bite d me dicati o n. 
T he C R O/ A pellis will classif y maj or a n d mi n or pr ot oc ol de viati o ns per t he a gree d pr ot oc ol 
de viati o n ma na ge m e nt pl a n. T he A pellis st u d y tea m will re vie w t he pr ot o c ol de viati o ns a n d t h eir 
classificati o n t hr o u g h o ut t he st u d y a n d b ef ore data base l oc k.  
N u m ber a n d p erce nta ge of s u bjects wit h pr ot oc ol de viati o n will be ta b ulate d b y i m p ort a nce of 
de viati o n  f or safet y set i n Part 1 a n d I T T set i n Part 2.  
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 0  of 3 2                                        C o nfi de ntial  
6.  
E F FI C A C Y A N A L Y S IS  
All efficac y a nal ys es will be s u m marize d f or eac h st u d y part. Efficac y data will als o be a nal yze d 
b y tr eat me nt gr o u p i n Part 2. H y p ot hesis testi n g will be perf or me d f or p art 2 bet wee n t w o treat me nt 
gr o u ps.  
U nless ot her wise s pecifi e d, baseli ne f or all efficac y a n al ys es is defi ne d as t he last n o n -missi n g 
meas ure me nt  rec or de d pri or t o ta ki n g t he first d os e of st u d y dr u g. 
All CIs will be prese nte d as 2 -si de d 9 0 % a n d/ or 9 5 % CIs. All statistical tests will be 2-si de d 
h y p ot hesis tests perf or me d at t he 1 0 % le vel of si g nifica nce.  
T he pr i mar y effic ac y a n al yses will be perf or me d f or full anal ysis set ( F A S). T he s u p p orti ve 
effic ac y a n al ys es will be perf or me d f or Int e nt -t o-T reat (I T T) set. 
6. 1  
A n al ys is of Pri m a r y Effic ac y E n d p oi nt 
N ot A p plica ble.  
6. 2  
A n al ysis of Sec o n d ar y Effic a c y E n d p oi nts 
6. 2. 1  Ti me -t o-e v e nt e n d p oi nts  
T he f oll o wi n g ti me -t o-e v e nt e n d p oi nts are d efi ne d as:   
•  H os pital le n gt h of sta y: i nitiati o n of st u d y dr u g ( Da y 1, f or Part 1) or ra n d o mizati o n date 
(f or Part 2) t o h os pital disc har ge. F or s u bjects wit h deat h of a n y ca us e  or wit h dra wal of 
st u d y p artici pati o n, h os pital le n gt h of sta y will be i m p ute d wit h t he l o n gest h os pital le n gt h 
of sta y o bs er ve d i n t he st u d y . 
•  O verall s ur vi val: i nitiati o n of st u d y dr u g ( Da y 1, f or Part 1) or ra n d o mizati o n date (f or Part 
2) t o deat h of a n y ca use; ce ns ore d at t he last da y k n o w n t o be ali ve.  
•  T otal d urati o n of mec h a nical ve ntilati o n defi n e d as da ys o n m ec ha nical ve ntilati o n d uri n g 
t he st u d y partici pati o n, calc ulate d as f oll o ws:  
o  F or s u bjects wit h deat h of a n y ca use (or wit h dra wal of  st u d y p artici pati o n), t otal 
d urati o n of mec h a nical ve ntilati o n  will be i m p ute d wit h t he l o n gest d urati o n 
o bser ve d i n t he st u d y.   
•  F or a n y s u bject w h o is o n mec ha nical ve ntilati o n at t he i nitiati o n of st u d y dr u g ( Da y 
1 , f or Part 1) or at t he ra n d o mizati o n date (f or Part 2), t otal d urati o n of mec ha nical 
ve ntilati o n is calc ulate d fr o m Da y 1 or ra n d o mizati o n date . 
•  F or a n y s u bject w h o is n ot o n mec ha nical ve ntilati o n at t he i nitiati o n of st u d y dr u g 
( Da y 1, f or Part 1) or at t he ra n d o mizati o n date (f or Part 2), patie nt will be e xcl u de d.  
•  T otal d urati o n of o x y ge n t hera p y defi ne d as da ys o n 
mec h a nical ve ntilati o n or 
s u p ple me ntal o x y ge n d uri n g t he st u d y partici p ati o n, calc ulate d as f oll o ws:  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 1  of 3 2                                        C o nfi de ntial  
•  F or s u bjects wit h deat h of a n y ca use (or wit h dra wal of st u d y p artici pati o n ), t otal 
d urati o n of o x y ge n t hera p y  will be i m p ute d wit h t he l o n gest d urati o n o bser ve d i n 
t he st u d y.  
•  F or a n y s u bject w h o is o n mec ha nical ve ntilati o n or s u p ple me ntal o x y ge n at t he 
i nitiati o n of st u d y dr u g ( Da y 1, f or Part 1) or at t he ra n d o mizati o n date (f or Part 2), 
t otal d urati o n of o x y ge n t hera p y is c alc ulate d fr o m Da y 1 or ra n d o mizati o n date . 
•  F or a n y s u bject w h o is n ot o n mec h a nical v e ntilati o n or s u p ple me nt al o x y g e n at t h e 
i nitiati o n of st u d y dr u g ( Da y 1, f or Part 1) or at t he ra n d o mizati o n date (f or Part 2), 
patie nt  will be e x cl u de d.  
T he p -val u e s will be fr o m a 2 -si de d u n str atifie d L o g-ra n k t est a n d stratifi e d L o g -ra n k test b y t he 
ra n d o mizati o n stratificati o n fact ors [ nee d of m ec h a nical ve ntilati o n ( yes vs n o) a n d a ge ( y o u n ger 
t ha n 6 5 years vs at least 6 5 years)] at 0. 1 si g nifica nt le vel f or e val u ati o n of treat me nt differe nce. 
T hese ti me -t o-e v e nt e n d p oi nts  will be s u m marize d via Ka pla n -Meier ( K M ) met h o d ol o g y usi n g 
t he 2 5t h, 5 0t h ( me dia n), a n d 7 5t h perce ntiles a n d pre-s pecifie d ti me p oi nts, eac h wit h ass oci ate d 2-
si de d 9 0 % c o nfi de nce i nter vals. P oi nt esti mate of hazar d rati o will be o btai ne d fr o m a C o x 
re gressi o n m o del wit h treat me nt a n d t he ra n d o mi zati o n stratificati o n fact ors as fi x e d fact ors a n d 
t he 9 0 % CI will be o btai ne d usi n g Wal d met h o d.   
 
6. 2. 2  Se q ue nti al Or g a n F ail ur e Assess me nt ( S O F A) sc ore  
Or ga n fail ure st at us will be assess e d usi n g t he S O F A sc ore  (see Ta ble 1), w hic h assess es 6  or ga n 
s yste ms: res pir ati o n, c oa g ulati o n, li ver, car di o vas c ular, ce ntral ner v o us s yste m , a n d re nal  (Ferreira 
et al., 2 0 0 1). A s u bject wi ll be defi ne d as bei n g free of or ga n fail ure w he n t he S O F A s c ore is zer o. 
T he S O F A s c ore will be assesse d at b aseli ne o n Da y 1 a n d as liste d i n t he s c he d ule of assess me nt 
(S O A ), bas e d o n w orst d ail y v al ues. S O F A sc ore at eac h as sess me nt a n d c ha n ges fr o m baseli ne 
o ver ti me  will be s u m mariz e d usi n g descri pti ve statistics.   
T a ble 1 : Se q ue nti al Or g a n F ail ure Assess me nt ( S O F A) Sc ori n g 
V ari a bles  
0  
1  
2  
3  
4  
Res pir ati o n  
P a O 2/ Fi O2, m m H g 
> 4 0 0  
≤4 0 0  
≤3 0 0  
≤2 0 0 a  
≤1 0 0 a 
or S p O 2/ Fi O2, m m H g 
≥5 1 2  
≥3 5 7 t o < 5 1 2  
≥2 1 4 t o < 3 5 7  
≥8 9 t o < 2 1 4  
< 8 9  
C o a g ul ati o n  
Platelets  ×  1 0 3/ µ L 
> 1 5 0  
≤1 5 0  
≤1 0 0  
≤5 0  
≤2 0  
Li ver  
Bilir u bi n, m g/ d L b 
< 1. 2  
1. 2 -1. 9  
2. 0 -5. 9  
6. 0 -1 1. 9  
> 1 2. 0  
C ar di o v asc ul ar   
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 2  of 3 2                                        C o nfi de ntial  
H y p ote nsi o n  
N o h y p o -
te nsi o n 
M A P 
< 7 0  m m  H g  
D o pa mi n e ≤5 
or d o b uta mi n e 
(a n y d ose)c 
D o pa mi n e > 5, 
e pi n e p hri n e ≤0. 1, 
or n ore pi ne p hri n e 
≤0. 1 c 
D o pa mi n e > 1 5, 
e pi n e p hri n e > 0. 1, 
or 
n ore pi ne p hri n e 
> 0. 1 c 
Ce ntr al ner v o us s yste m  
Glas g o w C o ma Scale sc ore d, e 
1 5  
1 3 -1 4  
1 0 -1 2  
6 -9  
< 6  
Re n al  
Creati ni ne, m g/ d L  
or uri ne o ut p ut  (m L/ d) f 
< 1. 2  
1. 2 t o 1. 9  
2. 0 t o 3. 4  
3. 5 t o 4. 9 or 
< 5 0 0  
> 5. 0  or < 2 0 0  
A b bre viati o ns: Fi O 2  =  fracti o n of i ns pire d o x y ge n; M A P =  mea n arterial press ure.  
a Val ues are wit h res pirat or y s u p p ort  
b T o c o n vert bilir u bi n fr o m m g/ d L t o µ m ol/ L , m ulti pl y b y 1 7. 1 
c A dre ner gic a ge nts  a d mi nister e d f or at least 1 h o ur ( d oses are gi ve n i n µ g/ k g/ mi n).  
d F or s u bj ects w h o are i nt u bate d, t he ver bal res p o nse is sc ore d as:  
5 –  See ms a ble t o tal k  
3 –  Q uesti o na ble a bilit y t o tal k  
1 –  Ge nerall y u nres p o nsi ve  
e F or s u bj ects w h o are se d ate d, use a n  esti mate d sc ore f or Glas g o w C o ma Scale  (t he ass u m pti o n is 1 5, if n o ot her 
fact ors t ha n se d ati o n affect Gl as g o w C o ma Scale sc ore ). 
f T o c o n vert creati ni ne fr o m m g/ d L t o µ m ol/ L , m ulti pl y b y 8 8. 4 
S o urce: Ferreira et al. 2 0 0 1 . 
6. 3  
A n al ys is of E x pl or at or y E n d p oi nts 
6. 3. 1  Prese nce of acti ve S A R S -C o V -2 i nfecti o n o n at t he e n d -of -tre at me nt visit 
Viral R N A assess me nt will be perf or me d at  t he e n d-of -treat me nt visit. I n t he case w here viral R N A 
assess me nt  data is u n a v aila ble or patie nt die d d uri n g t he st u d y , t hat s u bject will be treate d as 
ha vi n g a p ositi ve viral R N A test res ult . Fis her e x act  a n d/ or c hi -s q uare test will be use d t o c o m pare 
t he pr o p orti o n of s u bjects w h o ha ve n e g ati ve vir al R N A test res ult  bet wee n t w o treat me nt gr o u ps .  
6. 3. 2  I nci de nce, d ur ati o n, a n d e xte nt of ne w o x y ge n t her a p y use  (re-i niti ati o n 2 4 h o urs or 
m o re af ter cess ati o n of pri or o x y ge n t her a p y) 
T he n u m ber a n d perce nta ge of patie nts re p orti n g ne w o x y ge n t hera p y use  (i.e., mec ha nical 
ve ntilati o n or s u p ple me ntal o x y ge n t hera p y) as well as t y p es of ne w o x y g e n t hera p y us e  will be 
ta b ulate d b y treat me nt gr o u ps. T h e d urati o n of ne w o x y ge n t hera p y us e will be calc ulate d fr o m 
t he re-i nitiati o n of o x y ge n t hera p y us e. F or s u bjects wit h deat h of a n y ca us e or wit h dra wal of st u d y 
partici pati o n  after t h e re-i nitiati o n of o x y ge n t hera p y use, t he d urati o n of ne w o x y ge n t hera py us e 
will be i m p ute d wit h t he l o n gest d urati o n o bser ve d i n t he st u d y. T he d urati o n of ne w o x y ge n  
t hera p y use will be prese nte d b y d escri pti ve statistics.  
6. 3. 3  I nci de nce, d ur ati o n, a n d e xte nt of ne w mec h a nic al ve ntil ati o n  use (re -i niti ati o n 2 4 
h o urs or m o re aft er cess ati o n of pri or  mec h a nic al ve ntil ati o n ) 
T he n u m ber a n d perce nt a ge of patie nts re p orti n g n e w mec ha nical ve ntilati o n  use , a n d t y p es of ne w 
mec ha nic al ve ntilati o n  use  will be ta b ulate d b y treat me nt gr o u ps. T h e d urati o n of ne w mec h a nical 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 3  of 3 2                                        C o nfi de ntial  
ve ntilati o n use will be calc ulate d fr o m t he re -i nitiati o n of mec ha nical ve ntilati o n use. F or s u bjects 
wit h deat h of a n y ca use or wit h dra wal of st u d y p artici pati o n  after t he re-i nitiati o n of mec ha nical 
ve ntilati o n use , t he d urati o n of ne w mec ha nical v e ntilati o n use will be  i m p ute d wit h t he l o n gest 
d urati o n o bser ve d i n t he st u d y. T he d urati o n of ne w mec ha nical ve ntilati o n  use will be prese nte d 
b y des cri pti ve statistics.  
6. 3. 4  
 
 
 
 
 
 
7.  
S A F E T Y A N A L Y SI S  
Safet y e n d p oi nts i ncl u de A Es, cli nical la b orat or y varia bles, vital si g ns, a n d E C G varia bles .  
U nless ot her wise s pecifi e d, a ll safet y a nal ysis will be perf or me d b y st u d y part a n d tr eat me nt gr o u p 
f or t he safet y set. 
7. 1  
A d verse E ve n ts  
A d verse e v e nts ( A Es ) will be c o de d usi n g t he  m ost rece nt versi o n of  Me d D R A  ( versi o n 2 3. 0). 
A d verse e ve nt s e verit y l e vel will be classifie d i nt o mil d, m o derate, s e vere  b y i n vesti gat ors . F or 
i nci de nce s u m maries, a missi n g se verit y of a n A E will be c o nser v ati vel y i m p ute d as se v ere . 
Ha n dli n g r ules f or missi n g se v erit y of A Es are d es cri be d i n Secti o n 1 2. 6. 5 .  
A Es are cl assifie d as rel ate d t o st u d y dr u g if A Es are d efi nitel y or p ossi bl y relate d t o st u d y dr u g. 
A n y A Es wit h missi n g or u n k n o w n relati o ns hi p will be c o nsi dere d as relate d t o st u d y dr u g  (Secti o n 
1 2. 6. 6) . 
Treat me nt e mer ge nt a d v erse e v e nts ( T E A Es) are defi ne d as t h ose A Es t hat de vel o p or w orse n  i n 
se verit y after t he first d os e of st u d y dr u g  a n d u p t o 3 0  ( + 7) da ys be y o n d t he l ast d ose of st u d y  dr u g . 
All  s u m maries of A Es d escri be d i n t his s ecti o n will be o n T E A Es. A n o verall s u m mar y of t he 
n u m ber of s u bjects wit h T E A Es as well as t he t otal n u m ber of e ve nt s will be prese nte d, i n cl u di n g 
t he n u m ber a n d perce nta ge of s u bjects wit h  
•  a n y T E A Es,  
•  treat me nt-e mer ge nt seri o us a d verse e ve nts  ( S A Es),  
•  treat me nt-relate d T E A Es,  
•  treat me nt-relate d S A Es,  
•  i nf usi o n site reacti o n T E A Es,  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
C CI


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 4  of 3 2                                        C o nfi de ntial  
•  T E A Es lea di n g t o d ose m o dificati o n  ( d ose re d u cti o n or i nterr u pti o n),  
•  T E A Es lea di n g t o treat m e nt disc o nti n uati o n, 
•  T E A Es lea di n g t o st u d y disc o nti n uati o n,  
•  T E A Es lea di n g t o deat h.  
 
T he n u m ber a n d perce nt a ge of patie nts re p orti n g T E A Es will be ta b ulate d b y  S O C a n d P T; b y 
S O C, P T, a n d ma xi m u m se verit y.   
I n s u m mar y, the f oll o wi n g t y pes of t a bles will als o be pr o vi de d:  
•  T E A Es b y S O C a n d P T  
•  T E A Es b y S O C , P T  a n d m a xi m u m se verit y 
•  Treat me nt -e mer ge nt S A Es b y S O C a n d P T  
•  Treat me nt -relate d T E A E s b y S O C a n d P T   
•  Treat me nt -relate d S A E s b y S O C a n d P T  
•  I nf usi o n site reacti o n T E A Es b y S O C a n d P T  
•  T E A E s lea di n g t o d ose m o dificati o n  b y S O C a n d P T  
•  T E A E s lea di n g t o treat m e nt disc o nti n uati o n b y S O C a n d P T  
•  T E A Es lea di n g t o st u d y disc o nti n uati o n b y S O C a n d P T  
•  T E A Es lea di n g t o deat h b y S O C a n d P T  
If a S O C or P T was re p orte d m ore t ha n o nce f or a s u bject, t he s u bject w o ul d o nl y be c o u nte d o nce 
i n t he i nci de nce f or t hat S O C or P T. F or s u bjects e x perie nci n g t he sa me P T at m ulti ple se verities, 
t he occ urre nce of t he A Es wit h t he ma xi m u m se verit y will be c o u nt e d i n t he a nal ysis of i nci de n ce 
b y se v erit y. F or s u bjects e x perie nci n g t he sa me P T at m ulti ple relati o ns hi p le vels, t he oc c urre nce 
of t he A Es wit h t he str o n gest relati o ns hi p t o st u d y dr u g will be c o u nte d i n t he a nal ysis of i nci de n ce 
b y relati o ns hi p t o st u d y dr u g.  
T he f oll o wi n g listi n g will be pr o vi de d f or t he Safet y P o p ulati o n:  
•  All A Es  
•  Seri o us A d verse E v e nts  
•  A Es lea di n g t o d ose m o dificati o n  
•  A Es lea di n g t o treat me nt disc o nti n uati o n  
•  A Es lea di n g t o st u d y disc o nti n uati o n  
•  A Es lea di n g t o Deat h  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
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7. 2  
Cli nic al L a b or at or y D at a  
T he detaile d la b para met er list is s u m marize d i n Ta ble 2 ( Pa ge 4 7 ) of st u d y pr ot oc ol A P L 9-C O V -
2 0 1 a me n d me nt 3 . Co nti n u o us la b orat or y para meters will be n or malize d b y c o n v erti n g val ues i n 
ori gi nal u nits t o val ues i n SI u nits a n d classifie d as n or mal, a b n or mal l o w, or a b n or mal hi g h o n 
n or mal ra n ges s u p plie d b y t he l ocal la b orat ories a n d u p o n e m pl o yi n g sta n d ar dizati o n.   
O bser ve d v al ues a n d c ha n ge fr o m b aseli ne of cli nical la b orat or y data ( ser u m c h e mistr y, 
he mat ol o g y, c o a g ulati o n, c o m ple me nt acti vati o n  a n d i nfla m mati o n , a n d c o nti n u o us uri nal ysis 
para meters ) will be s u m marize d at eac h a n al ysis visit. C ate g orical la b orat ory data will als o be 
ta b ulate d b y the n u m ber a n d perce nta ge of patie nts  of eac h cate g or y at eac h a nal ysis visit.   
Fre q u e nc y of a b n or mal ( o ut -of -ra n ge) la b orat or y val ues will be ta b ulate d b y a n al ysis visit.  
If l a b val ues are be y o n d d etecta ble li mit, t he detect a ble li mits will be use d f or a nal ysis. T he ori gi nal 
c ollecte d val ue s will be prese nte d i n t he listi n gs.  
Cli nical la b orat or y dat a will be prese nt e d i n listi n gs . O ut of ra n ge la b orat or y res ults wit h t heir 
c orres p o n di n g c ha n ges fr o m baseli ne will be liste d  i n se parate listi n gs. 
7. 3  
Vit al Si g ns  
O bser ve d v al ue a n d c ha n ge fr o m bas eli ne  of vit al si g ns (i n cl u di n g s yst olic a n d diast olic bl o o d 
press ure, res pirati o n rate, o x y ge n sat ur ati o ns, heart rate, a n d te m perat ure)  will be s u m marize d at 
eac h a nal ysis visit.  
O bser ve d v al u es a n d c ha n ges fr o m baseli ne val ues will be liste d. I n t he listi n g, val ues of p ote ntial 
cli nical i m p orta nce will be fla g ge d.  T h ese are d efi ne d as:  
T a ble 2 : Criteri a f or P ote nti all y Cli nic all y Si g nific a nt Vit al Si g ns 
 
Vit al  Si g n P ar a meter  
 
Fl a g  
Cri teri a 
O bser ve d  V al ue  
C h a n ge  fr o m B aseli ne  
S yst olic bl o o d press ure  
( m m H g) 
Hi g h  
≥1 8 0  
I ncrease of ≥2 0  
L o w  
≤9 0  
Decrease of ≥2 0  
Diast olic bl o o d press ure ( m m H g)  
Hi g h  
≥1 0 5  
I ncrease of ≥1 5  
L o w  
≤5 0  
Decrease of ≥1 5  
Heart rate  
( beats per mi n ute) 
Hi g h  
≥1 2 0  
I ncrease of ≥1 5  
L o w  
≤5 0  
Decrease of ≥1 5  
7. 4  
Electr oc a r di o gr a m ( E C G)  
O bser ve d val ue s a n d c ha n ge s fr o m baseli ne f or E C G para m eter s (i ncl u di n g h eart rate, P R i nter val, 
R R i nter val, Q R S i nter val, Q T i nter val,  a n d Q Tc i nter val ) will be s u m mari ze d b y a n al ysis visit.  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
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N u m ber a n d perce nt a ge of s u bjects wit h a b n or mal E C G i nter pretati o n will als o be s u m marize d  at 
eac h a nal ysis visit.  
E C G data will als o be prese nte d i n listi n g.  
 
 
 
8.  
P H A R M A C O KI N E TI C A N A L Y SI S  
8. 1  
Dr u g C o nce ntr ati o n  
T he o bser ve d  val ues  a n d c ha n ges fr o m baseli ne of A P L -9 c o nce ntrati o ns will be s u m marize d f or 
p har mac o ki netic ( P K ) set at eac h sc he d ul e d ti me p oi nt usi n g descri pti ve statistics (i ncl u di n g at 
least mea n, S D, C V, Mi n, Ma x, Ge o metric Mea n, a n d % C V). T h e n u m ber a n d perce nta ge of 
s u bjects wit h a B L Q val ue will als o be ta b ulate d. T he ha n dli n g of B L Q i n t he s u m mar y ta bl e is 
descri be d i n Secti o n  8. 2 .  
Li ne ar a n d l o g -li near i n di vi d ual c o nce ntrati o n pr ofile pl ots a gai nst t he act ual st u d y visit will be 
pr o d uce d b y  st u d y part a n d treat me nt gr o u p .  
Li ne ar a n d l o g -li near m ea n c o nce ntrati o n  pl ots a gai ns t t he act ual st u d y visit will be ge n erat e d b y 
st u d y p art a n d treat me nt gr o u p. T he n u m ber of s u bjects c o ntri b uti n g t o eac h mea n val ue at a visit 
will be prese nte d a b o ve t he x -a xis . 
A listi n g of c o nce ntrati o n data will be prese nte d b y st u d y part a n d treat me nt gr o u p. T he act ual 
ti me, de viati o n , a n d perce nt de viati o n fr o m n o mi nal ti me will be liste d.  
All s u m maries a n d a nal yses of t he p har m ac o ki netic data will be base d o n t he P K  set. 
8. 2  
H a n dli n g B L Q V al ues  
A P L -9  c o nce ntr ati o ns re p orte d as bel o w t he li mit of q ua nti ficati o n ( B L Q) will be ta ke n as zer o f or 
li near pl ots, a n d e q ual t o t he l o wer li mit of q ua ntificati o n ( L L O Q) f or se mi-l o garit h mic pl ots. F or 
t he c o m p utati o n of descri pti ve statistics, B L Q will be ta ke n as zer o, e x ce pt f or t he calc ul ati o n of 
t he ge o metric mea n w here t he L L O Q will be use d.  
F or t he esti mati o n of P K para meters, c o n ce ntr ati o ns t hat are rec or de d as B L Q pri or t o t he first 
q ua ntifia ble val ue will be set t o 0. C o nce ntrati o ns t hat are rec or de d at t he e n d of t he sa m pli n g 
peri o d (i.e. n o f urt her q u a nti fia ble c o n ce ntrati o ns) will be set t o missi n g a n d will n ot be use d f or 
t he esti mati o n of para meter val ues. If a B L Q v al ue falls bet w ee n t w o q ua ntifia ble c o nce ntrati o ns 
t he val ue will be s et e q u al t o t he L L O Q, u nl ess its e x cl usi o n ca n b e j ustifie d (e. g. i m pla usi bilit y 
gi ve n t he pr ofile o bser ve d a n d k n o w n P K pr o perti es).  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 7  of 3 2                                        C o nfi de ntial  
9.  
P H A R M A C O D Y N A MI C A N A L Y SI S  
9. 1  
P h ar m a c o d y n a mi c D at a  
T he p har mac o d y na mic ( P D ) e n d p oi nts will be e val uate d usi n g t h e P D P o p ulati o n.  
O bser ve d  val ues, c ha n ges fr o m bas eli ne a n d perce nta ge  c ha n ges fr o m bas eli ne  i n P D e n d p oi nts 
will be s u m marize d b y st u d y part a n d treat me nt gr o u p  at eac h pr ot oc ol s pecifie d ti me p oi nt usi n g 
descri pti ve statistics . P D mar kers i ncl u de t h e f oll o wi n g: 
•  c o m ple me nt acti vati o n ( C 3, C 3a, C 4, C 4a, B b, C 5a, T C C, a n d alter nati ve c o m pl e me nt 
pat h wa y he m ol ytic acti vit y [ A H 5 0]) , 
•  c oa g ul o pat h y (retic ul oc yte c o u nt, sc hist oc yt es, lactate de h y dr o ge n ase, D -di mer, ferriti n, 
ha pt o gl o bi n, fi bri n o ge n ),  
•  i nfla m mat or y c yt o ki nes ( C-reacti ve pr otei n, t u m or necr osis fact or α, I L-1 β, a n d I L -6).  
S pa g hetti pl ots f or i n di vi d ual o bser ve d val ues a n d i n di vi d ual c h a n ges fr o m bas eli ne will be 
prese nte d gra p hicall y. Act ual sa m pli n g ti mes will be use d f or t he gra p hical pres e ntati o n of 
i n di vi d ual data.  
O bs er ve d val ues, c h a n ge s fr o m baseli ne, a n d perce nt a ge c ha n ges fr o m baseli ne will als o be 
prese nte d gra p hicall y b y  st u d y p art a n d treat me nt gr o u p . N o mi nal sa m pli n g ti mes will be use d f or 
t he dis pla y i n  pl ots.  
P D para meters will be liste d t o get her wit h c ha n ge s fr o m baseli ne a n d perce nta ge c h a n ges fr o m 
baseli ne b y st u d y p art a n d treat me nt gr o u p.  
1 0.  
I N T E RI M A N A L Y SI S  
T here is n o pla n ne d i nteri m a nal ysis . 
1 1.  
I N D E P E N D E N T D A T A M O NI T O RI N G C O M MI T T E E  
T he i n de p e n de nt d ata m o nit ori n g c o m mittee ( D M C) f or t his st u d y will be a p p oi nte d b y t he s p o ns or 
i n acc or da nce wit h its sta n dar d pr oce d ures. T h e re mit, r oles, a n d res p o nsi bilities of t he D M C  will 
be s pecifie d i n a se p arate D M C  c h arter.  T he a n al ysis will b e perf or me d  base d o n a se parate 
statistical a nal ysis pla n. 
1 2.  
D A T A H A N D LI N G C O N V E N TI O N S   
1 2. 1  
Ge ner al D at a R e p orti n g C o n ve nti o ns  
Cate g orical v aria bles will be ta b ulat e d as n u m ber of s u bjects a n d perce nta ge of t otal n u m ber of 
s u bjects i n t he gi v e n a nal ysis set as n ote d f or eac h cate g or y. Perce nta ges will be re p orte d t o o n e 
deci mal place.  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 8  of 3 2                                        C o nfi de ntial  
Descri pti ve statistics will be use d t o s u m marize c o nti n u o us varia bles i ncl u di n g n u m ber of s u bjects, 
mea n, sta n dar d de viati o n ( S D), me dia n, first q ua ntile ( Q 1), t hir d q ua ntile ( Q 3), mi ni m u m , a n d 
ma xi m u m.  Mea n , me dia n , Q 1 a n d Q 3 will be re p orte d t o 1 m ore deci mal place t ha n t he ra w data, 
w hile t he S D will be re p orte d t o 2 m ore d eci mal pl aces t ha n t he ra w data. Mi ni m u m a n d ma xi m u m 
will be re p orte d t he s a me as t he ori gi nal data.  
I n ge neral, all a nal ys es will be perf or me d b y st u d y part a n d treat me nt gr o u ps  u nl ess ot her wise 
s pecifie d. S u bject s pecifi c listi n gs will be pr o vi de d b y st u d y part, treat me nt, s u bject I D, visit a n d 
date , if a p plica bl e.   
All s u m maries a n d statistical a nal ysis will be perf or me d b y S A S v 9. 4 or lat er.  
1 2. 2  
Defi niti o n of St u d y D a ys  
U nless ot her w ise state d, st u d y d a ys of a n assess me nt  or e ve nt are defi ne d as n u m ber of da ys 
relati ve t o t he patie nt’s first d ose date.  
•  F or ass ess me nt/e ve nt o n/after t he first d ose date, st u d y da ys are calc ulate d as  
  Date of ass ess me nt/e ve nt –  t he first d ose date + 1 
•  F or ass ess me nt/e ve nt bef ore t he first d ose d ate, st u d y da ys are calc ul ate d as  
        Date of ass ess me nt/e ve nt –  t he first d ose d ate 
1 2. 3  
Defi niti o n of B aseli ne  
U nless ot her wis e state d, baseli ne is d efi ne d as t h e last n o n -missi n g m eas ure me nt pri or t o or o n t he 
first a d mi nistrati o n of st u d y dr u g ( St u d y Da y 1). Baseli ne ca n be o n t he sa me date as t he first d ose, 
gi ve n t he meas ure me nt is e x pecte d pri or t o first d ose w he n o nl y dat e i nf or mati o n is a vaila ble.  If 
t here are re p eate d me as ur e me nts wit h m ore t ha n o ne e val ua ble res ult f or t he  visit  w hic h c o ul d n ot 
be disti n g uis he d b y ti me , mea n val ue will be defi n e d as baseli ne.  
1 2. 4  
Defi niti o n of Visit Wi n d o ws  
Data will be s u m marize d a n d a n al yze d base d o n t he list of visits s pecifie d i n t he sc h e d ule of 
assess me nts  ( S O A) of t he pr ot oc ol. All t he p ost -baseli ne rec or ds will be assi g ne d t o a n a p pr o priat e 
a nal ysis visit usi n g t he r ules bel o w:  
•  F or t he p ost -baseli ne visits, t he l o wer a n d t he u p per b o u n d f or t he a nal ysis visit wi n d o ws 
are defi ne d as t he mi d p oi nts of t he tar get date  of t he sc he d ule d visits.  
•  If t h e date of ass ess me nt falls i n bet wee n t he l o wer b o u n d a n d t he u p per b o u n d f or a visit 
as s pecifie d i n t he sc he d ule of assess me nts of t he pr ot oc ol, t he n it will be assi g ne d t o t hat 
visit.  
•  If t he i nter val se p arati n g 2 sc he d ule d visits is a n e ve n n u m ber of da ys, t he mi d dle da y will 
be i ncl u de d i n t he l o wer b o u n d of t he ne xt visit.  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  2 9  of 3 2                                        C o nfi de ntial  
•  E n d of Treat me nt visit f or s u bjects w h o disc o nti n ue d  t he st u d y earl y a n d u nsc he d ule d visits 
will be ma p pe d t o p ost -b aseli ne sc h e d ule d visits  if t he y fall i n a sc h e d ule d visit wi n d o w. 
If assess me nt res ult is a vaila ble i n t he ori gi nal p ost-baseli ne sc he d ule d visit, t he n t he rec or d 
will be use d i n t h e a n al ysis. If ass ess me nt fr o m t he ori gi nal p ost -b aseli ne sc he d ule d visit 
is u na vaila ble, t he n t he assess me nt res ult ma p pe d fr o m u nsc he d ule d/e n d of treat me nt visit 
will be use d f or a n al ysis. If t here are m ore t ha n o ne u nsc he d ule d/e n d of treat me nt visits 
ma p pe d t o t he sa me wi n d o w, t he o ne cl oser t o t he tar get da y will be use d  f or a nal ysis. If 
m ore t ha n o ne visi ts ha ve t he e q ual dista nce t o t he tar get da y, t he n t he earlier o ne will be 
use d  f or a nal ysis. If m ore t ha n o ne visits o n t he sa me da y, t he ti me or t he se q ue nce n u m b er 
will be use d t o select t he earlier rec or d. If m ore t h a n o ne visits o n t he sa me da y a n d c oul d 
n ot be differe ntiate d b y t he ti me or t he se q ue nce n u m ber, mea n val ue will be use d f or 
a nal ysis .  
1 2. 5  
Re pe ate d or U nsc he d ule d Assess me nts  
F or re peat e d meas ur e me nts wit h m ore t ha n o ne e val ua ble res ult at t he sa m e visit, mea n val ue will 
be use d f or a nal ysis.  F or re peat e d meas ure me nts wit h o nl y o ne e val ua ble res ult at t he sa me visit, 
t he n t he e val ua ble assess me nt will be use d f or a nal ysis. F or u nsc he d ule d meas ure me nts, t he 
rec or ds will be ma p pe d t o sc he d ule d p ost-baseli n e visits acc or di n g t o visit wi n d o ws des c ri be d i n 
secti o n 1 2. 4 a b o ve. 
T he re p eate d a n d u nsc he d ule d meas ure m e nts will be prese nt e d i n t he listi n gs.  
1 2. 6  
H a n dli n g of Missi n g, U n use d, a n d S p uri o us D at a  
1 2. 6. 1  Missi n g D ate of I n vesti g ati o n al Pr o d uct  
W he n t he date of t h e last d ose of i n vesti gati o nal pr o d uct is missi n g f or a s u bject i n t he safet y set, 
all eff orts s h o ul d b e ma de t o o btai n t he d ate fr o m t he i n vesti gat or. If it is still missi n g after all 
eff orts, t he n t he l ast visit  date will  be use d i n t he calc ulati o n of treat me nt d urati o n.  
1 2. 6. 2  Missi n g or P arti al D ates  f or Me dic ati o ns  
W he n deter mi ni n g pri or or c o nc o mita nt me dicati o ns, partial start dates of pri or a n d c o n c o mita nt 
me dicati o ns will be ass u me d t o be t he earliest p ossi ble date c o nsiste nt wit h t he partial date.  
•  Me dicati o n start d ates wit h a missi n g d a y a n d n o n -missi n g m o nt h a n d year will be ass u me d 
t o ha ve o cc urre d o n t he first da y of t h e n o n-missi n g m o nt h, e x ce pt f or me dicati o ns 
occ urri n g i n t he sa me m o nt h a n d year as t h e first d ose of i n vesti gati o nal dr u g, i n w hic h 
case t he start date will be t he first d os e date.  
•  Me dicati o n start d ates wit h missi n g da y a n d m o nt h a n d n o n -missi n g year will be ass u me d 
t o ha ve occ urre d o n t h e first da y of t he n o n-missi n g year (i. e., 0 1 J a n uar y).  
•  A missi n g me dicati o n start date will be c o de d as t he first d ose date.  
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  3 0  of 3 2                                        C o nfi de ntial  
•  Me dicati o ns  t hat are n ot o n g oi n g a n d ha ve a me dicati o n st o p date wit h a missi n g da y a n d 
n o n -missi n g m o nt h a n d year will be ass u me d t o ha ve st o p pe d o n t he last da y of t he n o n -
missi n g m o nt h, e x ce pt f or me dicati o ns st o p i n t h e sa me m o nt h a n d year as t he last st u d y 
date,  i n w hic h case t he st o p date will be t he last st u d y dat e. 
•  Me dicati o ns t hat are n ot o n g oi n g a n d ha v e a me dicati o n st o p date wit h missi n g da y a n d 
m o nt h a n d n o n -missi n g year will be ass u me d t o ha ve st o p pe d o n t he last da y of t he n o n -
missi n g year (i.e.,  3 1  Dec e m ber), e x ce pt f or me di cati o ns st o p i n t he sa m e year as t he l ast 
st u d y date, i n w hic h cas e t he st o p date will be t he last st u d y date. 
I m p utati o n of missi n g or partial dates f or me dicati o ns is use d o nl y t o deter mi ne w het her a n e ve nt 
is pri or or c o nc o mita nt m e dicati o n, data listi n gs will prese nt t he missi n g or p artial date as rec or de d 
i n t he e C R F. 
1 2. 6. 3  Missi n g or P arti al D ates f or Pr oce d ure s  
F or rec or ds wit h a missi n g or p artial pr oce d ure date, t he f oll o wi n g steps  will be e m pl o ye d t o 
deter mi ne w het h er t he pr oce d u re is pri or or c o n c o mita nt: 
•  Pr oce d ure start dates wit h a missi n g da y a n d n o n -missi n g m o nt h a n d year will be ass u me d 
t o ha ve occ urre d o n t he first da y of t he n o n-missi n g m o nt h, e x ce pt f or pr oce d ures occ urri n g 
i n t he sa me m o nt h a n d year as t he first d ose of st u d y tr eat me nt, i n w hic h cas e t he start date 
will be t he first d ose date.  
•  Pr oce d ure start dates wit h missi n g da y a n d m o nt h a n d n o n -missi n g year will be ass u me d 
t o ha ve occ urre d o n t h e first da y of t he n o n-missi n g year (i. e., 0 1 J a n uar y).  
•  A missi n g pr oce d ure  start date will be c o de d as t he first d ose date .  
•  Pr oce d ures t h at are n ot o n g oi n g a n d h a ve a pr oce d ure st o p date wit h a missi n g da y a n d 
n o n -missi n g m o nt h a n d year will be ass u me d t o ha ve st o p pe d o n t he last da y of t he n o n -
missi n g m o nt h, e x ce pt f or pr oc e d ure st o p i n t he sa me m o nt h a n d year as t he last st u d y d ate, 
i n w hic h case t he st o p d ate will be t he last st u d y d ate. 
•  Pr oce d ures t hat are n ot o n g oi n g a n d ha ve a pr oce d ure st o p date wit h missi n g da y a n d m o nt h 
a n d n o n -missi n g year will be ass u me d t o h a ve st o p pe d o n t he last d a y of t he n o n -missi n g 
year (i.e.,  3 1  Dece m ber), e x ce pt f or pr oce d ure st o p i n t he sa me year as t he l ast st u d y d ate, 
i n w hic h case t he st o p d ate will be t he last st u d y d ate. 
I m p utati o n of missi n g or partial dates f or pr oce d ures is use d o nly t o deter mi ne w het her a pr oce d ure 
is pri or or c o nc o mita nt pr oce d ure, data listi n gs will prese nt t he missi n g or p artial date as rec or de d 
i n t he e C R F. 
1 2. 6. 4  Missi n g or P arti al D ate s f or A d verse E ve nts  
W he n t he date of t he a d v erse e v e nt  is missi n g or partial f or a s u bject i n t he safet y set, all eff orts 
s h o ul d be ma de t o res ol ve t he f ull date fr o m t he i n vesti gat or.  T he f oll o wi n g c o n ve nti o ns will be 
use d t o i m p ute partial  dates f or a d verse e ve nts. N ot e t hat t he i m p ute d val ues o utli ne d here ma y n ot 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  3 1  of 3 2                                        C o nfi de ntial  
al wa ys pr o vi d e t he  m ost c o nser vati ve date. U n der  t h ose circ u msta n ces, t h e i m p ute d val ue ma y be 
re place d b y a dat e t hat will lea d t o a m ore c o nser vati ve a nal ysis.  
1. St art D ates  
•  If t he year is u n k n o w n, t he n t he d ate will n ot be i m p ute d a n d will be assi g ne d a missi n g 
val ue.   
•  If t he m o nt h is u n k n o w n, t he n: If t he year matc h es t he first d ose date year, t he n i m p ute t he 
m o nt h a n d da y of t he first d ose date. Ot her wise, assi g n ‘Ja n uar y’.  
•  If t he d a y is u n k n o w n, t he n: If t he m o nt h a n d year matc h t h e first d os e d ate m o nt h a n d 
year, t h e n i m p ute t he d a y of t he first d ose d ate. Ot h er wise, assi g n t he first da y of t he m o nt h.  
2. St o p D ates  
•  If t he year is u n k n o w n, t he n t he d ate will n ot be i m p ute d a n d will be assi g ne d a missi n g 
val ue.  
•  If t he m o nt h is u n k n o w n, t he n assi g n ‘ Dece m ber’, e x cept f or t he e ve nt st o p i n t he sa me 
year as t h e last st u d y d ate, i n w hic h cas e t he st o p date will be t he last st u d y date.  
•  If t he da y is u n k n o w n, t h e n assi g n t he last da y of t he m o nt h, e x ce pt f or t he e ve nt st o p i n 
t he sa me m o nt h a n d year as t he last st u d y date, i n w hic h case t he st o p date will be t he last 
st u d y date. 
 
If t he st o p date is c o m plete a n d t he i m p ute d start date is after t he st o p date, t he n t he start date will 
be i m p ute d usi n g t he st o p date.   
I m p utati o n of missi n g or partial dates f or a d v erse e ve nts is use d o nl y t o deter mi ne w het h er a n 
a d verse e v e nt is tr eat me nt -e mer ge nt a n d calc ul ati o n of d urati o n of a d verse e v e nts; data listi n gs 
will prese nt t he missi n g or partial date as rec or de d i n t he e C R F.  
1 2. 6. 5  Missi n g Se verit y Assess me nt f or A d verse E ve nts  
•  If se v erit y is missi n g f or a n A E starti n g pri or t o t h e date of t he first d ose of i n vesti gati o nal 
pr o d uct, t he n a se v erit y of “ Mil d” will be assi g ne d.   
•  If t he se v erit y is missi n g f or a n A E starti n g o n or after t he date of t he first d ose of 
i n vesti gati o nal pr o d u ct, t he n a se verit y of “ Se vere” will be assi g n e d.   
T he i m p ute d val ues f or s e verit y assess me nt will be use d f or i nci de nce s u m maries, w hile t he act ual 
val ues rec or de d i n t he e C R F will be use d i n data listi n gs.  
1 2. 6. 6  Missi n g Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct f or A d verse E ve nts  
If t h e relati o ns hi p t o i n vesti gati o nal pr o d uct is missi n g f or a n A E starti n g o n or after t he date of 
t he first d ose of i n vesti gati o nal pr o d uct, a ca us alit y of “ Relate d ” will be assi g ne d.   
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D


A pellis P har mace utical, I nc                                                          Cli nical Pr ot oc ol A P L 9 -C O V -2 0 1  
Statistical A nal ysis Pla n V 2 . 0                                                                                               
  
A pellis P har mace uticals, I n c                      Pa ge  3 2  of 3 2                                        C o nfi de ntial  
1 2. 6. 7  Detect a ble Li mits of Cli nic al L a b or at or y V ari a bl es 
La b res ults be y o n d t he detecta ble li mits will be re p orte d as detecta ble li mits f or calc ulati n g 
descri pti ve statistics. Ori gi nal val u es will be liste d.  
1 3.  
A N A L Y SI S S O F T W A R E  
Statistical a nal ys es will b e perf or me d usi n g Versi o n 9. 4 ( or n e wer) of S A S  o n a s uita bl y q ualifie d 
e n vir o n me nt.  
1 4.  
C H A N G E S T O A N A L Y S E S   
1 4. 1  
C h a n ges t o A n al yses S pecifie d i n t he pr ot oc ol  
N ot a p plica ble  
1 4. 2  
C h a n ges f r o m A n al yses S pecifie d i n t he Pre vi o us Versi o n of t he S A P  
 
 
2 , Clarifie d f ull a nal ysis set defi niti o n i n secti o n 4. 4. 
“T he f ull a nal ysis set ( F A S) set will i ncl u de all s u bjects w h o recei ve at least o ne d os e of st u d y 
treat me nt.” i n S A P v 1. 0 has bee n u p date d t o “ T he f ull a nal ysis set ( F A S) set will i ncl u de all 
ra n d o mize d s u bjects w h o recei v e at least o ne d os e of st u d y tr eat me nt.”.  
T he se nte n ce “ T he f ull a nal ysis set is t he sa m e as t he safet y set i n t his st u d y .”  I n SA P v 1. 0 has 
bee n delet e d.  
3, Re m o ve d per pr ot oc ol set a n d effi cac y a nal ysis base d o n per pr ot oc ol set.  
4 , A d de d stratifie d L o g-ra n k test a n d C o x re gressi o n met h o d f or a nal ysis of ti me-t o-e ve nt 
e n d p oi nts i n secti o n 6. 2. 1.  
5 , U p date d t he w or di n g i n secti o n 6. 3. 1 f or clar it y per st u d y t ea m c o m me nts.  
1 5.  
R E F E R E N C E S  
A R D S Defi niti o n Tas k F orce, Ra nieri V M, R u be nfel d G D, et al. Ac ute res pirat or y distress  
s y n dr o me: t he Berli n Defi niti o n. J A M A. 2 0 1 2; 3 0 7( 2 3): 2 5 2 6-2 5 3 3. d oi: 
1 0. 1 0 0 1/ja ma. 2 0 1 2. 5 6 6 9.  
Ferreira F L, B ota D P, Br oss A, Mel ot C, Vi nce nt J L. Serial e val uati o n of t he S O F A sc ore t o  
pre dict o utc o me i n criticall y ill patie nts. J A M A. 2 0 0 1; 2 8 6( 1 4): 1 7 5 4 -1 7 5 8. d oi:  
1 0. 1 0 0 1/ja ma. 2 8 6. 1 4. 1 7 5 4 . 
 
 
 
D o c u Si g n E n v el o p e I D: 6 E 4 3 C 3 C 5- 7 B 0 0- 4 7 E 4- 8 7 9 2- 1 8 B 7 D 1 2 A 5 3 E D
C CI