A Randomized, Double-Blind, Placebo Controlled Dose-Ranging Study of Auxora in Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome
Phase: PHASE2
Conditions: Acute Pancreatitis, Systemic Inflammatory Response Syndrome
Sponsor: CalciMedica, Inc.

 
 
 
 
 
 
CM4620-203 Protocol 
 
A Randomized, Double-Blind, Placebo Controlled Dose Ranging Study of Auxora in Patients 
with Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome 
(CARPO) 
Version:  4.0 
Issue Date:  October 5, 2023 
 
 
Clinical Trial Number:  NCT04681066 
 
 
 
 
 
 
 
 
 

1 
 
CM4620-203 
A Randomized, Double-Blind, Placebo Controlled 
Dose-Ranging Study of Auxora in Patients with 
Acute Pancreatitis and Accompanying Systemic 
Inflammatory Response Syndrome (CARPO) 
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:  4.0 
Issue Date:  October 05, 2023 
IND  123533 
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. 
.~._~. CalciMedica 
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SPONSOR APPROVAL AND SIGNATURE PAGE
Sudarshan Hebbar, MD
Chief Medical Officer
Date
Andrew Cunningham, MD
Senior Vice President, Clinical Development 
Date
( 
DocuSigned by: 
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Signer Name: Sudarshan Hebbar 
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Signing Reason: I approve this document 
Signing Time: 10/9/2023 I 5:23:17 PM PDT 
732B16E369D74416B6B6AE164D8A9C32 
( 
DocuSigned by: 
I a~~ ~~) 
1ttD 
V 
Signer Name: Andy Cunningham, MD 
L
Signing Reason: I approve this document 
Signing Time: 10/9/2023 I 5:20:59 PM PDT 
BE2370D8E006454AB92C665D175B6585 
10/9/2023 
10/9/2023 
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SYNOPSIS 
Protocol 
Number: 
CM4620-203 
Protocol Title: 
A Randomized, Double-Blind, Placebo Controlled Dose Ranging Study 
of Auxora in Patients with Acute Pancreatitis and Accompanying Systemic 
Inflammatory Response Syndrome (CARPO) 
Sponsor: 
CalciMedica, Inc. 
505 Coast Blvd. South, Suite 307 
La Jolla, CA 92037 USA 
Study Phase: 
2b 
Number of 
Patients and 
Sites: 
Approximately 216 patients with acute pancreatitis (AP) and accompanying 
systemic inflammatory response syndrome (SIRS) will be randomized at 
approximately 45 sites. 
CM4620-IE 
Dose and 
Route of 
Administration: 
Patients randomized to receive Auxora (also known as CM4620 
(zegocractin) Intravenous Emulsion) will receive one of three dose levels, 
2.0 mg/kg (1.25 mL/kg), 1.0 mg/kg (0.625 mL/kg), and 0.5 mg/kg (0.3125 
mL/kg), every 24 hours (±1 hour) for three consecutive days for a total of 
three infusions (Section 5.3). 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. Patients randomized to receive Placebo will receive 
one of three dose volumes, 1.25 mL/kg, 0.625 mL/kg, and 0.3125 mL/kg, 
every 24 hours (±1 hour) for three consecutive days for a total of three 
infusions (Section 5.3). 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. 
Objectives: 
Primary: 
 To assess the dose response and efficacy of three different dose levels 
of Auxora in patients with AP and accompanying SIRS; 
 To assess the time to medically indicated discharge in patients who are 
responders to early tolerance of solid food intake versus non-responders. 
Secondary: 
 To assess the safety and tolerability of varying doses of Auxora in 
patients with AP and accompanying SIRS.
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Inclusion 
Criteria: 
All of the following must be met for a patient to be randomized into the 
study: 
1. The diagnosis of AP has been established by the presence of abdominal 
pain consistent with AP together with at least 1 of the following 2 
criteria: 
a. Serum lipase > 3 times the upper limit of normal (ULN); 
b. Characteristic findings of AP on abdominal imaging; 
2. The diagnosis of SIRS has been established by the presence of at least 
two of the following four criteria: 
a. Temperature < 36°C or > 38°C; 
b. Heart rate > 90 beats/minute; 
c. Respiratory rate >20 breaths/minute or arterial carbon dioxide 
tension (PaCO2) <32 mmHg; 
d. White blood cell count (WBC) >12,000 mm3, or <4,000 mm3, or 
> 10% immature (band) forms; 
3. At least one of the following criteria is also present:  
a. A peripancreatic fluid collection or a pleural effusion on a contrast-
enhanced computed tomography (CECT) performed in the 24 hours 
before Consent or after Consent and before Randomization; 
b. Abdominal examination documenting either abdominal guarding or 
rebound tenderness; 
c. Hematocrit 44% for men or 
% for women; 
4. The patient is 
 
5. Lack of pancreatic necrosis, pancreatic calcifications, pancreatic 
pseudocysts and no evidence for previous necrosectomy or pancreatic 
surgery identified by CECT performed in the 24 hours before Consent 
or after Consent and before Randomization; 
6. A female patient of childbearing potential who is sexually active with a 
male partner is willing to practice acceptable methods of birth control 
for 180 days after the last dose of study drug. A female patient must not 
attempt to become pregnant for 180 days; 
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 180 days after the last dose of study drug. A male patient 
must not donate sperm for 180 days; 
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.
> 
~40 
~ 18 years of age; 
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Exclusion 
Criteria: 
Patients with any of the following conditions or characteristics must be 
excluded from randomizing: 
1. Expected survival <6 months; 
2. Suspected presence of cholangitis in the judgment of the treating 
physician; 
3. The patient has a known history of: 
a. Organ or hematologic transplant; 
b. HIV, hepatitis B, or hepatitis C infection; 
c. Chronic pancreatitis (Appendix 7); 
4. Current treatment with: 
a. Chemotherapy; 
b. Immunosuppressive medications or immunotherapy (Section 5.4 for 
list of prohibited immunosuppressive medications and 
immunotherapy); 
c. Pancreatic enzyme replacement therapy; 
d. Hemodialysis or Peritoneal Dialysis 
5. The patient is known to be pregnant or is nursing; 
6. The patient has participated in another study of an investigational drug 
or therapeutic medical device in the 30 days before randomization; 
7. Allergy to eggs or known hypersensitivity to any components of study 
drug. 
Study Design: 
This double blind, randomized, placebo-controlled study will evaluate the 
efficacy, safety, and tolerability of three different dose levels of Auxora in 
patients with AP and accompanying SIRS. 
 
Approximately 216 patients will be randomized 1:1:1:1 into one of 4 groups 
using a computer-generated randomization scheme accessed through an 
interactive voice/web response system (IXRS). Randomization will be first 
stratified by gender (male or female) and then by risk for organ failure in 
the gender subgroups (higher or lower). Higher risk for organ failure is 
2/FiO2 
Lower risk for organ failure is defined by the absence of either or both an 
elevated hematocrit and hypoxemia (Figure 4). The PaO2/FiO2 will be 
determined using an arterial blood gas or imputed using pulse oximetry 
(Appendix 5). 
defined by the presence of both an elevated hematocrit (HCT ?:44% for 
men or ?:40% for women) and hypoxemia (imputed PaO 
:S360). 
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All patients will have received a Screening CECT of the abdomen/pancreas 
before being randomized into the study. CECTs performed as standard of 
care (SOC) may be used as the Screening CECT but must have been 
performed in the 24 hours before Consent or after Consent and before 
Randomization (Section 8.12.12) 
 
The Start of First Infusion of Study Drug (SFISD) should occur within 8 hours 
of the patient or LAR providing informed consent. Patients randomized to 
Group 1 will receive 2.0 mg/kg of Auxora intravenously every 24 hours 
(±1 hour) for a total of three doses. Patients randomized to Group 2 will 
receive 1.0 mg/kg of Auxora intravenously every 24 hours (±1 hour) for a 
total of three doses. Patients randomized to Group 3 will receive 0.5 mg/kg 
of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. 
Patients randomized to Group 4 will receive emulsion without any active 
pharmaceutical ingredient. Patients in Group 4 will receive one of three 
randomly assigned dose volumes, 1.25 mL/kg, 0.625 mL/kg, or 0.3125 mL/kg,
which will be administered intravenously every 24 hours (±1 hour) for a 
total of three doses. (Section 5.3) 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, the upper limit of the volume of Auxora 
and volume of Placebo that will be administered will be 156.25 mL. The 
sponsor, investigators, pharmacists, and patients will be blinded to the 
assigned group. In the event of a medical emergency, investigators will be 
able to receive the treatment assignment if required to provide optimal care 
of the patient. 
 
For all 4 groups, a study physician or appropriately trained delegate will 
perform study-specific assessments at screening, at the baseline assessment, 
immediately prior to the SFISD, and then every 24 hours until 240 hours 
after the SFISD, or until discharge if earlier. If patients remain hospitalized 
at Day 12, assessments will then be performed every 48 hours starting on 
Day 12 until Day 28, or until discharge if earlier. Patients discharged from 
the hospital before Day 25 will return at Day 30 (+5 days) to perform the 
Day 30 assessments. If patients are discharged on Days 25-29, the Day 30 
assessments may be performed prior to discharge. 
 
Patients will receive another CECT of the abdomen/pancreas at the Day 30 
(±5 days) visit. All CECTs performed as SOC after randomization and 
before the Day 30 CECT will also be captured. A blinded central reader 
will read the Screening, Day 30, and any SOC CECTs obtained between 
randomization and the Day 30 visit. 
 
Patients will complete the modified American Neurogastroenterology and 
Motility Society Gastrointestinal Cardinal Symptom Index Daily Diary
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(mGCSI-DD) worksheet at the baseline assessment, at 96 hours, 168 hours, 
Day 14 and Day 21 (for patients who remain hospitalized on these days), on 
the day of discharge, and daily at bedtime after discharge until the Day 30 
visit. Patients who are discharged on Days 25-29 will not complete the 
mGCSI worksheet after discharge. 
 
It is recommended that all patients randomized in the study should receive 
care consistent with the 2018 American Gastroenterological Association 
(AGA) Institute Technical Review of the Initial Medical Management of 
Acute Pancreatitis. Patients should receive local SOC for the management 
of other medical conditions. 
 
In patients with AP, the AGA strongly recommends early oral feeding 
(within 24 hours) rather than keeping the patient nil per mouth (Nil per Os, 
NPO). Patients randomized into the study, therefore, will be offered a low 
fat, 500-calorie solid meal at each mealtime after the infusion of the first 
dose of study drug if alert and not on mechanical ventilation, or if not NPO 
for a planned surgery/medical procedure, or if not NPO because of an acute 
medical condition. If the patient does not wish to eat the solid meal when 
offered or is unable to tolerate the solid meal, they should then be offered a 
liquid meal. The same approach should occur at each subsequent mealtime 
until patient discharge. When patients eat a solid meal, it should be 
 of the meal and if they either vomited or 
experienced an increase in abdominal pain in the two hours after eating a 
meal. 
 
It is also recommended that all patients randomized in the study should not 
be discharged from the hospital until solid food is tolerated, abdominal pain 
has resolved or been adequately controlled, and there is no clinical evidence 
of infection that would necessitate continued hospitalization. Tolerating 
solid food is 
500-calorie solid meal 
without an increase in abdominal pain or vomiting. If the patient is not 
tolerating either solid or liquid meals, tube feedings should be considered. 
 
All protocol required laboratory testing, except biomarker and 
pharmacokinetic (PK) samples, will be performed at the local laboratory. 
Results from the biomarkers and PK blood samples collected as part of the 
protocol and being tested at a central lab will not be available to assist the 
Principal Investigator (PI) or treating physician in managing the patient.
> 
recorded if they ate ~50% 
defined as eating ~50% of a low fat, ~ 
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Efficacy 
Assessments: 
Efficacy assessments will include the following: 
 Enhanced Recovery Strategy for Tolerance of Solid Food 
 Modified Gastrointestinal Cardinal Symptom Index Score 
 CECT of the Pancreas 
 Pain Numeric Rating Scale (PNRS) score 
 Organ Failure scores 
 Vital sign measurements 
 Laboratory measurements  
 Concomitant medications 
Safety 
Assessments: 
Safety assessments will include the following: 
 Vital signs measurements 
 Laboratory measurements 
 Concomitant medications 
 Treatment-emergent adverse events (TEAEs) and serious adverse 
events (SAEs) 
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Efficacy 
Endpoints: 
Primary endpoint 
 Time to solid food tolerance 
Secondary endpoints: 
 Solid food tolerance at 48 hours, 72 hours, and 96 hours after the SFISD
and at discharge 
 Time to medically indicated discharge 
 Length of stay in the hospital 
 Length of stay in the intensive care unit (ICU) for patients admitted to 
the ICU 
 Re-hospitalization for AP by Day 30 
 Change in severity of AP by CTSI score from screening to Day 30 
 Deve
30% and >50%  
 
 
 Incidence, severity, and duration of organ failure 
 Mortality by Day 30 
 Change in pain score and opioid use 
Exploratory endpoints: 
 Development of infected pancreatic necrosis 
 Development of sepsis 
 Hospital procedures for the management of pancreatic necrosis 
 Change in GCSI-DD score 
 Change in albumin 
 Change in absolute neutrophil count (ANC)/absolute lymphocyte count 
(ALC) ratio and IL-6 levels 
 Change in urine neutrophil gelatinase-associated lipocalin (NGAL)
Safety 
Endpoints 
 The incidence of TEAEs and SAEs 
 The intensity and relationship of TEAEs and SAEs 
 Clinically significant changes in vital signs and safety laboratory results 
Pharmacokinetic 
Assessments: 
In patients at selected sites, sparse sampling of plasma will be employed for 
PK assessment after finishing the first and third doses of study drug.
Statistical 
Considerations 
Sample Size Calculations 
A sample size of 216 patients will be randomized into four groups on a 
1:1:1:1 basis, resulting in 54 patients randomized into each group. This 
sample size will provide 86% power for testing the difference in two 
populations having a median length of time of 72 and 144 hours, respectively, 
to tolerating solid food based on a log-rank test. This sample size will 
provide 80% power with a two-sided alpha of 0.05 (using the chi-squared 
test) to detect a 45% response rate for tolerating solid food in a Auxora
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• The persistence of SIRS 2:48 hours after the SFISD 
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dose group versus a 20% response rate in the Placebo group in the 72 hours 
after completion of the first study drug infusion. 
 
Treatment Populations 
 Modified Intent to Treat Population will consist of all randomized 
patients who receive any amount of study drug 
 The Per-Protocol Population (PP) will consist of all randomized patients 
who complete the study and have no major protocol violations 
 The PK population will consist of all randomized patients who receive 
any amount of active study drug and who have at least one post baseline 
PK sample analyzed 
 
A full Statistical Analysis Plan (SAP) detailing the primary and secondary 
efficacy analyses and the safety analyses, will be developed. Data evaluation 
will include all primary and secondary endpoints, and will be based on 
descriptive, exploratory, and inferential statistical methods. The number of 
patients per group, means, standard deviations, medians, quartiles, minimum 
and maximum values will be determined for continuous variables. Absolute 
and percentage frequencies will be determined for categorical variables. 
Handling of missing data and additional sensitivity analyses will be 
described in the statistical plan. 
 
 
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Table of Contents 
Sponsor Approval and Signature Page ........................................................................................... 2 
Synopsis .......................................................................................................................................... 3 
List of Tables ................................................................................................................................ 15 
List of Figures ............................................................................................................................... 15 
List of Terms and Abbreviations .................................................................................................. 16 
1 
INTRODUCTION ................................................................................................................. 19 
1.1 
Acute Pancreatitis ....................................................................................................... 19 
1.2 
Pathophysiology of Acute Pancreatitis ....................................................................... 20 
1.3 
Overview of CM4620 ................................................................................................. 22 
1.4 
Pre-Clinical Development of Zegocractin .................................................................. 22 
1.4.1 
Pre-Clinical Safety and Toxicology Studies .................................................. 22 
1.4.2 
Preclinical Efficacy Studies ........................................................................... 23 
1.5 
Clinical Development of Auxora ................................................................................ 25 
1.5.1 
Single Ascending Dose and Multiple Ascending Dose Studies .................... 25 
1.5.2 
Open Label Study in Patients with AP and SIRS .......................................... 27 
1.5.3 
Pharmacodynamic and Pharmacokinetic Study in Patients with AP ............ 30 
1.6 
Rationale for the Study and Selected Doses ............................................................... 31 
2 
OBJECTIVES AND ENDPOINTS ....................................................................................... 34 
2.1 
Primary Objectives...................................................................................................... 34 
2.2 
Secondary Objective ................................................................................................... 34 
2.3 
Efficacy Endpoints ...................................................................................................... 34 
2.4 
Safety Endpoints ......................................................................................................... 34 
3 
INVESTIGATIONAL PLAN ............................................................................................... 36 
3.1 
Study Design ............................................................................................................... 36 
3.2 
End of Study ............................................................................................................... 38 
3.3 
Sponsor Termination of the Study .............................................................................. 38 
4 
SELECTION OF PATIENTS ............................................................................................... 39 
4.1 
Inclusion Criteria ........................................................................................................ 39 
4.2 
Exclusion Criteria ....................................................................................................... 40 
4.3 
Re-Screening ............................................................................................................... 40 
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5 
TREATMENT OF PATIENTS ............................................................................................. 41 
5.1 
Overview ..................................................................................................................... 41 
5.2 
Enhanced Recovery Strategy for Tolerance of Solid Food ........................................ 41 
5.3 
Discharge Criteria ....................................................................................................... 41 
5.4 
Prohibited Medications ............................................................................................... 42 
5.5 
Compliance ................................................................................................................. 42 
6 
PROCEDURES ..................................................................................................................... 43 
6.1 
Randomization Procedures ......................................................................................... 43 
6.2 
Discontinuation and Withdrawal ................................................................................ 43 
7 
STUDY DRUG MATERIALS AND MANAGEMENT ...................................................... 44 
7.1 
Auxora Product Description ....................................................................................... 44 
7.2 
Placebo Product Description ....................................................................................... 44 
7.3 
Auxora and Placebo Storage ....................................................................................... 44 
7.4 
Auxora and Placebo Preparation ................................................................................. 45 
7.5 
Auxora and Placebo Administration ........................................................................... 45 
7.6 
Packaging and Labeling .............................................................................................. 45 
7.7 
Accountability, Handling and Disposal ...................................................................... 46 
8 
VISITS AND ASSESSMENTS ............................................................................................ 47 
8.1 
Screening..................................................................................................................... 47 
8.2 
Baseline Assessment ................................................................................................... 48 
8.3 
Randomization Using IXRS System ........................................................................... 48 
8.4 
Start of First Infusion of Study Drug (SFISD)............................................................ 48 
8.5 
24 hours ....................................................................................................................... 49 
8.6 
48 hours ....................................................................................................................... 49 
8.7 
72 hours ....................................................................................................................... 50 
8.8 
96, 120, 144, 168, 192, 216, 240 hours (±4 hours) ..................................................... 51 
8.9 
Days 12 to 28 (±4 hours) ............................................................................................ 51 
8.10 Day 30 (±5 days) ......................................................................................................... 52 
8.11 Discharge Date ............................................................................................................ 53 
8.12 Study Assessments ...................................................................................................... 53 
8.12.1 Demographics, Medical History and Medications ........................................ 53 
8.12.2 Concomitant Medications .............................................................................. 54 
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8.12.3 Abdominal Examination ................................................................................ 54 
8.12.4 Vital Signs ..................................................................................................... 54 
8.12.5 Arterial Blood Gas ......................................................................................... 54 
8.12.6 SpO2/FiO2 ...................................................................................................... 55 
8.12.7 Laboratory Analyses ...................................................................................... 55 
8.12.8 PK analysis .................................................................................................... 56 
8.12.9 Enhanced Recovery Strategy for Tolerance of Solid Food ........................... 56 
8.12.10 Modified ANMS GCSI-Daily Diary (mGCSI-DD) ...................................... 57 
8.12.11 Pain Numeric Rating Scale (PNRS) .............................................................. 57 
8.12.12 Contrast-Enhanced Computed Tomography (CECT) of the 
Abdomen/Pancreas ........................................................................................ 57 
8.12.13 Systemic Inflammatory Response Syndrome (SIRS) ................................... 58 
9 
ADVERSE EVENTS ............................................................................................................ 59 
9.1 
Definition of Adverse Event ....................................................................................... 59 
9.2 
Definition of Serious Adverse Event .......................................................................... 59 
9.3 
Eliciting Adverse Event Information .......................................................................... 60 
9.4 
Recording Adverse Events .......................................................................................... 60 
9.5 
Assessment of Relationship to Study Drug ................................................................ 61 
9.6 
Assessment of Severity ............................................................................................... 61 
9.7 
Reporting of Serious Adverse Events ......................................................................... 62 
9.8 
Suspected Pregnancy in a Woman of Childbearing Potential .................................... 63 
10 STATISTICAL METHODS ................................................................................................. 65 
10.1 General Considerations ............................................................................................... 65 
10.2 Sample Size ................................................................................................................. 65 
10.3 Study Assessments ...................................................................................................... 65 
10.4 Analysis Sets ............................................................................................................... 66 
10.4.1 Efficacy and Safety........................................................................................ 66 
10.4.2 Pharmacokinetics ........................................................................................... 66 
10.5 Disposition .................................................................................................................. 66 
10.6 Analysis of Demographic and Baseline Data ............................................................. 66 
10.7 Efficacy Analysis ........................................................................................................ 67 
10.8 Safety Analysis ........................................................................................................... 68 
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10.9 Independent Data Monitoring Committee .................................................................. 69 
11 ADMINISTRATIVE CONSIDERATIONS ......................................................................... 70 
11.1 Electronic Case Report Forms .................................................................................... 70 
11.2 Monitoring of the Study .............................................................................................. 70 
11.3 Inspection of Records ................................................................................................. 70 
11.4 Study Record Retention .............................................................................................. 70 
11.5 Study Conduct: Good Clinical Practice and Declaration of Helsinki ......................... 70 
11.6 Responsibilities of the Investigator and the IRB/EC .................................................. 71 
11.7 Confidentiality ............................................................................................................ 71 
11.8 Modification of the Protocol ....................................................................................... 71 
11.9 Informed Consent........................................................................................................ 72 
11.10 Protocol Deviations ..................................................................................................... 72 
11.11 Financial Disclosure.................................................................................................... 73 
11.12 Sponsor Obligations .................................................................................................... 73 
11.13 Investigator Documentation ........................................................................................ 73 
11.14 Clinical Study Insurance ............................................................................................. 74 
11.15 Use of Information ...................................................................................................... 74 
11.16 Publications ................................................................................................................. 74 
12 REFERENCES ...................................................................................................................... 75 
Appendix 1. 
Definition of Organ Failure and Sepsis ................................................................ 78 
Appendix 2. 
American Gastroenterological Association Institute Guideline on the Initial 
Management of Acute Pancreatitis ....................................................................... 80 
Appendix 3. 
CTSI Score ............................................................................................................ 81 
Appendix 4. 
Pain Numeric Rating Scale (PNRS) ..................................................................... 82 
Appendix 5. 
Imputed PaO2/FiO2 ............................................................................................... 83 
Appendix 6. 
Modified American Neurogastroenterology and Motility Society 
Gastrointestinal Cardinal Symptom Index Daily Dairy (mGCSI-DD) ................. 84 
Appendix 7. 
CT Findings in Chronic Pancreatitis ..................................................................... 85 
Appendix 8. 
Schedule of Events ................................................................................................ 86 
 
 
 
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List of Tables 
Table 1. 
SAD (CM4620-101) ................................................................................................... 25 
Table 2. 
MAD (CM4620-102) .................................................................................................. 26 
Table 3. 
Demographics and Baseline Characteristics of Patients in CM4620-201 .................. 28 
Table 4. 
Auxora Product Information ....................................................................................... 44 
Table 5. 
Conversion of O2 Flow to FiO2 ................................................................................... 55 
List of Figures 
Figure 1. Schema Showing the Activation of CRAC Channels Found on Pancreatic 
Acinar Cells Triggering a Series of Events Which Lead to Acute Pancreatitis. ......... 21 
Figure 2. Sites of action of Zegocractin in treating acute pancreatitis ....................................... 24 
Figure 3. Stimulated IL-2 production by WBCs in response to administration of Auxora ....... 31 
Figure 4. Higher versus Lower Risk of Organ Failure ............................................................... 36 
 
 
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List of Terms and Abbreviations 
Abbreviation 
Definition 
ABG 
arterial blood gas 
AE 
adverse event 
AGA 
American Gastroenterological Association 
ALC 
absolute lymphocyte count  
ALT 
alanine transaminase 
ANC 
absolute neutrophil count  
ANMS 
American Neurogastroenterology and Motility Society 
AP 
acute pancreatitis 
AST 
aspartate transaminase 
ATP 
adenosine triphosphate 
AUC 
Area under the concentration-time curve  
Ca2+ 
Calcium ion 
CCK 
cholecystokinin 
CECT 
Contrast-enhanced computed tomography 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration  
CMH 
Cochran Mantel-Haenszel 
CPK
Creatine kinase 
CR 
Complete response  
CRAC
calcium release-activated calcium 
CRF 
case report form 
CRP
C-Reactive Protein 
CTSI 
computed tomography severity index 
CV
cardiovascular
EC
Ethics Committee
ECG 
electrocardiogram 
eCRF
Electronic case report form 
EDC 
Electronic Data Capture 
EDTA
edetate disodium salt dehydrate 
ER 
endoplasmic reticulum 
ERCP 
endoscopic retrograde cholangiopancreatography
FAEE 
fatty acid ethyl ester
FDA 
U.S. Food and Drug Administration  
FiO2 
fraction of inspired oxygen 
GFR 
glomerular filtration rate 
GMP
Good Manufacturing Practice of Medicinal Products 
HCT 
Hematocrit  
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Abbreviation 
Definition 
Hr(s) 
hour(s) 
IC50 
Concentration producing a mean 50% inhibition 
ICH 
International Conference on Harmonization 
ICRAC 
calcium release-activated calcium current 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IP 
intraperitoneal 
IP3R 
inositol 1,4,5-trisphosphate (IP3) receptor 
IRB 
Institutional Review Board 
IV 
intravenous/intravenously 
IXRS 
interactive voice/web response system 
Kg 
kilogram 
L 
liter 
LAR 
legal authorized representative 
LDH 
lactate dehydrogenase 
LTF 
Lost to follow-up 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mGCSI-DD 
Modified American Neurogastroenterology and Motility Society Gastrointestinal 
Cardinal Symptom Index Daily Diary 
MITT
Modified Intent-to-treat Population
MPO
myeloperoxidase
NF- B
nuclear factor kappa B 
NFAT
nuclear translocation of Nuclear Factor of Activated T cells
NG 
nasogastric 
NGAL
Neutrophil gelatinase-associated lipocalin
NJ 
nasojejunal  
NOAEL
no observable adverse effect level 
NPO 
Nil per Os (Nil per Mouth) 
OR
odds ratio
Orai1 
Calcium release-activated calcium channel protein 1  
PaO2/FiO2 
P/F Ratio 
PI
Principal Investigator 
PD 
pharmacodynamic 
PK
pharmacokinetic
PNRS 
pain numeric rating scale 
popPK
population PK 
PP
Per-Protocol Population 
PT 
preferred Term 
K 
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Abbreviation 
Definition 
QTcF 
QT interval 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 
SC 
Supportive Care 
SFISD 
Start of First Infusion of Study Drug 
SIRS 
Systemic inflammatory response syndrome 
SOC 
Standard of care 
SOC 
System Organ Class 
SOCE 
Store-operated calcium entry 
SpO2 
Oxyhemoglobin percent saturation measured by pulse oximetry 
STIM1 
Stromal interaction molecule 1 
TEAE 
Treatment-emergent adverse event 
TLCS 
taurolithocholate acid sulphate 
Tmax 
time it takes for drug to reach maximum concentration  
ULN 
upper limit of normal 
VTBI 
Volume to be infused 
WBC 
White blood cell
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1 
INTRODUCTION 
1.1 
Acute Pancreatitis 
Acute pancreatitis (AP) is an acute inflammatory process of the pancreas with varying involvement 
of local tissues and/or more remote organ systems. Due to the dynamic nature of the disease, it 
leads to wide-ranging outcomes that evolve rapidly in any given patient with little predictability. 
There is no prescribed order of events that the disease course follows, beyond the basic concept 
of an early (usually <1-2 weeks) and a late (>1-2 weeks) phase, with the former characterised by 
varying degrees of pancreatic and systemic inflammation, and the latter by an anergic phase that 
can make patients susceptible to infection. 
Due to the evolving nature of AP, the severity may change during the course of the disease. The 
Atlanta classification of 2012 defines three degrees of severity: mild AP, moderately severe AP, 
and severe AP (Banks 2013). Terminology that is important in this classification includes 
transient organ failure, persistent organ failure, and local or systemic complications. Transient 
organ failure is organ failure that is present for < 48 hours. Persistent organ failure is defined as 
organ failure that persists for 
collections and acute necrotic collections, while systemic complications can be related to 
exacerbations of underlying co-morbidities. A new international classification, referred to as the 
rminant-
classification (Dellinger 2012). This classification is based on the actual local and systemic 
determinants of severity, rather than a description of events that are correlated with severity. The 
derivation of a classification based on the above principles results in four categories of severity: 
mild, moderate, severe, and critical. The determinant-based classification approach to severity 
has elicited a great deal of interest; nevertheless, the Atlanta classification remains the more 
commonly used standard against which severity of AP is assessed. 
AP can be subdivided into two histopathological subtypes: interstitial oedematous pancreatitis 
and necrotising pancreatitis. In the majority of cases, AP comprises clinically of a mild transitory 
form of oedematous-interstitial inflammation, which is self-limiting and resolves spontaneously. 
However, 15 20% of patients with AP will develop the more severe form of the disease 
(Whitcomb 2006). Necrotising pancreatitis most commonly manifests as necrosis involving both 
the pancreas and peripancreatic tissues and, less commonly, as necrosis of only the peripancreatic 
tissue or pancreatic parenchyma alone. Patients with peripancreatic necrosis alone have increased 
morbidity and intervention rates compared to patients with interstitial oedematous pancreatitis 
(Singh 2011). Repeated attacks of AP can result in chronic pancreatitis, which increases the risk 
of developing pancreatic cancer (Yadav 2013). 
Gallstones and alcohol misuse are long-established risk factors for AP. The next most common 
cause is thought to be endoscopic procedures, e.g., endoscopic retrograde cholangiopancreatography 
(ERCP). Other causes include surgery or trauma, metabolic problems, infections, hereditary 
.
However, many of these may be due to unidentified microlithiasis (cholesterol crystals, biliary 
2: 48 hours. Local complications include peripancreatic fluid 
'dete 
based classification of severity', has been proposed as an alternative to the Atlanta 
factors and drugs. A small residual group has no obvious cause and is labelled ''idiopathic '' 
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sludge, or small stones). Smoking is an independent risk factor, and its effects could be 
synergistic with those of alcohol (Lindkvist 2008; Tolstrup 2009). 
There are currently two primary aims in the initial treatment of patients with AP. The first aim is 
to provide supportive therapy, and to treat specific complications that may occur. The second 
aim is to limit the severity of pancreatic inflammation, necrosis, and systemic inflammatory 
response syndrome (SIRS) (Werner 2005). 
There is currently no approved pharmaceutical treatment for AP, regardless of the severity of the 
disease (Lankisch 2015). Fluid resuscitation is at the cornerstone of early treatment of AP 
(Lankisch 2015). Analgesics, usually opioids, are administered initially to manage the abdominal 
pain. Enteral feeding can also be used and is preferred over exclusive parenteral nutrition. Thus, 
patients are generally managed with supportive care, including fluid replacement, painkillers, 
oxygen, feeding via a tube or into a vein, and antibiotics. Severely ill patients with organ failure 
are managed aggressively using a variety of different treatment strategies. 
1.2 
Pathophysiology of Acute Pancreatitis 
The exocrine pancreas is a highly specialised secretory organ capable of synthesising, storing 
and releasing large quantities of digestive enzyme precursors into the small intestine, essential 
for the breakdown of food. Homeostasis of the functional cellular unit, the acinar cell, is 
therefore paramount for the smooth running of physiological processes; disruption can lead to 
severe damage of the pancreas, resulting in premature activation of zymogens, vacuolization and 
necrotic cell death, features typical of AP. 
The pancreatic acinar cells are responsible for synthesising digestive proenzymes such as 
trypsinogen, which, when secreted with pancreatic fluids, become activated in the gut to help 
digest food. This secretory process is regulated through cytosolic calcium levels in the pancreatic 
acinar cells. At physiological concentrations, the neurotransmitter acetylcholine and the hormone 
cholecystokinin (CCK) evoke repetitive short-lasting increases in cytosolic calcium ions (Ca2+) 
in pancreatic acinar cells, provided by Ca2+ release from internal stores such as the endoplasmic 
reticulum (ER) (Petersen 2006). Repetitive release of Ca2+ from internal stores triggers activation 
of store operated calcium entry (SOCE) through Calcium Release-Activated Calcium (CRAC) 
channels to replenish the stores from interstitial fluid and activates mitochondria to produce 
adenosine triphosphate (ATP) (Petersen 2011; Gerasimenko 2013). Both Ca2+ and ATP are 
required for the secretion of the digestive proenzymes and the accompanying fluid needed to 
wash the secreted proteases out of the duct system and into the gut (Petersen 2011). 
The triggers of AP, such as gallstones and alcohol, lead to massive and sustained release of ER 
Ca2+ stores, resulting in maintenance of high cytosolic Ca2+ levels and a Ca2+ depleted state of 
the stores (Muallem 1988). The sustained cytosolic Ca2+ elevation is due to excessive Ca2+ entry 
into the cells from the interstitial fluid following depletion of ER Ca2+ stores. Mechanistically, 
when the ER stores are depleted of Ca2+ the acinar cell attempts to refill the stores with Ca2+ 
entering through a plasma membrane CRAC channel, with Orai1 being the key Ca2+-conducting 
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component of the channel complex (Lur 2009). The opening of the Orai1 channel is activated by 
STIM1 in response to ER Ca2+ store depletion (Gerasimenko 2013). 
The massive release of ER Ca2+ followed by the sustained elevation in cytosolic Ca2+ causes the 
digestive enzymes to be activated inappropriately within the acinar cells, resulting in autodigestion 
(i.e., digestion of the pancreas and surrounding tissue), necrosis (Phillip 2014), and the characteristic 
features of AP. Elevated cytosolic Ca2+ also results in lower production of ATP by mitochondria, 
motes necrosis (Criddle 2016). 
Figure 1 shows the sequence of events leading to AP following activation of CRAC channels. 
Figure 1. Schema Showing the Activation of CRAC Channels Found on Pancreatic 
Acinar Cells Triggering a Series of Events Which Lead to Acute Pancreatitis. 
 
 
 
which limits the cell's ability to handle stress and further pro 
PANCREATIC ACINAR CELLS 
CRAC Channel Inhibitors 
y
ca2• 
Orail 
Response 
♦ Activation of digestive enzymes 
♦ Mitochondrial function, ATP levels 
♦ Cytokine production 
♦ Cell injury and necrosis 
Zymogen 
granules • 
•l•I• 
•••• 
Gallstones 
' ' ' • 
Alcohol 
' ' ' • 
Bile acids; Alcohol metabolites 
STIMl 
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1.3 
Overview of CM4620 
CM4620 (also known by the international nonproprietary name, zegocractin) 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 
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 zegocractin to inhibit CRAC channels was investigated by measuring the 
electrophysiological current (calcium release-activated calcium current; ICRAC) associated with 
calcium entry through CRAC channels in HEK293 cells stably expressing recombinant human 
Orai1/STIM1 (Wen 2015). 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 zegocractin at concentrations of 0.001, 0.01, 0.1, and 1 
µM. Zegocractin 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 
zegocractin. 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 
zegocractin produced nearly complete inhibition of the STIM1-independent ICRAC, indicating that 
Orai1 is a major site of action of the compound. 
1.4 
Pre-Clinical Development of Zegocractin 
1.4.1 
Pre-Clinical Safety and Toxicology Studies 
Safety pharmacology studies conducted in rats indicated no zegocractin-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 intravenously 
(IV) with Auxora (zegocractin intravenous emulsion). 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 zegocractin is 
neither mutagenic nor clastogenic. Hemolysis testing concluded that zegocractin placebo was 
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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 zegocractin is 
potentially phototoxic, so appropriate precautions are being taken in clinical trials. 
1.4.2 
Preclinical Efficacy Studies 
Non-clinical studies conducted in murine and human pancreatic acinar cells to date have 
demonstrated that by acting on CRAC channels in pancreatic acinar cells, zegocractin can protect 
these cells from pancreatitis-induced cell death and can reduce biochemical, immunological and 
histopathologic consequences of experimental AP when administered early in the course of the 
disease (Wen 2015; Waldron 2019). Zegocractin caused marked reductions in serum amylase 
activity, pancreatic trypsin activity, myeloperoxidase (MPO) activity (a marker of neutrophil 
infiltration) in the pancreas and lung and led to a significant reduction in pancreatic 
histopathology scores. Importantly, the non-clinical findings provide proof of concept that 
zegocractin has the potential to be effective in the treatment of AP regardless of the cause and 
support the administration of zegocractin as an IV infusion to humans. Additional non-clinical 
evidence supports the position that the effects of zegocractin on the pancreas are complimented 
by its ability to reduce inflammatory responses that can manifest clinically as SIRS. 
The protection offered by zegocractin in vitro has been confirmed in three diverse in vivo models 
representative of gallstone-, alcohol-, or hyper-stimulation induced AP (taurolithocholate acid 
sulphate [TLCS]-induced, fatty acid ethyl ester [FAEE]-induced and cerulein-induced 
pancreatitis models, respectively). Trypsin activity within pancreatic tissue, MPO activity within 
pancreatic and lung tissue, and histopathological indices of pancreatic damage, such as edema, 
inflammatory cell infiltration, vacuolization, and necrosis, were all markedly reduced following 
single 5-20 mg/kg intraperitoneal (IP) doses of CM4620 in the mouse (cerulein-induced AP), 
two 5 or 20 mg/kg IP doses of CM4620 in the mouse (TLCS-induced and FAEE-induced APs 
models) or one 4-hour IV infusion of CM4620 Nano-emulsion (the intended clinical dosage 
form, route of administration and infusion duration) at doses of 5-20 mg/kg in the rat (cerulein-
induced AP model) (Wen 2015; Waldron 2019). The timing of zegocractin administration relative to 
induction of pancreatitis was investigated in the TLCS-induced and FAEE-induced AP models 
and the results suggest that zegocractin 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 (Wen 2015). 
The potential for zegocractin to reduce SIRS through an inhibitory effect on immune cells has 
been investigated in vitro, ex vivo and as part of in vivo pancreatitis models. In vitro, zegocractin 
inhibited human neutrophil function and inhibited release of key inflammatory cytokines (IL-2, 
IFN  and IL-17) from human lymphocytes (IC50 4-138 nM). Results from ex vivo 
pharmacodynamic (PD) analyses in blood demonstrated that zegocractin was able to significantly 
reduce stimulated IL-2 secretion from T cells, and presumably other lymphocytes, in a dose-
dependent manner in Sprague Dawley rats and cynomolgus monkeys after 14 days of oral 
dosing. Further, the effects of zegocractin on MPO activity in the lung of mice in TLCS-induced 
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and FAEE-induced AP models and rats in the caerulein-induced AP model were assessed. MPO 
activity is a measure of neutrophil infiltration and when seen in the lung in these models it is 
indicative of a systemic inflammatory process analogous to SIRS in humans. Two IP doses of 
zegocractin at 20 mg/kg in mice (Wen 2015) or one 4-hour infusion of Auxora at 5 mg/kg in rats 
(Waldron 2019) were able to substantially reduce lung MPO activity (80% reduction in the mouse 
TLCS model, 73% reduction in the rat caerulein model). Lastly, in the IV infusion study in rats, 
Auxora significantly reduced IL-
that of MPO. 
In addition to the above, in vitro treatment with zegocractin protected mouse, rat and human 
pancreatic acinar cells from TLCS-induced necrosis or trypsinogen activation, blocked CCK-
induced nuclear translocation of Nuclear Factor of Activated T cells (NFAT) translocation in 
isolated mouse acinar cells, CCK-induced nuclear factor kappa B (NF- B) translocation in a rat 
acinar cell line, and lipopolysaccharide-induced expression of fibro-inflammatory mRNAs in 
mouse pancreatic stellate cells Furthermore, a single therapeutic IV infusion of Auxora in rat was 
shown to reduce markers of ER stress-associated cell death and apoptosis in rat pancreas 
(Waldron 2019). 
Figure 2 highlights the potential role of zegocractin in treating AP through its effects on both the 
acinar cell and the immune system: 
Figure 2. Sites of action of Zegocractin in treating acute pancreatitis 
 
 
 
 
6 and TNFa mRNA levels in both pancreas and lung, as well as 
Gallstones (bile acids) 
BIie acids and fatty acid 
esters cause excessive 
release of Ca2• from the 
ER In pancreatic acinar 
cells 
CRAC channels are over-
activated and more Ca2• 
enters and overloads cells 
Pancreatic Inflammation 
1( 
'
High Ca2' levels 
are toxic and lead 
to cellular 
dysfunction 
Alcoho (fatty acid ethyl esters) 
Cascade of 
~ 
Inflammatory 
T cells 
mediators 
\ 
Dysfunction of 
'
Ductal& 
Stellate cells 
Zegocr ctin 
-I 
Cell Injury causes the release 
activation of additional 
disease enzymes and 
Acute Lung Injury 
MaicrophageaT
Neutrophds 
Inflammation mediators 
"'-. 
_ Systemic Inflammatory 
~
sponse Syndrome (SIRS) 
Zegocractin 
Zegocractin 
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1.5 
Clinical Development of Auxora 
1.5.1 
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 Aurora 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 
IV = intravenous  
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 Auxora 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 
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 maximum serum concentration (Cmax) values and, as indicated above, to date there have 
been no clinically significant AEs reported during this phase. Plasma exposures, defined by the 
area under the concentration-time curve (AUC)0-24h, appear to be dose-proportional and reached a 
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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 
IV = intravenous  
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 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. 
Non-compartmental PK analysis of Group 1 in CM4620-102 (0.5 mg/kg) indicates that 
zegocractin 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 
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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 
zegocractin were followed for 1 year in a long-term extension study to assess for AEs and SAEs. 
In addition, PK levels were drawn in all 4 groups on Day 270 to further characterize the terminal 
phase and the prolonged period of minimal residual drug level. There were no SAEs and no 
adverse events rated moderate or severe in intensity in subjects followed for 365 days. 
A population PK (popPK) 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, resulting in 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. 
1.5.2 
Open Label Study in Patients with AP and SIRS 
CalciMedica has conducted a Phase 2a, 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 
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 
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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 PI. Cohort 4 received 2.08 mg/kg daily on Days 1 and 
2 and 1.6 mg/kg daily on Days 3 and 4 as planned. 
The first infusion of Auxora was started within 6 (up to 8) hours of the patient or legal authorized 
representative (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 CM4620-IE. 
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%) 
n = number; SC = Supportive Care 
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 
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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 (PTs) 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 PTs 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 PTs 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. 
The secondary objective of the study was to evaluate efficacy. Treatment with Auxora (all doses) 
resulted in more rapid restoration of gut function, less persistent SIRS, a greater percentage of 
patients with a reduction in the severity of AP by CTSI scoring, and a decreased length of 
hospital stay compared to SC alone. 
At 72 hours or Discharge (if earlier), 7 of 14 (50%) of patients receiving Auxora+SC (all doses) 
increase in pain, compared to 1 of 7 (14%) patients receiving SC alone. At Day 10 (216 hours or 
Discharge), 13 of 14 (92.9%) patients receiving Auxora+SC (all doses) were able to tolerate 
solid food compared to 3 of 7 (43%) patients receiving SC alone. The median (min, max) time to 
tolerating solid food for patients receiving the low dose regimen+SC was 57 hours (17, 121), for 
patients receiving the high dose regimen, 78.5 hours (39, 440) and for patients receiving only 
SC, 100 hours (22, 720). 
were able to tolerate solid food, defined as eating 2: 50% of a solid meal without vomiting or an 
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Five of 14 patients (35.7%) randomized to Auxora+SC (all doses) had persistent SIRS, defined 
compared to 5 of 7 patients (71.4%) in the SC alone group. 
A blinded central reader read all Screening, Day 5 or Discharge, and Unscheduled contrast-
enhanced computed tomography (CECT) scans and gave a score for the severity of AP using the 
CTSI scoring system. One patient treated with the high dose regimen+SC did not receive a CTSI 
score at either the Screening or Day 5 or Discharge CECTs. One patient treated with SC alone 
did not receive a CTSI score at Screening because contrast was not given. On the Screening 
CECT, 8 patients treated with Auxora-IE+SC (all doses) had moderate or severe AP based on the 
CTSI score. Three of the 8 (37.5%) patients with moderate or severe AP improved with 
treatment to have mild AP based on the CTSI score on the Day 5 or Discharge CECT. On the 
Screening CECT, 4 patients treated with SC alone had moderate or severe AP. None of the 4 
(0%) patients improved to have mild AP by the Day 5 or Discharge CECT. 
The median length of stay (min, max) for patients randomized to Auxora-IE+SC (all doses) and 
SC alone were 3.70 (1.5, 18.3) and 6.02 (1.1, 30.0) days, respectively. 
1.5.3 
Pharmacodynamic and Pharmacokinetic Study in Patients with AP 
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. 
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. 
as SIRS lasting continuously for~ 48 hours starting on or after the Day 1 (0 hour) assessment, 
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The results of the study showed a rapid decrease in IL-2 production by stimulated white blood cells 
with infusion of Auxora with rapid return after discontinuation (Figure 3). The study suggested 
that there would be no long-term immunomodulatory effects from the administration of Auxora. 
Figure 3. Stimulated IL-2 production by WBCs in response to administration of Auxora 
 
PD = pharmacodynamic; WBC = white blood cell 
1.6 
Rationale for the Study and Selected Doses 
Auxora has been well tolerated in healthy volunteers and in patients with AP, SIRS, and 
hypoxemia with no untoward safety findings. In addition, an array of efficacy signals was noted 
in the open label study. The safety of the compound and the noted efficacy signals warrant 
continued development of Auxora for patients with AP given that there are no approved products 
for the treatment of the disease. A randomized, double blind, placebo controlled, study would 
establish a clear proof of concept in patients with AP and SIRS, provide dose ranging data to 
support Phase 3 dosing, and evaluate a number of efficacy endpoints to inform Phase 3 endpoints. 
The dosing regimen for the current study includes three consecutive days of dosing at 0.5, 1.0 or 
2.0 mg/kg, each administered by 4-hour IV infusion The infusion duration and doses of 1.0 and 
2.0 mg/kg were selected based on the results from previous Phase 1 and 2a studies that suggested 
these doses would have beneficial effects in patients with AP and SIRS. The 0.5 mg/kg dose was 
included to determine if this dose could define the minimally effective dose of Auxora. 
From Phase 2a study CM4620-201, early tolerance of solid food was displayed in patients 
assigned to both the low and high dose regimens of Auxora (low dose regimen: 1.0 mg/kg on 
Day 1 and 1.4 mg/kg on Days 2-4; high dose regimen: 2.08 mg/kg on Days 1-2, 1.6 mg/kg on 
Days 3-4), although not all patients received the full 4 days of dosing because of early discharge. 
Additionally, no patients (0/6) in the high dose regimen group showed a worsening in their 
50 
~ 
N 
40 
::::i 
Cl) i;' 
:§ = 30 
:x <C 
di ~ 
... 
Cl) 
~= 
20 
C 
"'CII ·-
15 
IL 
10 
0 
Relationship of PD Readout 
and Concentration of CM4620 
(Mean ± SEM, n = 4) 
Pre-dose 
0.5 hr post 
Day2 
Discharge 
600 
.,, 
500 
s· 
!!!. 
s· &> 
400 
!!!5 
0 
0 
0:::, 
C. -
300 tiil 
Kl g: 
"< :::, 
200 -o 
:::, -
31: C') 
-
31: 
100 · 1 
0 
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Balthazar scores, indicative of increased pancreatic inflammation, whereas 2/8 patients (25%) in 
the low dose regimen group showed an increase in their scores. These data suggest that doses or 
systemic exposures associated with the high dose regimen provide the greatest opportunity for 
efficacy with acceptable tolerability. Since 75% of patients receiving the low dose regimen showed 
no worsening in their Balthazar scores, these doses may also be efficacious, albeit slightly less than 
those in the high dose regimen. The specific dose levels of 2.0 and 1.0 mg/kg were selected for the 
current study to closely match the Day 1 doses of the high and low dose regimens in the Phase 2a 
study, respectively. Doses notably higher than 2.0 mg/kg (1.25 mL/kg) were not selected as they 
carry increased risk of intolerance to either zegocractin or lipid load from the emulsion vehicle. 
The third dose level of 0.5 mg/kg was chosen to help define a minimum efficacious dose level. 
Adjustment of the zegocractin dose for body weight is based on covariate analysis from a popPK 
model that was developed from previous Phase 1 and Phase 2a studies. Dose adjustment is not 
being made for gender or race based on the absence of substantial covariate effects on the popPK 
model. The 3 dose levels selected are expected to achieve significant separation of plasma 
exposures on Day 1 (Cmax and AUC0-24) based on popPK modeling. Furthermore, 3 dose levels are 
considered adequate for dose-ranging studies, as described in International Conference on 
Harmonization (ICH) guidance E4. 
The choice of the lower dose level (0.5 mg/kg) is also supported by non-clinical and clinical 
PK/PD data. Studies in mouse and rat models of AP indicated that achieving a Cmax blood level 
of CM4620 in vivo close to or greater than the IC50 value in an in vitro whole blood assay of 
T lymphocyte function predicted efficacy in the animal model. Consistent with this idea, data 
from a small PK/PD study in AP patients (CM4620-202) showed that T lymphocyte function in 
an ex vivo whole blood assay was inhibited greater than 50% after a single dose of 2.08 mg/kg 
CM4620-IE, a dose level linked to signs of efficacy in the open-label study (CM4620-201). Analysis 
and modeling of clinical PK in patients receiving CM4620-IE indicates that Cmax values of CM4620 
after dosing at 0.5 mg/kg would fall close to the range of the IC50 value in an in vitro human 
whole blood assay of T lymphocyte function. Thus, if the animal models are predictive of human 
disease, the dose of 0.5 mg/kg CM4620-IE should mark the lower limit of the efficacious range. 
The dosing regimen for the current study includes 3 consecutive days of dosing at the same dose 
level. 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. Thus, the low 
dose regimen in Phase 2a study CM4620-201 (1.0 mg/kg on Day 1, 1.4 mg/kg on Days 2-4) was 
designed to achieve plasma exposures on Day 4 (AUC0-24) equivalent to those achieved on Day 7 
from the high dose group in the MAD study that received 7 daily doses of 1.0 mg/kg. Over an 
abundance of caution, the high dose regimen in the Phase 2a study (2.08 mg/kg on Days 1-2, 
1.6 mg/kg on Days 3-4) was designed to achieve plasma exposures on Day 4 that were only 
30% higher than those achieved with the low dose regimen. Using this approach, no drug-related 
AEs were noted in the Phase 2a study. Although well-conceived for safety reasons, these forced 
titration regimens complicated the interpretation of PK exposures. Therefore, simplified repeat 
fixed-dose regimens are being utilized in the current study, whereby the same dose level is 
administered on three consecutive days. Three days of dosing was chosen because it matches the 
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median number of doses administered in the Phase 2a study, where evidence of efficacy signals 
was established. 
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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives 
 To assess the dose response and efficacy of three different dose levels of Auxora in 
patients with AP and accompanying SIRS; 
 To assess the time to medically indicated discharge in patients who are responders to 
early tolerance of solid food intake versus non-responders. 
2.2 
Secondary Objective 
 To assess the safety and tolerability of varying doses of Auxora in patients with AP and 
accompanying SIRS. 
2.3 
Efficacy Endpoints  
 Primary endpoint 
o Time to solid food tolerance 
 Secondary endpoints: 
o Solid food tolerance at 48 hours, 72 hours, and 96 hours after the Start of First Infusion 
of Study Drug (SFISD) and at discharge 
o Time to medically indicated discharge 
o Length of stay in the hospital 
o Length of stay in the ICU for patients admitted to the ICU 
o Re-hospitalization for AP by Day 30 
o Change in severity of AP by CTSI score from screening to Day 30 
o Deve
30% and >50%  
o 
 
o Incidence, severity, and duration of organ failure 
o Mortality by Day 30 
o Change in pain score and opioid use 
 Exploratory endpoints: 
o Development of infected pancreatic necrosis 
o Development of sepsis 
o Hospital procedures for the management of pancreatic necrosis 
o Change in GCSI-DD score 
o Change in albumin 
o Change in absolute neutrophil count (ANC)/absolute lymphocyte count (ALC) ratio 
and IL-6 levels 
o Change in urine neutrophil gelatinase-associated lipocalin (NGAL) levels  
2.4 
Safety Endpoints 
 The incidence of TEAEs and SAEs 
• 
• 
• 
• 
• 
lopment of pancreatic necrosis ~ 
The persistence of SIRS ~48 hours after the SFISD 
• 
• 
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 The intensity and relationship of TEAEs and SAEs 
 Clinically significant changes in vital signs and safety laboratory results 
• 
• 
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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This double blind, randomized, placebo-controlled study will evaluate the efficacy, safety, and 
tolerability of three different dose levels of Auxora in patients with AP and accompanying SIRS. 
Approximately 216 patients will be randomized 1:1:1:1 into one of 4 groups using a computer-
generated randomization scheme accessed through an interactive voice/web response system 
(IXRS). Randomization will be first stratified by gender (male or female) and then by risk for 
organ failure in the gender subgroups (higher or lower). Higher risk for organ failure is defined 
hypoxemia (imputed PaO2/FiO2 
er risk for organ failure is defined by the absence of 
either or both an elevated hematocrit and hypoxemia (Figure 4). The PaO2/FiO2 will be 
determined using an arterial blood gas or imputed using pulse oximetry (Appendix 5). 
Figure 4. Higher versus Lower Risk of Organ Failure 
 
HCT = hematocrit  
All patients will have received a Screening CECT of the abdomen/pancreas before being 
randomized into the study. CECTs performed as standard of care (SOC) may be used as the 
Screening CECT but must have been performed in the 24 hours before Consent or after Consent 
and before Randomization (Section 8.12.12). 
The SFISD should occur within 8 hours of the patient or LAR providing informed consent. 
Patients randomized to Group 1 will receive 2.0 mg/kg of Auxora intravenously every 24 hours 
by the presence of both an elevated hematocrit (HCT ~44% for men or ~400/4 for women) and 
$360).Low 
I 
I 
Pa02/Fi02 
~ 360 
Male 
"-.._ 
Pa02/FJ02 
> 360 
Strat,flcat,on 
HCT <44% 
Lower Risk 
HCT<40% 
/ 
/ 
/ 
Female 
Pa02/FI02 
~ 360 
HCT:.:40% 
Pa02/Fl02 
> 360 
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(±1 hour) for a total of three doses. Patients randomized to Group 2 will receive 1.0 mg/kg of 
Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to 
Group 3 will receive 0.5 mg/kg of Auxora intravenously every 24 hours (±1 hour) for a total of 
three doses. Patients randomized to Group 4 will receive emulsion without any active 
pharmaceutical ingredient. Patients in Group 4 will receive one of three randomly assigned dose 
volumes, 1.25 mL/kg, 0.625 mL/kg, or 0.3125 mL/kg, which will be administered intravenously 
every 24 hours (±1 hour) for a total of three doses. (Section 5.3) 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, the upper limit of the volume of Auxora and volume of 
Placebo that will be administered will be 156.25 mL. The sponsor, investigators, pharmacists, and 
patients will be blinded to the assigned group. In the event of a medical emergency, investigators 
will be able to receive the treatment assignment if required to provide optimal care of the patient.  
For all 4 groups, a study physician or appropriately trained delegate will perform study-specific 
assessments at screening, at the baseline assessment, immediately prior to the SFISD, and then 
every 24 hours until 240 hours after the SFISD, or until discharge if earlier. If patients remain 
hospitalized at Day 12, assessments will then be performed every 48 hours starting on Day 12 
until Day 28, or until discharge if earlier. Patients discharged from the hospital before Day 25 
will return at Day 30 (+5 days) to perform the Day 30 assessments. If patients are discharged on 
Days 25-29, the Day 30 assessments may be performed prior to discharge. 
Patients will receive another CECT of the abdomen/pancreas at the Day 30 (±5 days) visit. All 
CECTs performed as SOC after randomization and before the Day 30 CECT will also be 
captured. A blinded central reader will read the Screening, Day 30, and any SOC CECTs 
obtained between randomization and the Day 30 visit.  
Patients will complete the modified American Neurogastroenterology and Motility Society 
(ANMS) Gastrointestinal Cardinal Symptom Index Daily Diary (mGCSI-DD) worksheet at the 
baseline assessment, at 96 hours, 168 hours, Day 14 and Day 21 (for patients who remain 
hospitalized on these days), on the day of discharge, and daily at bedtime after discharge until the 
Day 30 visit. Patients who are discharged on Days 25-29 will not complete the mGCSI 
worksheet after discharge. 
It is recommended that all patients randomized in the study should receive care consistent with 
the 2018 American Gastroenterological Association (AGA) Institute Technical Review of the 
Initial Medical Management of Acute Pancreatitis. Patients should receive local SOC for the 
management of other medical conditions. 
In patients with AP, the AGA strongly recommends early oral feeding (within 24 hours) rather 
than keeping the patient nil per mouth (Nil per Os, NPO). Patients randomized into the study, 
-calorie solid meal at each mealtime after the infusion of 
the first dose of study drug if alert and not on mechanical ventilation, or if not NPO for a planned 
surgery/medical procedure, or if not NPO because of an acute medical condition. If the patient 
does not wish to eat the solid meal when offered or is unable to tolerate the solid meal, they should 
then be offered a liquid meal. The same approach should occur at each subsequent mealtime until 
discharge. When patients eat a solid meal, it should be recorded if the
therefore, will be offered a low fat, 2'.:500 
y ate 2'.:50% of the meal and 
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if they either vomited or experienced an increase in abdominal pain in the two hours after the 
meal. 
It is also recommended that all patients randomized in the study should not be discharged from 
the hospital until solid food is tolerated, abdominal pain has resolved or been adequately 
controlled, and there is no clinical evidence of infection necessitating continued hospitalization. 
-calorie solid meal without an 
increase in abdominal pain or vomiting. If the patient is not tolerating either solid or liquid 
meals, tube feedings should be considered. 
All protocol required laboratory testing, except biomarker and PK samples, will be performed at 
the local laboratory. Results from the biomarkers and PK blood samples collected as part of the 
protocol and being tested at a central lab will not be available to assist the PI or treating 
physician in managing the patient. 
CalciMedica may submit amendments to the protocol to modify the planned doses, the dosing 
schedule, the infusion time, the number of sites in the study, the total number of patients 
randomized in the study, the number of patients randomized in each group, and the number of 
groups in the study. 
3.2 
End of Study 
The End of Study is considered the date on which the last patient randomized completes the Day 
30 visit, 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 recommendation from the Independent Data Monitoring Committee (IDMC) 
 A directive from the U.S. Food and Drug Administration (FDA)  
 A lack of enrollment 
 
Tolerating solid food is defined as eating ~50% of a low fat, ~500 
• 
• • 
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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. The diagnosis of AP has been established by the presence of abdominal pain consistent 
with AP together with at least 1 of the following 2 criteria: 
a. Serum lipase > 3 times the upper limit of normal (ULN); 
b. Characteristic findings of AP on abdominal imaging; 
2. The diagnosis of SIRS has been established by the presence of at least two of the 
following four criteria: 
a. Temperature < 36°C or > 38°C; 
b. Heart rate > 90 beats/minute; 
c. Respiratory rate >20 breaths/minute or arterial carbon dioxide tension (PaCO2) 
<32 mmHg; 
d. White blood cell count (WBC) >12,000 mm3, or <4,000 mm3, or > 10% immature 
(band) forms; 
3. At least one of the following criteria is present: 
a. A peripancreatic fluid collection or a pleural effusion on a CECT performed in the 24 
hours before Consent or after Consent and before Randomization; 
b. Abdominal examination documenting either abdominal guarding or rebound 
tenderness; 
c. Hematocrit 
% for men or 
% for women; 
4. The patient is 
 
 
5. Lack of pancreatic necrosis, pancreatic calcifications, pancreatic pseudocysts and no 
evidence for previous necrosectomy or pancreatic surgery identified by CECT performed 
in the 24 hours before Consent or after Consent and before Randomization. 
6. A female patient of childbearing potential who is sexually active with a male partner is 
willing to practice acceptable methods of birth control for 180 days after the last dose of 
study drug. A female patient must not attempt to become pregnant for 180 days; 
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 180 days after the last dose of 
study drug. A male patient must not donate sperm for 180 days; 
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. 
2:44 
2:40 
2: 18 years of age; 
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4.2 
Exclusion Criteria 
Patients with any of the following conditions or characteristics must be excluded from 
randomizing: 
1. Expected survival <6 months; 
2. Suspected presence of cholangitis in the judgment of the treating physician; 
3. The patient has a known history of: 
a. Organ or hematologic transplant; 
b. HIV, hepatitis B, or hepatitis C infection; 
c. Chronic pancreatitis (Appendix 7); 
4. Current treatment with: 
a. Chemotherapy; 
b. Immunosuppressive medications or immunotherapy (Section 5.4 for list of prohibited 
immunosuppressive medications and immunotherapy); 
c. Pancreatic enzyme replacement therapy; 
d. Hemodialysis or Peritoneal Dialysis; 
5. The patient is known to be pregnant or is nursing; 
6. The patient has participated in another study of an investigational drug or therapeutic 
medical device in the 30 days before randomization; 
7. Allergy to eggs or known hypersensitivity to any components of study drug. 
4.3 
Re-Screening 
A patient who fails the initial screening, may be rescreened once again (e.g. a reversible cause of 
screen failure has resolved and the subject meets all eligibility criteria).  
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5 
TREATMENT OF PATIENTS 
5.1 
Overview 
All patients randomized in the study should receive care consistent with the 2018 AGA Institute 
Technical Review of the Initial Medical Management of Acute Pancreatitis and local SOC for the 
management of other medical conditions. All protocol required laboratory testing, except 
biomarker and PK samples, will be performed at the local laboratory. Results from the 
biomarkers and PK blood samples collected as part of the protocol and being tested at a central 
lab will not be available to assist the PI or treating physician in managing the patient. 
All CECTs performed as part of the study from Screening to the Day 30 visit will be read by a 
blinded central reader; these scans may also be read locally as necessary and used by the PI or 
treating physician for patient management. 
5.2 
Enhanced Recovery Strategy for Tolerance of Solid Food 
Poor tolerance of solid food is proportional to severity in patients with AP, identified through 
an international Delphi process and validated in a study of 439 patients to be second to organ 
failure in the assessment of AP severity (Buxbaum 2018). Furthermore, as the Phase 2a study 
CM4620-201 showed a marked improvement in tolerance of solid food in association with 
CM4620 administration compared to placebo, this parameter will be measured as the primary 
efficacy endpoint. 
-calorie solid 
meal at each mealtime after the infusion of the first dose of study drug if alert and not on 
mechanical ventilation or if not NPO for a planned surgery/medical procedure, or if not NPO 
because of an acute medical condition. If the patient does not wish to eat the solid meal when 
offered or is unable to tolerate the solid meal, they should then be offered a liquid meal. The 
same approach should occur at each subsequent mealtime until discharge. When patients eat a 
experienced an increase in abdominal pain in the two hours after the meal. Tolerating solid food is 
 
-calorie solid meal without an increase in 
abdominal pain or vomiting in the two hours after the meal. The time when the patient receives a 
solid meal that is then tolerated shall be recorded. If the patient is not tolerating either solid or 
liquid meals, tube feedings should be considered as per the AGA Institute Guideline on Initial 
Management of Acute Pancreatitis. 
5.3 
Discharge Criteria 
The patient randomized to receive study drug should remain in the hospital until all 3 doses of 
study drug have been administered. The criteria for medically indicated discharge from the 
hospital are: 
 Abdominal pain has resolved or is controlled with medications; 
 Solid food is tolerated, which is defined as eating 
500 calorie solid 
meal without an increase in abdominal pain or vomiting; 
Patients randomized into the study will be offered a low fat, ~500 
solid meal, it should be recorded if they ate ~50% of the meal and if they either vomited or 
defined by the consumption of ~50% of a low fat, ~500 
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 There is no clinical evidence of an infection necessitating continued hospitalization. 
In the scenario where the PI or treating physician wants the infusion(s) to begin earlier than the 
24 hour +/- 1 hour window (e.g. the patient is ready to be discharged before all 3 doses of study 
drug have been administered and / or to facilitate an infusion time where study personnel are 
available), the PI or treating physician should contact the medical monitor to discuss whether it is 
appropriate to begin infusion earlier (up to 6 hours earlier) than the 24 hour +/- 1 hour protocol 
window. 
5.4 
Prohibited Medications 
Any medication, with the exception of those listed below, may be given at the discretion of the 
PI. Immunosuppressive medications/immunotherapy that should not be administered during the 
study include: 
 Chemotherapy 
 Cyclosporine, Tacrolimus 
 Sirolimus, Everolimus 
 Azathioprine 
 Cyclosphosphamide 
 Methotrexate 
 Mycophenolate 
 Leflunomide 
 Biologics/Monoclonals: such as, but not limited to, abatacept, adalimumab, 
alemtuzumab, anakinra, basilizimab, belimumab, bevacizumab, brodalumab, 
canakinumab, certolizumab, cetuximab, clazakizumab, daclizumab, eculizumab, 
etanercept, golimumab, guselkumab, infliximab, interferon, ixekizumab, muromonab, 
natalizumab, omalizumab, rituximab, secukinumab, tocilizumab, trastuzumab, 
ustekinumab, vedolizumab,  
 Baracitinib 
 Tofacitinib 
5.5 
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 
Randomization Procedures 
Approximately 216 patients will be randomized 1:1:1:1 into one of 4 groups using a computer-
generated randomization scheme accessed through an IXRS. Randomization will be first 
stratified by gender (male or female) and then by risk for organ failure in the gender subgroups 
(higher or lower). High risker for organ failure is defined by the presence of both an elevated 
2/FiO2 
er risk for organ failure is defined by the absence of either or both an elevated 
hematocrit and hypoxemia (Figure 4). The PaO2/FiO2 will be determined using an arterial blood 
gas or imputed using pulse oximetry (Appendix 5). 
6.2 
Discontinuation and Withdrawal 
The term treatment 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 as treatment discontinuation.  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 AE 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 
s discontinuation from study drug. The PI should also record the reason for 
the treatment discontinuation in the electric case report form (eCRF) and appropriate source 
documents at the site. Even if the patient meets the definition of treatment discontinuation, 
patient should be encouraged to continue participation in the study for all regularly scheduled 
assessments, for safety and for efficacy.   
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 will only be considered as lost to follow-up (LTF) after PI or designee documents they 
are unable to contact patient to complete final study assessment(s) or is unable to ascertain vital 
status (see Section 8.10).  
hematocrit (HCT ?:44% for men or ?:40% for women) and hypoxemia (imputed PaO 
:::;360). Low 
reasons for a patient' 
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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 colored, sterile, non-pyrogenic emulsion containing 1.6 mg/mL of the active 
pharmaceutical ingredient zegocractin. Auxora is supplied as an 80 mL fill in a 100 mL, single-
use glass vial. The drug product is formulated as an emulsion due to the low solubility 
of zegocractin in aqueous solution. 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: 
Auxora 
Dosage Form: 
Injectable Emulsion (Liquid) 
Concentration 
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. 
IV = intravenous  
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 zegocractin. 
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 at each monitoring 
or remote review visit. 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. The stability of Auxora and Placebo has been 
demonstrated to 36 months when stored at 2 to 8oC. 
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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 must be transferred to a 
sterile container a using sterile technique. Specific details on how to calculate and prepare 
Auxora and Placebo, as well as the specific components that will be used to administer Auxora 
and Placebo, will be provided in a Pharmacy Manual. The Pharmacy Manual will also contain 
tables detailing the selected dose level, and the concentration 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 (Section 5.3). 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. If a smaller gauge IV is 
required, please contact the medical monitor. 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 its review of the safety 
and tolerability data. CalciMedica will discuss with the PIs before implementation. For individual 
patients, if the administration of Auxora or Placebo is stopped because of a SAE that is 
considered to be probably or definitely related to Auxora or Placebo, the Medical Monitor must 
be immediately contacted. 
7.6 
Packaging and Labeling 
Preparation, packaging and labeling of Auxora or 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 as 
well as other country requirements, as applicable. 
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7.7 
Accountability, Handling and Disposal 
The PI or designee will ensure that deliveries of Auxora or Placebo from CalciMedica or its 
designee are received by a responsible person, and such deliveries are recorded; that Auxora or 
Placebo is handled and stored safely and properly; that Auxora or Placebo is only dispensed to 
study patients in accordance with the protocol; and that unused Auxora or 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 or Placebo. The pharmacy will maintain a record of Auxora or Placebo accountability. 
The procedure for blinding the administration of study drug, and maintain the blind during the 
study, will be developed and adapted for all sites. 
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8 
VISITS AND 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 unless already 
performed as part of SOC: 
 Record the time of the onset of abdominal pain that sent patient to ER 
 Record demographics and medical history 
 Record list of medications being taken prior to hospitalization 
 Record vital signs closest to the time of informed consent   
 Perform an abdominal examination specifically assessing for guarding and rebound 
tenderness (see Section 8.12.3) 
 Draw serum pregnancy test if the patient is a female of childbearing potential  analyze at 
local lab 
o If already performed as part of SOC, record results. Testing may be performed on 
blood drawn in the previous 12 hours prior to Consent or following consent but prior 
to randomization. 
 Draw a blood sample for serum lipase analyze at local lab 
o If already performed at local lab as part of SOC, record results. Testing may be 
performed on blood drawn in the previous 12 hours prior to Consent or following 
consent but prior to randomization.  
 Draw a blood sample for CBC, differential, and platelets analyze at local lab 
o If already performed at local lab as part of SOC, record results. Testing may be 
performed on blood drawn in the previous 12 hours prior to Consent or following 
consent but prior to randomization. 
 Determine if SIRS is present (see Section 8.12.13) 
 Obtain CECT of the abdomen/pancreas and determine if there is evidence of pleural 
effusion, peripancreatic fluid collection, pancreatic necrosis, pancreatic calcifications, 
pancreatic pseudocysts, and previous necrosectomy/previous pancreatic surgery are 
present on a CECT 
o If CECT already performed in the 24 hours prior to the patient or LAR providing 
informed consent, use results from that CECT (see Section 8.12.12) 
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If the patient satisfies all of the inclusion criteria and none of the exclusion criteria, immediately 
proceed to Baseline Assessment. 
8.2 
Baseline Assessment 
Perform the following prior to randomization: 
 Record height and weight 
 Record SpO2 and the FiO2 (see Section 8.12.6) closest but prior to the time of 
randomization 
 Record the 
pain numeric rating scale (PNRS) scale closest but prior 
to the time of randomization  
 Record the patient s symptoms using the mGCSI-DD worksheet closest but prior to the 
time of randomization 
 Draw blood samples for Serum Procalcitonin and Serum Chemistries - analyze at local lab. 
o If already performed at local lab as SOC, record results. Testing may be performed on 
blood drawn in the previous 12 hours of randomization. 
 Draw blood sample for Serum IL-6  send to central lab. May be performed on blood 
drawn in the previous 12 hours of randomization  
 Obtain urine sample for Urine NGAL - send to central lab. May be performed on urine 
collected in the previous 12 hours of randomization  
8.3 
Randomization Using IXRS System 
8.4 
Start of First Infusion of Study Drug (SFISD) 
The SFISD should begin within 8 hours of the patient or LAR providing informed consent. 
Perform the following procedures immediately prior to the SFISD: 
 Record concomitant medications 
 Infuse the first dose of study drug 
o Record the time of the SFISD 
o Record the time when the infusion is finished 
o Draw blood sample for PK as soon as possible after completion of the first infusion of 
study drug (within +2 hours) 
 Begin Enhanced Recovery Strategy for Tolerance of Solid Food (see Section 5.2) and 
continue daily until patient discharge. 
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8.5 
24 hours  
24 hours from the SFISD: 
 Record concomitant medications 
 Record vital signs closest to the scheduled time of assessment 
 
PNRS closest to the scheduled time of assessment 
 Record SpO2 and the FiO2 (see Section 8.12.6) closest to the scheduled time of 
assessment 
 Determine if, and when the patient tolerated solid food in the previous 24 hours (see 
Section 5.2) 
 Determine if the patient met the medically indicated discharge criteria in the previous 24 
hours (see Section 5.3) 
 Perform AE/SAE assessment 
 Prior to the infusion of the second dose of study drug: 
o Draw blood samples for CBC, differential, platelets, Serum Procalcitonin and Serum 
Chemistries - analyze at local lab. Testing may be performed on blood drawn in the 
previous 12 hours. 
o Draw blood sample for Serum IL-6  send to central lab. Testing may be performed 
on blood drawn in the previous 12 hours. 
o Draw blood sample for PK prior to the infusion of the second dose of study drug 
(within -30 min) - send to central lab. 
o Obtain urine sample for Urine NGAL-send to central lab. Testing may be performed 
on urine collected in the previous 12 hours. 
 Start the infusion of second dose of study drug 24 hours (±1 hour) from the SFISD 
(see Section 5.3) 
o Record the time when the infusion starts and finishes 
8.6 
48 hours  
48 hours from the SFISD: 
 Record concomitant medications 
 Record vital signs closest to the scheduled time of assessment 
 Record t
PNRS closest to the scheduled time of assessment 
 Record SpO2 and the FiO2 (see Section 8.12.6) closest to the scheduled time of 
assessment 
 Determine if, and when the patient tolerated solid food in the previous 24 hours (see 
Section 5.2) 
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 Determine if the patient met the medically indicated discharge criteria in the previous 24 
hours (see Section 5.3) 
 Perform AE/SAE assessment 
 Prior to the infusion of the third dose of study drug: 
o 
Draw blood samples for CBC, differential, platelets, Serum Procalcitonin and 
Serum Chemistries  analyze at local lab. Testing may be performed on blood 
drawn in the previous 12 hours. 
o 
Draw blood sample for Serum IL-6  send to central lab. Testing may be performed 
on blood drawn in the previous 12 hours. 
o 
Obtain urine sample for Urine NGAL - send to central lab. Testing may be 
performed on urine collected in the previous 12 hours. 
 Start the infusion of third dose of study drug 48 hours (±1 hours) from the SFISD 
(see Section 5.3) 
o 
Record the time that the infusion starts and finishes 
 Assess whether patient discharge is upcoming and whether mGCSI-DD worksheets need 
to be dispensed per Section 8.12.10. 
8.7 
72 hours 
For patients who remain hospitalized 72 hours from the SFISD: 
 Record concomitant medications 
 Record weight closest to the scheduled time of assessment 
 Record vital signs closest to the scheduled time of assessment 
 
PNRS closest to the scheduled time of assessment 
 Record SpO2 and the FiO2 (see Section 8.12.6) closest to the scheduled time of 
assessment 
 Determine if, and when the patient tolerated solid food in the previous 24 hours (see 
Section 5.2) 
 Determine if the patient met the medically indicated discharge criteria in the previous 24 
hours (see Section 5.3) 
 Perform AE/SAE assessment 
 Draw blood samples for CBC, differential, platelets, Serum Procalcitonin and Serum 
Chemistries  analyze at local lab. Testing may be performed on blood drawn in the 
previous 12 hours or + 2 hours from assessment. 
 Draw blood sample for Serum IL-6  send to central lab. Testing may be performed on 
blood drawn in the previous 12 hours or + 2 hours from assessment. 
 Draw blood sample for PK ± 2 hours  send to central lab 
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 Obtain urine sample for Urine NGAL - send to central lab. Testing may be performed on 
urine collected in the previous 12 hours or + 2 hours from assessment.  
 Assess whether patient discharge is upcoming and whether mGCSI-DD worksheets need 
to be dispensed per Section 8.12.10. 
8.8 
96, 120, 144, 168, 192, 216, 240 hours (±4 hours) 
For patients who remain hospitalized 96, 120, 144, 168, 192, 216, and 240 hours from the SFISD: 
 Record concomitant medications 
 Record vital signs closest to the scheduled time of assessment 
 
PNRS closest to the scheduled time of assessment 
 Record SpO2 and the FiO2 (see Section 8.12.6) closest to the scheduled time of 
assessment 
 Determine if, and when the patient tolerated solid food in the previous 24 hours (see 
Section 5.2) 
 Determine if the patient met the medically indicated discharge criteria in the previous 24 
hours (see Section 5.3)  
 Perform AE/SAE assessment 
 Assess whether patient discharge is upcoming and whether mGCSI-DD worksheets need 
to be dispensed per Section 8.12.10. 
 If the patient remains hospitalized 96 hours from the SFISD, 
symptoms using the mGCSI-DD worksheet 
 If the patient remains hospitalized 168 hours (Day 7) from the SFISD, record the 
-DD worksheet 
In addition, for patients who remain hospitalized 120, 168, and 216 hours from the SFISD: 
 Draw blood samples for CBC, differential, platelets, Serum Procalcitonin, and Serum 
Chemistries  analyze at local lab. Testing may be performed on blood drawn in the 
previous 12 hours or + 4 hours from assessment. 
 Draw blood sample for Serum IL-6  send to central lab. Testing may be performed on 
blood drawn in the previous 12 hours or + 4 hours from assessment. 
 Obtain sample for Urine NGAL - send to central lab. Testing may be performed on urine 
collected in the previous 12 hours or + 4 hours from assessment. 
8.9 
Days 12 to 28 (±4 hours) 
For patients who remain hospitalized 12, 14, 16, 18, 20, 22, 24, 26, and 28 days from the SFISD: 
 Determine if, and when the patient tolerated solid food in the previous 48 hours 
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 Determine if the patient met the medically indicated discharge criteria in the previous 48 
hours (see Section 5.3) 
 Perform AE/SAE assessment 
 Assess whether patient discharge is upcoming and whether mGCSI-DD worksheets need 
to be dispensed per Section 8.12.10. 
 If the patient remains hospitalized at Day 14 and Day 21, request the patient record their 
symptoms at bedtime using the mGCSI-DD worksheet (see Section 8.12.10). 
8.10 
Day 30 (±5 days) 
Patients who had been discharged from the hospital before Day 25, should return on Day 30 for 
the following assessments:  
 Record the 
etiology of the AP episode 
 Record weight 
 Perform CECT of the pancreas. May be performed in the 5 days before or after the visit. 
 Collect mGCSI-DD worksheets from the patient 
 Record concomitant medications 
 Record vital signs 
 
 
 Record SpO2 and the FiO2 (see Section 8.12.6) 
 Perform AE/SAE assessment 
 Draw blood samples for CBC, differential, platelets, Serum Procalcitonin, and Serum 
Chemistries  analyze at local lab 
 Draw blood sample for Serum IL-6  send to central lab 
 Draw a blood sample for PK - send to central lab 
 Obtain sample for Urine NGAL - send to central lab 
For patients discharged from the hospital on Days 25-29, the Day 30 assessments may be 
performed on the Day of discharge. 
 Patients who are discharged from the hospital on Days 25-29 will not complete the 
mGCSI-DD after discharge. They will only complete it on the day of discharge. 
For patients who remain hospitalized on Day 30, the following additional assessment will be 
performed: 
 Determine if, and when the patient tolerated solid food in the previous 48 hours 
 Determine if the patient met the medically indicated discharge criteria in the previous 48 
hours (see Section 5.3) 
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For patients that do not return for Day 30 visit and have not withdrawn consent, the Investigator 
or designee will continue to contact patient by phone to return for on-site visit up to eight weeks 
following visit date. Although an out of window visit assessment would be considered a protocol 
deviation, investigators should attempt to obtain as much as possible all of the Day 30 visit 
assessments, including the Day 30 CECT.   
If patient is not reachable by phone after four weeks following the planned Day 30 visit, the 
Investigator or designee will send certified letter to last known address to request patient to 
contact Investigator to either schedule Day 30 visit or at least confirm patient is still alive by 
telephone. If patient does not respond to certified letter or if patient had withdrawn consent, the 
Investigator or designee will check public records (e.g., vital records search) to determine if the 
patient had died prior to the scheduled Day 30 visit or can be assumed alive for the purposes of 
study follow-up.  
8.11 
Discharge Date 
The time and date of discharge will be recorded as well as if the patient meets criteria for 
medically indicated discharge. All patients will be trained to complete the mGCSI-DD and will 
complete the mGCSI-DD before leaving the hospital. If patients are discharged on Days 25-29, 
they may complete the Day 30 assessments on the day of discharge.  Following discharge, the 
Investigator or designee should contact patient by telephone once per week to confirm diary 
completion and patient agrees to return for Day 30 visit. 
If a patient is admitted to a hospital following discharge but prior to Day 30 visit, Investigator 
will report the reason for the hospitalization as per serious adverse event reporting guidelines 
(See Section 9.2 and Section 9.7).  As the patient is still within the study period, investigators or 
designee should resume collection of study procedures as per Schedule of Events (See 
Appendix 8). If patient is not admitted to the hospital where the study is being conducted, 
investigators are asked to record any procedures (i.e., invasive mechanical ventilation) received 
while patient was admitted during the study period within an unscheduled procedures form in the 
eCRF. 
8.12 
Study Assessments 
8.12.1 
Demographics, Medical History and Medications 
To the extent possible 
 medical history including family 
history of pancreatitis and smoking history will be collected at Screening. Demographic data will 
be collected and will include self-reported race, ethnicity and gender. Patients must be specifically 
questioned if they have had previous episodes of AP and if they have chronic pancreatitis, diabetes 
mellitus, hypertension, coronary or cerebrovascular disease, and chronic obstructive pulmonary 
disease, as well as those conditions noted in the exclusion criteria. The extent of alcohol 
consumption will be collected. Selected medications that were being taken prior to coming to the 
emergency department will be collected as will, if available, a baseline serum creatinine. 
given the patient's medical condition, a 
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8.12.2 
Concomitant Medications 
The name, dose and frequency of selected medications that were administered will be recorded. 
The time, dose, and route of administration of opioid pain medications that are actually 
administered will be recorded. Generic names should be used when possible. 
8.12.3 
Abdominal Examination 
An abdominal examination will be performed and recorded at Screening to assess if the patient 
has abdominal guarding or rebound tenderness. For eligibility purposes, an abdominal 
examination completed as SOC within 12 hours of consent or following consent but prior to 
randomization may be used for Inclusion Criterion 3b. Guarding is the voluntary contraction or 
involuntary spasm of the abdominal wall musculature to avoid pain from palpation of the 
abdomen and/or protect underlying inflamed viscera. Rebound tenderness is the elicitation of 
tenderness by rapidly and smoothly removing the examining hand. In addition, the presence or 
absence of the following symptoms should also be recorded at screening: bruising in the 
subcutaneous fatty tissue around the umbilicus and bruising in the flanks. 
8.12.4 
Vital Signs 
T
er minute), systolic and diastolic blood pressures 
and respiratory rate (breaths per minute) closest to the time of assessment should be recorded. If 
intra-abdominal pressures are being monitored, the pressure closest to the time of assessment 
should be recorded. 
8.12.5 
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. 
 
 
he patient's temperature, heart rate (beats p 
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8.12.6 
SpO2/FiO2 
The SpO2 will be determined using a hospital approved pulse oximeter. The PI or appropriately 
trained delegate 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 2009 
8.12.7 
Laboratory Analyses 
At Screening, a lipase, CBC, differential, and platelets, will be performed at the local lab. For 
eligibility purposes, the results of the CBC collected within 24 hours of consent or following 
consent but prior to randomization will be used to determine the presence of SIRS (see Section 
8.12.13) and a Hematocrit collected as SOC within 12 hours of consent or following consent but 
prior to randomization may be used for Inclusion Criterion 3c. 
CBC with Differential and Platelets will be performed at 24, 48 and 72 hours, and if the patient 
remains hospitalized, at 120, 168, and 216 hours following SFISD as well as at Day 30 
assessment. These samples will be sent to the local laboratory for analysis. 
Serum Chemistries and Serum Procalcitonin will be performed at Baseline, 24, 48 and 72 hours, 
and if the patient remains hospitalized, at 120, 168, and 216 hours following SFISD as well as at 
Day 30 assessment. These samples will be sent to the local laboratory for analysis. 
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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, 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 the laboratory tests because it is not offered at the site, it will 
not be performed on patients randomized at the site.  
Blood and urine samples for biomarker assessments (non-genetic testing) including, but not 
limited, to blood samples for IL-6 and urine samples for urine NGAL will be collected at 
baseline, 24, 48, and 72 hours, and if the patient remains hospitalized, at 120, 168, 216 hours 
following SFISD as well as at Day 30 assessment. A reference laboratory will analyze these 
blood and urine samples. The results of these assays will not be available to the PI or treating 
physician in managing the patient. It is the expectation that all sites participate in biomarker 
collection; however, if a site is unable to provide blood or urine samples for the biomarker 
analysis, this will be determined at study start and not considered a protocol deviation for that 
site. In addition, if a site is participating in biomarker collection but a patient does not want to 
provide biomarker samples this will be documented in the informed consent and not considered a 
protocol deviation. 
8.12.8 
PK analysis 
Blood samples for PK analysis will be drawn as soon as possible after the completion of the first 
infusion of study drug (within +2 hours), prior to the start of second infusion of study drug 
(within -30 min), and at 72 hours (±2 hours) from the SFISD. If the patient is discharged after the 
third infusion of study drug and prior to 72 hours from the SFISD, the blood sample will be 
drawn prior to discharge. A PK sample will also be drawn at Day 30. The date and time that the 
sample for PK analysis is drawn shall be recorded. All samples for PK analysis should be stored 
at either -20°C or -80°C until shipment on dry ice to the central laboratory. As with the 
biomarkers, it is the expectation that all sites participate in the PK sample collection; however, if 
a site is unable to provide blood for the PK analysis, this will be determined at study start and not 
considered a protocol deviation for that site. In addition, if a site is participating in PK collection 
but a patient does not want to provide PK samples this will be documented in the informed 
consent and not considered a protocol deviation. 
8.12.9 
Enhanced Recovery Strategy for Tolerance of Solid Food 
-calorie solid meal at each 
mealtime after the infusion of the first dose of study drug until discharge if alert and not on 
mechanical ventilation, or if not NPO for a planned surgery/medical procedure, or if not NPO 
because of an acute medical condition. See Section 5.2 for specific assessment procedures. 
Patients randomized into the study will be offered a low fat, 2:500 
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8.12.10 
Modified ANMS GCSI-Daily Diary (mGCSI-DD) 
The ANMS GCSI Daily Diary was designed to assess gastrointestinal symptoms associated with 
idiopathic and diabetic gastroparesis. It has been shown to be a reliable tool to evaluate 
dysmotility in patients with AP (Ma 2016). It will be used to assess gastrointestinal symptoms 
associated with AP in an exploratory manner. The mGCSI-DD has a 24-hour recall; thus, all 
items are designed to be self-administered on a daily basis. 
The patient training for completing the daily diary is provided by the PI or appropriately trained 
delegate. Patients should understand their disorder: AP, where there is an abnormally delayed 
emptying of food from the stomach because of inflammation in the pancreas. The mGCSI-DD 
recording sheet and instructions are reviewed with the patient prior to the patient starting the 
recording of daily symptoms in the diary. The symptom severity response items are reviewed: 
For each symptom listed below, please mark with an X the box that best describes the worst 
severity of each symptom during the past 24 hours. The next question asks you to record the 
number of times vomiting occurred in the last 24 hours. Please record the number of vomits 
(throwing up with food or liquid coming out) that occurred in the last 24 hours. Record zero, if 
you have not vomited during the past 24 hours. If you vomited, write down the number of all 
vomits. If you vomited once, record one. If you vomited three times during the day, record three. 
If you vomited three times, whether it was during the same trip to the bathroom or three separate 
trips, record three as the number of episodes of vomiting   
Patients discharged before Day 25 will complete the daily diary on the day of discharge, and then 
after discharge, daily at bedtime until the Day 30 visit. 
8.12.11 
Pain Numeric Rating Scale (PNRS) 
In patients who are able to self-report their pain, the Pain Numeric Rating Scale (Appendix 4) 
will be used to grade the severity of the abdominal pain. It should be recorded if an opioid 
analgesic had been given in the 2 hours prior to the PNRS determination. 
8.12.12 
Contrast-Enhanced Computed Tomography (CECT) of the 
Abdomen/Pancreas 
The recommended CECT protocol will consist of: 
 A non-ionic contrast bolus of 100-150cc will be administered at 3-5cc/second 
 Slice thicknesses will be 5 mm or less and will be obtained through the pancreas during 
the pancreatic phase (35 seconds after the start of the non-ionic contrast bolus) and 
through the entire abdomen during the portal venous phase (50 to 70 seconds after the 
start of the non-ionic contrast bolus) to visualize the pancreas and surrounding tissue 
 
If CECT is not available (e.g. medical contraindication to contrast medium used in CECT) and 
another appropriate imaging is available (e.g. MRI, MRCP), please contact medical monitor to 
discuss whether local SOC imaging can be used for eligibility and Day 30 purposes.  
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CECT contrast protocol may be altered to local SOC. The lack of perfusion of the pancreas on 
the CECT will be exclusionary. If a CECT had already been performed more than 24 hours but 
less than 48 hours before Consent, and there is a contraindication to repeating it, the PI should 
discuss with the medical monitor if the CECT may be used for evaluating the inclusion and 
exclusion criteria for the study.  
The PI or treating physician may also elect to delay the Day 30 CECT (±5 days) due to patient-
specific safety considerations but must inform the Medical Monitor of the decision. The PI or 
treating physician may also elect not to perform the CECT because of futility considerations, 
e.g., the patient is unlikely to survive in the next 48 hours but must discuss the decision with the 
Medical Monitor. 
The CECT may also be used to make the diagnosis of chronic pancreatitis. Patients with a 
diagnosis of chronic pancreatitis in the chart or who self-report chronic pancreatitis but 
are neither on enzyme replacement nor following up with a gastroenterologist as 
an outpatient, should be considered for the study after a careful review of a CECT (Appendix 7). 
If the findings in the mild-moderate or severe categories are not present on the CECT, please 
contact the medical monitor to discuss whether the patient would be appropriate for 
randomization if they meet the other inclusion and none of the exclusion criter
criteria do not exclude patients from randomization. 
The Screening and Day 30 CECTs will be read by a blinded central reader. They will also be 
read locally and may be used by the PI or treating physician, as needed, for patient management. 
If the patient undergoes additional CECTs at the discretion of the PI or treating physician from 
randomization to the Day 30 visit, the date of the CECT will be recorded and a blinded central 
reader will read the images. 
8.12.13 
Systemic Inflammatory Response Syndrome (SIRS) 
The physician, or appropriately trained designee will determine the presence of SIRS at 
Screening. The most extreme value for each criterion in the 24 hours before consent may be 
used. SIRS is defined as the presence of at least 2 of the 4 criteria: 
 Temperature < 36°C or > 38°C 
 Heart rate > 90 beats/minute 
 Respiratory rate > 20 breaths/minute or arterial carbon dioxide tension (PaCO2) 
< 32 mmHg 
 White blood cell count (WBC) >12,000 mm3, or < 4,000 mm3, or > 10% immature 
(band) forms 
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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 study drug 
 Is an important medical event 
-
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 
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 
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, the site is closed, 
or CalciMedica ends the trial, whichever is first. 
AEs 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 
 
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 
emergency) because the pre-existing condition worsens, the worsening condition should be 
captured as an AE. 
as, "how have you been feeling since your last visit?" to elicit any medically related changes in 
patient's participation in the 
• • 
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in the patient's source documents. If a planned procedure is performed early ( e.g., as an 
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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, 
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 
pation 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 AE for which there is a reasonable possibility that 
the drug caused the AE
CalciMedica determines that there is evidence to suggest a causal 
relationship between the drug and the AE (definite, probable, possible) regardless of the 
assessment 
 Adverse reaction means any AE 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 AE or suspected adverse reaction refers to an event or reaction that is not 
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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patient's partici 
possibility' means 
investigator's causality 
. For the purposes of IND safety reporting, 'reasonable 
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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. 
In addition, if any of the events below, which are commonly observed 
anticipated in 
this patient population, are reported as a SAE, they will not be reported to the regulatory 
authority as individual expedited reports except in unusual circumstances or if required by local 
regulations: 
 Hypoxemia and acute respiratory distress syndrome 
 Oliguria and acute kidney injury 
 Hypotension and shock 
 Bacteremia 
 Pneumonia 
 Obtundation 
 Splanchnic venous thrombosis 
 Abdominal compartment syndrome 
 Gastroparesis and ileus 
 Local complications of the pancreas and peripancreatic tissue 
 Percutaneous insertion of abdominal drains 
 Endoscopic necrosectomy 
 ERCP 
 Abdominal surgery including but not limited to cholecystectomy, pancreatic 
necrosectomy, and placement of pancreatic drains 
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 
and thus' 
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180 days after last dose of study drug. No contraception is required if a female patient or partner 
has undergone a bilateral salpingo-oophorectomy. 
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 180 days 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 9.3 or a more recent version 
(SAS Institute Inc., Cary, NC, USA). 
The statistical analysis plan (SAP) 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 SAP, if any. 
The statistical analysis approach will be descriptive, exploratory and inferential to determine the 
relationship between dose response and endpoints in identifying the optimal dose and primary 
endpoint(s); also, in identifying the priority order of sequential testing for secondary endpoints. 
10.2 
Sample Size 
A sample size of 216 patients will be randomized into four groups on a 1:1:1:1 basis, resulting in 
54 patients randomized into each group. This sample size will provide 86% power for testing the 
difference in two populations having a median length of time of 72 and 144 hours, respectively, 
to tolerating solid food based on a log-rank test. This sample size will provide 80% power with a 
two-sided alpha of 0.05 (using the chi-squared test) to detect a 45% response rate for tolerating 
solid food in a Auxora dose group versus a 20% response rate in the Placebo group in the 72 
hours after completion of the first study drug infusion. 
10.3 
Study Assessments 
Efficacy assessments will include: 
 Enhanced Recovery Strategy for Tolerance of Solid Food 
 Modified Gastrointestinal Cardinal Symptom Index Score 
 CECT of the Pancreas 
 PNRS score 
 Organ Failure scores 
 Vital sign measurements 
 Laboratory measurements  
 Concomitant medications 
Safety assessments will include: 
 Vital signs measurements 
 Laboratory measurements 
 Concomitant medications 
 TEAEs and SAEs 
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PK assessments and analyses will include: 
 Adding the plasma concentration data to the current population PK model to refine the 
model and covariate analysis 
 Using the revised population PK model to determine if AP disease severity alters PK 
properties of CM4620 
 Determining whether a relationship exists between plasma trough levels of CM4620 and 
patient response to Auxora (i.e., an exposure-response relationship) 
10.4 
Analysis Sets 
10.4.1 
Efficacy and Safety 
The efficacy analyses will be performed on the Modified Intent-to-treat Population (MITT) 
consisting of all randomized patients who receive any amount of study drug. 
As the sensitive analysis, the primary efficacy analyses will also be performed on the Per-Protocol 
Population (PP) consisting of all randomized patients who complete the study and have no major 
protocol violations. 
The safety analyses will be performed on MITT data set. 
10.4.2 
Pharmacokinetics 
The PK population will consist of all randomized patients who receive any amount of active 
study drug and who have at least one post baseline PK sample analyzed. 
10.5 
Disposition 
The number and percentage (n, %) of patients enrolled, screen failed, treated, completed study, 
and discontinued (with reason) will be summarized. Sample size for each analysis population 
will be identified for each treatment group. All screened patients will be included in the 
disposition analysis. 
10.6 
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. 
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10.7 
Efficacy Analysis 
The efficacy endpoints are the following: 
Primary endpoint 
 
Time to solid food tolerance 
Secondary endpoints 
 
Solid food tolerance at 48 hours, 72 hours, and 96 hours after the SFISD and at 
discharge 
 
Time to medically indicated discharge 
 
Length of stay in the hospital 
 
Length of stay in the ICU for patients admitted to the ICU 
 
Re-hospitalization for AP by Day 30 
 
Change in severity of AP by CTSI score from screening to Day 30 
 
 
 
 
 
Incidence, severity, and duration of organ failure 
 
Mortality by Day 30 
 
Change in pain score and opioid use 
Exploratory endpoints 
 
Development of infected pancreatic necrosis 
 
Development of sepsis 
 
Hospital procedures for the management of pancreatic necrosis 
 
Change in GCSI-DD score 
 
Change in albumin 
 
Change in ANC/ALC ratio and IL-6 levels 
 
Change in urine NGAL 
Time to solid food tolerance is the number of hours from the date and time of the SFISD for the 
patient to the first date and time the patient receives a solid meal that is tolerated, which is 
500-calorie solid meal without an increase in abdominal 
pain or vomiting in the two hours after completing the meal.  
Time to solid food tolerance for patients who could not tolerate solid food during the study will 
be censored on the latest date and time of food tolerance assessment.  
Time-to-event endpoints will be summarized using Kaplan-Meier analyses. The medians and 
quartiles of time-to-events will be summarized. Time to solid food tolerance will be compared 
between each treatment groups and the placebo group using the stratified log-rank test as the 
primary analysis. The tests will be at an alpha level of 0.05 without multiplicity adjustment. The 
stratification variables will include gender (male vs. female) and disease severity status (higher 
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Development of pancreatic necrosis 2:30% and >50% 
• 
The persistence of SIRS 2:48 hours after the SFISD 
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risk for organ failure defined by the presence 
 
and a PaO2/FiO2 
 (Figure 4). 
In addition, the hazard ratio (HR) and the 95% CI will be estimated using a Cox proportional-
hazard model with treatment group as the independent variable and stratified by the same 
randomization stratification factors as used for the log-rank test. 
Percentage of patients who tolerated solid food at 48, 72 and 96 hours from the SFISD will be 
summarized and plotted by treatment groups across time points. The solid food tolerance rate at 
72 hours will be compared between the treatment groups and the placebo group using a Cochran-
Mantel-Haenszel (CMH) test at an alpha level of 0.05 stratified by gender (male vs. female) and 
disease severity status (higher risk for organ failure defined by the presence 
 and a PaO2/FiO2 
 (see Figure 4). The 
Mantel-Haenszel weighted difference in complete response (CR) rate between the treatment 
groups and the placebo group and its 2-sided 95% CI will be provided. 
In addition, the odds ratio (OR) and the 95% CI will be estimated using a logistic regression 
model with treatment group as the independent variable and stratified by the same randomization 
stratification factors as used for the CMH test. 
Time to medically indicated discharge is the number of days from the SFISD to the date of 
meeting discharge criteria in Section 5.3 and will be compared between each treatment group 
and the placebo group using the stratified log-rank test.  patients who could tolerate solid food 
and who could not tolerate solid food at 48, 72, and 96 hours using Kaplan-Meier curve and log-
rank test. 
Other secondary and exploratory efficacy endpoints will be summarized with details described in 
the separate SAP. 
10.8 
Safety Analysis 
Safety will be assessed by subject 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.  TEAEs are defined as 
events that first occurred or worsened after the first dose of study drug. TEAEs will be mapped 
to the appropriate SOC and 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 as follows: 
 By maximum severity 
 Incidence by SOC (by severity grade and overall) 
 Incidence by PT (by severity grade and overall) 
:'.S360 before randomization 
for men, or ~40% for women, 
• • 
• 
of both a HCT ~44% for men, or ~40% for women, 
of both a HCT ~44% 
:'.S360 before randomization 
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The percentage of 30 day all-cause mortality will be calculated based on each subject's date of 
death relative to first dose of study treatment and tabulated by treatment groups. 
Laboratory test results will be used in the summary. The lower and upper reference range values 
for blood 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 PTs, 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. 
10.9 
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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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 visit or remotely review the site
 periodically and 
maintain necessary telephone and letter contact with the PI and his/her study staff. The site 
y activity by observing the conduct 
of the study at the site, reviewing study records and source documentation, 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 direct access to all study records to 
assist study-related monitoring and audits, Institutional Review Board/Ethics 
Committee/Research Ethics Board (IRB/EC) 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. 
's study activities 
monitor will maintain current knowledge of each site's stud 
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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 
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. 
of the patient ( or the patient's legal representative) except as necessary for monitoring and 
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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 its 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 Deviations 
The PI or designee must document any protocol deviation. Reporting of protocol deviations to 
the appropriate IRB/EC is the responsibility of the PI and must follow the applicable IRB/EC 
guidelines. A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. 
As referenced in ICH E3, the definition of important protocol deviations for a particular trial is 
determined in part by study design, the critical procedures, study data, subject protections 
described in the protocol, and the planned analyses of study data. In keeping with the flexibility 
of the guidance, sponsors can amend or add to the examples of important deviations provided in 
 
ICH E3 in consideration of a trial's requirements. 
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For the purposes of this study, an important protocol deviation is one that has an impact on 
subject safety, may substantially alter risks to subjects, may have an effect on the integrity of the 
dy. 
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. 
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 
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) 
 A current Curriculum Vitae for the PI and each sub-Investigator listed on Form FDA 
1572. Evidence of licensure must be noted on the Curriculum Vitae or a copy of the 
license must be provided.  
 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. 
study data, or may affect the subject's willingness to participate in the stu 
financially responsible for the treatment of the patient's 
• 
• 
• 
• 
• 
• 
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 Laboratory certifications and normal ranges for any laboratories used by the site for the 
conduct of the study. 
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. 
• 
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Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS, 
Acute Pancreatitis Classification Working G. Classification of acute pancreatitis--2012: revision 
of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102-11. 
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Buxbaum J, Quezada M, Chong B, Gupta N, Yu CY, Lane C, Da B, Leung K, Shulman I, Pandol 
S, Wu B. The Pancreatitis Activity Scoring System predicts clinical outcomes in acute 
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Byers SO, Friedman M, Sugiyama T. Mechanism underlying phosphatide-induced 
hypercholesterolemia. J Biol Chem. 1962;237:3375-80. 
Criddle DN. Reactive oxygen species, Ca(2+) stores and acute pancreatitis; a step closer to 
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Dellinger EP, Forsmark CE, Layer P, Levy P, Maravi-Poma E, Petrov MS, Shimosegawa T, 
Siriwardena AK, Uomo G, Whitcomb DC, Windsor JA, Pancreatitis Across Nations Clinical R, 
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Fowler AA, III, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR, 
2nd, Natarajan R, Brophy DF, Sculthorpe R, Nanchal R, Syed A, Sturgill J, Martin GS, 
Sevransky J, Kashiouris M, Hamman S, Egan KF, Hastings A, Spencer W, Tench S, Mehkri O, 
Bindas J, Duggal A, Graf J, Zellner S, Yanny L, McPolin C, Hollrith T, Kramer D, Ojielo C, 
Damm T, Cassity E, Wieliczko A, Halquist M. Effect of Vitamin C Infusion on Organ Failure 
and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute 
Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 
 
Freedman, S., & Forsmark, C. Chronic Pancreatitis: Clinical Manifestations and Diagnosis in 
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Gerasimenko JV, Gryshchenko O, Ferdek PE, Stapleton E, Hebert TO, Bychkova S, Peng S, 
Begg M, Gerasimenko OV, Petersen OH. Ca2+ release-activated Ca2+ channel blockade as a 
potential tool in antipancreatitis therapy. Proc Natl Acad Sci U S A. 2013;110(32):13186-91. 
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2018;154(4):1096-101. doi: 10.1053/j.gastro.2018.01.032. 
2019;322(13):1261-70. doi: 10.1001/jama.2019.11825. 
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Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet. 2015;386(9988):85-96. 
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Lindkvist B, Appelros S, Manjer J, Berglund G, Borgstrom A. A prospective cohort study of 
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Lur G, Haynes LP, Prior IA, Gerasimenko OV, Feske S, Petersen OH, Burgoyne RD, Tepikin 
AV. Ribosome-free terminals of rough ER allow formation of STIM1 puncta and segregation of 
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pancreatic acinar cell. I. Permeability properties. Am J Physiol. 1988;255(2 Pt 1):G221-8. 
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Tolstrup JS, Kristiansen L, Becker U, Gronbaek M. Smoking and risk of acute and chronic 
pancreatitis among women and men: a population-based cohort study. Arch Intern Med. 
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Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, 
Gomersall C, Sakr Y, Reinhart K, Investigators EIGo. International study of the prevalence and 
outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-9. 
Waldron RT, Chen Y, Pham H, Go A, Su HY, Hu C, Wen L, Husain SZ, Sugar CA, Roos J, 
Ramos S, Lugea A, Dunn M, Stauderman K, Pandol SJ. The Orai Ca(2+) channel inhibitor 
CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental 
acute pancreatitis. J Physiol. 2019;597(12):3085-105. doi: 10.1113/jp277856. 
Wen L, Voronina S, Javed MA, Awais M, Szatmary P, Latawiec D, Chvanov M, Collier D, 
Huang W, Barrett J, Begg M, Stauderman K, Roos J, Grigoryev S, Ramos S, Rogers E, Whitten 
J, Velicelebi G, Dunn M, Tepikin AV, Criddle DN, Sutton R. Inhibitors of ORAI1 Prevent 
Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis 
in 3 Mouse Models. Gastroenterology. 2015;149(2):481-92 e7. 
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Appendix 1. 
Definition of Organ Failure and Sepsis 
The definition of organ failure encompasses three organ systems, respiratory system, renal 
system and cardiovascular system. 
For the respiratory system, organ failure will be defined as: 
 PaO2/FiO2 300 determined by arterial blood gas or imputed using pulse oximetry, or 
 The use of high flow nasal cannula, non-invasive or invasive mechanical ventilation 
For the renal system, in patients without known chronic kidney disease (baseline eGFR 
 mL/min/1.73 m2), organ failure will be defined as: 
 An 
00% if the baseline creatinine is known from prior to 
the hospitalization for AP, or  
 A serum c
 
 The initiation of renal replacement therapy 
For patients with pre-existing chronic kidney disease (baseline GFR <60 mL/min/1.73 m2), 
organ failure will be defined as: 
 
300% if the baseline creatinine is known from prior to 
the hospitalization for AP, or 
 An increase of serum creatinine to a level >4.0 mg/dl, or 
 The initiation of renal replacement therapy 
For the cardiovascular system, organ failure will be defined as: 
 A systolic blood pressure <90 mmHg that is not fluid responsive, or 
 The use of either vasopressor or inotropic support 
 
Sepsis is the life-threatening organ dysfunction caused by a dysregulated host response to 
infection. For this study, organ dysfunction in the setting of infection will be defined by the 
presence of one of the following criteria: 
 PaO2/FiO2 300 determined by arterial blood gas or imputed using pulse oximetry 
 The use of noninvasive or invasive mechanical ventilation 
 Platelet count <100 x103/uL 
 
 
 The use of vasopressor or inotropic support 
 
 mg/dL in patients without pre-existing chronic kidney disease 
• 
• 
~60 
< 
• 
increase in serum creatinine ~3 
• 
reatinine ~1.9 mg/dL, or 
• 
• 
An increase in serum creatinine ~ 
• 
• 
• 
• 
• 
• 
• 
< 
• 
Total bilirubin ~2.0 mg/dL 
• 
• 
Serum creatinine ~1.9 
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 Serum creatinine >4.0 mg/dL in patients with pre-existing chronic kidney disease 
 
the hospitalization for acute pancreatitis 
 The initiation of renal replacement therapy 
Modified Marshall Scoring System: Organ Dysfunction in Acute Pancreatitis 
 
 
0 
(None) 
1 
(None) 
2 
(Mild) 
3 
(Moderate) 
4 
(Severe) 
Respiratory PaO2/FiO2 
>400 
301-400 
201-300 
101-200 
 
Renal 
Serum Cr 
mg/dL 
<1.4  
1.4-1.8 
1.9-3.6 
3.7-4.9 
>4.9 
CV 
no inotrope 
SBP mmHg 
 
<90 fluid 
responsive 
<90 
not fluid 
responsive 
<90, 
pH <7.3 
<90, 
pH <7.2 
CV = cardiovascular  
Adapted from Banks 2013 
• 
• 
An increase in serum creatinine 2:300% if the baseline creatinine is known from prior to 
• 
:::;100 
2:90 
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Appendix 2. 
American Gastroenterological Association Institute Guideline 
on the Initial Management of Acute Pancreatitis 
 
Recommendation 
Strength 
Quality 
1a. 
In patients with AP, the AGA suggests using goal-directed therapy for 
fluid management. 
Comment: The AGA makes no recommendation whether normal saline 
 
Conditional 
Very Low
1b.
In patients with AP, the AGA suggests against the use of HES fluids 
Conditional 
Very Low
2 
In patients with predicted severe AP and necrotizing AP, the AGA 
suggests against the use of prophylactic antibiotics 
Conditional 
Low 
3 
In patients with acute biliary pancreatitis and no cholangitis, the AGA 
suggests against the routine use of urgent ERCP 
Conditional 
Low 
4 
In patients with AP, the AGA recommends early (within 24 h) oral 
feeding as tolerated, rather than keeping the patient nil per os 
Strong  
Moderate 
5 
In patients with AP and inability to feed orally, the AGA recommends 
enteral rather than parenteral nutrition 
Strong 
Moderate 
6 
In patients with predicted severe or necrotizing pancreatitis requiring 
enteral tube feeding, the AGA suggests either NG or NJ route 
Conditional 
Low 
7 
In patients with acute biliary pancreatitis, the AGA recommends 
cholecystectomy during the initial admission rather than after discharge Strong 
Moderate 
8 
In patients with acute alcoholic pancreatitis, the AGA recommends 
brief alcohol intervention during admission 
Strong 
Moderate 
AGA = American Gastroenterological Association; AP = acute pancreatitis; ERCP = endoscopic retrograde 
cholangiopancreatography; HES = hydroxyethyl starches; NG = nasogastric; NJ = nasojejunal  
Adapted from Crockett 2018 
or Ringer's lactate is used 
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Appendix 3. 
CTSI Score 
Grade CT Finding 
Points 
A 
Normal pancreas 
0 
B 
Enlargement of pancreas 
1 
C 
Inflammatory changes in pancreas and peripancreatic fat 
2 
D 
Ill-defined single peripancreatic fluid collection 
3 
E 
Two or more poorly defined peripancreatic fluid collections 4 
 
Pancreatic Necrosis Points
None 
0 
<30% 
2 
30-50% 
4 
>50% 
6 
Adapted from Balthazar 2002 
 
The CTSI score is the sum of the Balthazar and Pancreatic Necrosis scores: 
 0-3: mild acute pancreatitis 
 4-6: moderate acute pancreatitis 
 7-10: severe acute pancreatitis 
• 
• 
• 
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Appendix 4. 
Pain Numeric Rating Scale (PNRS) 
 
 
Pain Numeric Rating Scale 
1. On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain 
imaginable, how would you rate your pain RIGHT NOW. 
0 
No 
Pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
,vorst Pain 
Imaginable 
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Appendix 5. 
Imputed 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 
0.3 
122 
133 
148 
151 
155 
158 
162 
167 
171 
177 
182 
189 
196 
203 
213 
223 
236 
252 
273 
0.35 
105 
114 
127 
129 
132 
136 
139 
143 
147 
151 
156 
162 
168 
174 
182 
191 
202 
216 
234 
0.4 
92 
100 
111 
113 
116 
119 
122 
125 
129 
132 
137 
141 
147 
153 
159 
168 
177 
189 
205 
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 2019 
 
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Appendix 6. 
Modified American Neurogastroenterology and Motility Society Gastrointestinal Cardinal 
Symptom Index Daily Dairy (mGCSI-DD) 
 
None 
Mild 
Moderate 
Severe 
Very 
Severe 
Nausea (feeling sick to your stomach as if you are going to vomit or throw up) 
 
 
 
 
Not able to finish a normal sized meal (for a healthy person) 
 
 
 
 
Feeling excessively full after meals 
 
 
 
 
Abdominal Pain (around or above the navel) 
 
 
 
 
The next question asks you to record the number of times vomiting occurred in the last 24 hours. Please record the number of vomits 
(throwing up with food or liquid coming out) that occurred in the last 24 hours. Record zero, if you have not vomited during the past 24 
hours. If you vomited, write down the number of all vomits. If you vomited once, record one. If you vomited three times during the day, 
record three. If you vomited three times, whether it was during the same trip to the bathroom or three separate trips, record three as the 
number of episodes of vomiting. 
During the past 24 hours, how many episodes of vomiting did you have: _______________________
In thinking about your pancreatitis, what was the overall severity of your 
symptoms over the past 24 hours 
 
 
 
 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
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Appendix 7. 
CT Findings in Chronic Pancreatitis 
 
Adapted from Freedman 2020 
CT findings in chronic pancreatitis 
Grade 
ormal 
Equivocal 
Mild-moderate 
Severe 
CT findings 
o abnormal findings on a good-quality study 
visualizing he entire gland 
One of the follo ing: 
■ Mild dilatation of the pancreatic duct (2 
to 4 mm) in the body of he gland 
• Gland enlargement ~2-fol normal 
One of the precedi g findings plus at least 
o e of the following: 
■ Pancreatic due dilata Ion ( 4 mm) 
■ Pancreatic due lrregularl y 
■ Cav ty (les) < 10 mm 
■ Parenchymal heterogeneity 
■ Increased echogeniclty of duct wall 
• Irregular contour of he head or body 
• Focal necrosis or loss of parenchyma 
Mild/ moderate features plus one or more of 
the ollowing: 
• Cavity (ies) > 10 mm 
• In raductal 1lling de ects 
• Calculi/pancreatic calci 1ca ion 
■ Due al obstru ion (stricture) 
■ Severe duct dlla a ion or Irregularity 
■ Contiguous organ invasion 
CT: computed tomography. 
UpToDat 
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Appendix 8. 
Schedule of Events 
 
Screening 
If Eligible, 
Baseline 
Assessment R SFISD 
24 (±1) 
Hoursi
48 (±1) 
Hoursi
72 (±2) 
Hours
96, 144, 192, 
240 (±4) 
Hoursh,k 
120, 168,  
216 (±4) 
Hoursh,k 
Days 12-28 
Q48 (±4) 
Hoursh,k 
Day 30 (±5) 
Days
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Xl 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
List of Medications 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
 
 
 
X 
X 
X 
X 
X 
X 
 
X
Height 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
X 
 
 
 
X
Vital Signs 
X 
 
 
 
X 
X 
X 
X 
X 
 
X
Abdominal Exam 
X 
 
 
 
 
 
 
 
 
 
 
PNRS 
 
X 
 
 
X 
X 
X 
X 
X 
 
X
Serum Lipase 
Xa 
 
 
 
 
 
 
 
 
 
 
CBC+diff+Platelets 
Xa 
 
 
 
Xa 
Xa 
Xa 
 
Xa 
 
Xa
Presence of SIRSb 
X 
 
 
 
 
 
 
 
 
 
 
SpO2+FiO2 
 
X 
 
 
X 
X 
X 
X 
X 
 
X
CECT of Pancreasc 
X 
 
 
 
 
 
 
 
 
 
X
Serum Pregnancy Test 
Xa 
 
 
 
 
 
 
 
 
 
 
Randomize Patientd 
 
 
X 
 
 
 
 
 
 
 
 
Serum Chemistries 
 
Xa 
 
 
Xa 
Xa 
Xa 
 
Xa 
 
Xa
Serum Procalcitonin 
 
Xa 
 
 
Xa 
Xa 
Xa 
 
Xa 
 
Xa
Serum Biomarkere 
 
X 
 
 
X 
X 
X 
 
X 
 
X
Urine Biomarkere 
 
X 
 
 
X 
X 
X 
 
X 
 
X
Administer Study Drug 
 
 
 
X 
Xi 
Xi 
 
 
PK samplee 
 
 
 
Xj 
Xj 
 
Xj 
 
 
 
Xj
Medically Indicated Discharge 
Criteriaf 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Enhanced Recovery Strategyg 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xm
mGCSI-DDh 
 
Xh 
 
 
Xh 
Xh 
Xh
AE/SAE Evaluation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X
Telephone Contacts, as needed 
 
Following patient discharge, Investigator or designee should contact patient at least once weekly to confirm diary 
completion, Day 30 visit schedule and assess for AE/SAEs. 
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AE = adverse event; CECT = contrast-enhanced computed tomography; PK = pharmacokinetics; mGCSI-DD = Modified American Neurogastroenterology and Motility 
Society Gastrointestinal Cardinal Symptom Index Daily Diary; PI = Principal Investigator; PNRS = Pain Numeric Rating Scale; SAE = serious adverse event; SFISD 
= Start of First Infusion of Study Drug 
a. Blood sample for serum pregnancy test, serum lipase and CBC+diff+Platelets at Screening will be analyzed at local laboratory. May use results obtained as standard 
of care if blood drawn in the previous 12 hours prior to consent or following consent but prior to randomization. Following screening, all protocol-required blood 
samples, except as noted in Footnote e
previous 12 hours of randomization.  For all later assessment times, blood drawn in the previous 12 hours maybe used (except PK). 
b. The most extreme value for each criterion in the 24 hours before consent or following consent but prior to randomization may be used.  
c. A CECT already performed in the 24 hours prior to the patient or LAR providing informed consent may be used as the Screening CECT. In addition to the Screening 
and the Day 30 visit CECTs, CECTs performed as standard of care after randomization and to 25 days after SFISD will be captured and submitted for central reading. 
If the CECT is performed 25 to 29 days after SFISD, it will substitute for the Day 30 visit CECT scan and will be captured. 
d. Hematocrit collected as standard of care within 12 hours of consent or following consent but prior to randomization may be used for Inclusion Criterion 3c.
e. Biomarker blood and urine samples and blood samples for PK will be analyzed at central laboratory. If site or patient does not participate in these assessments this 
will be documented at start of study and will not be considered a protocol deviation. 
f. Determine if patient had met the medically indicated discharge criteria within the prior 24- or 48-hour visit assessment.  
g. 
-calorie solid meal at each mealtime after the infusion of the first dose of study drug until discharge if alert and not on 
mechanical ventilation, or if not NPO for a planned surgery/medical procedure, or if not NPO because of an acute medical condition. If the patient does not wish to 
eat the solid meal when offered or is unable to tolerate the solid meal, they should then be offered a liquid meal. Determine 
the meal without vomiting or having abdominal pain in the two hours after the meal. 
h. The mGCSI-DD score will be completed by all eligible patients at the baseline assessment and on the day of discharge, which will vary by patient as shown in 
schedule above. In addition, if the patient remains hospitalized at 96 and/or 168 hours and/or at Day 14 and/or Day 21 patient should be requested to record their 
symptoms at bedtime using the mGCSI-DD worksheet. Patients will be trained on completing the mGCSI-DD worksheet. Upon discharge, patient will record the 
mGCSI-DD score daily before bedtime until the Day 30 visit. 
i. In the scenario where the PI or treating physician wants the infusion(s) to begin earlier than the 24 +/- 1 hour window, the PI or treating physician should contact the 
medical monitor to discuss whether it is appropriate to begin infusion earlier (up to 6 hours earlier) than the 24 +/- 1 hour protocol window. 
j. Blood samples for PK analysis will be drawn as soon as possible after the completion of the first infusion of study drug (within +2 hours), prior to the start of second 
infusion of study drug (within -30 min), at 72 hours (±2 hours) from the SFISD, and at the Day 30 visit. If the patient is discharged after the third infusion of study 
drug and prior to 72 hours from the SFISD, the blood sample will be drawn prior to discharge. 
k. Study assessments continue daily, or every other day, as noted in schedule of events until discharge or the Day 30 visit. All patients return for Day 30 assessments if 
discharged earlier than Day 25. 
l. At the Day 30 visit (or at the time of death if before D
 
m. Only patients who remain hospitalized at Day 30. 
 
" ", will be analyzed at local laboratory. Baseline blood samples including biomarkers may be performed on blood drawn in the 
Patients will be offered a low fat, 2':500 
for each meal if the patient ate 2':50% of 
ay 30), record the Investigator's opinion on the etiology of the episode of AP. 
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