Clinical trial NCT04345614
Conditions: Pneumonia
Keywords: COVID-19 Coronavirus Pneumonia Calcium release-activated calcium channel (CRAC) inhibitors CM4620 Auxora
Sponsor: CalciMedica, Inc.
Start date: 2020-04-08; Completion date: 2021-07-30
Enrollment: 314 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Part 1 of this trial enrolled 30 patients to receive Auxora (formerly CM4620) in a 2:1 randomized, open label trial of patients with severe and critical COVID-19 pneumonia. Part 2 of this study randomized 284 patients and was a randomized, double blind, placebo-controlled (RCT) study that evaluated the efficacy, safety, and the pharmacokinetic profile of Auxora in patients with severe COVID-19 pneumonia. The number of patients with an imputed PaO2/FiO2 \>200 randomized into the study was capped at 26. Another 258 patients with a PaO2/FiO2 ≤200 were enrolled. Patients with an estimated PaO2/FiO2 of 75-200 were stratified to ensure balanced randomization between the Auxora and placebo arms. Subgroup analyses were performed to explore how time to recovery is influenced by baseline variables and to evaluate the treatment effect at different levels of each of these variables. The dose of Auxora was 2.0 mg/kg (1.25 mL/kg) administered at 0 hour, and then 1.6 mg/kg (1 mL/kg) at 24 hours and 1.6 mg/kg (1 mL/kg) at 48 hours from the SFISD. The dose of placebo was 1.25 mL/kg administered at 0 hour and then 1 mL/kg at 24 hours and 1 mL/kg at 48 hours from the SFISD. Remdesivir, corticosteroids and convalescent plasma were allowed. The infusion of Auxora / Placebo started within 12 hours from the time the patient or LAR provided informed consent. Efficacy analyses will be presented by treatment group (Auxora vs Placebo) based on the Efficacy Analysis Set of the imputed PaO2/FiO2 ≤200 subgroup, except where it is specified otherwise. The statistical analysis approach was designed to assess the significance of the primary and first secondary endpoint using the Benjamini and Hochberg method to control the overall trial level alpha level.

Detailed description:

Arms: arm 1: Patients were randomized 1:1 to receive either Auxora or standard of care arm 2: Patients were randomized 1:1 to receive either Auxora or standard of care arm 3: Patients were randomized 1:1 to receive Auxora or Placebo arm 4: Patients were randomized 1:1 to receive Auxora or Placebo
Interventions: intervention 1: Auxora (Part 1) intervention 2: Standard of Care (Part 1) intervention 3: Auxora (Part 2) intervention 4: Placebo (Part 2)
Intervention descriptions: intervention 1: Auxora will be given at 2.0 mg/kg (1.25 mL/kg) on Day 1 and then 1.6 mg/kg (1.0 mL/kg) on Days 2 and 3. All doses of Auxora will be administered intravenously (IV) over 4 hours. intervention 2: Patients received standard of care intervention 3: Auxora will be given at 2.0 mg/kg (1.25 mL/kg) on Day 1 and then 1.6 mg/kg (1.0 mL/kg) on Days 2 and 3. All doses of Auxora will be administered intravenously (IV) over 4 hours. intervention 4: Placebo will be given at 2.0 mg/kg (1.25 mL/kg) on Day 1 and then 1.6 mg/kg (1.0 mL/kg) on Days 2 and 3. All doses of Placebo will be administered intravenously (IV) over 4 hours.

Protocol documents:
Prot_000.pdf: 
CM4620-204 
A Randomized Double Blind, Placebo-Controlled Study 
of Auxora for the Treatment of 
Severe COVID-19 Pneumonia (CARDEA) 
Sponsor: 
CalciMedica, Inc. 
505 Coast Boulevard South, Suite 307 
La Jolla, CA 92037 
Sponsor Medical Contact: Sudarshan Hebbar, MD
(816) 838-7105 – Mobile
sudarshan@calcimedica.com – Email
FOR QUALIFIED INVESTIGATORS AND THEIR IRB/EC ONLY 
Version: 8.1; NCT04345614 
Issue Date: March 31, 2021 
Confidentiality Statement 
The information contained in this document is confidential and proprietary property 
of CalciMedica, Inc. Any distribution, copying, or disclosure is strictly prohibited 
unless federal regulations or state law requires such disclosure. Prior written 
authorization of CalciMedica, Inc. is required for any disclosure or use of the 
information contained herein. Persons to whom the information is disclosed must know 
that it is confidential and that it may not be further disclosed by them. 


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SPONSOR APPROVAL AND SIGNATURE PAGE 
Sudarshan Hebbar MD 
Chief Medical Officer 
Date 
Kenneth A. Stauderman Ph.D. 
Chief Scientific Officer 
Date 
07-Apr-2021
07-Apr-2021


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SYNOPSIS 
Protocol 
Number: 
CM4620-204 
Protocol Title 
for Part 2: 
A Randomized Double Blind, Placebo-Controlled Study of Auxora for the 
Treatment of Severe COVID-19 Pneumonia (CARDEA) 
Protocol Title 
for Part 1 
(closed): 
A Randomized Controlled Open-Label Study of CM4620 Injectable 
Emulsion (CM4620-IE) in Patients with Severe COVID-19 Pneumonia 
Sponsor: 
CalciMedica, Inc. 
505 Coast Blvd. South, Suite 307 
La Jolla, CA 92037 USA 
Study Phase: 
2 
Number of 
Patients and 
Sites: 
Initially, up to 400 patients with confirmed COVID-19 pneumonia and 
receiving supplemental oxygen were to be randomized 1:1 to Auxora 
(formerly known as CM4620-IE) or Placebo at up to approximately 40 
enrolling sites. 
Auxora Dose 
and Route of 
Administration: 
2.0 mg/kg (1.25 mL/kg) of Auxora will be administered at 0 hour and 
1.6 mg/kg (1 mL/kg) will be administered at both 24 hours and 48 hours 
from the Start of the First Infusion of Study Drug (SFISD). 
Auxora will be administered intravenously as a continuous infusion over 
4 hours via a bag and tubing compatible with lipid emulsions and using a 
1.2-micron filter. 
Placebo Dose 
and Route of 
Administration 
Placebo will consist of the emulsion without any active pharmaceutical 
ingredient CM4620. 1.25 mL/kg of Placebo will be administered at 0 hour 
and 1 mL/kg will be administered at both 24 and 48 hours from the SFISD. 
Placebo will be administered intravenously as a continuous infusion over 
4 hours via a bag and tubing compatible with lipid emulsions and using a 
1.2-micron filter. 
Hypothesis: 
Auxora, a calcium release-activated calcium (CRAC) channel inhibitor, 
potently blocks the production and release of pro-inflammatory cytokines 
from immune cells, including those elevated by SARS-CoV-2 infection 
(e.g., IFN-γ, IL-6, IL-17 and TNFα) and may interrupt the cascade of events 
leading to acute lung injury (ALI) and acute respiratory distress syndrome 
(ARDS) in patients with severe COVID-19 pneumonia. It may further directly 
protect the lung through a local effect on CRAC channels and modulation of 
NFAT-induced activation of the lung endothelium. Recently published 
literature showed that a CRAC channel inhibitor similar to Auxora was 
beneficial in animal models of lung injury by both a direct effect on pulmonary 
endothelial cells, as well as a systemic effect on CRAC channels of immune 
cells. Lending further support are in vivo efficacy data showing decreases in 
lung IL-6, TNFα, and myeloperoxidase (MPO) mRNA production after 


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treatment with Auxora in animals with experimental acute pancreatitis, a 
known cause of ALI/ARDS, and data from a Phase 2a study in patients with 
acute pancreatitis and accompanying SIRS with hypoxemia at presentation 
that showed both a reduction in significantly elevated IL-6 levels and 
improved oxygenation in patients treated with Auxora. 
Auxora is given intravenously, is distributed into the lung within 2 to 
4 hours of the start of infusion, has a rapid onset of activity with IL-2 
production being decreased by >50% at the end of the infusion, and does not 
appear to have long term immune-modulatory effects with recovery of IL-2 
production 24 hours after the end of the infusion. 
Auxora holds promise as a potential treatment for patients with severe 
COVID-19 pneumonia, especially those with progressive respiratory 
dysfunction due to cytokine storm, and given the lack of effective 
treatments, clinical development was initiated. 
Objectives: 
Primary: 
• To assess the clinical efficacy of Auxora in patients with severe 
COVID-19 pneumonia 
Secondary: 
• To assess the safety and tolerability of Auxora in patients with severe 
COVID-19 pneumonia 
• To assess the pharmacokinetic profile of Auxora in patients with severe 
COVID-19 pneumonia 
Inclusion 
Criteria: 
All of the following must be met for a patient to be randomized into the study: 
1. Has laboratory-confirmed SARS-CoV-2 infection as determined by 
polymerase chain reaction (PCR) or other commercial or public health 
assay in any specimen, as documented by either of the following: 
o PCR positive in sample collected < 72 hours prior to randomization; 
o PCR positive in sample collected ≥ 72 hours prior to randomization, 
with inability to obtain a repeat sample (e.g. due to lack of testing 
supplies, or limited testing capacity, or results taking >24 hours, etc.) 
or progressive disease suggestive of ongoing SARS-CoV-2 infection;  
2. At least 1 of the following symptoms: 
o Fever, cough, sore throat, malaise, headache, muscle pain, dyspnea at 
rest or with exertion, confusion, or respiratory distress; 
3. At least 1 of the following signs at Screening or noted in the 24 hours 
before Screening: 
o PaO2/FiO2 ≤200 when receiving supplemental oxygen. The 
PaO2/FiO2 may be estimated from pulse oximetry (Appendix 1) or 
determined by arterial blood gas; 
o If SpO2 ≥97%, must be receiving 10L or more of supplemental oxygen; 


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4. The presence of a respiratory infiltrate or abnormality consistent with 
pneumonia that is documented by either a CXR or CT scan of the lungs; 
5. The patient is ≥18 years of age; 
6. A female patient of childbearing potential must not attempt to become 
pregnant for 39 months, and if sexually active with a male partner, is 
willing to practice acceptable methods of birth control for 39 months 
after the last dose of study drug; 
7. A male patient who is sexually active with a female partner of 
childbearing potential is willing to practice acceptable methods of birth 
control for 39 months after the last dose of study drug. A male patient 
must not donate sperm for 39 months; 
8. The patient is willing and able to, or has a legal authorized representative 
(LAR) who is willing and able to, provide informed consent to 
participate, and to cooperate with all aspects of the protocol. 
Exclusion 
Criteria: 
Patients with any of the following conditions or characteristics must be 
excluded from randomizing: 
1. Expected survival or time to withdrawal of life-sustaining treatments 
expected to be <7 days. 
2. Do Not Intubate order; 
3. Home mechanical ventilation (noninvasive ventilation or via tracheotomy) 
except for continuous positive airway pressure or bi-level positive 
airway pressure (CPAP/BIPAP) used solely for sleep-disordered 
breathing; 
4. PaO2/FiO2 ≤75 at the time of Screening. The PaO2/FiO2 may be estimated 
from pulse oximetry (Appendix 1) or determined by arterial blood gas; 
5. Noninvasive positive pressure ventilation; 
6. Invasive mechanical ventilation via endotracheal intubation or 
tracheostomy; 
7. ECMO; 
8. Shock defined by the use of vasopressors; 
9. Multiple organ dysfunction or failure; 
10. Positive Influenza A or B testing if tested as local standard of care; 
11. The patient has a history of: 
a. Organ or hematologic transplant; 
b. HIV; 
c. Active hepatitis B, or hepatitis C infection; 


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12. Current treatment with: 
a. Chemotherapy; 
b. Immunosuppressive medications or immunotherapy (Section 5.3 
for list of prohibited immunosuppressive medications and 
immunotherapy) at the time of consent; 
c. Hemodialysis or Peritoneal Dialysis; 
13. Have a history of venous thromboembolism (VTE) (deep vein 
thrombosis [DVT] or pulmonary embolism [PE]) within 12 weeks prior 
to screening or have a history of recurrent (> 1) VTE; 
14. The patient is known to be pregnant or is nursing; 
15. Currently participating in another study of an investigational drug or 
therapeutic medical device at the time of consent; 
16. Allergy to eggs or any of the excipients in study drug. 
Study Design: 
Part 1 was a randomized open-label study that consisted of two arms. In one 
arm, 60 patients who were receiving low flow supplemental oxygen at 
Screening were to randomize 2:1 to Auxora or standard of care. In the other 
arm, 60 patients who were receiving high flow supplemental oxygen 
delivered using high flow nasal cannula at Screening were to randomize 2:1 
to Auxora or standard of care. The independent safety committee conducted 
a review after the first 12 patients were dosed in the low-flow arm. The 
committee recommended continuing the trial unchanged until the next safety 
review committee meeting. After the initial independent safety committee 
review, the FDA asked for a limitation of further enrollment in the open-
label study and for the study to transition to a blinded, placebo-controlled 
study. Both arms of Part 1 ceased further enrollment and follow-up of 
patients enrolled in Part 1 was to Day 30 only. 
Part 2 is a randomized, double blind, placebo-controlled study in which 
initially up to 400 patients receiving supplemental oxygen at Screening, and 
who meet all of the inclusion criteria and none of the exclusion criteria, were 
to be randomized 1:1 to receive Auxora plus standard of care or Placebo plus 
standard of care. After a blinded analysis of the mechanical ventilation and 
death rate in the subgroup of patients with an imputed PaO2/FiO2 >200 were 
randomized into the study, the number of patients in the subgroup was capped 
at 26. The study sample size remained 320 for patients with an imputed 
PaO2/FiO2 ≤200. When enrolling both subgroups, patients were stratified to 
ensure balanced randomization between the Auxora and Placebo arms. 
The dose of Auxora will be 2.0 mg/kg (1.25 mL/kg) administered at 0 hour, 
and then 1.6 mg/kg (1 mL/kg) at 24 hours and 1.6 mg/kg (1 mL/kg) at 
48 hours from the SFISD. The dose of Placebo will be 1.25 mL/kg 
administered at 0 hour and then 1 mL/kg at 24 hours and 1 mL/kg at 


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48 hours from the SFISD. The SFISD should occur within 12 hours of the 
patient or LAR providing informed consent. The dosing will be based on 
actual body weight obtained at the time of hospitalization or screening for 
the study. As described in the pharmacy manual, there will be an upper limit 
of the absolute dose (volume) of Auxora and volume of Placebo that will be 
administered for patients weighing more than 125kg. 
A study physician or appropriately trained delegate will perform assessments 
at Screening, immediately prior to the SFISD, and immediately prior to each 
subsequent infusion. At 72 hours after the SFISD, the patient will be assessed 
every 24 hours (±4 hours) until 240 hours after the SFISD, then q48 hours 
until Day 30 after the SFISD, or until discharge if earlier. Patients who are 
discharged before Day 25 after the SFISD will be followed-up at Day 30 
(±5 days) and Day 60 (±5 days) for a safety and mortality assessment. 
After the first 50 patients were randomized in Part 2, an Independent Data 
Monitoring Committee (IDMC) evaluated safety data from the study and 
agreed with capping the number of patients with an imputed PaO2/FiO2 >200 
at 26 and to continue the study enrolling only patients with an imputed 
PaO2/FiO2 <200. The IDMC will again review the safety data after the 70th 
patient in the imputed PaO2/FiO2 <200 subgroup completes or discontinues 
from the study and when the 200th patient in the imputed PaO2/FiO2 <200 
subgroup is randomized into the study. 
A sample size re-estimation procedure will be applied when the first 70 
patients in imputed PaO2/FiO2 ≤200 subgroup have completed or 
discontinued from the study. The IDMC will perform the procedure and will 
recommend to CalciMedica to increase or not increase the study sample size. 
No ongoing study patients will be included in this sample size re-estimation 
procedure. The sample size will be re-estimated to provide a conditional 
power of 90%, based on the evaluation of the treatment efficacy. 
All patients enrolled in the study should receive care consistent with local 
standard of care. Patients with worsening respiratory failure should receive 
conservative intravenous fluid strategies such as FACTT LITE. All patients 
should receive pharmacological prophylaxis to prevent the development of 
venous thromboembolic disease. The type and dose of prophylaxis should be 
determined by local standard of care. 
Patients enrolled in the study should receive dexamethasone, or equivalent 
dose of another corticosteroid, as standard of care. If patients are not 
receiving dexamethasone at the time of randomization into CARDEA, 
starting dexamethasone during the hospitalization should be considered. If 
the patient is already receiving dexamethasone at the time of randomization, 
dexamethasone should be continued on its established dosing schedule. The 
COVID-19 Treatment Guidelines Panel of the National Institutes of Health 
recommends using dexamethasone (at a dose of 6 mg per day, given orally or 


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intravenously, for up to 10 days) in patients with COVID-19 who require 
supplemental oxygen. Before initiating dexamethasone, the potential risks and 
benefits of administering corticosteroids should be assessed including risks 
for hyperglycemia and secondary infections. At this time, it is not known 
whether other corticosteroids, such as prednisone, methylprednisolone, or 
hydrocortisone, will have a similar benefit to dexamethasone. Of note, the 
dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, 
methylprednisolone 32 mg, and hydrocortisone 160 mg. 
If patients are not receiving remdesivir at the time of randomization into 
CARDEA, starting remdesivir during the hospitalization may be considered. 
If the patient is already receiving remdesivir at the time of randomization, 
remdesivir should be continued on its established dosing schedule. The 
suggested dose of remdesivir for adults weighing ≥40 kg and not requiring 
invasive mechanical ventilation and/or ECMO is a single dose of 200 mg 
infused intravenously over 30 to 120 minutes on Day 1 followed by once-
daily maintenance doses of 100 mg infused intravenously over 30 to 
120 minutes for 4 days (days 2 through 5). If a patient does not demonstrate 
clinical improvement, treatment may be extended for up to 5 additional days 
(i.e., up to a total of 10 days). Auxora and remdesivir should not infuse at the 
same time but should be given sequentially but may be given in any order. 
Patients may also be considered for the administration of convalescent 
plasma in the study as per local standard of care. 
Immunosuppressive medications or immunotherapies are prohibited in patients 
randomized into the study (Section 5.3) for list of prohibited medications). The 
use of dextromethorphan is discouraged in patients randomized into the study. 
Efficacy 
Endpoints: 
Primary Efficacy Endpoint 
• Time to recovery 
Secondary Efficacy Endpoints 
• All-Cause Mortality at Day 60 
• All-Cause Mortality at Day 30 
• Proportion of patients requiring invasive mechanical ventilation or dying 
during the 60 days from the SFISD 
• Proportion of patients requiring invasive mechanical ventilation during 
the 60 days from the SFISD 
• Difference in outcomes measured by a 8-point ordinal scale through 
Day 12 
• Difference in outcomes measured by a 8-point ordinal scale through 
Day 30 
• Number of Days in the Hospital 


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• Number of Days in the ICU 
Safety 
Endpoints 
Safety endpoints will include the following: 
• The incidence of TEAEs and SAEs 
• The intensity and relationship of TEAEs and SAEs 
• Clinically significant changes in vital signs and safety laboratory results 
Sample Size 
Calculation 
In the initial design of Part 2 of the study, 320 patients in the imputed 
PaO2/FiO2 ≤200 subgroup and 80 patients in the imputed PaO2/FiO2 >200 
subgroup were to have been randomized. A constant recovery rate ratio of 
1.43 was assumed for patients receiving Auxora compared to Placebo in 
both subgroups. In order to provide power of approximate 90% to detect 
a difference in the recovery rate ratio of approximately1.43 by a stratified 
2-sided log-rank test at an overall 0.05 alpha level, given the 1:1 randomization, 
it was determined that the study would require 330 recovery events. With the 
study length of 60 days, the assessment of time to recovery required a 
sample size of 400 patients. 
The enrollment of patients in the subgroup with an imputed PaO2/FiO2 >200 
was stopped early because a blinded analysis of the data from the first 26 
patients in the subgroup randomized into the study showed a low rate of 
mechanical ventilation or death. This finding was consistent with Part 1 of 
the study where no patients with an imputed PaO2/FiO2 >200 required 
mechanical ventilation or died. The Part 2 study sample size was then 
reevaluated given that the primary endpoint would focus on the subgroup of 
patients with an imputed PaO2/FiO2 ≤200. A two group log-rank test with a 
0.05 two-sided significance level would have 90% power to detect a 
difference in the recovery rate ratio of approximately 1.49 in the 320 patients 
with an imputed PaO2/FiO2 ≤200 who were randomized 1:1 to Auxora or 
Placebo. To further ensure that the sample size of 320 patients in the 
imputed PaO2/FiO2 ≤200 subgroup is an adequate sample size, a sample size 
re-estimation procedure will be applied when the first 70 patients in imputed 
PaO2/FiO2 ≤200 subgroup have completed or discontinued from the study. 
The IDMC will perform the procedure and will recommend to CalciMedica 
to increase or not increase the study sample size. No ongoing study patients 
will be included in this sample size re-estimation procedure.  
 
 


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Table of Contents 
Sponsor Approval and Signature Page ........................................................................................... 2 
Synopsis .......................................................................................................................................... 3 
List of Tables ................................................................................................................................ 13 
List of Terms and Abbreviations .................................................................................................. 14 
1 
INTRODUCTION ................................................................................................................. 16 
1.1 
COVID-19................................................................................................................... 16 
1.2 
Overview of CM4620 ................................................................................................. 17 
1.3 
Pre-Clinical Development of CM4620 ....................................................................... 18 
1.3.1 Pre-Clinical Safety and Toxicology Studies ................................................... 18 
1.3.2 Preclinical Efficacy Studies ............................................................................ 18 
1.4 
Clinical Development of Auxora ................................................................................ 19 
1.4.1 Single Ascending Dose and Multiple Ascending Dose Studies ..................... 19 
1.4.2 Open Label Study in Patients with Acute Pancreatitis and SIRS ................... 21 
1.5 
Pharmacodynamic and Pharmacokinetic Study in Patients with Acute Pancreatitis .. 23 
1.6 
Rationale for the Study and Selected Doses ............................................................... 24 
2 
OBJECTIVES AND ENDPOINTS ....................................................................................... 26 
2.1 
Primary Objective ....................................................................................................... 26 
2.2 
Secondary Objectives.................................................................................................. 26 
2.3 
Endpoints .................................................................................................................... 26 
3 
INVESTIGATIONAL PLAN ............................................................................................... 27 
3.1 
Study Design ............................................................................................................... 27 
3.2 
End of Study ............................................................................................................... 28 
3.3 
Sponsor Termination of the Study .............................................................................. 28 
4 
SELECTION OF PATIENTS ............................................................................................... 29 
4.1 
Inclusion Criteria ........................................................................................................ 29 
4.2 
Exclusion Criteria ....................................................................................................... 29 
4.3 
Re-Screening ............................................................................................................... 30 
5 
TREATMENT OF PATIENTS ............................................................................................. 31 
5.1 
Overview ..................................................................................................................... 31 
5.2 
Discharge Criteria ....................................................................................................... 31 
5.3 
Prohibited Medications ............................................................................................... 32 
5.4 
Compliance ................................................................................................................. 32 


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6 
PROCEDURES ..................................................................................................................... 33 
6.1 
Enrollment Procedures ................................................................................................ 33 
6.2 
Discontinuation and Withdrawal ................................................................................ 33 
7 
STUDY DRUG MATERIALS AND MANAGEMENT ...................................................... 34 
7.1 
Auxora Product Description ....................................................................................... 34 
7.2 
Placebo Product Description ....................................................................................... 34 
7.3 
Auxora and Placebo Storage ....................................................................................... 34 
7.4 
Auxora and Placebo Preparation ................................................................................. 34 
7.5 
Auxora and Placebo Administration ........................................................................... 35 
7.6 
Packaging and Labeling .............................................................................................. 35 
7.7 
Accountability, Handling and Disposal ...................................................................... 35 
8 
VISITS AND STUDY SPECIFIC ASSESSMENTS ............................................................ 36 
8.1 
Screening..................................................................................................................... 36 
8.2 
Baseline Laboratory Assessment ................................................................................ 36 
8.3 
Randomization ............................................................................................................ 36 
8.4 
Start of First Infusion of Study Drug (SFISD) 0 hour ................................................ 37 
8.5 
24 hours ....................................................................................................................... 37 
8.6 
48 hours ....................................................................................................................... 38 
8.7 
72 hours ....................................................................................................................... 38 
8.8 
96, 144, 192 and 240 hours ......................................................................................... 39 
8.9 
120, 168, and 216 hours .............................................................................................. 39 
8.10 Days 12 to 28 .............................................................................................................. 40 
8.11 Day 60 and Day 30 ..................................................................................................... 40 
8.12 Discharge Date ............................................................................................................ 40 
8.13 Study Assessments ...................................................................................................... 40 
8.13.1 Concomitant Medications ............................................................................... 41 
8.13.2 Vital Signs ....................................................................................................... 41 
8.13.3 Arterial Blood Gas .......................................................................................... 41 
8.13.4 SpO2/FiO2 ....................................................................................................... 41 
8.13.5 Laboratory Analyses ....................................................................................... 42 
8.13.6 PK Samples ..................................................................................................... 42 
9 
ADVERSE EVENTS ............................................................................................................ 43 
9.1 
Definition of Adverse Event ....................................................................................... 43 
9.2 
Definition of Serious Adverse Event .......................................................................... 43 
9.3 
Eliciting Adverse Event Information .......................................................................... 44 


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9.4 
Recording Adverse Events .......................................................................................... 44 
9.5 
Assessment of Relationship to Study Drug ................................................................ 45 
9.6 
Assessment of Severity ............................................................................................... 45 
9.7 
Reporting of Serious Adverse Events ......................................................................... 46 
9.8 
Suspected Pregnancy in a Woman of Childbearing Potential .................................... 47 
10 STATISTICAL METHODS ................................................................................................. 49 
10.1 General Considerations ............................................................................................... 49 
10.2 Sample Size ................................................................................................................. 49 
10.3 Study Endpoints .......................................................................................................... 50 
10.4 Analysis Sets ............................................................................................................... 50 
10.4.1 All Subjects Analysis Set ................................................................................ 50 
10.4.2 Efficacy Analysis Set ...................................................................................... 51 
10.4.3 Safety Analysis Set ......................................................................................... 51 
10.5 Schedule of Analyses .................................................................................................. 51 
10.6 Disposition .................................................................................................................. 51 
10.7 Analysis of Demographic and Baseline Data ............................................................. 51 
10.8 Efficacy Analysis ........................................................................................................ 52 
10.8.1 Primary Efficacy Analysis .............................................................................. 52 
10.8.2 Secondary Efficacy Analyses ......................................................................... 52 
10.8.3 Mortality at Days 60 and 30............................................................................ 53 
10.8.4 Proportion of Patients Requiring Invasive Mechanical Ventilation or Dying 
During the 60 Days from the SFISD ............................................................. 53 
10.8.5 Proportion of Patients Requiring Invasive Mechanical Ventilation During the 
60 Days from the SFISD ............................................................................... 53 
10.8.6 Differences in Outcomes Measured by an 8-Point Ordinal Scale At Day 12 . 53 
10.8.7 Difference in Outcomes Measured by an 8-Point Ordinal Scale at Day 30 ... 53 
10.8.8 Number of Days in the Hospital ..................................................................... 53 
10.8.9 Number of Days in the ICU ............................................................................ 54 
10.8.10 Subgroup and Exploratory Analyses ............................................................. 54 
10.9 Safety Analysis ........................................................................................................... 54 
10.10 PK Analysis ................................................................................................................ 55 
10.11 Interim Sample Size Re-estimation ............................................................................ 55 
11 ADMINISTRATIVE CONSIDERATIONS ......................................................................... 57 
11.1 Electronic Case Report Forms .................................................................................... 57 
11.2 Monitoring of the Study .............................................................................................. 57 


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11.3 Inspection of Records ................................................................................................. 57 
11.4 Study Record Retention .............................................................................................. 57 
11.5 Study Conduct: Good Clinical Practice and Declaration of Helsinki ......................... 57 
11.6 Responsibilities of the Investigator and the IRB/EC .................................................. 58 
11.7 Confidentiality ............................................................................................................ 58 
11.8 Modification of the Protocol ....................................................................................... 58 
11.9 Informed Consent........................................................................................................ 59 
11.10 Protocol Violations and Deviations ............................................................................ 59 
11.11 Financial Disclosure.................................................................................................... 60 
11.12 Sponsor Obligations .................................................................................................... 60 
11.13 Investigator Documentation ........................................................................................ 60 
11.14 Clinical Study Insurance ............................................................................................. 61 
11.15 Use of Information ...................................................................................................... 61 
11.16 Publications ................................................................................................................. 61 
11.17 Independent Data Monitoring Committee .................................................................. 61 
12 REFERENCES ...................................................................................................................... 62 
Appendix 1. 
Estimated PaO2/FiO2 ............................................................................................. 64 
Appendix 2. 
Schedule of Events ................................................................................................ 65 
 
List of Tables 
Table 1. 
SAD (CM4620-101) ................................................................................................... 19 
Table 2. 
MAD (CM4620-102) .................................................................................................. 20 
Table 3. 
Demographics and Baseline Characteristics of Patients in CM4620-201 .................. 22 
Table 4. 
Auxora Product Information ....................................................................................... 34 
Table 5. 
Conversion of O2 Flow to FiO2 ................................................................................... 41 
Table 6. 
Relationship Between the Observed Recovery Ratio at Interim Analysis and the 
Re-estimated Sample Size to Reach 90% Conditional Power .................................... 56 
 
 


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List of Terms and Abbreviations 
Abbreviation 
Definition 
ABG 
arterial blood gas 
AE 
adverse event 
ALI 
acute lung injury 
ALT 
alanine transaminase 
AP 
acute pancreatitis 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
BIPAP 
bi-level positive airway pressure 
CFR 
Code of Federal Regulations 
COVID-19 
Disease from infection with coronavirus 2019 or SARS-CoV-2 
CPAP 
continuous positive airway pressure 
CPK 
creatine kinase 
CRAC 
calcium release-activated calcium 
CRF 
case report form 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
EDC 
Electronic Data Capture 
EDTA 
edetate disodium salt dehydrate 
FAEE 
fatty acid ethyl ester 
FiO2 
fraction of inspired oxygen 
G-CSF 
granulocyte-colony stimulating factor 
GMP 
Good Manufacturing Practice of Medicinal Products 
HCP 
Health Care Professional 
Hr(s) 
hour(s) 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IFNγ 
interferon-gamma 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
kilogram 
L 
liter 
LAR 
legal authorized representative 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat Population 
MPO 
myeloperoxidase 
NOAEL 
no observable adverse effect level 
PaO2 
Partial Pressure of Oxygen (arterial) 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PT 
preferred Term 
QTcF 
QT corrected for HR using Fridericia's method 
SAD 
single ascending dose 
SAE 
Serious adverse event 
SaO2 
arterial blood oxygen saturation measured directly 
SAP 
Statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
Supportive Care 
SFISD 
Start of First Infusion of Study Drug 
SIRS 
Systemic inflammatory response syndrome 
SOC 
System Organ Class 
SOCE 
Store-operated calcium entry 
SpO2 
Oxyhemoglobin percent saturation  
TEAE 
Treatment-emergent adverse event 
VTBI 
Volume to be infused 


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1 
INTRODUCTION 
1.1 
COVID-19 
COVID-19 is a disease caused by a novel beta-coronavirus, designated SARS-CoV-2, which is 
in the same subgenus as the severe acute respiratory syndrome (SARS) virus. It was initially 
identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of 
China. It rapidly spread, resulting in an epidemic throughout China, followed by a worldwide 
pandemic. Person-to-person spread of SARS-CoV-2 is thought to occur mainly via respiratory 
droplets, resembling the spread of influenza. The incubation period for COVID-19 is thought to 
be within 14 days following exposure, with most cases occurring approximately 4 to 5 days after 
exposure. 
In a report from the Chinese Center for Disease Control and Prevention that included 44,672 
confirmed infections, 81% of cases were mild and without pneumonia; 14% were severe with 
dyspnea, hypoxia, or >50% lung involvement on imaging within 24 to 48 hours; and 5% were 
critical with respiratory failure, shock, or multi-organ dysfunction The case-fatality rate was 
2.3% with older age being associated with increased mortality. The case-fatality rate in critically 
ill patients was 49% (Wu and McGoogan 2020). 
In a report of 1099 patients from China, the most common symptoms of COVID-19 were fever 
(43.8% on admission and 88.7% during hospitalization) and cough (67.8%) (Guan et al., 2020). 
Ground-glass opacity was the most common radiological finding on chest-computed tomography 
(CT), and only 2.9% of patients with severe disease did not have a radiographic or CT abnormality. 
Lymphocytopenia was present in 83.2% of patients upon admission to the hospital. Risk factors 
for progression of disease were identified in a univariate analysis as age >50, lymphocyte count 
<1500/mm3, and a serum ferritin level >400 ng/mL (Ji et al., 2020). In a retrospective study of 
201 patients with confirmed COVID-19 pneumonia, older age was a risk factor for the 
development of ARDS and for progression of ARDS to death; in this study, 41.8% of patients 
developed ARDS and 21.9% of patients died (Wu et al., 2020). 
Accumulating evidence suggests that a cytokine profile characterized by hyperinflammation 
marks severe COVID 19 disease. Increased IL-2, IL-7, granulocyte-colony stimulating factor 
(G-CSF), interferon-gamma (IFNγ) inducible protein-10 (IP-10; CXCL10), monocyte 
chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1α), and 
TNFα were associated with COVID-19 disease severity in one study (Huang et al., 2020); 
elevated IL-6 was noted to be an important predictor for mortality in multiple studies (Ruan et 
al., 2020, Wu et al., 2020); and a case report of a 50-year old man who died of COVID-19 
documented an increased concentration of highly proinflammatory CCR6+ Th17 CD4 T cells 
along with CD8 T cells harboring high concentrations of cytotoxic granules (Xu et al., 2020). 
The pathophysiology of lung disease in COVID-19 has been described in two patients who 
underwent lung lobectomies for adenocarcinoma and were retrospectively found to have had 
COVID-19 at the time of the operation (Tian et al., 2020). Pathologic findings from these two 
patients were consistent with the exudative phase of ALI with edema and prominent 


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proteinaceous exudates, vascular congestion, and inflammatory clusters with fibrinoid material 
and multinucleated giant cells. Hyaline membrane formation had not yet occurred in either of 
these two cases. 
Treatment for patients with mild disease is isolation in an outpatient setting with a focus on 
prevention of transmission to others. Severe disease warrants supportive care in the hospital with 
oxygen and ventilatory support as needed. Dexamethasone has been recommended as standard of 
care for patients with Covid-19 who are receiving supplemental oxygen only or are on mechanical 
ventilation. Remdesivir has received emergency use authorization in the United States for the 
treatment of Covid-19. No specific therapies for the respiratory complications of COVID-19 
exist and investigational agents are currently being studied. Treatment guidelines from China's 
National Health Commission include the IL-6 inhibitor tocilizumab for severe infection, 
although clinical data are limited. An effective therapy for severe or critical COVID-19 would 
target the hyperinflammation that characterizes severe COVID-19 pneumonia and protect the 
lung from injury. 
1.2 
Overview of CM4620 
CM4620 is a potent and selective inhibitor of CRAC channels. CRAC channels are composed of 
the pore-forming plasma membrane protein Orai1 and the calcium-sensing ER gating-protein 
STIM1. Low levels of calcium within the ER cause the STIM1 protein to oligomerize and move 
to locations closely apposed to Orai1. When STIM1 binds to Orai1, the Orai1 Ca2+ pore opens, 
permitting entry of extracellular calcium into the cell through the CRAC channel. This process is 
referred to as store-operated calcium entry (SOCE) and evidence suggests that SOCE through 
CRAC channels plays a critical role in the degradation and necrosis of pancreatic acinar cells in 
patients with AP. 
The potential for CM4620 to inhibit CRAC channels was investigated by measuring the 
electrophysiological current (ICRAC) associated with calcium entry through CRAC channels in 
HEK293 cells stably expressing recombinant human Orai1/STIM1. Cellular recordings were 
performed using the whole-cell patch clamp method. Measurements of ICRAC were made after the 
addition of extracellular 10 mM calcium chloride and subsequent administration of CM4620 at 
concentrations of 0.001, 0.01, 0.1, and 1 µM. CM4620 was able to inhibit ICRAC in a 
concentration-dependent manner, producing a mean 50% inhibition (IC50) value of 119 nM. 
Rapid and complete inhibition was achieved at 1 µM of CM4620. Evaluations were performed to 
further elucidate the site of action of CM4620. A mutation in Orai1 (Orai1-V102C) is known to 
produce constitutively active CRAC channels without the need for STIM1. In this evaluation, 
successive concentrations of CM4620 produced nearly complete inhibition of the STIM1-
independent ICRAC, indicating that Orai1 is a major site of action of the compound. 


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1.3 
Pre-Clinical Development of CM4620 
1.3.1 
Pre-Clinical Safety and Toxicology Studies 
Safety pharmacology studies conducted in rats indicated no CM4620-induced adverse effects on 
central nervous or respiratory systems. Dose-limiting adverse clinical and cardiovascular effects 
were noted in a single telemetered cynomolgus monkey dosed at 25 mg/kg IV with Auxora. 
Cardiovascular data at lower doses (1, 3 and 10 mg/kg) showed transient, non-dose-related, 
slight-to-moderate increases in systolic/diastolic arterial blood pressures and negative chronotropic 
effects (mild and non-adverse) at all doses and in placebo treated animals. 
Repeat-dose toxicity studies conducted in both rats and monkeys showed no observable adverse 
effect levels (NOAELs) of 25 mg/kg/day and 3 mg/kg/day, respectively. In vitro genetic toxicity 
studies were negative in the Ames bacterial reverse mutation assay and weakly positive/equivocal 
in a micronucleus assay conducted in human peripheral blood lymphocytes. A subsequent in vivo 
micronucleus study conducted in rats involving two different endpoints (bone marrow micronucleus 
and liver Comet assays) showed no evidence of DNA reactivity. Based on the results of the 
complete battery of genotoxicity testing, the weight of evidence indicates that CM4620 is neither 
mutagenic nor clastogenic. Hemolysis testing concluded that CM4620 placebo was compatible 
with human plasma and non-hemolytic in human blood. Specific local tolerance studies to 
examine irritation/inflammation at the injection site were not performed, but no evidence of 
compound-related or vehicle-related local irritation was observed in the repeat-dose toxicity 
studies in rat and monkey. Finally, in vitro 3T3 results indicated that CM4620 is potentially 
phototoxic, so appropriate precautions are being taken in clinical trials. 
1.3.2 
Preclinical Efficacy Studies 
Support for the idea that CRAC channel inhibition could be useful in the treatment of lung injury 
comes from preclinical data examining the effects of BTP2, a widely used research CRAC channel 
inhibitor, as well as Auxora. BTP2 was shown to attenuate lipopolysaccharide-induced lung injury 
in mice and ventilator-induced lung injury in rats. Using a rat model of acute pancreatitis (AP), 
intravenous (IV) infusion of Auxora was noted to decrease lung myeloperoxidase activity 
(i.e., neutrophil infiltration) and mRNA levels of the pro-inflammatory cytokines TNFα and 
IL-6. Finally, knockdown of Orai1 in mice, which reduces CRAC channel activity, inhibited 
TNFα-induced cytokine expression (including IL-6) and myeloperoxidase activity in lung tissue. 
Potential efficacy of CM4620 in treating acute lung injury was established in three diverse in 
vivo models of AP that cause both pancreatic damage and lung inflammation (TLCS-induced, 
FAEE-induced, and caerulein-induced acute pancreatitis models). Myeloperoxidase activity 
within lung tissue, as well as trypsin activity, myeloperoxidase activity and histopathological 
indices (edema, inflammatory cell infiltration, vacuolization, and necrosis) in pancreas tissue, 
were all markedly reduced following a single IP dose of CM4620 in the mouse caerulein-induced 
pancreatitis model, two IP doses of CM4620 in the mouse TLCS-induced and FAEE-induced 
pancreatitis models, and one 4-hour IV infusion of CM4620 Nanoemulsion (the intended clinical 
dosage form, route of administration and infusion duration) in the rat caerulein-induced 


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pancreatitis model. The timing of CM4620 administration relative to induction of pancreatitis was 
investigated in the TLCS-induced and FAEE-induced pancreatitis models, and the results suggested 
that CM4620 may be more effective in minimizing pancreatic injury and subsequent downstream 
events if it is administered early in the course of disease, although later administration retains 
effectiveness in halting disease progression. The timing of administration for prevention or 
treatment of lung injury was not investigated. 
1.4 
Clinical Development of Auxora 
1.4.1 
Single Ascending Dose and Multiple Ascending Dose Studies 
CalciMedica has conducted two Phase 1 studies of Auxora in healthy subjects: a single ascending 
dose (SAD) study (CM4620-101) and a multiple ascending dose (MAD) study (CM4620-102). 
In CM4620-101 (Table 1), 32 healthy subjects were enrolled in five groups and randomized in a 
3:1 ratio to receive a single dose of active versus placebo. The dose levels for each group are noted 
in Table 1. The dose volume of the emulsion was fixed at 1.3 mL/kg for all subjects in the SAD 
study groups, and Auxora or placebo was administered via a 4-hour IV infusion. 
Table 1. SAD (CM4620-101) 
Group 
Active Treatment 
Number of Active 
Treatment Subjects 
Number of Placebo 
Treatment Subjects 
IV Dose Volume 
(mL/kg) 
1 
0.1 mg/kg 
6 
2 
1.3 
2 
0.24 mg/kg 
3 
1 
1.3 
3 
0.48 mg/kg 
3 
1 
1.3 
4 
1.0 mg/kg 
6 
2 
1.3 
5 
2.1 mg/kg 
6 
2 
1.3 
 
Of the 32 enrolled subjects, there were no serious adverse events (SAE) or adverse events (AE) 
classified as moderate or severe in intensity. There were three clinical AEs that were all 
classified as mild in intensity. Two of the AEs were considered possibly related and one was 
considered unlikely or unrelated to study treatment. In each case, no action was taken with 
respect to study treatment because of the AEs. No laboratory abnormalities were observed that 
were considered clinically significant. There were vehicle-related increases in serum triglyceride 
and cholesterol levels noted in some subjects that returned to baseline within 24 hours. There 
was no evidence of any sustained treatment related increase in systolic or diastolic blood 
pressure. In addition, cardiac function, monitored by continuous electrocardiographic recording 
and serial biomarker testing, showed no evidence of any treatment related effect on heart rate, 
QTcF, cardiac troponin-T or B-type natriuretic peptide levels. 
In the SAD study (CM4620-101), interim non-compartmental pharmacokinetic (PK) analysis 
indicates that CM4620 likely distributes to three compartments. Plasma concentrations of 
compound rise steadily during the 4-hour infusion, with Tmax achieved at the end of infusion 
(4 hours). After the end of infusion, there is a rapid and prominent distribution phase followed by 


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a prolonged period of residual drug levels. The terminal elimination phase has not yet been fully 
characterized as it appears to be much longer than was anticipated based on pre-clinical PK data 
in mouse, rat, dog and monkey. Plasma concentrations during the terminal phase are approximately 
5% of Cmax values and, as indicated above, to date there have been no clinically significant AEs 
reported during this phase. Plasma exposures, defined by AUC0-24h, appear to be dose-proportional 
and reached a maximum of 6710 ng*h/mL in Group 5, which is 4.3-fold below the mean AUC24h 
in monkey at the NOAEL (29,000 ng*hr/mL). 
In the MAD study (Table 2) of Auxora (CM4620-102), subjects in the first group were randomized 
to receive a single dose of active treatment, 0.50 mg/kg, versus placebo for seven consecutive 
days. Eight healthy subjects were enrolled in the first group, with five receiving active treatment 
and three receiving placebo. One of the subjects received placebo at the maximum dose volume of 
emulsion, 1.3 mL/kg, for 7 days, whereas all others were dosed on a weight-based adjustment of 
dose volume. There were no SAEs and no AEs classified as moderate or severe in intensity. 
There were 15 clinical AEs that were all classified as mild. In each case, no action was taken 
with respect to study treatment because of the AEs. No laboratory abnormalities were observed 
that were considered clinically significant. 
Table 2. MAD (CM4620-102) 
Group 
Active Treatment 
Daily for 7 days 
Number of Active 
Treatment Subjects 
Number of Placebo 
Treatment Subjects 
IV Dose Volume 
(mL/kg) 
1 
0.5 mg/kg 
5 
3 
0.3125a 
2 
1.0 mg/kg 
6 
2 
0.625 
a one placebo patient received maximum dose volume of 1.3 mL/kg 
 
Subjects in the second group of CM4620-102 were randomized to receive a single dose of active 
treatment, 1.0 mg/kg, versus placebo for seven consecutive days. Eight healthy subjects were 
enrolled in the second group, with six receiving active treatment and two receiving placebo for 
seven consecutive days. There were no SAEs and no AEs classified as moderate or severe in 
intensity. There were three AEs that were all classified as mild in intensity. In each case, no action 
was taken with respect to study treatment because of the AEs. No laboratory abnormalities were 
observed that were considered clinically significant. 
There were vehicle-related increases in serum triglyceride noted in some subjects in both groups 
with levels returning to baseline within 24 hours. Cholesterol levels accumulated in some subjects 
in both groups with daily dosing, but the increases were not considered clinically significant and 
were related to the vehicle. Thus, the largest rise in cholesterol levels was in the subject who 
received placebo at the maximum dose volume of emulsion. The rise in cholesterol is believed to 
be due to the release of tissue cholesterol induced by the lecithin in the emulsion (Byers et al., 1962), 
was noted in the pre-clinical studies in monkeys, and was reversible with cessation of dosing. 
There was no evidence of any sustained treatment related increase in systolic or diastolic blood 
pressure. In addition, cardiac function, monitored by continuous electrocardiographic recording 
and serial biomarker testing, showed no evidence of any sustained treatment related effect on 
heart rate, QTcF or B-type natriuretic peptide levels. 


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Non-compartmental PK analysis of Group 1 in CM4620-102 (0.5 mg/kg) indicates that CM4620 
accumulated in plasma, with a 2.6-fold increase in systemic exposure (AUC24h) on Day 7 compared 
to Day 1 of dosing, consistent with modeling simulations. Cmax accumulated 1.6-fold (geometric 
mean of 363 ng/mL on Day 7). The geometric mean of the AUC24h on Day 7 was 3190 ng*hr/mL, 
which is 9.1-fold below the NOAEL AUC24h in monkey (29,000 ng*hr/mL). PK analysis of 
Group 2 in CM4620-102 (1.0 mg/kg) indicates that CM4620 accumulated in plasma, with a 
2.6-fold increase in AUC24h on Day 7 compared to Day 1 of dosing, consistent with modeling 
simulations. Cmax accumulated 1.4-fold (geometric mean 637 ng/mL on Day 7). The geometric 
mean of the AUC24h on Day 7 was 6830 ng*hr/mL, which is 4.2-fold below the NOAEL AUC24h 
in monkey (29,000 ng*hr/mL). After the end of 7 days of infusion, there remained a prolonged 
period of residual drug levels in both MAD groups that remained significantly lower than the 
Cmax on Day 7. A 3rd group of healthy subjects in the MAD was not dosed, despite the benign 
safety profile, because of the prolonged period of residual drug levels noted in the previous 
groups of healthy subjects. 
Subjects in Groups 4 and 5 of the SAD study and Groups 1 and 2 of the MAD study who received 
CM4620 were followed for 1 year in a long-term extension study to assess for adverse events 
and serious adverse events. In addition, PK levels were drawn in all 4 groups on Day 270 to 
further characterize the terminal phase and the prolonged period of residual drug level. There 
were no serious adverse events and no adverse events rated moderate or severe in intensity in 
subjects followed for 365 days. 
A population PK model was built using the data from the SAD and MAD studies. The model 
suggested three compartments for distribution as well as gender and body weight-dependent 
differences in exposures. The model showed that females have a higher volume of distribution 
compared to males, potentially explaining the lower plasma AUC24h values versus males, and 
that patients with higher body weights will have a lower AUC. The model was then used to 
identify the dosing regimens for the first and second phases of the open-label study described 
below. 
1.4.2 
Open Label Study in Patients with Acute Pancreatitis and SIRS 
CalciMedica has conducted a Phase 2, open-label, dose-response, multi-center study of Auxora in 
patients with AP and accompanying SIRS and hypoxemia (CM4620-201). One patient was 
randomized having SIRS alone at Screening. The primary objective of the study was to evaluate 
safety and tolerability; the secondary objective was to evaluate efficacy and the PK profile of 
Auxora. 
The study consisted of 2 phases; the Initial Phase consisted of 2 concurrently enrolled cohorts 
and the Second Phase consisted of 2 concurrently enrolled cohorts. In total, it was planned to 
have 4 Cohorts containing 24 adult male and female patients with AP and accompanying SIRS 
and hypoxemia. In the Initial Phase, 4 female patients were to be randomized in a 3:1 ratio to 
receive Auxora + Supportive Care (SC) or SC alone (Cohort 1). Concurrently, 4 male patients 
were to be randomized in a 3:1 ratio to receive Auxora + SC or SC alone (Cohort 2). Doses were 
to be 1.0 mg/kg on Day1 and 1.4 mg/kg daily on Days 2, 3 and 4 (low dose regimen). In the 
Second Phase, 8 female patients were to be randomized in a 3:1 ratio to receive Auxora + SC or 
SC alone (Cohort 3). Concurrently, 8 male patients were to be randomized in a 3:1 ratio to 


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receive Auxora + SC or SC alone (Cohort 4). Planned doses for both Cohorts 3 and 4 were to be 
2.08 mg/kg daily on Days 1 and 2 and 1.6 mg/kg daily on Days 3 and 4 (high dose regimen). 
The decision to start Cohort 3 in the Second Phase was made after CalciMedica reviewed the 
available efficacy, safety and tolerability data from Cohort 1 and discussed this with the Principal 
Investigator (PI). At this point, a decision was made to administer patients in Cohort 3 with the 
same dose level and schedule as in Cohort 1, as efficacy was observed in Cohort 1. Cohort 3, 
therefore, received the same dose level and schedule as Cohort 1, 1.0 mg.kg on Day1 and 
1.4 mg/kg daily on Days 2, 3 and 4. The decision to start Cohort 4 in the Second Phase of the 
study was made after CalciMedica reviewed the available efficacy, safety and tolerability data 
from Cohort 2 and discussed this with the Principal Investigator. Cohort 4, therefore, received 
the original planned dose level and schedule; 2.08 mg/kg daily on Days 1 and 2 and 1.6 mg/kg 
daily on Days 3 and 4. 
The first infusion of Auxora was started within 6 (up to 8) hours of the patient or LAR providing 
informed consent and was administered as a continuous IV infusion over 4 hours. Subsequent 
infusions were to be started every 24 hours (± 1 hour) from the start of the first infusion. In patients 
receiving Auxora+SC (all doses), there were 9 patients of 14 patients (64%) who did not receive all 
4 scheduled doses, 7 of 9 patients because of rapid clinical improvement leading to early discharge 
and 2 of 9 patients because of study drug discontinuation. Five of 8 patients (63%) receiving the 
low dose regimen+SC and 4 of 6 patients (67%) receiving the high dose regimen+SC did not 
receive all 4 doses of Auxora. 
The demographic information and baseline characteristics for the patients enrolled in the study 
are noted in Table 3. 
Table 3. Demographics and Baseline Characteristics of Patients in CM4620-201 
Treatment 
Auxora+SC 
low dose regimen 
(N = 8) 
Auxora+SC 
high dose regimen 
(N = 6) 
Auxora+SC 
TOTAL 
(N = 14) 
SC Alone 
 
(N = 7) 
Median Age (years) 
Min, Max 
55 
26, 66 
43.5 
37, 55 
50.5 
26, 66 
54 
40, 72 
Gender, n% 
Female 5 (63%) 
Male 3 (38%) 
Female 0 
Male 6 (100%) 
Female 5 (36%) 
Male 9 (64% 
Female 4 (57%) 
Male 3 (43%) 
Race, n% 
Asian 1 (13%) 
Black 1 (13%) 
White 6 (75%) 
Asian 0 
Black 2 (33%) 
White 4 (67%) 
Asian 1 (7%) 
Black 3 (21%) 
White 10 (71%) 
Asian 0 
Black 3 (43%) 
White 4 (57%) 
Median Weight (kg) 
Min, Max 
86 
56.2, 108.9 
92.8 
84.8, 113.8 
87.5 
56.2, 113.8 
93.1 
59, 108.9 
BMI (kg/m2) 
Min, Max 
31.6 
22, 44.4 
28.9 
25, 38.2 
30.3 
22, 44.4 
34 
23.8, 41.6 
Hx Type 2 
Diabetes Mellitus 
2 (25%) 
1 (17%) 
3 (21%) 
1 (14%) 
Hx Hypertension 
4 (50%) 
4 (67%) 
8 (57%) 
6 (86%) 


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The primary objective of this study was to assess the safety and tolerability of Auxora in patients 
with AP and accompanying SIRS and Hypoxemia. In this study, the low dose regimen+SC and 
the high dose regimen+SC were well tolerated in patients with AP and SIRS, with no evidence of 
untoward safety or tolerability findings. 
Treatment-emergent AEs (TEAEs) were reported in 7 of 8 patients (88%) receiving the low dose 
regimen+SC, 5 of 6 patients (83%) receiving the high dose regimen+SC, and 3 of 7 patients 
(43%) receiving SC alone. Severe TEAEs were reported in 0 of 8 (0%) patients receiving the low 
dose regimen+SC, 2 of 6 (33%) receiving the high dose regimen+SC, and 2 of 7 (29%) receiving 
SC alone. There were 3 TEAEs in 2 patients leading to discontinuation of the study drug. Both 
patients received the high dose regimen+SC. 
Two different TEAE preferred terms were reported in 2 or more patients receiving the low dose 
regimen+SC: Hypokalemia in 2 of 8 patients (25%) and Headache in 2 of 8 patients (25%). 
Three different TEAE preferred terms were reported in 2 or more patients receiving the high 
dose regimen+SC: Malnutrition, Confusional State and Acute Respiratory Distress Syndrome 
were each reported in 2 of 6 patients (33%). There were no TEAE preferred terms reported in 
2 or more patients receiving SC alone. 
There was 1 TEAE of Chromaturia in a patient receiving the high dose regimen+SC for which 
the causality was considered Possible. There were no other TEAEs, for which the causality was 
considered Possible, Probable or Definite. 
SAEs were reported in 2 of 8 patients (25%) receiving the low dose regimen+SC, 1 of 6 patients 
(17%) receiving the high dose regimen+SC and 2 of 7 patients (29%) receiving SC alone. There 
was 1 death during the study. This patient, who received the high dose regimen+SC, experienced 
an SAE of Hypoxic-Ischemic Encephalopathy for which the outcome was fatal. The SAE was 
considered severe and the outcome was designated recovered/resolved with sequelae. Causality 
was considered to be Unrelated. 
There were no untoward changes in vital signs, oxygenation, and laboratory values associated 
with treatment with either the low dose or high dose regimen of Auxora. 
1.5 
Pharmacodynamic and Pharmacokinetic Study in Patients with Acute 
Pancreatitis 
In Study CM4620-202, A Pharmacodynamic and Pharmacokinetic Study of Auxora in Patients 
with Acute Pancreatitis, patients with AP (regardless of the presence of SIRS and/or hypoxemia) 
were administered a single IV infusion of 2.08 mg/kg Auxora and blood, plasma and serum were 
collected for analysis. It was planned to initially enroll 5 patients and then to enroll an additional 
4 patients as needed. Ultimately, 7 patients were screened for the study, and all 7 enrolled in and 
completed the study. On Days 1 and 2, blood and plasma samples for PD and PK analyses, 
respectively, were obtained 30 minutes after completing the administration of Auxora and 
24 hours from the start of the administration of Auxora. In patients hospitalized at Day 5 and 10, 
blood and plasma samples were obtained; if discharged earlier, samples were obtained at the 
time of discharge. After discharge, patients returned to the hospital on Day 30 to provide final 
blood and plasma samples. 


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Of the 7 patients, 5 (71%) were male and 2 (29%) were female. The median (min, max) age in all 
7 patients was 42 (29, 54) years. The age range was 38 to 54 years in males and 29 to 35 years in 
females. The weight range was 49.4 to 102.1 kg and the BMI range was 19.3 to 32.2. Of the 
7 patients, 4 (57%) were black or African and 3 (43%) were white. There were no (0%) Hispanic 
or Latino patients enrolled in the study. The cause of AP was alcohol in 5 of the 7 patients, 
hypertriglyceridemia in 1 of the 7, and unknown in the other. 
A total of 3 patients experienced 7 TEAEs during the study. One (1) patient experienced a TEAE 
of Melena and a TEAE of bursitis, 1 patient had a TEAE of Pancreatitis Acute (which was also 
an SAE), and 1 patient experienced TEAEs of Pneumonia, Alcohol Withdrawal Syndrome, 
Pyrexia and Respiratory Distress (which was also an SAE). Of the 7 TEAEs, there were 3 mild, 
2 moderate and 2 severe TEAEs. The 2 severe TEAEs (Pancreatitis Acute and Respiratory 
Distress) were also SAEs. The causality of the 7 TEAEs to Auxora was Unrelated for 5 TEAEs 
and Unlikely for 2 TEAEs. 
1.6 
Rationale for the Study and Selected Doses 
For patients with coronavirus 2019 (COVID-19), morbidity and mortality can arise from host 
immune responses. These responses can lead to a “cytokine storm,” which in turn causes acute 
lung injury (ALI), acute respiratory distress syndrome (ARDS), death, or permanently 
compromised pulmonary function in those who survive. Therapeutic agents that reduce cytokine 
release and ALI/ARDS could be life-saving in patients infected with severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, as well as other 
infectious agents. 
CalciMedica is developing Auxora, a calcium release-activated calcium (CRAC) channel 
inhibitor, for the treatment of patients with acute inflammatory conditions, similar to ALI and 
ARDS. It potently blocks the production and release of pro-inflammatory cytokines from 
immune cells, including interleukin-2 (IL-2), IL-6, IL-17 and tumor necrosis factor-alpha 
(TNFα), interrupting the cascade of events leading to ALI and ARDS. Thus, treatment with 
Auxora could prevent patients with COVID-19 from developing the life-threatening effects of 
pro-inflammatory cytokine cascade and ALI/ARDS, while further preventing permanent 
pulmonary tissue scarring. 
Human clinical studies of Auxora further support the use of the drug to treat ALI/ARDS. The 
evidence for the effect of Auxora on systemic inflammation is found in the differences in the 
SIRS score, percent of hospital days without SIRS, and persistence of SIRS in treated versus 
standard of care patients in Study CM4620-201. Persistent SIRS, defined as SIRS lasting 
continuously for ≥ 48 hours, is a specific risk factor for the development of organ failure, most 
commonly respiratory failure, in patients with AP. The effect of Auxora on elevated IL-6 levels 
may be particularly relevant to its potential efficacy in patients with severe COVID-19 pneumonia 
as elevated IL-6 appears to drive the respiratory complications of the virus. A total of 8 patients 
treated with Auxora in Studies CM4620-201 and CM4620-202 (7 patients and 1 patient, 
respectively) had a maximum IL-6 level ≥150 pg/mL in the first 24 hours, with 2 of the patients 
in Study CM4620-201 having IL-6 levels greater than 1000 pg/mL. Three (3) patients treated 
with standard of care in Study CM4620-201 had a maximum IL-6 level ≥150 pg/mL in the first 


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24 hours. Treatment with Auxora decreased IL-6 levels to below 150 pg/mL in 7 of 8 patients, 
while only 1 of 3 patients treated with standard of care had IL-6 levels that dropped below this 
threshold. 
Results of the PD ex vivo blood assay of lymphocyte function in Study CM4620-202 indicated 
that Auxora at or near Cmax inhibited CRAC channel-dependent stimulated IL-2 secretion by 
approximately 57%. The inhibitory effect of Auxora dissipated over the next 1-2 days, 
demonstrating pharmacological reversal. This result suggests that long-term immunosuppression 
is unlikely to result from therapy with Auxora. 
The dosing regimen for the current study includes 3 consecutive days of dosing. The derivation 
of this regimen comes from both the Phase 1 MAD and Phase 2a studies, in that the dosing 
regimens for the Phase 2a open-label study were chosen based on maximum systemic exposures 
observed in the Phase 1 MAD study that were well tolerated. Population PK-modeling based on 
critically ill AP patients was performed and confirmed that the simulated plasma exposures 
(AUC24hr and Cmax) with the 3-day dosing regimen would not cross the established NOAEL 
exposures in any patient. The three days of dosing is expected to provide robust decreases in 
IL-6 levels and stabilization of respiratory status. 


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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
• To assess the clinical efficacy of Auxora in patients with severe COVID-19 pneumonia 
2.2 
Secondary Objectives 
• To assess the safety and tolerability of Auxora in patients with severe COVID-19 
pneumonia 
• To determine the pharmacokinetic profile of Auxora in patients with severe COVID-19 
pneumonia 
2.3 
Endpoints 
• Primary efficacy endpoint: 
o Time to recovery 
• Secondary efficacy endpoints: 
o All-Cause Mortality at Day 60 
o All-Cause Mortality at Day 30 
o Proportion of patients requiring invasive mechanical ventilation or dying during the 
60 days from the SFISD 
o Proportion of patients requiring invasive mechanical ventilation during the 60 days 
from the SFISD 
o Difference in outcomes measured by the 8-point ordinal scale through Day 12 
o Difference in outcomes measured by the 8-point ordinal scale through Day 30 
o Number of Days in the Hospital 
o Number of Days in the ICU 
• Safety endpoints 
o The incidence of TEAEs and SAEs 
o The intensity and relationship of TEAEs and SAEs 
o Clinically significant changes in vital signs and safety laboratory results 


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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
Part 1 was a randomized open-label study that consisted of two arms. In one arm, 60 patients who 
were receiving low flow supplemental oxygen at Screening were to randomize 2:1 to Auxora or 
standard of care. In the other arm, 60 patients who were receiving high flow supplemental oxygen 
delivered using high flow nasal cannula at Screening were to randomize 2:1 to Auxora or standard 
of care. The independent safety committee conducted a review after the first 12 patients were 
dosed in the low-flow arm. The committee recommended continuing the trial unchanged until the 
next safety review committee meeting. After the initial independent safety committee review, the 
FDA asked for a limitation of further enrollment in the open-label study and for the study to 
transition to a blinded, placebo-controlled study. Both arms of Part 1 ceased further enrollment 
and follow-up of patients enrolled in Part 1 was to Day 30 only. 
Part 2 is a randomized, double blind, placebo-controlled study in which initially up to 400 
patients receiving supplemental oxygen at Screening, and who meet all of the inclusion criteria 
and none of the exclusion criteria, were to be randomized 1:1 to receive Auxora plus standard of 
care or Placebo plus standard of care. After a blinded analysis of the mechanical ventilation and 
death rate in the subgroup of patients with an imputed PaO2/FiO2 >200 were randomized into the 
study, the number of patients in the subgroup was capped at 26. The study sample size remained 320 
for patients with an imputed PaO2/FiO2 ≤200. When enrolling both subgroups, patients were 
stratified to ensure balanced randomization between the Auxora and Placebo arms. 
The dose of Auxora will be 2.0 mg/kg (1.25 mL/kg) administered at 0 hour, and then 1.6 mg/kg 
(1 mL/kg) at 24 hours and 1.6 mg/kg (1 mL/kg) at 48 hours from the SFISD. The dose of Placebo 
will be 1.25 mL/kg administered at 0 hour and then 1 mL/kg at 24 hours and 1 mL/kg at 48 hours 
from the SFISD. The SFISD should occur within 12 hours of the patient or LAR providing 
informed consent. The dosing will be based on actual body weight obtained at the time of 
hospitalization or screening for the study. As described in the pharmacy manual, there will be an 
upper limit of the absolute dose (volume) of Auxora and volume of Placebo that will be 
administered for patients weighing more than 125kg. 
A study physician or appropriately trained delegate will perform assessments at Screening, 
immediately prior to the SFISD, and immediately prior to each subsequent infusion. At 72 hours 
after the SFISD, the patient will be assessed every 24 hours (±4 hours) until 240 hours after the 
SFISD, then q48 hours until Day 30 after the SFISD, or until discharge if earlier. Patients who 
are discharged before Day 25 after the SFISD will be followed-up at Day 30 (±5 days) and Day 
60 (±5 days) for a safety and mortality assessment. 
After the first 50 patients were randomized in Part 2, an Independent Data Monitoring 
Committee (IDMC) evaluated safety data from the study and agreed with capping the number of 
patients with an imputed PaO2/FiO2 >200 at 26 and to continue the study enrolling only patients 
with an imputed PaO2/FiO2 <200. The IDMC will again review the safety data after the 70th 
patient in the imputed PaO2/FiO2 <200 subgroup completes the study and when the 200th patient 
in the imputed PaO2/FiO2 <200 subgroup is randomized into the study. 


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A sample size re-estimation procedure will be applied when the first 70 patients in the imputed 
PaO2/FiO2 ≤200 subgroup have completed or discontinued from the study. The IDMC will 
perform the procedure and will recommend to CalciMedica to increase or not increase the study 
sample size. No ongoing study patients will be included in this sample size re-estimation 
procedure. The sample size will be re-estimated to provide a conditional power of 90%, based on 
the evaluation of the treatment efficacy. . 
3.2 
End of Study 
The End of Study is considered the date on which the last patient randomized completes the visit 
on Day 60, unless CalciMedica terminates the study early. 
3.3 
Sponsor Termination of the Study 
CalciMedica intends to complete the study as outlined. CalciMedica reserves the right, however, 
to terminate the study at any time because of: 
• A directive from the FDA 
• A lack of enrollment 
• A recommendation from the IDMC 


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4 
SELECTION OF PATIENTS 
4.1 
Inclusion Criteria 
All of the following must be met for a patient to be randomized into the study: 
1. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain 
reaction (PCR) or other commercial or public health assay in any specimen, as 
documented by either of the following: 
o PCR positive in sample collected < 72 hours prior to randomization; or 
o PCR positive in sample collected ≥ 72 hours prior to randomization, with inability to 
obtain a repeat sample (e.g. due to lack of testing supplies, or limited testing capacity, 
or results taking >24 hours, etc.) or progressive disease suggestive of ongoing 
SARS-CoV-2 infection; 
2. At least 1 of the following symptoms: 
o Fever, cough, sore throat, malaise, headache, muscle pain, dyspnea at rest or with 
exertion, confusion, or respiratory distress; 
3. At least 1 of the following signs at Screening or noted in the 24 hours before Screening: 
o PaO2/FiO2 ≤200 when receiving supplemental oxygen. The PaO2/FiO2 may be 
estimated from pulse oximetry (Appendix 1) or determined by arterial blood gas; 
o If SpO2 ≥97%, receiving 10L or more of supplemental oxygen; 
4. The presence of a respiratory infiltrate or abnormality consistent with pneumonia that is 
documented by either a CXR or CT scan of the lungs; 
5. The patient is ≥18 years of age; 
6. A female patient of childbearing potential must not attempt to become pregnant for 
39 months, and if sexually active with a male partner, is willing to practice acceptable 
methods of birth control for 39 months after the last dose of study drug; 
7. A male patient who is sexually active with a female partner of childbearing potential is 
willing to practice acceptable methods of birth control for 39 months after the last dose of 
study drug. A male patient must not donate sperm for 39 months; 
8. The patient is willing and able to, or has a legal authorized representative (LAR) who is 
willing and able to, provide informed consent to participate, and to cooperate with all 
aspects of the protocol. 
4.2 
Exclusion Criteria 
Patients with any of the following conditions or characteristics must be excluded from randomizing: 
1. Expected survival or time to withdrawal of life-sustaining treatments expected to be <7 days; 
2. Do Not Intubate order; 


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3. Home mechanical ventilation (noninvasive ventilation or via tracheotomy) except for 
continuous positive airway pressure or bi-level positive airway pressure (CPAP/BIPAP) 
used solely for sleep-disordered breathing; 
4. PaO2/FiO2 ≤75 at the time of Screening. The PaO2/FiO2 may be estimated from pulse 
oximetry (Appendix 1) or determined by arterial blood gas; 
5. Noninvasive positive pressure ventilation; 
6. Invasive mechanical ventilation via endotracheal intubation or tracheostomy; 
7. ECMO; 
8. Shock defined by the use of vasopressors; 
9. Multiple organ dysfunction or failure; 
10. Positive Influenza A or B testing if tested as local standard of care; 
11. The patient has a history of: 
a. Organ or hematologic transplant; 
b. HIV 
c. Active hepatitis B, or hepatitis C infection; 
12. Current treatment with: 
a. Chemotherapy; 
b. Immunosuppressive medications or immunotherapy (see Section 5.3 for list of 
prohibited immunosuppressive medications and immunotherapy) at the time of consent; 
c. Hemodialysis or Peritoneal Dialysis; 
13. Have a history of venous thromboembolism (VTE) (deep vein thrombosis [DVT] or 
pulmonary embolism [PE]) within 12 weeks prior to screening or have a history of 
recurrent (> 1) VTE; 
14. The patient is known to be pregnant or is nursing; 
15. Currently participating in another study of an investigational drug or therapeutic medical 
device at the time of consent; 
16. Allergy to eggs or any of the excipients in Auxora. 
4.3 
Re-Screening 
A patient who fails the initial screening because either the clinical symptoms or signs noted in 
inclusion criteria 2 or 3 were not present may be rescreened twice again within 48 hours of the 
original screening. 


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5 
TREATMENT OF PATIENTS 
5.1 
Overview 
All patients enrolled in the study should receive care consistent with local standard of care. 
Patients with worsening respiratory failure should receive conservative intravenous fluid 
strategies such as FACTT LITE. All patients should receive pharmacological prophylaxis to 
prevent the development of venous thromboembolic disease. The type and dose of prophylaxis 
should be determined by local standard of care. 
Patients enrolled in the study should receive dexamethasone, or equivalent dose of another 
corticosteroid, as standard of care. If patients are not receiving dexamethasone at the time of 
randomization into CARDEA, starting dexamethasone during the hospitalization should be 
considered. If the patient is already receiving dexamethasone at the time of randomization, 
dexamethasone should be continued on its established dosing schedule. The COVID-19 Treatment 
Guidelines Panel of the National Institutes of Health recommends using dexamethasone (at a dose 
of 6 mg per day, given orally or intravenously, for up to 10 days) in patients with COVID-19 who 
require supplemental oxygen. Before initiating dexamethasone, the potential risks and benefits of 
administering corticosteroids should be assessed including risks for hyperglycemia and secondary 
infections. At this time, it is not known whether other corticosteroids, such as prednisone, 
methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, 
the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 
32 mg, and hydrocortisone 160 mg. 
If patients are not receiving remdesivir at the time of randomization into CARDEA, starting 
remdesivir during the hospitalization may be considered. If the patient is already receiving 
remdesivir at the time of randomization, remdesivir should be continued on its established dosing 
schedule. The suggested dose of remdesivir for adults weighing ≥40 kg and not requiring invasive 
mechanical ventilation and/or ECMO is a single dose of 200 mg infused intravenously over 30 to 
120 minutes on Day 1 followed by once-daily maintenance doses of 100 mg infused intravenously 
over 30 to 120 minutes for 4 days (days 2 through 5). If a patient does not demonstrate clinical 
improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). 
Auxora and remdesivir should not infuse at the same time but should be given sequentially in 
any order. 
Patients may also be considered for the administration of convalescent plasma in the study as per 
local standard of care. 
Immunosuppressive medications or immunotherapies are prohibited in patients randomized into 
the study (Section 5.3 for list of prohibited medications). The use of dextromethorphan is 
discouraged in patients randomized into the study. 
5.2 
Discharge Criteria 
Patients should remain in the hospital until all 3 doses of study drug have been administered. 


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If the patient is ready to be discharged before all doses of study drug have been administered, the 
PI or treating physician should contact the Medical Monitor prior to discharging the patient. 
5.3 
Prohibited Medications 
Any medication, with the exception of those listed below, may be given at the discretion of the 
PI. Medications that should not be administered during the study to patients randomized in the 
study include: 
• Chemotherapy 
• Cyclosporine, Tacrolimus 
• Sirolimus, Everolimus 
• Azathioprine 
• Cyclosphosphamide 
• Methotrexate 
• Mycophenolate 
• Leflunomide 
• Biologics/Monoclonals: abatacept, adalimumab, alemtuzumab, anakinra, basilizimab, 
belimumab, bevacizumab, brodalumab, canakinumab, certolizumab, cetuximab, 
clazakizumab, daclizumab, eculizumab, etanercept, golimumab, infliximab, interferon, 
ixekizumab, muromonab, natalizumab, omalizumab, rituximab, sarilumab, secukinumab, 
tocilizumab, trastuzumab, ustekinumab, vedolizumab 
• Baricitinib 
• Tofacitinib 
Note further use of Dextromethorphan is discouraged. 
5.4 
Compliance 
Only the PI or his/her appropriately trained study staff will administer study drug to patients 
randomized in the trial in accordance with the protocol. Study drug must not be used for any 
reasons other than that described in the protocol. 


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6 
PROCEDURES 
6.1 
Enrollment Procedures 
Patients will be randomized 1:1 to Auxora plus local standard of care versus Placebo plus local 
standard of care. 
6.2 
Discontinuation and Withdrawal 
The term discontinuation refers to a patient or PI discontinuing the administration of study drug 
before all 3 doses are administered despite the patient remaining in the hospital. Patients who do 
not receive all 3 doses because the treating physician discharged them from the hospital will not 
be considered to have discontinued study medication. 
Patients have the right to discontinue the administration of study drug at any time for any reason, 
without prejudice to their medical care. The PI may discontinue the administration of study drug 
because of an adverse event or change in medical status that raises a safety concern about the 
patient receiving additional doses of study drug. The PI must discontinue the administration of 
study drug if the patient is diagnosed with a new or recurrent malignancy, or if the patient was 
concomitantly administered a prohibited medication. If possible, the PI should contact the 
Medical Monitor to review the reasons for a patient’s discontinuation from study drug. The PI 
should also record the reason for the discontinuation in the eCRF and appropriate source 
documents at the site. Even if the patient discontinues receiving study drug, diligence should 
occur to ensure that all study visits and assessments are completed. 
Withdrawal refers only to the complete withdrawal of the patient from the study because of the 
withdrawal of consent. The PI should inform the Medical Monitor of the withdrawal of consent 
and record the withdrawal of consent in the eCRF and appropriate source documents at the site. 
Patients who ask for a new DNI order after randomization into the study should be discontinued 
from the study and no further assessments will be performed other than the mortality assessment 
at Days 60 and 30. 
 


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7 
STUDY DRUG MATERIALS AND MANAGEMENT 
7.1 
Auxora Product Description 
Auxora is to be administered as an IV infusion and is supplied as a translucent, white to yellowish, 
sterile, non-pyrogenic emulsion containing 1.6 mg/mL of the active pharmaceutical ingredient 
CM4620. Auxora is supplied as an 80 mL fill in a 100 mL single-use glass vial. Auxora contains 
egg phospholipids, medium chain triglycerides, glycerin, edetate disodium salt dehydrate (EDTA), 
sodium hydroxide (as needed to adjust pH), and sterile water for injection (Table 4). 
Table 4. Auxora Product Information 
Product Name: 
CM4620 Injectable Emulsion 
Dosage Form: 
Injectable Emulsion (Liquid) 
Concentration of CM4620 1.6 mg/mL 
Route of Administration 
IV 
Physical Description 
Translucent, non-separated, white to yellowish emulsion 
Inactive Ingredients 
Sterile Water for Injection USP, Egg Phospholipid NF (80% Phosphatidylcholine), 
Medium Chain Triglycerides NF, Glycerin USP, and Edetate Disodium Salt 
Dihydrate (EDTA) USP. Sodium Hydroxide and Hydrochloric Acid may be added 
to adjust the pH. 
Manufacturer 
Bioserv Corporation 
San Diego, CA 92121 
 
7.2 
Placebo Product Description 
Matching Placebo is to be administered as an IV infusion and is supplied as a translucent, white 
to yellowish, sterile, non-pyrogenic emulsion carrier containing no active pharmaceutical 
ingredient. Placebo is supplied as an 80 mL fill in a 100 mL single-use vial. Placebo contains the 
same ingredients as Auxora except that it does not contain CM4620. 
7.3 
Auxora and Placebo Storage 
Auxora and Placebo must be maintained in a secure location with refrigerated temperature 
conditions of 2 to 8°C (36 to 46°F). Precaution should be taken to ensure that the Auxora and 
Placebo do not freeze. Temperature logs should be maintained and available during monitor 
review. When a temperature is noted outside the range of 2°C to 8°C lasting for 24 hours or 
more, or if the temperature exceeds 20°C (68°F), or is below 0°C (32°F), CalciMedica or its 
designee must be notified as soon as possible. The stability of Auxora and Placebo has been 
demonstrated to 24 months and is being evaluated for longer periods in ongoing studies. 
7.4 
Auxora and Placebo Preparation 
The study pharmacist and/or designee will be responsible for the preparation and dispensation 
of Auxora and Placebo. Prior to administration, Auxora and Placebo both must be transferred to 
a sterile container a using sterile technique. Specific details on how to prepare Auxora and 
Placebo, as well as the specific components that will be used to administer both Auxora and 


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Placebo, will be provided in the Pharmacy Manual. The Pharmacy Manual will also contain 
tables detailing the selected dose level and volume of administration of Auxora and Placebo. 
7.5 
Auxora and Placebo Administration 
Both Auxora and Placebo will be administered intravenously over 4 hours at a constant rate of 
infusion. They will be administered every 24 hours (±1 hours) for three consecutive days for a 
total of 3 doses. The dose and volume of Auxora, and the volume of Placebo, that will be 
administered will be calculated using the patient weight obtained at the time of hospitalization 
or during screening. A line into a peripheral or central vein may be used for the infusion. The 
peripheral IV should be 20 gauge in size or larger. The peripheral IV or central line port should be 
dedicated when administering Auxora or Placebo other than 0.9% normal saline. Auxora and 
Placebo are compatible with 0.9% normal saline. The IV tubing used to administer Auxora and 
Placebo must contain a 1.2 micron filter. The Pharmacy Manual will contain a recommended 
procedure to prime the IV tubing and flush the tubing, but this may be adapted to local nursing 
standards. 0.9% normal saline may be used to clear the line to ensure that the volume to be 
infused (VTBI) is completely administered. If the administration of Auxora or Placebo is stopped 
because of a technical reason, such as failure of the IV site, or IV pump malfunction, the 
administration of Auxora or Placebo should be resumed when the technical reason is resolved, 
and continued at the same rate until the infusion is completed. The total amount of time for the 
start of infusion to end of infusion of Auxora or Placebo should be recorded. 
CalciMedica may modify at any time the administered doses of Auxora or volumes of Placebo, the 
days of infusion, the timing of the infusion and the rate of infusion based on review of the safety 
and tolerability data by the IDMC. If the administration of Auxora or Placebo is stopped because 
of a serious adverse event that is considered to be probably or definitely related to Auxora or 
Placebo, the Medical Monitor must be immediately contacted. 
Although the administration of the infusion should be set up to be completed over four hours, it 
is expected that there will be minor variability based on the equipment used and calibration of 
the equipment. The acceptable infusion timeframe is 4 hours (+/- 30 minutes). 
7.6 
Packaging and Labeling 
Preparation, packaging and labeling of Auxora and Placebo will be in accordance with current Good 
Manufacturing Practice of Medicinal Products (GMP) guidelines. Medication labels will comply 
with legal requirements for labeling of investigational products in the United States and the UK. 
7.7 
Accountability, Handling and Disposal 
The PI or designee will ensure that deliveries of Auxora and Placebo from CalciMedica or its 
designee are received by a responsible person, and such deliveries are recorded; that Auxora and 
Placebo are handled and stored safely and properly; that Auxora and Placebo are only dispensed 
to study patients in accordance with the protocol; and that unused Auxora and Placebo is returned 
to CalciMedica or its designee or disposed of using standard procedures approved of in advance 
by CalciMedica or its designee. Appropriately trained study staff will administer all doses of 
Auxora and Placebo. The pharmacy will maintain a record of Auxora and Placebo accountability. 


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8 
VISITS AND STUDY SPECIFIC ASSESSMENTS 
8.1 
Screening 
The PI or designee must provide informed consent to the patient, or LAR, allowing the patient or 
LAR adequate time to consider, ask questions and receive answers, prior to agreeing to participate. 
• Record the time of the patient or LAR provides informed consent 
After informed consent is obtained, the following procedures are to be performed: 
• Record Vital Signs 
• Record Weight: may use weight obtained as part of standard of care 
• Record results of Influenza A, B and Respiratory Panel if performed as local standard of 
care 
• Record results of Sars-CoV-2 testing 
• Record results of CXR or CT scan documenting a pulmonary infiltrate 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and FiO2 at the time closest to the Screening assessment 
• Complete and record results of pregnancy test for women of child-bearing potential 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
If the patient satisfies all of the inclusion criteria and none of the exclusion criteria, proceed to 
baseline assessment. 
8.2 
Baseline Laboratory Assessment 
• Draw blood samples for daily laboratory monitoring 
• Draw blood samples for every-72-hour laboratory monitoring 
• Draw blood samples for IL-6 and IL-2R anytime between screening and just prior to 
SFISD 
After drawing blood samples, proceed to randomization. These blood tests may be performed on 
blood already drawn in the previous 12 hours prior to randomization.  
8.3 
Randomization 
• Randomize patient as per study randomization procedure. 


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8.4 
Start of First Infusion of Study Drug (SFISD) 0 hour 
The SFISD should begin within 12 hours of the patient or LAR providing informed consent. 
Perform the following procedures immediately prior to the SFISD: 
• Record concomitant medications 
• If the time between randomization and the SFISD is >6 hours: 
o Record the current vital signs 
o Record the current SpO2 and the FiO2 
o Record ABG and time drawn if performed as part of standard of care 
• Infuse the first dose of study drug 
o Record the time of the SFISD 
o Record the time when the infusion is finished 
8.5 
24 hours  
24 (±2 hours) hours from the SFISD: 
• Record concomitant medications 
• Record vital signs 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and the FiO2 at the time of the assessment 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
• Perform AE/SAE assessment 
• Draw blood samples for daily laboratory monitoring prior to the second infusion of study 
drug (-2 hour). Daily laboratory monitoring may be performed on blood drawn in the 
previous 12 hours 
• Draw blood for PK analysis together with daily laboratory monitoring. The PK 
specimens may be obtained from blood drawn in the previous 12 hours. The time of the 
draw must be recorded 
• Start the infusion of second dose of study drug 24 hours (±1 hour) from the SFISD 
o Record the time when the infusion starts and finishes 


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8.6 
48 hours 
48 hours (±2 hours) from the SFISD: 
• Record concomitant medications 
• Record vital signs 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and the FiO2 at the time of the assessment 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
• Perform AE/SAE assessment 
• Draw blood samples for daily laboratory monitoring prior to the third infusion of study 
drug (-2 hour). Daily laboratory monitoring may be performed on blood drawn in the 
previous 12 hours 
• Draw blood for PK analysis together with daily laboratory monitoring. The PK specimens 
may be obtained from blood drawn in the previous 12 hours. The time of the draw must 
be recorded 
• Start the infusion of third dose of study drug 48 hours (±1 hour) from the SFISD 
o Record the time that the infusion starts and finishes 
8.7 
72 hours 
For patients who remain hospitalized 72 (±2 hours) from the SFISD: 
• Record concomitant medications 
• Record vital signs 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and the FiO2 at the time of the assessment 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
• Perform AE/SAE assessment 
• Draw blood samples for daily laboratory monitoring. Daily laboratory monitoring may be 
performed on blood drawn in the previous 12 hours 
• Draw blood samples for every-72-hour laboratory monitoring. 72-hour laboratory 
monitoring may be performed on blood drawn in the previous 12 hours 
• Draw blood for PK analysis together with daily laboratory monitoring. The PK specimens 
may be obtained from blood drawn in the previous 12 hours. The time of the draw must 
be recorded 


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8.8 
96, 144, 192 and 240 hours 
For patients who remain hospitalized 96, 144, and 192 hours (±4 hours) from the SFISD: 
• Record concomitant medications 
• Record vital signs 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and the FiO2 at the time of the assessment 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
• Perform AE/SAE assessment 
• Draw blood sample for IL-6 and IL-2R at 96 hours. IL-6 and IL-2R may be performed on 
blood drawn in the previous 12 hours 
• Draw blood samples for every 72-hour laboratory monitoring at 144 hours. 72-hour 
laboratory monitoring may be performed on blood drawn in the previous 12 hours 
• Draw blood samples for daily laboratory monitoring. Daily laboratory monitoring may be 
performed on blood drawn in the previous 12 hours 
8.9 
120, 168, and 216 hours 
For patients who remain hospitalized 120, 168, and 216 hours (±4 hours) from the SFISD: 
• Record concomitant medications 
• Record vital signs 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and the FiO2 at the time of the assessment 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
• Perform AE/SAE assessment 
• Draw blood samples for daily laboratory monitoring. Daily laboratory monitoring may be 
performed on blood drawn in the previous 12 hours 
• Draw blood samples for every 72-hour laboratory monitoring at 216 hours. 72-hour 
laboratory monitoring may be performed on blood drawn in the previous 12 hours 


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8.10 
Days 12 to 28 
For patients who remain hospitalized 12, 14, 16, 18, 20, 22, 24, 26, and 28 days (±4 hours) from 
the SFISD: 
• Record concomitant medications 
• Record vital signs 
• Record the lowest SpO2 in the previous 24 hours and the time it was performed. The FiO2 
at the time of the SpO2 measurement will also be recorded 
• Record the SpO2 and the FiO2 at the time of the assessment 
• Record ABG and time drawn if performed as part of standard of care 
• Complete Daily Assessment – Ordinal Scale 
• Perform AE/SAE assessment 
Patients discharged prior to Day 12 with the need for supplemental oxygen will be contacted on 
Day 12 to determine if they are still receiving supplemental oxygen. 
8.11 
Day 60 and Day 30 
Patients who have been discharged from the hospital before Day 25, will be followed-up on Day 
30 (±5 days) for an AE/SAE assessment as well as to determine if they are receiving 
supplemental oxygen. For patients discharged from the hospital on Days 25-29, the final 
inpatient safety assessment will substitute for the Day 30 safety and mortality assessment. The 
Day 30 safety and mortality assessment may be conducted with an HCP. 
Patients, who have been discharged from the hospital before Day 55, will be contacted on Day 
60 (±5 days) to determine if they are receiving supplemental oxygen, experienced any symptoms 
suggestive of long COVID, and developed any SAEs since the Day 30 assessment. The Day 60 
assessment will be completed as a final inpatient safety assessment for patients who remain 
hospitalized or are discharged from the hospital on Days 55-59. 
8.12 
Discharge Date 
The time and date of initial discharge will be recorded, any re-admission and subsequent 
discharge date, as well as if the patient was sent home on oxygen when discharged, and if the 
patient was sent to a nursing home. 
8.13 
Study Assessments 
The Daily Assessment-Ordinal Scale will be filled out daily for all patients. 


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8.13.1 
Concomitant Medications 
The name, dose and frequency of medications that were administered will be recorded. Generic 
names should be used when possible. The administration of convalescent plasma, plus the 
number of units administered, should be recorded as a concomitant medication. 
8.13.2 
Vital Signs 
The patient’s temperature, heart rate (beats per minute), systolic and diastolic blood pressures 
and respiratory rate (breaths per minute) closest to the time of assessment should be recorded.  
8.13.3 
Arterial Blood Gas 
If an arterial blood gas (ABG) has been performed as supportive care, the time of the draw and 
following results will be recorded: the pH, PaO2, PaCO2, SaO2 and FiO2. 
8.13.4 
SpO2/FiO2 
The SpO2 will be determined using a hospital approved pulse oximeter. The PI or appropriately 
trained study coordinator should review the pulse oximetry waveform determining the SpO2 to 
attest to its adequacy. The FiO2 at the time of the SpO2 measurement will be recorded. For patients 
with assisted breathing, the FiO2 is read from the controlled oxygen source e.g. Venturi masks, 
ventilator and CPAP/BIPAP systems with calibrated oxygen blenders. For patients breathing 
unassisted i.e. room air, the FiO2 is recorded as 0.21. If a patient is on an uncontrolled oxygen 
source, the following table provides the estimated FiO2: 
Table 5. Conversion of O2 Flow to FiO2 
Supplemental Oxygen 
L/min 
Estimated FiO2 (%) 
Nasal Cannula 
Face Mask 
Face Mask 
with Reservoir 
Room Air 
21 
 
 
1 
24 
 
 
2 
28 
 
 
3 
32 
 
 
4 
36 
 
 
5 
40 
40 
 
6 
44 
50 
60 
7 
 
50 
70 
8 
 
60 
80 
9 
 
60 
90 
10 
 
60 
95 
Adapted from Vincent et al., 2009 


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8.13.5 
Laboratory Analyses 
CBC with Differential and Serum Chemistries will be performed daily through Day 10. 
Ferritin, C-reactive protein, Procalcitonin and D-Dimer will be drawn at the baseline assessment 
and then every 72 hours until 216 hours. 
Blood samples for biomarkers, such as IL-6 and IL-2R, will be drawn twice, once between 
screening and SFISD and again at 96 hours. If a site is unable to collect blood samples for 
biomarkers at any time point these tests will not be performed. 
CBC results that should be reported in the eCRFs include absolute or percent neutrophil and 
lymphocyte counts. Serum chemistries reported in CRFs should include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, as well as 
magnesium, total protein, albumin, prealbumin, alkaline phosphatase, alanine transaminase 
(ALT), aspartate transaminase (AST), total bilirubin, lactate dehydrogenase (LDH), total 
cholesterol, triglycerides, and creatine kinase (CPK). If a site is unable to perform any of these 
laboratory tests or it is not part of the standard of care testing for the patient, it will not be 
performed. 
A reference laboratory will analyze the blood samples for serum biomarkers, such as IL-6 and 
IL-2R. 
8.13.6 
PK Samples 
At selected sites that are able to draw blood samples for PK analysis, the samples for PK analysis 
will be drawn daily on the days after patients are dosed. The date and time that the blood sample 
for PK analysis was drawn shall be recorded. All samples for PK analysis should be stored at -
20°C (or -80°C for no more than 35 days) until shipment on dry ice to the bio-analysis laboratory. 
If a site is unable to collect the PK sample at any time point, the PK analysis will not be 
performed. 


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9 
ADVERSE EVENTS 
9.1 
Definition of Adverse Event 
An adverse event (AE) is defined as any untoward medical event in a patient regardless of its 
causal relationship to study treatment. An AE can be any unfavorable and unintended sign 
(including any clinically significant medical test abnormality), symptom, or disease temporally 
associated with the use of study drug, whether or not it is considered related to study drug 
administration. Included in this definition is any newly occurring event or previous condition that 
has increased in severity or frequency since the administration of study drug. 
A medical test abnormality (e.g., laboratory test value, vital sign recording, ECG finding, 
physical examination finding) will be considered clinically significant and consequently recorded 
as an AE only if it meets one of the following criteria: 
• Induces clinical signs or symptoms 
• Requires active intervention 
• Requires interruption or discontinuation of study medication 
9.2 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose and regardless of causality that: 
• Results in death 
• Is life-threatening 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function 
• Is a congenital anomaly or birth defect in an offspring of a patient receiving Auxora 
• Is an important medical event 
The term “life-threatening” refers to an event in which the patient was at immediate risk of death 
at the time of the event. It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not need any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during study drug administration or the thirty days thereafter. Certain pregnancy 
outcomes will require submission as an SAE. 


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9.3 
Eliciting Adverse Event Information 
At every AE/SAE assessment, the patient must be asked a standard, non-directed question, such 
as, “how have you been feeling since your last visit?” to elicit any medically related changes in 
their well-being. In addition, the hospital chart and other documents relevant to patient safety 
must be reviewed when the patient is in the hospital. 
9.4 
Recording Adverse Events 
Recording of AEs must begin after randomization. All conditions present before randomization, 
including untoward medical events during Screening, should be documented as medical history. 
Documentation shall continue until the patient dies, the patient withdraws consent, or the 
patient’s participation in the study ends. Information to be collected includes: 
• Type of event 
• Date of onset 
• Date of resolution 
• Investigator-specified relationship to study drug and assessment of severity 
• Seriousness 
• Any action taken 
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents, but when documenting the AE, only the total duration and the 
greatest severity should be recorded in the case report form. AEs characterized as intermittent 
require documentation of onset and duration. 
All AEs reported or observed during the study must be followed to resolution. Or, if not fully 
resolved, until the condition has stabilized, the patient dies, withdraws consent, or CalciMedica 
ends the trial (whichever is first). 
Adverse events resulting from concurrent illnesses, reactions to concurrent medications, or 
progression of disease states must also be reported. Pre-existing conditions (present before the 
start of the AE collection period) are considered concurrent medical conditions and should NOT 
be recorded as AEs. However, if the patient experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded as an AE. Investigators 
should ensure that the AE term recorded captures the change in condition (e.g., “worsening of…”). 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s). 
Elective procedures (surgeries or therapies) performed to manage/treat conditions that existed 
prior to the patient enrolling in the trial should not be recorded as AEs but should be documented 
in the patient’s source documents. If a planned procedure is performed early (e.g., as an 
emergency) because the pre-existing condition worsens, the worsening condition should be 
captured as an AE. 


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9.5 
Assessment of Relationship to Study Drug 
The Investigator must use the following classification and criteria to characterize the relationship 
or association of study drug in causing or contributing to the AE: 
• Unrelated: This relationship suggests that there is no association between study drug and 
the reported event 
• Unlikely: This relationship suggests that there is an unlikely association between study 
drug and the reported event 
• Possible: This relationship suggests that treatment with study drug caused or contributed 
to the AE. That is, the event follows a reasonable temporal sequence from the time of 
study drug administration, and/or follows a known response pattern to the study drug, but 
could have been produced by other factors 
• Probable: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action 
of the drug, known or previously reported adverse reactions to the drug or class of drugs, 
or judgment based on the Investigator’s clinical experience, the association of the event 
with study drug administration seems likely 
• Definite: This relationship suggests a definite causal relationship exists between study 
drug administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear 
to explain the event 
9.6 
Assessment of Severity 
The Investigator must use the following criteria to rate the intensity of the AE: 
• Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
• Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
• Severe: Symptoms causing inability to perform usual social and functional activities 
 
 


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9.7 
Reporting of Serious Adverse Events 
The Investigator is responsible for reporting to CalciMedica or designee within 24 hours from 
the time when site personnel learn about the event, all SAEs that are observed or reported by the 
patient during the study (from randomization until the patient dies, the patient withdraws 
consent, or the patient’s participation in the study ends) regardless of the relationship to study 
drug or clinical significance. Any additional information that becomes available later should be 
submitted within 1 working day of receipt. All SAEs reported or observed during the study must 
be followed to resolution or until the Investigator deems the event to be chronic or the patient to 
be stable. CalciMedica or its designee may contact the Investigator to obtain additional 
information on any SAE that has not resolved at the time the patient completes the study. SAEs 
ongoing at database lock will be noted as such. The PIs are also responsible for informing their 
IRB/EC of any SAEs at their site. SAE correspondence with IRBs/ECs must be submitted to 
CalciMedica or its designee for filing. 
A study manual will contain the details needed to report SAEs. If any questions on SAEs, contact 
information is as follows: 
• SAE reporting email address: CalciMedicaSafety@safety-sphere.com 
• SAE phone number: 844-965-1070 (toll free) 
• SAE Fax number: 1 (833) 292-6393 
 
CalciMedica will notify the FDA in a written safety report of any suspected adverse reaction or 
adverse reaction associated with the use of Auxora that is serious and unexpected. 
• Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means CalciMedica determines that there is evidence 
to suggest a causal relationship between the drug and the adverse event (definite, 
probable, possible) regardless of the investigator’s causality assessment 
• Adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the drug 
caused the event 
• Serious, as defined in Section 9.2 
• Unexpected adverse event or suspected adverse reaction refers to an event or reaction that 
is not listed in the investigator’s brochure or is not listed at the specificity or severity that 
has been observed 
CalciMedica or its designee will notify the FDA of any unexpected serious suspected adverse 
reactions associated with the use of Auxora that are fatal or life threatening as soon as possible 
but no later than seven calendar days after the initial receipt of the information. Initial 
notification will be followed by a written report within fifteen calendar days. 


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CalciMedica or its designee will notify the FDA of any unexpected serious suspected adverse 
reactions associated with the use of Auxora that are not fatal or life threatening fifteen calendar 
days. 
CalciMedica or its designee will provide copies of any reports to regulatory agencies regarding 
unexpected serious suspected adverse reactions associated with the use of Auxora to the 
Investigators for review and submission to the IRB/EC. 
The Safety Monitoring Plan (SMP) will contain specific study pause criteria for the occurrence 
of severe unexpected serious suspected adverse reactions associated with the use of Auxora. 
In addition, the following serious adverse events that are commonly observed in this patient 
population will not be reported to the regulatory authority as individual expedited reports except 
in unusual circumstances: 
• Hypoxemia and acute respiratory distress syndrome 
• Oliguria and acute kidney injury 
• Hypotension and shock, including septic shock 
• Disseminated Intravascular Coagulation 
• Venous and Arterial Thromboembolism 
• Leukocytosis and Leukopenia 
• Thrombocytopenia 
• Lymphopenia 
• Hyperbilirubinemia or Transaminitis 
• Rhabdomyolysis 
• Bacteremia 
• Pneumonia 
• Pleural Effusion 
• Obtundation 
• Gastroparesis and ileus 
9.8 
Suspected Pregnancy in a Woman of Childbearing Potential 
A female patient of childbearing potential is a female who is not surgically sterile (no history of 
a bilateral salpingo-oophorectomy) and is not postmenopausal for at least 1 year. 
A female patient of childbearing potential who receives study drug and is sexually active with 
a male partner, and a male patient who receives study drug and is sexually active with a female 
of childbearing potential, must be willing to use two highly effective methods of contraception 
(e.g., barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception) for 39 
months after last dose of study drug. No contraception is required if a female patient or partner 
has undergone a bilateral salpingo-oophorectomy. 


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Two of the following methods of birth control must be practiced unless a sexually active female 
patient or partner of childbearing potential has undergone a bilateral salpingo-oophorectomy: 
• Male partner has a vasectomy for at least six months duration 
• Use of an intrauterine device 
• Use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) 
• Double barrier contraception with the male partner using a condom and the female using 
a contraceptive sponge, spermicidal jelly or cream or diaphragm plus spermicidal jelly or 
cream 
The Investigator should be immediately informed if a female patient or partner of childbearing 
potential suspects she is pregnant up to 39 months after last dose of study drug. If the female 
patient is receiving study drug when discovered to be pregnant, the study drug should be 
immediately discontinued. If a pregnancy is confirmed, the Investigator must immediately report 
a pregnancy and record the event using a Pregnancy Report Form. Pregnancy is not considered 
an AE, but the Investigator must follow a pregnant patient or partner. The Investigator must 
report follow-up information regarding the course of the pregnancy, including perinatal or 
neonatal outcome. Infants resulting from such pregnancies should be assessed for normality at 
birth and should be followed for 6 months to assess for development milestones. CalciMedica or 
its designee may contact the Investigator to request additional information throughout the course 
of the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional 
reporting in the eCRF and on an SAE form: 
• Congenital anomaly/birth defect 
• Stillbirth 
• Spontaneous miscarriage 


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10 
STATISTICAL METHODS 
10.1 
General Considerations 
Data summaries and listings will be generated using SAS version 9.4 or a more recent version 
(SAS Institute Inc., Cary, NC, USA). 
The statistical analysis plan and/or the clinical study report will provide additional details of the 
analysis, which may include details of missing and, if applicable, unused data, as well as additional 
sensitivity analyses of the primary and secondary variables. The clinical study report will describe 
deviations from the statistical analysis plan, if any. 
The statistical analysis approach will be designed to assess the significance of the primary and 
first secondary endpoint using the Benjamini and Hochberg method to control the overall trial 
level alpha level. The statistical analysis approach will be descriptive, exploratory and inferential 
for the other secondary and exploratory endpoints. 
10.2 
Sample Size 
In the initial design of Part 2 of the study, 320 patients in the imputed PaO2/FiO2 ≤200 subgroup 
and 80 patients in the imputed PaO2/FiO2 >200 subgroup were to have been randomized. A 
constant recovery rate ratio of 1.43 was assumed for patients receiving Auxora compared to 
Placebo in both subgroups. In order to provide power of approximate 90% to detect a difference 
in the recovery rate ratio of approximately1.43 by a stratified 2-sided log-rank test at an overall 
0.05 alpha level, given the 1:1 randomization, it was determined that the study would require 
330 recovery events. With the study length of 30 days, the assessment of time to recovery 
required a sample size of 400 patients. 
The enrollment of patients in the subgroup with an imputed PaO2/FiO2 >200 was stopped early 
because a blinded analysis of the data from the first 26 patients in the subgroup randomized into 
the study showed a low rate of mechanical ventilation or death. This finding was consistent with 
Part 1 of the study where no patients with an imputed PaO2/FiO2 >200 required mechanical 
ventilation or died. 
The Part 2 study sample size was then reevaluated given that the primary endpoint would focus 
on the subgroup of patients with an imputed PaO2/FiO2 ≤200. A two group log-rank test with a 
0.05 two-sided significance level would have 90% power to detect a difference in the recovery 
rate ratio of approximately 1.49 in the 320 patients with an imputed PaO2/FiO2 ≤200 who were 
randomized 1:1 to Auxora or Placebo. 
To further ensure that the sample size of 320 patients in the imputed PaO2/FiO2 ≤200 subgroup is 
an adequate sample size, a sample size re-estimation procedure will be applied when the first 70 
patients in the imputed PaO2/FiO2 ≤200 subgroup have completed or discontinued from the 
study. The IDMC will perform the procedure and will recommend to CalciMedica to increase or 
not increase the study sample size. No ongoing study patients will be included in this sample size 
re-estimation procedure. The sample size will be re-estimated to provide a conditional power of 
90%, based on the evaluation of the treatment efficacy. The sample size re-estimation procedure 


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will not allow for a reduction in the planned sample size of 320 for the imputed PaO2/FiO2 ≤200 
subgroup. If the study randomizes 600 patients in the imputed PaO2/FiO2 ≤200 subgroup it will 
provide 90% power if the recovery rate ratio is 1.34. 
10.3 
Study Endpoints 
Efficacy endpoints will include: 
Primary Endpoint 
• Time to recovery 
Secondary Endpoints 
• All-Cause Mortality at Day 60 
• All-Cause Mortality at Day 30 
• Proportion of patients requiring invasive mechanical ventilation or dying during the 60 
days from the SFISD 
• Proportion of patients requiring invasive mechanical ventilation during the 60 days from 
the SFISD 
• Differences in outcomes as measured by an 8-point ordinal scale at Day 12 
• Differences in outcomes as measured by an 8-point ordinal scale at Day 30 
• Number of Days in the Hospital 
• Number of Days in the ICU 
Tertiary Endpoints 
• Change in PaO2/FiO2 
The primary analyses of the efficacy endpoints will be based on the patients in the imputed 
PaO2/FiO2 ≤200 subgroup. 
Safety endpoints will include: 
• Vital signs measurements 
• Laboratory measurements 
• Concomitant medications 
• Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) 
10.4 
Analysis Sets 
10.4.1 
All Subjects Analysis Set 
The All-Subjects Analysis Set will contain information from all screened patients, including 
those who did not meet the study entry criteria or did not receive a study treatment. 


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10.4.2 
Efficacy Analysis Set 
Efficacy analyses will be based on the ITT principle. The Efficacy Analysis Set will include data 
from patients randomly assigned to study treatment. All data will be included and no patients 
excluded because of protocol violations. For the analysis of efficacy data, patients will be 
included in the treatment group according to their randomly assigned treatment. In addition, a 
modified intent to treat (completer set) efficacy analysis of patients who received three doses of 
study drug, or have been discharged by their physician prior to receiving all three doses, will also 
performed. 
10.4.3 
Safety Analysis Set 
The Safety Analysis Set will include data from all patients randomly assigned to study treatment 
who receive any amount of Auxora or Placebo. All data will be included and no patients 
excluded because of protocol violations. 
For safety data analysis, patients will be included in the treatment group according to the 
treatment they actually receive. 
10.5 
Schedule of Analyses 
Data listings and summary tables will be reviewed by the IDMC when 50 patients are first 
randomized, then when 70 subjects with an imputed PaO2/FiO2 ≤200 have completed the study, 
and finally when 200 patients with an imputed PaO2/FiO2 ≤200 are randomized. The primary 
purpose of the IDMC reviews is to ensure the safety of study patients as well as an additional 
purpose of enhancing the quality of trial conduct. The final analysis will be conducted when all 
randomized patients, based on the planned or the re-estimated sample size, complete the study. 
10.6 
Disposition 
The number and percentage (n, %) of patients screened, enrolled, treated, completed study, and 
discontinued (with reason) will be summarized. All screened patients will be included in the 
disposition analysis. 
10.7 
Analysis of Demographic and Baseline Data 
Patient demographic and baseline characteristics will be summarized by mean, standard deviation, 
median, minimum, and maximum for continuous variables; and by counts and percentages for 
categorical variables. Summaries will be provided separately for each treatment group and both 
treatment groups combined. 


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10.8 
Efficacy Analysis 
Efficacy analyses will be presented by treatment group (Auxora vs Placebo) based on the Efficacy 
Analysis Set of the imputed PaO2/FiO2 ≤200 subgroup, except where it is specified otherwise. 
This section describes the analyses conducted at the final analysis time point when all randomized 
patients (based on the planned or the re-estimated sample size) have completed or discontinued 
from the study, assuming that the study is continued after IDMC reviews. 
Recovery is defined as satisfying categories 6, 7, or 8 on the 8-point ordinal scale:  
• Hospitalized, not requiring supplemental oxygen or ongoing medical care 
• Discharged, requiring supplemental oxygen 
• Discharged, not requiring supplemental oxygen 
The 8-point ordinal scale is defined as  
1. Death 
2. Hospitalized, requiring invasive mechanical ventilation or Extracorporeal Membrane 
Oxygenation (ECMO) 
3. Hospitalized, requiring non-invasive ventilation or high flow supplemental oxygen 
4. Hospitalized, requiring low flow supplemental oxygen 
5. Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care  
6. Hospitalized, not requiring supplemental oxygen or ongoing medical care 
7. Discharged, requiring supplemental oxygen 
8. Discharged, not requiring supplemental oxygen 
10.8.1 
Primary Efficacy Analysis 
Time to recovery of the imputed PaO2/FiO2 ≤200 subgroup is the primary endpoint and is 
defined as the number of days from the SFISD to the date of recovery. Failure to recovery and 
death are both censored at Day 61. 
Time to recovery will be displayed using a Kaplan-Meier estimate and will be compared between 
the 2 treatment groups using a stratified log-rank test stratified by the baseline imputed 
PaO2/FiO2 of ≤100 vs. >100 with an overall 2 sided alpha level of 0.05 using the Benjamini and 
Hochberg method. 
In addition, the recovery rate ratio and the 95% CI will be estimated using a Cox proportional-
hazard model with treatment as the independent variable. 
10.8.2 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be defined in more detail in the statistical analysis plan. All-
Cause Mortality at Days 60 and 30 will be analyzed for significance along with time to recovery 


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using the Benjamini and Hochberg method to control overall trial level 2 sided alpha level of 
0.05. The additional secondary endpoints defined in Session 10.3 will be compared between the 
two treatment groups and the analysis will be descriptive, exploratory and inferential. 
10.8.3 
Mortality at Days 60 and 30 
Proportion and 95% CI All-cause mortality at Day 60 and 30 will be displayed using a Colpper-
Pearson interval and will be compared between the 2 treatment groups using a Cochran-Mantel-
Haenszel test stratified by the baseline imputed PaO2/FiO2 of ≤100 vs. >100. 
10.8.4 
Proportion of Patients Requiring Invasive Mechanical Ventilation or 
Dying During the 60 Days from the SFISD 
Proportion of patients requiring invasive mechanical ventilation or dying is defined as the 
proportion at study Day 60. Day 60 rate for each treatment group will be estimated by the 
Kaplan-Meier procedure. Hypothesis testing will be based on the Kaplan-Meier estimates and 
standard errors estimated by Greenwood formula. 
10.8.5 
Proportion of Patients Requiring Invasive Mechanical Ventilation During 
the 60 Days from the SFISD 
Proportion of patients requiring invasive mechanical ventilation is defined as the proportion at 
study Day 60. Day 60 rate for each treatment group will be estimated by the Kaplan-Meier 
procedure. Hypothesis testing will be based on the Kaplan-Meier estimates and standard errors 
estimated by Greenwood formula. 
10.8.6 
Differences in Outcomes Measured by an 8-Point Ordinal Scale At Day 12 
Proportion of patients in each category of 8-point ordinal scale will also be calculated for each 
treatment group, and odds ratio will be estimated at Day 12. The proportion will be compared 
between the 2 treatment groups using a proportional odds model with fixed factor of treatment 
groups. 
8-point ordinal scale will be imputed based on LOCF method based on the scale at discharge if 
the patient is discharged from hospital with the ordinal scale of 7 or 8. 
10.8.7 
Difference in Outcomes Measured by an 8-Point Ordinal Scale at Day 30 
The analysis will be the same as the Day 12 analysis but extended at Day 30. 
10.8.8 
Number of Days in the Hospital 
The date of each hospital admission and discharge will be collected for each patient. The number 
of days when patients are still alive and out of hospital during the first 28 Days of the study will 


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be summarized by treatment group and compared between the 2 treatment groups using an 
analysis of variance model, which includes treatment group in the model. 
10.8.9 
Number of Days in the ICU 
The analysis will be the same as the number of days in the hospital 
10.8.10 
Subgroup and Exploratory Analyses 
Subgroup analyses will be performed to explore how time to recovery is influenced by baseline 
variables and to evaluate the treatment effect at different levels of each of these variables. The 
Kaplan-Meier analysis and Cox model will be performed by subgroup levels of the baseline 
variables listed below: 
• Age (<75, ≥75) 
• Baseline PaO2/FiO2 (>200, ≤100, 101-200, 201-300, all randomized patients) 
• Receiving high flow oxygenation versus low flow oxygenation at randomization 
• Race (White, Black, Asian, Other). 
• Gender (Male, Female) 
• BMI (<30, ≥30) 
• Remdesivir (being already administered at randomization, administration started after 
randomization, never administered) 
• Dexamethasone (being already administered at randomization, administration started 
after randomization, never administered) 
• Remdesivir and Dexamethasone (being already administered together at randomization or 
administered together starting after randomization) 
• Convalescent plasma (being administered at randomization, administration started after 
randomization, never administered) 
Additional subgroups may also be further described in the Statistical Analysis Plan. 
10.9 
Safety Analysis 
Safety will be assessed by patient reported and Investigator observed AEs along with clinical 
laboratory tests (hematology and chemistries), and vital signs. Safety variables will be tabulated 
by treatment groups and presented for all treatment patients. Exposure to study treatments, 
reasons for discontinuation, deaths and causes of deaths will be tabulated. Treatment-emergent 
AEs (TEAEs) are defined as events that first occurred or worsened after the first dose of study 
drug. TEAEs will be mapped to the appropriate System Organ Class (SOC) and Preferred Term 
(PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries will be provided for all AEs, AEs considered related to study treatment, SAEs, and 
related SAEs, AE leading to treatment discontinuation and AE leading to death as follows: 
• By maximum severity 


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• Incidence by SOC (by severity grade and overall) 
• Incidence by PT (by severity grade and overall) 
Laboratory test results will be used in the summary. The lower and upper reference range values 
for tests from the laboratories will be used to grade the lab results to low, normal and high Shift 
tables will display (1) shift from baseline grade to the worst grade, and (2) shift from baseline 
grade to the last grade. 
Vital signs will be summarized by visit using proportion of patients with each vital sign being 
too high or too low according to conventionally accepted vital sign normal ranges. 
Concomitant medication will be coded by the WHO Drug Dictionary and summarized by 
Therapeutic subgroup and preferred terms, using counts and percentages. Concomitant medications 
are the medications taken with a start date on or after the start of the administration of study 
treatment, or those with a start date before the start of the administration of study treatment and 
a stop date on or after the start of the administration of study treatment. 
Descriptive statistics will include mean, standard deviation, minimum, median, and maximum 
for guadecitabine and decitabine PK concentrations. 
10.10 PK Analysis 
Descriptive statistics will include mean, standard deviation, minimum, median, and maximum 
for PK parameters and concentrations. 
The relationship between exposure and response will be assessed based on the PK data and 
efficacy/safety data collected in this study. The methods will include a population PK modeling 
approach using the sparse data collected. The details of population PK modeling and full results 
of the exposure response analyses will be reported in a separate document, and the summary of 
key findings will be included in the clinical study report. 
10.11 Interim Sample Size Re-estimation 
A sample size re-estimation procedure will be applied when the first 70 patients in the imputed 
PaO2/FiO2 ≤200 subgroup have completed or discontinued from the study. The IDMC will 
perform the procedure and will recommend to CalciMedica to increase or not increase the study 
sample size. The conduction power of the time to recovery will be calculated based on the 
conditional power analysis of the time to recovery by assuming the interim estimated parameter 
values as the estimates of these parameters. Sample size will be re-estimated at the interim 
analysis to provide a conditional power of 90%, based on the interim evaluation of the treatment 
efficacy. The study will use a sequential design with O’Brien-Fleming critical boundary (O'Brien 
and Fleming 1979) at the interim analysis to control type I error. In case of sample size 
modification, the final critical boundary will be adjusted to control type I error (Gao et al., 2008). 
Based on the estimated standard error of 0.25 from part 1 data, the relationship between the 
observed recovery ratio at interim analysis and the re-estimated sample size to reach 90% 
conditional power is shown in the following table: 


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Table 6. Relationship Between the Observed Recovery Ratio at Interim Analysis and the 
Re-estimated Sample Size to Reach 90% Conditional Power 
O’Brien-Fleming boundary at the interim analysis, interim analysis at information fractions 0.25, Standard error of 
log(recovery ratio) =0.25 
Observed recovery 
ratio at interim 
analysis 
Conditional power 
based on interim 
estimation  
Sample size (events) 
to reach 90% 
conditional power 
based on interim 
estimation 
Conditional power 
based on recovery 
ratio = 1.37 
Sample size (events) 
to reach 90% 
conditional power on 
recovery ratio = 1.37 
1.57 
97% 
214 (178) 
 
 
1.47 
90% 
290 (241) 
 
 
1.44 
86% 
320 (266) 
 
 
1.40 
80% 
384 (318) 
 
 
1.39 
78% 
400 (332) 
 
 
1.37 
67% 
438 (363) 
 
 
1.34 
59% 
500(415) 
 
 
1.31 
59% 
600(503) 
 
 
1.20 
28% 
1414(1174) 
64% 
507(421) 
1.10 
8% 
5648(4688) 
56% 
563(468) 
1.05 
 
 
52.2% 
596(495) 
1.00 
 
 
48% 
630(523) 
Based on the above relationship, the following sample size re-estimation rule is proposed for this 
study at the interim analysis of the 70 patients in the imputed PaO2/FiO2 ≤200 subgroup: 
• Recovery rate ratio <1.05, increase sample size >600 for imputed PaO2/FiO2 ≤200 
subgroup 
• Recovery rate ratio 1.05 to <1.34, increase sample size to 600 for imputed PaO2/FiO2 ≤200 
subgroup 
• Recovery rate ratio 1.34 to 1.38, increase sample size to 500 for imputed PaO2/FiO2 ≤200 
subgroup 
• Recovery rate ratio 1.39 to 1.43, increase sample size to 400 for imputed PaO2/FiO2 ≤200 
subgroup 
• Recovery rate ratio ≥1.44, do not increase sample size for imputed PaO2/FiO2 ≤200 
subgroup 


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11 
ADMINISTRATIVE CONSIDERATIONS 
11.1 
Electronic Case Report Forms 
The study will use an Electronic Data Capture (EDC) system that is 21 CFR Part 11 compliant to 
electronically capture data for all screened and randomized patients. 
11.2 
Monitoring of the Study 
The site monitor, as a representative of CalciMedica, will closely follow the conduct of the 
study. The site monitor will collaborate with the study site to maintain necessary telephone and 
email contact with the PI and his/her study staff. The site monitor will maintain current 
knowledge of each site’s study activity by observing the conduct of the study at the site, 
reviewing study records and source documentation (remote monitoring), and discussing the 
conduct of the study with the PI and his/her study staff. 
11.3 
Inspection of Records 
The PI, his/her study staff and the study site will provide access to all study records to assist 
study-related monitoring and audits, Institutional Review Board/Ethics Committee/Research 
Ethics Board reviews, and regulatory inspections. In the event of an audit, the PI agrees to allow 
CalciMedica or its representatives and relevant regulatory authorities access to all study records. 
If any regulatory agency schedules an audit, the PI should promptly notify CalciMedica or its 
representatives and promptly forward to CalciMedica copies of any audit reports he/she receives. 
11.4 
Study Record Retention 
The PI or his/her study staff must retain essential documents for at least 2 years after the last 
approval of a marketing application in an ICH region. They should retain these documents longer 
if required because of regulatory requirements or because of an agreement with CalciMedica. 
11.5 
Study Conduct: Good Clinical Practice and Declaration of Helsinki 
CalciMedica will design the clinical study, shall implement it, and report it in accordance with 
the ICH Harmonized Guideline for Good Clinical Practice, with applicable local regulations 
(e.g., European Directive 2001/83/EC and US Code of Federal Regulations Title 21), and with 
the ethical principles laid down in the Declaration of Helsinki. 
The PI agrees to conduct the study in accordance with the ICH Guideline for Good Clinical 
Practice, with applicable local regulations (e.g., European Directive 2001/83/EC and US Code of 
Federal Regulations Title 21) and with the principles of the Declaration of Helsinki. The PI must 
conduct all aspects of this study in accordance with all national, state and local laws or regulations. 


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11.6 
Responsibilities of the Investigator and the IRB/EC 
A properly constituted IRB/EC must review and approve the protocol and the proposed informed 
consent form before the start of the study at the site. The PI or his/her study staff must provide 
CalciMedica or its designee a signed and dated statement that the IRB/EC has approved the 
protocol and the informed consent form before consenting patients for the study. Prior to starting 
the study, the PI will sign a protocol signature page confirming that he/she will conduct the study 
in accordance with this protocol and he/she will give CalciMedica or its designee and regulatory 
authorities access to all relevant data and records. 
The IRB/EC chairperson or designee must sign all IRB/EC approvals and must identify the 
IRB/EC by name and address, the clinical protocol, and the date of approval. 
The PI is responsible for obtaining reviews of the clinical research at intervals specified by the 
IRB/EC. The specified intervals should not exceed 1 year. The PI must supply CalciMedica or its 
designee written documentation of the reviews of the clinical research. 
11.7 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient (or the patient’s legal representative) except as necessary for monitoring and 
auditing by CalciMedica or its designee, inspections by relevant regulatory authorities, or 
reviews by the IRB/EC. 
The PI, all study staff and all co-workers involved in the study may not disclose or use for any 
purpose other than the conduct of the study any data, record or other unpublished confidential 
information disclosed to them for the purpose of the study. They must obtain prior written 
agreements from CalciMedica or its designee for the disclosure of any said confidential 
information to other parties. 
11.8 
Modification of the Protocol 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments. Amendments (substantial/non-substantial) require regulatory approval and IRB/EC 
approval or notification. Only after approval by CalciMedica, the PI, the IRB/EC, and if applicable 
the regulatory authorities, will the protocol amendments become effective. In cases when the 
protocol is amended to enhance patient safety, the amendment may be implemented but must be 
immediately submitted to the IRB/EC and regulatory authorities. 
The revision number and date of the amendment will be recorded on the title page of the protocol. 
The PI is responsible for informing the IRB/EC of all problems involving risks to patients. In 
case of urgent safety measures, CalciMedica or its designee will immediately notify the PIs and 
relevant regulatory authorities. 


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11.9 
Informed Consent 
Because the study will be conducted under a United States Investigational New Drug Application, 
informed consent that is in compliance with Title 21 of the United States Code of Federal 
Regulations (CFR) Part 50 will be obtained from each patient or LAR before the patient enters 
the study or before any unusual or non-routine procedure is performed. For sites outside the 
United States, the signed informed consent form will be obtained in compliance with local 
regulations, ICH E6 (R2) and the principles of the Declaration of Helsinki. 
CalciMedica or it’s designee may provide to the PI or his/her study staff an informed consent 
form template. The informed consent form must be reviewed by CalciMedica or its designee 
before the PI or his/her study staff submits it to the IRB/EC. After CalciMedica or its designee 
review the informed consent form, the PI or his/her study staff will submit it to the IRB/EC for 
review and approval. If the informed consent form is revised during the course of the study, 
CalciMedica or its designee must agree with revisions before the PI or his/her study staff submits 
it to the IRB/EC. The study staff must provide CalciMedica or its designee a copy of the revised 
informed consent form after IRB/EC approves it. All patients or LARs affected by the revision 
must sign the revised informed consent form after the IRB/EC approves it. 
Before enrolling in the study, each prospective patient or LAR will receive a full explanation of 
the study and review the approved informed consent form. Once the PI or designee is assured 
that the patient or LAR understands the implications of participating in the study, he/she will ask 
the patient or LAR to give consent for the patient to participate in the study by signing the 
informed consent form. 
A patient may participate in the study only after providing consent using an IRB/EC approved 
informed consent form. A LAR of the patient may provide informed consent on behalf of the 
patient under conditions authorized by local laws and regulations. The patient or LAR must 
provide informed consent before the patient undergoes any study-specific procedures described 
in the protocol. The PI or designee will provide a copy of the informed consent form to the 
patient and/or LAR. The process of obtaining informed consent must also be documented in the 
patient source documents. 
11.10 Protocol Violations and Deviations 
The PI or designee must document any protocol deviation or violation. Reporting of protocol 
deviations and violations to the appropriate IRB/EC is the responsibility of the PI and must 
follow the applicable IRB/EC guidelines. 
Major protocol deviations are a subset of protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
patient’s rights, safety, or well-being. 
If there is an immediate hazard to the patient, the PI may deviate from the protocol without prior 
approval from CalciMedica or its designee and the IRB/EC but must notify CalciMedica or its 
designee and IRB/EC of the deviation as soon as he/she is able to do so. 


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11.11 Financial Disclosure 
PIs and sub-investigators are required to provide financial disclosure information prior to starting 
the study. In addition, the PIs and sub-investigators must provide CalciMedica or its designee 
with updated information if any relevant changes occur during the course of the study and for 
one year following the completion of the study. 
Any PIs, sub-Investigators or study staff with a vested financial interest in the success of the 
study may not participate in the study. 
11.12 Sponsor Obligations 
CalciMedica or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during Screening. In addition, CalciMedica is not 
financially responsible for the treatment of the patient’s underlying disease. 
11.13 Investigator Documentation 
Before beginning the study, the PI will be asked to comply with ICH E6 (R2) 8.2 and title 21 
CFR by providing to CalciMedica or designee the following documents: 
• The IRB/EC approval of the protocol 
• The IRB/EC approved informed consent form 
• Any written information regarding the study that will be provided to the patient or LAR 
• A Form FDA 1572, fully executed, and all updates on new fully executed Form FDA 
1572 (Unless granted an exemption by the FDA and in compliance with local 
regulations) 
• Curricula Vitae for the PI and each sub-Investigator listed on Form FDA 1572. Evidence 
of licensure must be noted on the Curricula Vitae or a copy of the license must be 
provided. The Curricula Vitae must be current within 3 years before site participates in 
the study 
• Completed financial disclosure forms to allow CalciMedica or designee to submit 
complete and accurate certification or disclosure statements required under US Title 
21 CFR 54. In addition, the PI and sub-Investigators must provide to CalciMedica or 
designee a commitment to update this information promptly if any relevant changes occur 
during the course of the study and for 1 year following completion of the study 
• Laboratory certifications and normal ranges for any laboratories used by the site for the 
conduct of the study 


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11.14 Clinical Study Insurance 
CalciMedica has subscribed to an insurance policy, covering in its terms and provisions its legal 
liability for injuries caused to participating persons and arising out of this research that is 
performed strictly in accordance with the scientific protocol as well as with applicable law and 
professional standards. 
11.15 Use of Information 
All information supplied by CalciMedica to the PI and his/her study staff is privileged and 
confidential. The PI and his/her study staff agree to use this information to accomplish the study 
and not to use it for other purposes without consent from CalciMedica. Furthermore, the PI and 
his/her study staff are obligated to provide CalciMedica with complete data obtained during the 
study. The information obtained from the clinical study will be used towards the development of 
Auxora, and may be disclosed to regulatory authorities, other Investigators, corporate partners or 
consultants as required. 
11.16 Publications 
CalciMedica Inc. reserves the right to review all planned communications and manuscripts based 
on the results of this study. This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but rather to allow CalciMedica to 
confirm the accuracy of the data, to protect proprietary information, and to provide comments 
based on information that may not yet be available to the study investigators. CalciMedica Inc. 
supports communication and publication of study results whatever the findings of the study. 
CalciMedica Inc. also encourages disclosure of any conflict of interest from all authors or 
investigators when manuscripts are submitted for publication. 
11.17 Independent Data Monitoring Committee 
An IDMC will be convened and will monitor safety for this study on an ongoing basis. An IDMC 
charter will govern the IDMC and will describe the scope of responsibilities of the IDMC. If the 
IDMC recommends alteration of the dosing regimen because of safety issues, the FDA and other 
regulatory agencies will be notified as appropriate. The IDMC responsibilities include protecting 
the safety of the study patients and making recommendations to CalciMedica concerning the 
conduct of the study. 


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12 
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Appendix 1. 
Estimated PaO2/FiO2 
SpO2 
 
0.7 
0.75 
0.8 
0.81 
0.82 
0.83 
0.84 
0.85 
0.86 
0.87 
0.88 
0.89 
0.9 
0.91 
0.92 
0.93 
0.94 
0.95 
0.96 
FiO2 
0.21 
174 
191 
211 
216 
221 
226 
232 
238 
245 
252 
260 
269 
279 
291 
304 
319 
337 
360 
390 
0.24 
153 
167 
185 
189 
193 
198 
203 
208 
214 
221 
228 
236 
244 
254 
266 
279 
295 
315 
341 
0.27 
136 
148 
164 
168 
172 
176 
180 
185 
190 
196 
202 
209 
217 
226 
236 
248 
262 
280 
303 
0.28 
132 
143 
157 
161 
164 
168 
175 
179 
182 
189 
196 
204 
211 
218 
229 
239 
254 
271 
293 
0.3 
122 
133 
148 
151 
155 
158 
162 
167 
171 
177 
182 
189 
196 
203 
213 
223 
236 
252 
273 
0.32 
116 
125 
138 
141 
144 
147 
153 
156 
159 
166 
172 
178 
184 
191 
200 
209 
222 
238 
256 
0.35 
105 
114 
127 
129 
132 
136 
139 
143 
147 
151 
156 
162 
168 
174 
182 
191 
202 
216 
234 
0.36 
103 
111 
122 
125 
128 
131 
136 
139 
142 
147 
153 
158 
164 
169 
178 
186 
197 
211 
228 
0.4 
92 
100 
111 
113 
116 
119 
122 
125 
129 
132 
137 
141 
147 
153 
159 
168 
177 
189 
205 
0.44 
84 
91 
100 
102 
105 
107 
111 
114 
116 
120 
125 
130 
134 
139 
145 
152 
161 
173 
186 
0.45 
81 
89 
98 
101 
103 
106 
108 
111 
114 
118 
121 
126 
130 
136 
142 
149 
157 
168 
182 
0.5 
73 
80 
89 
91 
93 
95 
97 
100 
103 
106 
109 
113 
117 
122 
128 
134 
142 
151 
164 
0.55 
67 
73 
81 
82 
84 
86 
89 
91 
94 
96 
99 
103 
107 
111 
116 
122 
129 
138 
149 
0.6 
61 
67 
74 
76 
77 
79 
81 
83 
86 
88 
91 
94 
98 
102 
106 
112 
118 
126 
136 
0.65 
56 
62 
68 
70 
71 
73 
75 
77 
79 
81 
84 
87 
90 
94 
98 
103 
109 
116 
126 
0.7 
52 
57 
63 
65 
66 
68 
70 
71 
73 
76 
78 
81 
84 
87 
91 
96 
101 
108 
117 
0.75 
49 
53 
59 
60 
62 
63 
65 
67 
69 
71 
73 
75 
78 
81 
85 
89 
94 
101 
109 
0.8 
46 
50 
55 
57 
58 
59 
61 
63 
64 
66 
68 
71 
73 
76 
80 
84 
89 
95 
102 
0.85 
43 
47 
52 
53 
55 
56 
57 
59 
61 
62 
64 
67 
69 
72 
75 
79 
83 
89 
96 
0.9 
41 
44 
49 
50 
52 
53 
54 
56 
57 
59 
61 
63 
65 
68 
71 
74 
79 
84 
91 
0.95 
39 
42 
47 
48 
49 
50 
51 
53 
54 
56 
58 
60 
62 
64 
67 
71 
75 
80 
86 
1 
37 
40 
44 
45 
46 
47 
49 
50 
51 
53 
55 
57 
59 
61 
64 
67 
71 
76 
82 
 
Adapted from Fowler et al., 2019 


CM4620-204 
CalciMedica, Inc 
Version 8.1 (March 31, 2021) 
Confidential 
65 
Appendix 2. 
Schedule of Events 
 
Screen 
If Eligible, 
Baseline 
Assessment 
R 
0 hour 
24 (±2) 
hours 
48 (±2) 
hours 
72 (±2) 
hours 
96, 144, 192, 240 
hours 
(±4 hours) 
120, 168, 216 
hours 
 (±4 hours) 
Days 
12-28g 
(±4 hours) 
Days 
30, 60 e  
(±5 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Daily Assessment - Ordinal Scale 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Weight and Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs a including SpO2 and FiO2 
X 
 
 
X f 
X 
X 
X 
X 
X 
X 
 
Arterial Blood Gas b 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Pathogen Testing-COVID-19 diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
CXR or CT scan of the lungs 
X 
 
 
 
 
 
 
 
 
 
 
Influenza A, B and Respiratory Panelc 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test in WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Daily Laboratory Monitoringi 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
PK Analysish 
 
 
 
 
X 
X 
X 
 
 
 
 
Q72 hour Laboratory Monitoringi 
 
X 
 
 
 
 
X 
X 
X 
 
 
AE/SAE Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Randomize patient 
 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
X 
X 
X 
 
 
 
 
 
Serum biomarkersd 
X 
 
 
 
 
X d 
 
 
 
Hospitalized patients will complete all assessments. Patients will complete the Day 12 assessment if discharged home on oxygen prior today 12. All patients will complete the 
Day 30 and Day 60 assessment. 
a. Vital Signs will include temperature, heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, and SpO2 by pulse oximetry. For the SpO2, both the values at 
the time of the assessment and the lowest noted from the time of the last assessment shall be recorded. The FiO2 shall be recorded at the time of each SpO2 recording. 
b. Arterial blood gas results obtained as standard of care shall be recorded. 
c. If performed as local standard of care. 
d. Blood samples for serum biomarkers, such as IL-6 and IL-2R, will be shipped to a reference lab and results may not be available to the clinical team while managing the 
patient. The serum biomarkers, such as IL-6 and IL-2R, will be obtained prior to SFISD and again at 96 hours and may be performed on blood drawn in the previous 12 hours. 
e. Day 30 will be phone call assessment for patients who were discharged prior to Day 25; Day 60 will be a phone call assessment for patients discharged prior to Day 55 
f. 0-hour vital signs required only if screening vital signs were measured >6 hours prior to SFISD. 
g.  Patients discharged prior to Day 12 with the need for supplemental oxygen will be contacted on Day 12 to determine if they are still receiving supplemental oxygen. 
h.  PK samples will be drawn at selected sites. Blood may be drawn for PK analysis together with daily laboratory monitoring and may be obtained from blood drawn in the 
previous 12 hours. The time of the draw must be recorded. 
i. Daily and Q72 hour laboratory monitoring may be performed on blood drawn in the previous 12 hours. Q 72 hours labs will be performed at 72, 144 and 216 hours 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN FOR PART II 
Protocol CM4620-204 
A Randomized Double Blind, Placebo-Controlled Study 
of Auxora for the Treatment of 
Severe COVID-19 Pneumonia (CARDEA) 
PREPARED BY: 
NAME: 
POSITION: 
VERSION: 
DATE: 
Jeffrey Zhang, PhD. 
Principle Statistician, Princeton 
Pharmatech Final 2.0; NCT04345614
17 August 2021 


Protocol No. CM4620-204 
Statistical Analysis Plan for Pan II 
CalciMedica Inc. 
APPROVAL FORM 
Statistical Analysis Plan for Part ll 
Protocol No. 
CM4620-204 
Protocol Title A Randomized Double Blind, Placebo-Controlled Study of Auxora for the 
Treatment of Severe COVID-19 Pneumonia (CARDEA) 
Version 
Final 2.0 
Date 
17 August 2021 
Author 
Jeffrey Zhang, PhD, 
Principle Statistician, Princeton Pham1atech LLC 
APPROVED BY: 
Jeffrey Zhang, PhD 
Principle Statistician, Princeton Pharmatech LLC 
Sudarshan Hebbar, MD 
Chief Medical Officer, CalciMedica, Inc. 
CONFIDENTIAL 
Date 
Date 
Page 2 
17-Aug-2021


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 3 
CONFIDENTIAL 
DOCUMENT HISTORY - CHANGES COMPARED TO PREVIOUS FINAL 
VERSION OF SAP 
Date 
Outcome 
to 
update 
Reason for update 
Section and title 
impacted (Current) 
Mar-31-2021 
First version 
Creation of final version 
NA 
Aug-15-2021 
Amendment 1 
(Second 
Version) 
Clarification of the data collection 
period for the time to recovery per 
FDA comment 
5.1 Efficacy endpoint 
Remove Completer Analysis Set. 
The completer analysis set analysis is 
changed to as treated analysis using 
safety analysis set 
6 Analysis 
Populations 
Add additional analysis for 
Concomitant Medications of 
Vasopressors, Corticosteroids, 
Antivirals And Anticoagulants 
8.3.3 Concomitant 
Medications 
Add additional sensitivity analysis 
for the  prohibited 
immunosuppressive medications or 
immunotherapies and convalescent 
plasma treatment based on 
hypothesis censoring rule per FDA 
comment  
8.4.3 Sensitivity 
Analyses 
Add additional supplementary 
analysis for including the baseline 
imputed PaO2/FiO2 of ≥201 
stratification group in the analysis set 
per FDA comment. 
8.4.4 and 8.5.4 
Supplementary 
Analyses 
Clarification of the censoring rule 
details 
8.5 Secondary 
Endpoint Analysis 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 4 
CONFIDENTIAL 
Table of Contents 
Approval Form .................................................................................................................................2 
Document History - Changes compared to previous final version of SAP .....................................3 
Table of Tables ................................................................................................................................6 
List of Terms and Abbreviations .....................................................................................................7 
1 INTRODUCTION .....................................................................................................................8 
2 STUDY OBJECTIVES ..............................................................................................................8 
2.1 Primary Objective .............................................................................................................8 
2.2 Secondary Objectives ........................................................................................................8 
3 STUDY DESIGN.......................................................................................................................8 
3.1 Overall Study Design ........................................................................................................8 
3.2 Schedule of Study Procedures...........................................................................................9 
4 SAMPLE SIZE ........................................................................................................................10 
5 STUDY ENDPOINTS .............................................................................................................10 
5.1 Efficacy Endpoints ..........................................................................................................10 
5.1.1 Primary Endpoint ................................................................................................10 
5.1.2 Key Secondary Endpoint ....................................................................................11 
5.1.3 Supportive Secondary Endpoints ........................................................................11 
5.2 Safety Endpoints .............................................................................................................11 
5.3 Pharmacokinetic Endpoint ..............................................................................................11 
5.4 Pharmacodynamic Endpoint ...........................................................................................11 
5.5 Health-economics Endpoint ............................................................................................11 
6 ANALYSIS POPULATIONS .................................................................................................12 
6.1 All-Subjects Analysis Set................................................................................................12 
6.2 Efficacy Analysis Set ......................................................................................................12 
6.3 Safety Analysis Set .........................................................................................................12 
7 TIMINGS OF ANALYSES .....................................................................................................12 
7.1 Safety Review .................................................................................................................12 
7.2 Interim Sample Size Re-estimation and Futility Analysis ..............................................12 
7.3 Final Analysis .................................................................................................................13 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 5 
CONFIDENTIAL 
8 STATISTICAL ANALYSES ..................................................................................................13 
8.1 General Considerations ...................................................................................................13 
8.1.1 Number of Digits to Report ................................................................................13 
8.1.2 Significance Level and Confidence Interval .......................................................13 
8.1.3 Descriptive Statistics Values to Calculate ..........................................................13 
8.1.4 Derived Variables ...............................................................................................14 
8.1.5 Missing Data .......................................................................................................15 
8.1.6 Pooling of Sites ...................................................................................................15 
8.2 Subject Disposition .........................................................................................................15 
8.3 Demographic, Other Baseline Characteristics and Medication ......................................15 
8.3.1 Demographic and Baseline Characteristic ..........................................................15 
8.3.2 Comorbidity ........................................................................................................16 
8.3.3 Concomitant Medications ...................................................................................16 
8.4 Primary Endpoint Analysis .............................................................................................16 
8.4.1 Definition of Endpoint ........................................................................................16 
8.4.2 Main Analytical Approach ..................................................................................17 
8.4.3 Sensitivity Analyses ............................................................................................17 
8.4.4 Supplementary Analyses .....................................................................................18 
8.5 Secondary Endpoint Analyses ........................................................................................18 
8.5.1 Key Secondary Efficacy Analysis ......................................................................18 
8.5.2 Main Analytical Approach ..................................................................................19 
8.5.3 Sensitivity Analyses ............................................................................................19 
8.5.4 Supplementary Analyses .....................................................................................20 
8.5.5 Supportive Secondary Efficacy Analysis............................................................20 
8.6 Tertiary Endpoint Analysis .............................................................................................21 
8.6.1 Change in Imputed PaO2/FiO2 Ratio ..................................................................21 
8.7 Safety Analysis ...............................................................................................................23 
8.7.1 Study Medication Exposure ................................................................................23 
8.7.2 Adverse Events ...................................................................................................23 
8.7.3 Additional Safety Assessments ...........................................................................24 
8.8 Other Analyses ................................................................................................................25 
8.8.1 Other Variables and/or Parameters .....................................................................25 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 6 
CONFIDENTIAL 
8.8.2 Subgroup Analyses .............................................................................................25 
9 INTERIM ANALYSIS ............................................................................................................26 
9.1 Interim Sample Size Re-estimation and Futility Analysis ..............................................26 
9.1.1 Critical Boundary Adjustment ............................................................................27 
10 VALIDATION .........................................................................................................................28 
11 PROGRAMMING AND DATA PRESENTATION CONVENTIONS .................................28 
12 BIBLIOGRAPHY ....................................................................................................................29 
Table of Tables 
Table 1 
Schedule of Assessments .............................................................................................. 9 
Table 2 
Number of Decimal Places (DP)................................................................................. 13 
Table 3 
Look up table for conversion SpO2 to PaO2 ............................................................... 21 
Table 4 
Relationship Between the Observed Recovery Ratio at Interim Analysis and the 
Re-estimated Sample Size to Reach 90% Conditional Power .................................... 26 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 7 
CONFIDENTIAL 
List of Terms and Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
CI 
Confidence interval 
COVID-19 
Disease from infection with coronavirus 2019 or SARS-CoV-2 
CM 
Concomitant medication 
CS 
Clinically significant 
DP 
Decimal places 
eCRF 
Electronic data collection form 
ECMO 
Extracorporeal membrane oxygenation 
IDMC 
Independent data monitoring committee 
LOCF 
Last observation carried forward 
MedDRA 
Independent safety review committee 
MMRM 
Mixed-effect model repeated measure 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SFISD 
Start of first infusion of study drug 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures and listings 
ULN 
Upper limit of normal 
WHO 
World health organization 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 8 
CONFIDENTIAL 
1 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the CM4620-204 Protocol version 8.1 dated 
31 March 2021. The plan covers statistical analysis of efficacy and safety data to assess the 
efficacy and safety of Auxora compared to Placebo in patients with severe COVID-19 
Pneumonia. The SAP is for the analysis of Part 2 of the CM4620-204 study. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To assess the clinical efficacy of Auxora in patients with severe COVID-19 pneumonia 
2.2 
Secondary Objectives 

To assess the safety and tolerability of Auxora in patients with severe COVID-19
pneumonia

To assess the pharmacokinetic profile of Auxora in patients with severe COVID-19
pneumonia
3 
STUDY DESIGN 
3.1 
Overall Study Design 
Part 2 is a randomized, double blind, placebo-controlled study in which initially up to 400 
patients receiving supplemental oxygen at Screening, and who meet all of the inclusion criteria 
and none of the exclusion criteria, were to be randomized 1:1 to receive Auxora plus standard of 
care or Placebo plus standard of care. After a blinded analysis of the mechanical ventilation and 
death rate in the subgroup of patients with a baseline imputed PaO2/FiO2 >200 who were 
randomized into the study, the number of patients in this subgroup were capped at 26. The study 
sample size remained 320 for patients with a baseline imputed PaO2/FiO2 ≤200. When enrolling 
both subgroups, patients were stratified to ensure balanced randomization between the Auxora 
and Placebo arms. 
The dose of Auxora will be 2.0 mg/kg (1.25 mL/kg) administered at 0 hour, and then 1.6 mg/kg 
(1 mL/kg) at 24 hours and 1.6 mg/kg (1 mL/kg) at 48 hours from the SFISD. The dose of 
Placebo will be 1.25 mL/kg administered at 0 hour and then 1 mL/kg at 24 hours and 1 mL/kg at 
48 hours from the SFISD. The SFISD should occur within 12 hours of the patient or LAR 
providing informed consent. The dosing will be based on actual body weight obtained at the time 
of hospitalization or screening for the study. As described in the pharmacy manual, there will be 
an upper limit of the absolute dose (volume) of Auxora and volume of Placebo that will be 
administered for patients weighing more than 125kg. 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 9 
CONFIDENTIAL 
A study physician or appropriately trained delegate will perform assessments at Screening, 
immediately prior to the SFISD, and immediately prior to each subsequent infusion. At 72 hours 
after the SFISD, the patient will be assessed every 24 hours (±4 hours) until 240 hours after the 
SFISD, then q48 hours until Day 30 after the SFISD, or until discharge if earlier. Patients who 
are discharged before Day 25 after the SFISD will be followed-up at Day 30 (±5 days) for a 
safety and mortality assessment. Patients who are discharged before Day 55 after the SFISD will 
be followed up at Day 60 (±5 days) for a safety and mortality assessment. 
3.2 
Schedule of Study Procedures 
Table 1 
Schedule of Assessments 
Screen 
If Eligible, 
Baseline 
Assessment 
R 
0 
hour 
24 
(±2) 
hours 
48 
(±2) 
hours 
72 
(±2) 
hours 
96, 144, 192, 
240 hours 
(±4 hours) 
120, 168, 
216 hours 
 (±4 hours) 
Days 
12-28g 
(±4 hours) 
Days 
30, 60e 
(±5 days) 
Informed Consent 
X 
Daily Assessment - Ordinal Scale 
X 
X 
X 
X 
X 
X 
X 
Weight and Height 
X 
Vital Signsa including SpO2 and
FiO2 
X 
Xf 
X 
X 
X 
X 
X 
X 
Arterial Blood Gasb
X 
X 
X 
X 
X 
X 
X 
X 
Pathogen Testing-COVID-19 
diagnosis 
X 
CXR or CT scan of the lungs 
X 
Influenza A, B and Respiratory 
Panelc
X 
Daily Laboratory Monitoringi 
X 
X 
X 
X 
X 
X 
PK Analysish 
X 
X 
X 
Q72 hour Laboratory Monitoringi 
X 
X 
X 
X 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Randomize patient 
X 
Study Drug Administration 
X 
X 
X 
IL-6 and IL-2Rd
X 
Xd 
Hospitalized patients will complete all assessments. Patients will complete the Day 12 assessment if discharged home on oxygen 
prior today 12. All patients will complete the Day 30 assessment. 
a. Vital Signs will include temperature, heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, and SpO2 by 
pulse oximetry. For the SpO2, both the values at the time of the assessment and the lowest noted from the time of the last
assessment shall be recorded. The FiO2 shall be recorded at the time of each SpO2 recording.
b. Arterial blood gas results obtained as standard of care shall be recorded.
c. If performed as local standard of care.
d. Blood samples for IL-6 and IL-2R will be shipped to a reference lab and results may not be available to the clinical team
while managing the patient. The IL-6 and IL-2R will be obtained prior to randomization and again at 96 hours. The IL-6 and
IL-2R may be performed on blood drawn in the previous 12 hours.
e. Day 30 will be phone call assessment for patients who were discharged prior to Day 25. ; Day 60 will be a phone call
assessment for patients discharged prior to Day 55
f. 0-hour vital signs required only if screening vital signs were measured >6 hours prior to SFISD.
g.  Patients discharged prior to Day 12 with the need for supplemental oxygen will be contacted on Day 12 to determine if they
are still receiving supplemental oxygen.
h.  PK samples will be drawn at selected sites. Draw blood for PK analysis together with daily laboratory monitoring. The PK
specimens may be obtained from blood drawn in the previous 12 hours. The time of the draw must be recorded.
i. Daily and Q72 hour laboratory monitoring may be performed on blood drawn in the previous 12 hours. Q 72 hours labs will


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 10 
CONFIDENTIAL 
be performed at 72, 144 and 216 hours 
4 
SAMPLE SIZE 
In the initial design of Part 2 of the study, 320 patients in the baseline imputed PaO2/FiO2 ≤200 
subgroup and 80 patients in the baseline imputed PaO2/FiO2 >200 subgroup were to have been 
randomized. A constant recovery rate ratio of 1.43 was assumed for patients receiving Auxora 
compared to Placebo in both subgroups. In order to provide power of approximate 90% to detect 
a difference in the recovery rate ratio of approximately1.43 by a stratified 2-sided log-rank test at 
an overall 0.05 alpha level, given the 1:1 randomization, it was determined that the study would 
require 330 recovery events. With the study length of 30 days, the assessment of time to recovery 
required a sample size of 400 patients.  
The enrollment of patients in the subgroup with a baseline imputed PaO2/ FiO2 >200 was stopped 
early because a blinded analysis of the data from the first 26 patients in the subgroup randomized 
into the study showed a low rate of mechanical ventilation or death. This finding was consistent 
with Part 1 of the study where no patients with a baseline imputed PaO2/FiO2 >200 required 
mechanical ventilation or died. 
The Part 2 study sample size was then reevaluated given that the primary endpoint would focus 
on the subgroup of patients with a baseline imputed PaO2/FiO2 ≤200. A two group log-rank test 
with a 0.05 two-sided significance level would have 90% power to detect a difference in the 
recovery rate ratio of approximately 1.49 in the 320 patients with a baseline imputed PaO2/FiO2 
≤200 who were randomized 1:1 to Auxora or Placebo. 
To further ensure that the sample size of 320 patients in the baseline imputed PaO2/FiO2 ≤200 
subgroup is an adequate sample size, a sample size re-estimation procedure will be applied when 
the first 70 patients in the baseline imputed PaO2/FiO2 ≤200 subgroup have completed or 
discontinued from the study. The IDMC will perform the procedure and will make a nonbinding 
recommendation to CalciMedica to increase or not increase the study sample size. No ongoing 
study patients will be included in this sample size re-estimation procedure. The sample size will 
be re-estimated to provide a conditional power of 90%, based on the evaluation of the treatment 
efficacy. The sample size re-estimation procedure will not allow for a reduction in the planned 
sample size of 320 for the baseline imputed PaO2/FiO2 ≤200 subgroup. If the study randomizes 
600 patients in the baseline imputed PaO2/FiO2 ≤200 subgroup it will provide 90% power if the 
recovery rate ratio is 1.34. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoints 
5.1.1 
Primary Endpoint 
Time to recovery through Day 60 visit 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 11 
CONFIDENTIAL 
5.1.2 
Key Secondary Endpoint 
All-cause mortality at Day 60 visit 
5.1.3 
Supportive Secondary Endpoints 

All-cause mortality at Day 30 visit

Proportion of patients requiring invasive mechanical ventilation or dying during the
60 days from the SFISD

Proportion of patients requiring invasive mechanical ventilation during the 60 days from
the SFISD

Differences in outcomes as measured by an 8-point ordinal scale at Day 12

Differences in outcomes as measured by an 8-point ordinal scale at Day 30

Number of Days in the Hospital

Number of Days in the ICU
The primary analyses of the efficacy endpoints will be based on the patients in the baseline 
imputed PaO2/FiO2 ≤200 subgroup. 
5.2 
Safety Endpoints 

Vital signs measurements

Laboratory measurements

Concomitant medications

Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
5.3 
Pharmacokinetic Endpoint 
Not applicable for this SAP. 
5.4 
Pharmacodynamic Endpoint 
Not applicable for this SAP. 
5.5 
Health-economics Endpoint 
Not applicable for this SAP. 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 12 
CONFIDENTIAL 
6 
ANALYSIS POPULATIONS 
6.1 
All-Subjects Analysis Set 
The All-Subjects Analysis Set will contain information from all screened subjects, including 
those who did not meet the study entry criteria or did not receive a study treatment. 
6.2 
Efficacy Analysis Set 
Efficacy analyses will be based on the ITT principle. The Efficacy Analysis Set will include data 
from all subjects randomly assigned to study treatment. All data will be included and no subjects 
excluded because of protocol violations. For the analysis of efficacy data, subjects will be 
included in the treatment group according to their randomly assigned treatment. 
Unless otherwise noted, all efficacy analyses will be performed using the Efficacy Analysis Set 
of the baseline imputed PaO2/FiO2 ≤200 subgroup. All Efficacy Tests data will be listed. 
6.3 
Safety Analysis Set 
The Safety Analysis Set will include data from all subjects randomly assigned to study treatment 
who receive any amount of Auxora or Placebo. All data will be included and no subjects 
excluded because of protocol violations. For safety data analysis, subjects will be included in the 
treatment group according to the treatment they actually receive. 
7 
TIMINGS OF ANALYSES 
7.1 
Safety Review 
After the first 50 patients were randomized in Part 2, an IDMC evaluated safety data from the 
study. The IDMC will make a suggestion whether to continue the study without changes, or 
consider terminating the study due to a safety issue. The IDMC will again review the safety data 
when 70 patients with a baseline imputed PaO2/FiO2 ≤200 have completed the study, and finally 
when 200 patients with a baseline imputed PaO2/FiO2 ≤200 are randomized in Part 2 of the 
study. Adhoc safety reviews can be requested by the IDMC or sponsor during the study. 
7.2 
Interim Sample Size Re-estimation and Futility Analysis 
One unblinded interim sample size re-estimation was planned and was conducted by the IDMC 
when 70 patients in the baseline imputed PaO2/FiO2 ≤200 subgroup had completed the study. No 
ongoing study patients were included in this sample size re-estimation procedure. The sample 
size was re-estimated based on the interim estimation of the treatment recovery rate. The interim 
estimation of the recovery rate was also used in the non-binding futility analysis. 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 13 
CONFIDENTIAL 
7.3 
Final Analysis 
The final analysis will be conducted when all randomized patients, based on the planned or the 
re-estimated sample size, complete the study. 
8 
STATISTICAL ANALYSES 
8.1 
General Considerations 
The statistical evaluation will be performed using SAS® Version 9.4 or later.
In general, descriptive statistical methods will be used to summarize the data from this study. 
Unless stated otherwise, the term “descriptive statistics” refers to number of patients (n), mean, 
median, standard deviation (SD), minimum and maximum for continuous data, and frequencies 
and percentages for categorical data. Safety and efficacy summaries will be performed on the 
efficacy and safety analysis sets, respectively. 
8.1.1 
Number of Digits to Report 
Table 2 
Number of Decimal Places (DP) 
Statistic 
Specification 
Apply to 
Minimum, maximum 
Same number of DPs as the data 
provided in the datasets 
All original, i.e., non-derived, data 
provided in the datasets 
Mean, median, confidence intervals 
One more DP than the raw data 
All 
SD, SE 
Two more DP than the raw data 
All 
Percentages 
1 DP 
All 
p-values
3 DP 
All 
Odds Ratio 
2 DP 
All 
Hazard Ratio 
3 DP 
All 
8.1.2 
Significance Level and Confidence Interval 
The statistical tests will be performed as two-sided with significance level of 5%. The confidence 
intervals will be determined with a confidence level of 95%. 
8.1.3 
Descriptive Statistics Values to Calculate 
Where appropriate, variables will be summarized descriptively (frequency and percent will be 
summarized for categorical variables; mean, SD, median, minimum, and maximum will be 
presented for continuous variables) by strata, study visit, and by treatment group. 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 14 
CONFIDENTIAL 
The denominator for the percentages will be the total number of subjects in the treatment group 
and Analysis Set being presented, unless otherwise specified (e.g., on some occasions, 
percentages may be calculated based on the total number of subjects with available data at a 
particular visit and/or time point). 
8.1.4 
Derived Variables 
8.1.4.1 
Definition(s) of Baseline(s) 
Unless otherwise specified, the baseline values are the last available assessment before or at the 
SFISD. If multiple measurements are recorded on the same day, the last measurement recorded 
prior to the dose of study medication will be used as the baseline value. If these multiple 
measurements occur at the same time or time is not available, then the average of these 
measurements (for continuous data) or the worst among these measurements (for categorical 
data) will be considered as the baseline value. Baseline imputed PaO2/FiO2 is the worst value in 
the 24 hours before screening. 
8.1.4.2 
Study Time 
For patients enrolled in the study, the first dose of study medication will be administered on 
study hour 0. The study time in hours for an event is defined as event date and time – date and 
time of SFISD. The study day is defined as event date – date of SFISD + 1 day. 
8.1.4.3 
Definition(s) of (Percent) Change from Baseline(s) 
For numerical variables, change from baseline will be calculated as the post-baseline value 
minus the baseline value. If percent change from baseline is required, then percent change from 
baseline will be calculated as the change from baseline divided by the baseline value, multiplied 
by 100. If baseline value cannot be determined for a particular variable, the change from baseline 
and percent change from baseline will not be calculated. 
8.1.4.4 
Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as AEs that started or worsened in severity on or 
after the SFISD. 
All adverse events will be coded from the reported term using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 23.0 or the later version. 
8.1.4.5 
Concomitant Medications 
All concomitant medications will be coded using the WHO drug dictionary (B3 WHO Drug 
Dictionary Enhanced – Sep 2019 or the later version). 


Protocol No. CM4620-204 
CalciMedica Inc. 
Statistical Analysis Plan for Part II 
Page 15 
CONFIDENTIAL 
8.1.4.6 
Lab Values Below/above the Limit of Quantitation Deriving 
The lab values below the limit of quantification (BLQ) are collected in the form like “< 2” in the 
clinical data base. In this case the numeric value of the lab is a missing value. The cut-off value 
‘2’ will be used to impute the missing value for this case. Similarly, for the lab values above the 
limit of quantification, the cut-off value will be used for the numeric value of the lab. Local labs 
are used in this study and all lab parameters will be standardized to common SI units. 
8.1.5 
Missing Data 
Missing data will not be imputed in the summary of safety endpoints at each time point. The 
missing data imputation methods for efficacy analyses are described in Section 8. 
Imputation of missing or incomplete dates will be performed on AEs and concomitant 
medications (procedures) conservatively for determining the timing relative to the dose of study 
product unless otherwise specified. Partial or missing dates will be listed as recorded in the 
electronic case report form (eCRF). 
8.1.6 
Pooling of Sites 
Data collected from all sites will be pooled together for the analysis. 
8.2 
Subject Disposition 
The number of patients who enter screening will be summarized, and the percentage of these 
patients who fail to meet entry criteria will be reported for total subjects. Screen failures will be 
summarized in total and by each reason for screen failure. 
Subject disposition will be summarized for patients’ completion status of study treatment, status 
of outcome/discharge, and corresponding discontinue reasons in tables for each treatment group 
and then total subjects. The data listing for subject discontinuation will be generated. 
8.3 
Demographic, Other Baseline Characteristics and Medication 
8.3.1 
Demographic and Baseline Characteristic 
Patient demographic and baseline characteristics will be summarized by mean, SD, median, 
minimum, and maximum for continuous variables; and by counts and percentages for categorical 
variables. Summaries will be provided separately for each treatment group and then total 
subjects. The following subject demographic and baseline characteristic are summarized. The 
demographic variables consist of age, age category (18-39, 40-64, 65+), sex, ethnicity and race. 
Baseline characteristics include height, weight, body mass index (BMI), time from symptom 
onset to randomization in days, baseline scores on 8-point ordinal scale, baseline imputed 
PaO2/FiO2 and category (≤200, ≥201), baseline d-dimer, baseline ferritin, and baseline CRP. 
Efficacy and Safety Analysis Sets will be used for the summaries. 


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Other baseline variables such as relevant medical history or other medically relevant criteria 
could also be included in the baseline tables. 
The 8-point ordinal scale is defined as: 
Scale 
Description 
1 
Death 
2 
Hospitalized, requiring invasive mechanical ventilation or ECMO 
3 
Hospitalized, requiring noninvasive mechanical ventilation or high flow supplemental oxygen 
4 
Hospitalized, requiring low flow supplemental oxygen 
5 
Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care 
6 
Hospitalized, not requiring supplemental oxygen or ongoing medical care 
7 
Discharged, requiring supplemental oxygen 
8 
Discharged, not requiring supplemental oxygen 
 
8.3.2 
Comorbidity 
A summary table of the number and percentage of patients by the category of comorbidity will 
be produced for patients in the Efficacy Analysis Set. The summary will be provided by 
treatment groups and then by total treatment groups. Comorbidity will be sorted alphabetically 
by categories of comorbidity. The number and percentage of patients with none, one and two or 
more categories of comorbidities will also be summarized. Listings for comorbidity will also be 
provided. 
8.3.3 
Concomitant Medications 
Concomitant medication is defined as any medication, other than study medication, which is 
taken on or after the start day of treatment. The concomitant medication data will be coded using 
World Health Organization Drug Dictionary (B3 WHO Drug DDE – Sep 2019 or the later 
version). The number and percentage of subjects taking concomitant medications will be 
summarized overall and by ATC level 2 terms, preferred drug names and treatment groups. A 
separate listing for concomitant medications will also be provided. 
Concomitant Medications of Vasopressors, Corticosteroids, Antivirals And Anticoagulants for 
COVID-19 Newly Started on or After Day 1 of Study Treatment will be summarized by 
treatment group. 
8.4 
Primary Endpoint Analysis 
8.4.1 
Definition of Endpoint 
Time to recovery through the Day 60 visit in the 8-point ordinal scale is the primary endpoint. 


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The primary estimand corresponding to the primary endpoint is defined as: 
1. Treatment: 2.0 mg/kg (1.25 mL/kg) of Auxora administered at 0 hour and 1.6 mg/kg 
(1 mL/kg) administered at both 24 hours and 48 hours from the Start of the First Infusion 
of Auxora with local standard of care. 
2. Population: Severe COVID-19 pneumonia patients with a baseline imputed PaO2/FiO2 
≤200. 
3. Variable: Time to recovery defined as time from SFISD to the first time a patient 
achieves the scale of 6, 7 or 8 on the 8-point ordinal scale for at least 24 hours. 
4. Population level summary: Median difference using Kaplan-Meier estimate 
Intercurrent events under consideration: 1) prohibited immunosuppressive medications or 
immunotherapies. 2) convalescent plasma treatment, 3) treatment discontinuation and 4) death. 
The null and alternative hypotheses are: 
 Null hypothesis H0: Time to recovery curves are the same between the two treatment 
arms 
 Alternative hypothesis H1: Time to recovery are different between the two treatment 
arms 
8.4.2 
Main Analytical Approach 
Time to recovery through Day 60 visit will be displayed using a Kaplan-Meier estimate and will 
be compared between the 2 treatment groups using stratified log-rank test stratified by baseline 
imputed PaO2/FiO2 screening of ≤100 vs. >100. Prohibited immunosuppressive medications or 
immunotherapies, convalescent plasma treatment and treatment discontinuation will be ignored 
(treatment policy strategy). Death will be treated as not recovered and time to recovery will be 
censored at Day 65 (composite strategy). Patients, including withdrawal of consent patients, will 
be censored at the last ordinal scale assessment if no recovery event is observed during the study 
(administrative censoring). The trial level Type I error of 0.05 between the two tests of the 
primary endpoint analysis and the key secondary endpoint analysis is controlled using the 
Benjamini and Hochberg method. 
8.4.3 
Sensitivity Analyses 
There are three planned sensitivity analyses that target the primary estimand. The first will be to 
relax the assumption that the baseline imputed PaO2/FiO2 is a confounding factor, so the analysis 
will be repeated but without stratification by the baseline imputed PaO2/FiO2 of ≤100 vs. >100. 
This analysis implies the baseline risk is the same across strata.  
The second sensitivity analysis is based on a different administrative censoring rule and same 
analysis as the main analysis will be performed. Patients will be censored at the last ordinal scale 
assessment before or on the outcome visit if no recovery event is observed before or on the 


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outcome visit. This is to address the data collection limitation between the Day 30 outcome visit 
and Day 60 visit assessment related to the assessment of the primary endpoint. 
The third sensitivity analysis is based on a different censoring rule for the prohibited 
immunosuppressive medications or immunotherapies and convalescent plasma treatment. In this 
sensitivity analysis, all data after the prohibited immunosuppressive medications or 
immunotherapies and convalescent plasma treatment will be excluded from the analysis. The 
time to recovery will be censored at the beginning of the prohibited immunosuppressive 
medications or immunotherapies or convalescent plasma treatment. 
8.4.4 
Supplementary Analyses 
There are four planned supplementary analyses. 
The first supplementary analysis changes the population level summary to the recovery rate ratio. 
The recovery rate ratio and the 95% CI will be estimated using a Cox proportional hazard model 
with treatment as the independent variable. 
The second supplementary analysis changes the population level summary to the recovery rate 
ratio. The recovery rate ratio and the 95% CI will be estimated using a stratified Cox 
proportional hazard model with treatment as the independent variable and stratified by the 
baseline imputed PaO2/FiO2 of ≤100 vs. >100. 
The third supplementary analysis changes the population to the safety analysis set and the same 
analysis as the main analysis will be performed except that treatment group will be based on 
actual treatment received. 
The forth supplementary analysis changes the population to the efficacy analysis set including 26 
subjects from baseline imputed PaO2/FiO2 of ≥ 201 stratification group and the same analysis as 
the main analysis will be performed. 
8.5 
Secondary Endpoint Analyses 
8.5.1 
Key Secondary Efficacy Analysis 
All-cause mortality at Day 60 visit is the key secondary endpoint. 
The primary estimand corresponding to the key secondary primary endpoint is defined as: 
1. Treatment: 2.0 mg/kg (1.25 mL/kg) of Auxora administered at 0 hour and 1.6 mg/kg 
(1 mL/kg) administered at both 24 hours and 48 hours from the Start of the First Infusion 
of Auxora with local standard of care. 
2. Population: Severe COVID-19 pneumonia patients with a baseline imputed PaO2/FiO2 
≤200. 
3. Variable: Dying by the Day 60 study follow-up visit. 


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4. Population level summary: difference in proportion of dying 
Intercurrent events under consideration: 1) prohibited immunosuppressive medications or 
immunotherapies. 2) convalescent plasma treatment, and 3) treatment discontinuation. 
The null and alternative hypotheses are: 
 Null hypothesis H0: Proportion of dying by Days 60 is the same between the two 
treatment arms  
 Alternative hypothesis H1: Proportion of dying by Days 60 is different between the two 
treatment arms 
8.5.2 
Main Analytical Approach 
Proportion and 95% CI All-cause mortality at Day 60 visit will be displayed using a Clopper-
Pearson interval and will be compared between the 2 treatment groups using a Cochran-Mantel-
Haenszel test stratified by the baseline imputed PaO2/FiO2 of ≤100 vs. >100. Prohibited 
immunosuppressive medications or immunotherapies, convalescent plasma treatment and 
treatment discontinuation will be ignored (treatment policy strategy).  
Patients with unknown death status at Day 60 visit will be treated as alive for the analysis if 
recovered during the study. Specifically, all patients who recovered, were discharged, and/or had 
30 day follow up where they remained recovered, will be imputed at Day 60 as being 
alive/recovered if data is missing. Patients who discontinued from study before or on Day 1 and 
Day 60 survival follow up status as unknown are excluded from the primary analysis. This is not 
expected to introduce a bias in favor of either treatment arm since the clinical status is not likely 
to be affected within two days by the study treatment administered on Day 1. 
To protect the trial level type 1 error rate at α=5% (two sided) between the two tests of the 
primary endpoint analysis and the key secondary endpoint analysis, the Benjamini and Hochberg 
testing strategy is used. Test statistics for Time to recovery and All-cause mortality at Day 60 are 
positive correlated and Hochberg testing strategy will protect the trial level type 1 alpha level. 
8.5.3 
Sensitivity Analyses 
There are three planned sensitivity analyses that both target the primary estimand. The first will be 
to relax the assumption that the baseline imputed PaO2/FiO2 is a confounding factor; the analysis 
will therefore be repeated but without stratification by the baseline imputed PaO2/FiO2 of ≤100 
vs. >100. This analysis implies the baseline risk is the same across strata. The second sensitivity 
analysis is to examine the potential effects of missing death data due to dropout using tipping 
point sensitivity analysis. In the third analysis, day 60 death rate for each treatment group will be 
estimated by the Kaplan-Meier procedure. Hypothesis testing will be based on the Kaplan-Meier 
estimates and standard errors estimated by Greenwood formula using the log-log transformation 
of the survival function stratified by the baseline imputed PaO2/FiO2 of ≤100 vs. >100. 


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8.5.4 
Supplementary Analyses 
There are two planned supplementary analyses. 
The first supplementary analysis changes the population to the safety analysis set. The analysis 
will be the same analysis as the main analysis except that treatment group will be based on actual 
treatment received. 
The second supplementary analysis changes the population to the efficacy analysis set including 
26 subjects from baseline imputed PaO2/FiO2 of ≥ 201 stratification group and the same analysis 
as the main analysis will be performed. 
8.5.5 
Supportive Secondary Efficacy Analysis 
8.5.5.1 
All-cause mortality at Day 30 visit 
The analysis will be the same as the Day 60 visit analysis. 
8.5.5.2 
Proportion of patients requiring invasive mechanical ventilation or dying 
during the 60 days from the SFISD 
Time to requiring invasive mechanical ventilation is defined as time from SFISD to the first time 
the patient requiring invasive mechanical ventilation or dying. Proportion of patients requiring 
invasive mechanical ventilation or dying is defined as the proportion at study Day 60. Day 60 
rate for each treatment group will be estimated by the Kaplan-Meier procedure. Hypothesis 
testing will be based on the Kaplan-Meier estimates and standard errors estimated by Greenwood 
formula using the log-log transformation of the survival function stratified by the baseline 
imputed PaO2/FiO2 of ≤100 vs. >100. Subjects who do not have death or require invasive 
mechanical ventilation in the record will be censored on the last known status date 
(administrative censoring). Patients who recovered, were discharged, had 30 day follow up 
where they remained recovered, and did not use invasive mechanical ventilation during the 
study, will be censored at Day 65 as being alive/recovered without event if data is missing. 
8.5.5.3 
Proportion of patients requiring invasive mechanical ventilation during the 
60 days from the SFISD 
The analysis will be the same as the proportion of patients requiring invasive mechanical 
ventilation or dying during the 60 days from the SFISD. Subjects who have death and do not 
require invasive mechanical ventilation will be censored on the date of death (hypothetical 
strategy). Patients who recovered, were discharged, had 30 day follow up where they remained 
recovered, and did not use invasive mechanical ventilation during the study, will be censored at 
Day 65 as being alive/recovered without event if data is missing. 


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8.5.5.4 
Differences in Outcomes Measured by an 8-Point Ordinal Scale at Day 12 
Proportion of patients in each category of 8-point ordinal scale at Day 12 will be calculated for 
each treatment group, and the odds ratio will be estimated. The proportion will be compared 
between the 2 treatment groups using a proportional odds model with fixed factor of treatment 
groups. 
8-point ordinal scale will be imputed based on LOCF method based on the scale at discharge if 
the patient is discharged from hospital with the ordinal scale of 7 or 8 (composite strategy). 8-
point ordinal scale will be imputed as 1 after the death (composite strategy). 
8.5.5.5 
Differences in Outcomes Measured by an 8-Point Ordinal Scale at Day 30  
The analysis will be the same as the Day 12 analysis but extended at Day 30. 
8.5.5.6 
Number of Days in the Hospital 
The date of each hospital admission and discharge will be collected for each patient. The number 
of days when patients are in hospital during the first 28 Days of the study will be summarized by 
treatment group and compared between the 2 treatment groups using an analysis of variance 
model, which includes treatment group in the model, which includes treatment group as the fixed 
effect in the model. 
Two sets of analyses will be conducted. The first analysis is to assess patient benefit; the number 
of days in the hospital will be deﬁned as 28 if the patient dies due to COVID-19 (composite 
strategy). The second analysis is to assess healthcare systems benefit; the number of days in the 
hospital before the patient’s death will be used in the analysis (while alive strategy). 
8.5.5.7 
Number of Days in the Hospital 
The analysis will be the same as the number of days in the hospital 
8.6 
Tertiary Endpoint Analysis 
8.6.1 
Change in Imputed PaO2/FiO2 Ratio 
SpO2 and FiO2 will be examined at each scheduled time point. Worst value within the previous 
24 hours at each scheduled time point will also be recorded. Conversion from SpO2 to PaO2 will 
follow Table 3. 
Table 3 
Look up table for conversion SpO2 to PaO2 
Measured SpO2 (%) 
Imputed PaO2 (mmHg) 
100* 
167*§ 
99* 
132* 
98* 
104* 


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97* 
91* 
96 
82 
95 
76 
94 
71 
93 
67 
92 
64 
91 
61 
90 
59 
89 
57 
88 
55 
87 
53 
86 
51 
85 
50 
84 
49 
83 
47 
82 
46 
81 
45 
80 
44 
79 
43 
78 
42 
77 
42 
76 
41 
75 
40 
74 
39 
73 
39 
72 
38 
71 
37 
70 
37 
69 
37 
* Generally considered unreliable on the basis of the sigmoidal shape of the hemoglobin-oxygen dissociation curve 
§ Based on SpO2 99.5%. 
 
Mean changes from baseline to each post-baseline visit and time point will be summarized by 
treatment groups for both at visit imputed PaO2/FiO2 value and worst value within the previous 
24 hours of the visit imputed PaO2/FiO2 value. 
Change from baseline over time in the imputed PaO2/FiO2 will be analyzed using a mixed effect 
model repeat measurement (MMRM) model with an unstructured covariance structure (if model 
is estimable). The analysis model will include Baseline value of the endpoint as a covariate, 
study day and treatment as fixed effect, study day by treatment as interaction, and subjects as 
random effect. Point estimates, 95% CIs and p-values for the difference between the Auxora 
treated patients and local standard care group at each scheduled time point will be obtained. 


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Similar analysis to the above analysis will be conducted for the change from baseline over time 
in the imputed PaO2/FiO2 endpoint using the last observation carried forward method as the 
missing value imputation method. 
8.7 
Safety Analysis 
The safety evaluation will be purely descriptive using descriptive statistics (N, mean, SD, median 
minimum and maximum) or frequency tables where appropriate using Safety Analysis Set, 
unless otherwise specified. No imputation will be made in case of missing values. 
8.7.1 
Study Medication Exposure 
Number of doses of double-blind study medication will be summarized in table and presented in 
data listing for the safety population. 
8.7.2 
Adverse Events 
Adverse events will be coded using MedDRA dictionary. If an incomplete or missing onset date 
was collected for an AE, the imputation method of missing data specified in Section 8.1.4.4 will 
be applied. Treatment-emergent AEs (TEAEs) are defined as AEs that started or worsened in 
severity on or after the SFISD. 
The relationship to study treatment for each AE will be classified as ‘Unrelated’, ‘Unlikely’, 
‘Possible’, ‘Probable’, ‘Definite’. AEs classified as ‘Possible,’ ‘Probable’ and Definite will be 
analyzed as ‘Related’ in the AE summaries. Data listings, patient narratives, etc. will present the 
relationship to study treatment as collected on the CRF. 
8.7.2.1 
Tabulations of TEAEs 
The frequency and incidence of TEAEs will be summarized by System Organ Class (SOC) and 
Preferred Term (PT) by treatment and then by overall treatment. The actual version of the 
MedDRA coding dictionary used will be noted in the clinical study report. The SOC is sorted by 
alphabetic order; then within SOC, PT is sorted by descending counts under Auxora column, 
then descending counts under Placebo column, then alphabetic order for PTs with the same 
count. 
Each of the summaries will be done at the subject level. Multiple occurrences of the same event 
within a subject will be counted once in the summaries by System Organ Class and PT. 
All AEs for each subject, including multiple occurrences of the same event, will be presented in 
full in a comprehensive listing including subject number, treatment, severity, seriousness, action 
taken, outcome, relationship to treatment, onset/stop date and duration. 
The data listings for serious TEAE and TEAE leading to discontinuation of study treatment will 
be generated as well. 


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8.7.2.2 
Adverse Event Overview 
An overview of AEs will be presented by the actual treatment received overall and consisting of 
the number and percentage of patients experiencing at least one event for the following AE 
categories: 
 Any TEAEs 
 TEAEs related to study treatment 
 Serious TEAEs 
 Serious TEAEs related to study treatment 
 TEAEs leading to discontinuation of study treatment 
 TEAEs leading to death 
8.7.2.3 
Adverse Event by SOC and PT 
The following summaries of AEs will be generated: 
 Incidence of TEAEs 
 Incidence of TEAEs related to study treatment 
 Incidence of serious TEAEs 
 Incidence of serious TEAEs related to study treatment 
 Incidence of TEAEs leading to discontinuation of study treatment 
 Incidence of TEAEs leading to death 
 Incidence of severe TEAEs 
8.7.3 
Additional Safety Assessments 
8.7.3.1 
Vital Signs 
Vital signs will include temperature, systolic and diastolic blood pressure, respiratory rate 
(breaths per minute), heart rate (beats per minute). 
Vital signs will be examined at each scheduled visit and time point. Clinically-significant, 
treatment-emergent findings will be reported as AEs. 
In addition, vital signs results will be flagged as potentially clinically significant (PCS) if they meet 
the criteria which are defined below. 
 Pulse rate >140 bpm. 
 Pulse rate <45 bpm. 


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 Diastolic blood pressure >100 mmHg. 
 Systolic blood pressure >155 mmHg. 
 Systolic blood pressure <60 mmHg. 
 Body temperature ≥39°C. 
The number and percent of patients meeting each PCS criterion at each scheduled visit and time 
point will be summarized by the actual treatment and then by the overall treatment. 
8.7.3.2 
Laboratory Analyses 
CBC with Differential, Serum Chemistries, Ferritin, C-reactive protein, Procalcitonin and D-
Dimer will be performed. 
Laboratory values by visit will be summarized as boxplots. The lower and upper reference range 
values for lab tests will be used to grade the lab results to low, normal and high categories. Shift 
tables will display: 
1. Shift from baseline category to the worst category; 
2. Shift from baseline category to the last category. 
8.8 
Other Analyses 
8.8.1 
Other Variables and/or Parameters 
Biomarkers will be measured at baseline and with subsequent assessments at various timepoints 
up to 240 hours. Log-transformation will be applied when necessary. Change from baseline over 
time will be analyzed using a mixed effect model repeat measurement (MMRM) model with an 
unstructured covariance structure (if model is estimable). The analysis model will include Baseline 
value of the endpoint as a covariate, study day and treatment as fixed effect, study day by 
treatment as interaction, and subjects as random effect. Point estimates, 95% CIs and p-values 
for the difference between the Auxora treated patients and local standard care group at each 
scheduled time points will be obtained. 
8.8.2 
Subgroup Analyses 
Subgroup analyses will be performed to explore how time to recovery through Day 60 visit and 
mortality at Day 60 visit are influenced by baseline variables and to evaluate the treatment effect 
at different levels of each of these variables. The Kaplan-Meier analysis, Cox model and CMH 
test will be performed by subgroup levels of the baseline variables listed below: 
 Age (<65, ≥65) 
 Baseline CRF calculated imputed PaO2/FiO2 (≤100, 101-200, ≥201) 


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 Race (White, Black, Asian, Other). 
 Gender (Male, Female) 
 BMI (<30, ≥30) 
 Remdesivir (being already administered at randomization, administration started after 
randomization, never administered) 
 Dexamethasone (being already administered at randomization, administration started 
after randomization, never administered) 
 Remdesivir and Dexamethasone (being already administered together at randomization or 
administered together starting after randomization) 
 Convalescent plasma (being administered at randomization, administration started after 
randomization, never administered) 
9 
INTERIM ANALYSIS 
9.1 
Interim Sample Size Re-estimation and Futility Analysis 
One unblinded interim sample size re-estimation is planned and was conducted by the IDMC 
when 70 patients in the baseline imputed PaO2/FiO2 ≤200 subgroup have completed the study. 
In the protocol plan, the conduction power of the time to recovery will be calculated based on the 
conditional power analysis of the time to recovery by assuming the interim estimated parameter 
values as the estimates of these parameters. Sample size will be re-estimated at the interim 
analysis to provide a conditional power of 90%, based on the interim evaluation of the treatment 
efficacy. The study will use a sequential design with O’Brien-Fleming critical boundary (O'Brien 
and Fleming 1979) at the interim analysis to control type I error. In case of sample size 
modification, the final critical boundary will be adjusted to control type I error (Gao et al., 2008). 
Based on the estimated standard error of 0.25 from Part 1 data, the relationship between the 
observed recovery ratio at interim analysis and the re-estimated sample size to reach 90% 
conditional power is shown in the following table: 
Table 4 
Relationship Between the Observed Recovery Ratio at Interim Analysis and the 
Re-estimated Sample Size to Reach 90% Conditional Power 
O’Brien-Fleming boundary at the interim analysis, interim analysis at information fractions 0.25, Standard error of 
log(recovery ratio) =0.25 
Observed recovery 
ratio at interim 
analysis 
Conditional power 
based on interim 
estimation  
Sample size (events) 
to reach 90% 
conditional power 
based on interim 
estimation 
Conditional power 
based on recovery 
ratio = 1.37 
Sample size (events) 
to reach 90% 
conditional power on 
recovery ratio = 1.37 
1.57 
97% 
214 (178) 
 
 
1.47 
90% 
290 (241) 
 
 


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1.44 
86% 
320 (266) 
 
 
1.40 
80% 
384 (318) 
 
 
1.39 
78% 
400 (332) 
 
 
1.37 
67% 
438 (363) 
 
 
1.34 
59% 
500(415) 
 
 
1.31 
59% 
600(503) 
 
 
1.20 
28% 
1414(1174) 
64% 
507(421) 
1.10 
8% 
5648(4688) 
56% 
563(468) 
1.05 
 
 
52.2% 
596(495) 
1.00 
 
 
48% 
630(523) 
 
Based on the above relationship, the following sample size re-estimation rule is proposed for this 
study at the interim analysis of the 70 patients in the imputed PaO2/FiO2 ≤200 subgroup: 
 Recovery rate ratio <1.05, increase sample size >600 for imputed PaO2/FiO2 ≤200 
subgroup 
 Recovery rate ratio 1.05 to <1.34, increase sample size to 600 for imputed PaO2/FiO2 ≤200 
subgroup 
 Recovery rate ratio 1.34 to 1.38, increase sample size to 500 for imputed PaO2/FiO2 ≤200 
subgroup 
 Recovery rate ratio 1.39 to 1.43, increase sample size to 400 for imputed PaO2/FiO2 ≤200 
subgroup 
 Recovery rate ratio ≥1.44, do not increase sample size for imputed PaO2/FiO2 ≤200 
subgroup 
The sample size re-estimation rule was updated and a non-binding futility analysis was added 
prior to the conduct of the interim sample size re-estimation. The updated sample size re-
estimation rule was based on the promising zone with re-estimated sample size of 500 patients. 
The study used a sequential design with O’Brien-Fleming critical boundary (O'Brien and 
Fleming 1979) at the interim analysis to control type I error. In case of sample size modification, 
the final critical boundary will be adjusted to control type I error (Gao et al., 2008). The detailed 
promising zone rule is described in the separate interim statistical analysis plan and was finalized 
before the interim sample size re-estimation. 
9.1.1 
Critical Boundary Adjustment 
If the sample size is modified to a new information time 𝑇𝑛𝑒𝑤, the second critical boundary,  
𝑐2 = 1.96 will be modified according to Gao et al., 2008: 
 


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𝐶𝑛𝑒𝑤=
1
√𝑇𝑛𝑒𝑤{
√𝑇𝑛𝑒𝑤−𝑡𝑖𝑛𝑡𝑒𝑟𝑖𝑚
√𝑇−𝑡𝑖𝑛𝑡𝑒𝑟𝑖𝑚
(𝐶2√𝑇−𝑆𝑖𝑛𝑡𝑒𝑟𝑖𝑚)} +
𝑆𝑖𝑛𝑡𝑒𝑟𝑖𝑚
√𝑇𝑛𝑒𝑤. 
 
This adjustment properly controls the type I error. 
10 
VALIDATION 
The tables, figures and listings (TFLs) planned in this SAP will be programmed using SAS 
software version 9.4 (or above). The TFLs will be quality checked by the statistics team at 
Princeton Pharmatech using SAS software version 9.4 (or above). 
11 
PROGRAMMING AND DATA PRESENTATION CONVENTIONS 
Listings will be presented in treatment, subject, visit (where applicable) and date (where 
applicable) order. Listings will be produced (landscape in MS Word) using PROC REPORT. 
Summary tabulations will be presented by treatment group (and overall if appropriate), 
scheduled visit order (if appropriate). Continuous data summaries will present (unless stated 
otherwise) number of observations, mean, standard deviation, median, minimum and maximum. 
Categorical data summaries will present the number of observations and the corresponding 
percentage. 
 
 


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Statistical Analysis Plan for Part II 
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CONFIDENTIAL 
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BIBLIOGRAPHY 
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